{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T22:29:41Z","timestamp":1775773781436,"version":"3.50.1"},"reference-count":114,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,12,16]],"date-time":"2022-12-16T00:00:00Z","timestamp":1671148800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Bruker BioSpin GmbH"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>The complex manifestations of COVID-19 are still not fully decoded on the molecular level. We combined quantitative the nuclear magnetic resonance (NMR) spectroscopy serum analysis of metabolites, lipoproteins and inflammation markers with clinical parameters and a targeted cytokine panel to characterize COVID-19 in a large (534 patient samples, 305 controls) outpatient cohort of recently tested PCR-positive patients. The COVID-19 cohort consisted of patients who were predominantly in the initial phase of the disease and mostly exhibited a milder disease course. Concerning the metabolic profiles of SARS-CoV-2-infected patients, we identified markers of oxidative stress and a severe dysregulation of energy metabolism. NMR markers, such as phenylalanine, inflammatory glycoproteins (Glyc) and their ratio with the previously reported supramolecular phospholipid composite (Glyc\/SPC), showed a predictive power comparable to laboratory parameters such as C-reactive protein (CRP) or ferritin. We demonstrated interfaces between the metabolism and the immune system, e.g., we could trace an interleukin (IL-6)-induced transformation of a high-density lipoprotein (HDL) to a pro-inflammatory actor. Finally, we showed that metadata such as age, sex and constitution (e.g., body mass index, BMI) need to be considered when exploring new biomarkers and that adding NMR parameters to existing diagnoses expands the diagnostic toolbox for patient stratification and personalized medicine.<\/jats:p>","DOI":"10.3390\/metabo12121277","type":"journal-article","created":{"date-parts":[[2022,12,19]],"date-time":"2022-12-19T04:54:13Z","timestamp":1671425653000},"page":"1277","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Quantitative Serum NMR Spectroscopy Stratifies COVID-19 Patients and Sheds Light on Interfaces of Host Metabolism and the Immune Response with Cytokines and Clinical Parameters"],"prefix":"10.3390","volume":"12","author":[{"given":"Titus","family":"R\u00f6ssler","sequence":"first","affiliation":[{"name":"Werner Siemens Imaging Center, Department for Preclinical Imaging and Radiopharmacy, Eberhard Karls University T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0260-3203","authenticated-orcid":false,"given":"Georgy","family":"Berezhnoy","sequence":"additional","affiliation":[{"name":"Werner Siemens Imaging Center, Department for Preclinical Imaging and Radiopharmacy, Eberhard Karls University T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6919-6273","authenticated-orcid":false,"given":"Yogesh","family":"Singh","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics & Applied Genomics, University Hospital T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claire","family":"Cannet","sequence":"additional","affiliation":[{"name":"Bruker BioSpin GmbH, Applied Industrial and Clinical Division, 76275 Ettlingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tony","family":"Reinsperger","sequence":"additional","affiliation":[{"name":"Bruker BioSpin GmbH, Applied Industrial and Clinical Division, 76275 Ettlingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hartmut","family":"Sch\u00e4fer","sequence":"additional","affiliation":[{"name":"Bruker BioSpin GmbH, Applied Industrial and Clinical Division, 76275 Ettlingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manfred","family":"Spraul","sequence":"additional","affiliation":[{"name":"Bruker BioSpin GmbH, Applied Industrial and Clinical Division, 76275 Ettlingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manfred","family":"Kneilling","sequence":"additional","affiliation":[{"name":"Werner Siemens Imaging Center, Department for Preclinical Imaging and Radiopharmacy, Eberhard Karls University T\u00fcbingen, 72076 T\u00fcbingen, Germany"},{"name":"Department of Dermatology, Eberhard Karls University T\u00fcbingen, 72076 T\u00fcbingen, Germany"},{"name":"Cluster of Excellence iFIT (EXC 2180) \u201cImage-guided and Functionally Instructed Tumor Therapies\u201d, Medical Faculty, Eberhard Karls University T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1386-3350","authenticated-orcid":false,"given":"Uta","family":"Merle","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine IV, University Hospital Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4672-6395","authenticated-orcid":false,"given":"Christoph","family":"Trautwein","sequence":"additional","affiliation":[{"name":"Werner Siemens Imaging Center, Department for Preclinical Imaging and Radiopharmacy, Eberhard Karls University T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/S0140-6736(22)00100-3","article-title":"COVID-19 will continue but the end of the pandemic is near","volume":"399","author":"Murray","year":"2022","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1891","DOI":"10.1515\/cclm-2021-0414","article-title":"Could metabolomics drive the fate of COVID-19 pandemic? A narrative review on lights and shadows","volume":"59","author":"Mussap","year":"2021","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Li, B., He, X., Jia, W., and Li, H. (2017). Novel Applications of Metabolomics in Personalized Medicine: A Mini-Review. Molecules, 22.","DOI":"10.3390\/molecules22071173"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1016\/j.cell.2008.08.026","article-title":"Metabolic Phenotyping in Health and Disease","volume":"134","author":"Holmes","year":"2008","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Letertre, M.P.M., Giraudeau, P., and de Tullio, P. (2021). Nuclear Magnetic Resonance Spectroscopy in Clinical Metabolomics and Personalized Medicine: Current Challenges and Perspectives. Front. Mol. Biosci., 8.","DOI":"10.3389\/fmolb.2021.698337"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.3389\/fmolb.2021.737039","article-title":"Metabolic and lipidomic markers differentiate COVID-19 from non-hospitalised and other intensive care patients","volume":"8","author":"Schmelter","year":"2021","journal-title":"Front. Mol. Biosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.1021\/acs.jproteome.0c00876","article-title":"NMR Spectroscopic Windows on the Systemic Effects of SARS-CoV-2 Infection on Plasma Lipoproteins and Metabolites in Relation to Circulating Cytokines","volume":"20","author":"Lodge","year":"2021","journal-title":"J. Proteome Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4139","DOI":"10.1021\/acs.jproteome.1c00458","article-title":"Integrative Modeling of Plasma Metabolic and Lipoprotein Biomarkers of SARS-CoV-2 Infection in Spanish and Australian COVID-19 Patient Cohorts","volume":"20","author":"Masuda","year":"2021","journal-title":"J. Proteome Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"6350","DOI":"10.1038\/s41598-021-85788-0","article-title":"Metabolomics analysis reveals a modified amino acid metabolism that correlates with altered oxygen homeostasis in COVID-19 patients","volume":"11","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Bruzzone, C., Bizkarguenaga, M., Gil-Redondo, R., Diercks, T., Arana, E., Garcia de Vicuna, A., Seco, M., Bosch, A., Palazon, A., and San Juan, I. (2020). SARS-CoV-2 Infection Dysregulates the Metabolomic and Lipidomic Profiles of Serum. iScience, 23.","DOI":"10.2139\/ssrn.3648224"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1640","DOI":"10.1021\/acs.jproteome.1c00977","article-title":"1H qNMR-Based Metabolomics Discrimination of Covid-19 Severity","volume":"21","author":"Correia","year":"2022","journal-title":"J. Proteome Res."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Baranovicova, E., Bobcakova, A., Vysehradsky, R., Dankova, Z., Halasova, E., Nosal, V., and Lehotsky, J. (2021). The Ability to Normalise Energy Metabolism in Advanced COVID-19 Disease Seems to Be One of the Key Factors Determining the Disease Progression\u2014A Metabolomic NMR Study on Blood Plasma. Appl. Sci., 11.","DOI":"10.3390\/app11094231"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Ballout, R.A., Kong, H., Sampson, M., Otvos, J.D., Cox, A.L., Agbor-Enoh, S., and Remaley, A.T. (2021). The NIH Lipo-COVID Study: A Pilot NMR Investigation of Lipoprotein Subfractions and Other Metabolites in Patients with Severe COVID-19. Biomedicines, 9.","DOI":"10.33774\/chemrxiv-2021-dctkq"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4428","DOI":"10.1021\/acs.jproteome.0c00537","article-title":"Quantitative In-Vitro Diagnostic NMR Spectroscopy for Lipoprotein and Metabolite Measurements in Plasma and Serum: Recommendations for Analytical Artifact Minimization with Special Reference to COVID-19\/SARS-CoV-2 Samples","volume":"19","author":"Loo","year":"2020","journal-title":"J. Proteome Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e4637","DOI":"10.1002\/nbm.4637","article-title":"Uneven metabolic and lipidomic profiles in recovered COVID-19 patients as investigated by plasma NMR metabolomics","volume":"35","author":"Bizkarguenaga","year":"2022","journal-title":"NMR Biomed."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"108186","DOI":"10.1016\/j.diabres.2020.108186","article-title":"Hyperglycemia and the worse prognosis of COVID-19. Why a fast blood glucose control should be mandatory","volume":"163","author":"Ceriello","year":"2020","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Pang, Z., Zhou, G., Chong, J., and Xia, J. (2021). Comprehensive Meta-Analysis of COVID-19 Global Metabolomics Datasets. Metabolites, 11.","DOI":"10.3390\/metabo11010044"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Ghini, V., Meoni, G., Pelagatti, L., Celli, T., Veneziani, F., Petrucci, F., Vannucchi, V., Bertini, L., Luchinat, C., and Landini, G. (2022). Profiling metabolites and lipoproteins in COMETA, an Italian cohort of COVID-19 patients. PLoS Pathog., 18.","DOI":"10.1371\/journal.ppat.1010443"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Meoni, G., Ghini, V., Maggi, L., Vignoli, A., Mazzoni, A., Salvati, L., Capone, M., Vanni, A., Tenori, L., and Fontanari, P. (2021). Metabolomic\/lipidomic profiling of COVID-19 and individual response to tocilizumab. PLoS Pathog., 17.","DOI":"10.1371\/journal.ppat.1009243"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Fuertes, M., Correig, X., Vallv\u00e9, J.C., and Amig\u00f3, N. (2020). Human Serum\/Plasma Glycoprotein Analysis by 1H-NMR, an Emerging Method of Inflammatory Assessment. J. Clin. Med., 9.","DOI":"10.3390\/jcm9020354"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1373\/clinchem.2014.232918","article-title":"GlycA: A Composite Nuclear Magnetic Resonance Biomarker of Systemic Inflammation","volume":"61","author":"Otvos","year":"2015","journal-title":"Clin. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/S1359-6101(02)00054-0","article-title":"\u03b11-Acid glycoprotein: An acute phase protein with inflammatory and immunomodulating properties","volume":"14","author":"Hochepied","year":"2003","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1186\/s12986-018-0300-0","article-title":"Consumption of regular-fat vs reduced-fat cheese reveals gender-specific changes in LDL particle size\u2014A randomized controlled trial","volume":"15","author":"Raziani","year":"2018","journal-title":"Nutr. Metab."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.aca.2019.07.026","article-title":"The effect of sampling procedures and day-to-day variations in metabolomics studies of biofluids","volume":"1081","author":"Andreassen","year":"2019","journal-title":"Anal. Chim. Acta"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"17026","DOI":"10.1038\/s41598-018-35232-7","article-title":"Lipoprotein markers associated with disability from multiple sclerosis","volume":"8","author":"Gafson","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3976","DOI":"10.1021\/acs.analchem.0c04952","article-title":"Diffusion and Relaxation Edited Proton NMR Spectroscopy of Plasma Reveals a High-Fidelity Supramolecular Biomarker Signature of SARS-CoV-2 Infection","volume":"93","author":"Lodge","year":"2021","journal-title":"Anal. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4426","DOI":"10.1021\/acs.analchem.1c05389","article-title":"Exploration of Human Serum Lipoprotein Supramolecular Phospholipids Using Statistical Heterospectroscopy in n-Dimensions (SHY-n): Identification of Potential Cardiovascular Risk Biomarkers Related to SARS-CoV-2 Infection","volume":"94","author":"Masuda","year":"2022","journal-title":"Anal. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1038\/s41586-020-2588-y","article-title":"Longitudinal analyses reveal immunological misfiring in severe COVID-19","volume":"584","author":"Lucas","year":"2020","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1038\/s41392-021-00679-0","article-title":"The signal pathways and treatment of cytokine storm in COVID-19","volume":"6","author":"Yang","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e13429","DOI":"10.1111\/eci.13429","article-title":"Deciphering the COVID-19 cytokine storm: Systematic review and meta-analysis","volume":"51","author":"Mulchandani","year":"2021","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1001\/jama.2020.17052","article-title":"Cytokine Levels in Critically Ill Patients With COVID-19 and Other Conditions","volume":"324","author":"Kox","year":"2020","journal-title":"JAMA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1016\/S2213-2600(20)30404-5","article-title":"Cytokine elevation in severe and critical COVID-19: A rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes","volume":"8","author":"Leisman","year":"2020","journal-title":"Lancet Respir. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1016\/j.immuni.2021.05.010","article-title":"Longitudinal analysis reveals that delayed bystander CD8+ T cell activation and early immune pathology distinguish severe COVID-19 from mild disease","volume":"54","author":"Bergamaschi","year":"2021","journal-title":"Immunity"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Singh, Y., Trautwein, C., Fendel, R., Krickeberg, N., Berezhnoy, G., Bissinger, R., Ossowski, S., Salker, M.S., Casadei, N., and Riess, O. (2021). SARS-CoV-2 infection paralyzes cytotoxic and metabolic functions of the immune cells. Heliyon, 7.","DOI":"10.1016\/j.heliyon.2021.e07147"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"827","DOI":"10.3389\/fimmu.2020.00827","article-title":"Reduction and Functional Exhaustion of T Cells in Patients With Coronavirus Disease 2019 (COVID-19)","volume":"11","author":"Diao","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Luo, M., Liu, J., Jiang, W., Yue, S., Liu, H., and Wei, S. (2020). IL-6 and CD8+ T cell counts combined are an early predictor of in-hospital mortality of patients with COVID-19. JCI Insight, 5.","DOI":"10.1172\/jci.insight.139024"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4744","DOI":"10.1002\/jmv.27917","article-title":"Immunophenotyping of lymphocytes and monocytes and the status of cytokines in the clinical course of Covid-19 patients","volume":"94","author":"Idiz","year":"2022","journal-title":"J. Med. Virol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1006\/smim.1998.0138","article-title":"Role of early cytokines, including alpha and beta interferons (IFN-\u03b1\\\u03b2), in innate and adaptive immune responses to viral infections","volume":"10","author":"Biron","year":"1998","journal-title":"Semin. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Zhang, Q., Bastard, P., Liu, Z., Le Pen, J., Moncada-Velez, M., Chen, J., Ogishi, M., Sabli, I.K.D., Hodeib, S., and Korol, C. (2020). Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science, 370.","DOI":"10.1126\/science.abd4570"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e105896","DOI":"10.15252\/embj.2020105896","article-title":"Blood molecular markers associated with COVID-19 immunopathology and multi-organ damage","volume":"39","author":"Chen","year":"2020","journal-title":"EMBO J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1126\/science.abc6027","article-title":"Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients","volume":"369","author":"Hadjadj","year":"2020","journal-title":"Science"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1038\/s41590-020-00840-x","article-title":"Untuned antiviral immunity in COVID-19 revealed by temporal type I\/III interferon patterns and flu comparison","volume":"22","author":"Galani","year":"2021","journal-title":"Nat. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1016\/j.cell.2017.04.004","article-title":"Metabolic Instruction of Immunity","volume":"169","author":"Buck","year":"2017","journal-title":"Cell"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1038\/s41366-021-00804-7","article-title":"Metabolic dysfunction and immunometabolism in COVID-19 pathophysiology and therapeutics","volume":"45","author":"Batabyal","year":"2021","journal-title":"Int. J. Obes."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1373\/clinchem.2017.272344","article-title":"Use of Metabolomics in Improving Assessment of Dietary Intake","volume":"64","author":"Bhupathiraju","year":"2018","journal-title":"Clin. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"ofac063","DOI":"10.1093\/ofid\/ofac063","article-title":"An Outpatient Management Strategy Using a Coronataxi Digital Early Warning System Reduces Coronavirus Disease 2019 Mortality","volume":"9","author":"Lim","year":"2022","journal-title":"Open Forum Infect. Dis."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1515\/cclm-2020-0369","article-title":"Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): A meta-analysis","volume":"58","author":"Henry","year":"2020","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1093\/ije\/dyab012","article-title":"The role of C-reactive protein as a prognostic marker in COVID-19","volume":"50","author":"Stringer","year":"2021","journal-title":"Int. J. Epidemiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"e23618","DOI":"10.1002\/jcla.23618","article-title":"Ferritin in the coronavirus disease 2019 (COVID-19): A systematic review and meta-analysis","volume":"34","author":"Cheng","year":"2020","journal-title":"J. Clin. Lab. Anal."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"4307","DOI":"10.1021\/ac051972y","article-title":"Impact of Analytical Bias in Metabonomic Studies of Human Blood Serum and Plasma","volume":"78","author":"Teahan","year":"2006","journal-title":"Anal. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1038\/nrd.2016.32","article-title":"Emerging applications of metabolomics in drug discovery and precision medicine","volume":"15","author":"Wishart","year":"2016","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_52","unstructured":"Robert Koch Institut (2022, October 13). Bericht zu Virusvarianten von SARS-CoV-2 in Deutschland. 26 May 2021. Available online: https:\/\/www.rki.de\/DE\/Content\/InfAZ\/N\/Neuartiges_Coronavirus\/DESH\/Bericht_VOC_2021-05-26.pdf?__blob=publicationFile."},{"key":"ref_53","unstructured":"(2022, December 12). B.I. Methods\u2014Enabling Standardization of IVDr by NMR: Using Bruker IVDr Methods for Urine\/ Plasma\/ Serum Quantification. Available online: https:\/\/www.bruker.com\/de\/products-and-solutions\/mr\/nmr-clinical-research-solutions\/b-i-methods.html."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1006\/jmra.1995.1176","article-title":"An Improved Diffusion-Ordered Spectroscopy Experiment Incorporating Bipolar-Gradient Pulses","volume":"115","author":"Wu","year":"1995","journal-title":"J. Magn. Reson. Ser. A"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"4213","DOI":"10.1039\/D2AN01097F","article-title":"Direct Low Field J-Edited DIffusional Proton NMR Spectroscopic Measurement of COVID-19 Inflammatory Biomarkers in Human Serum","volume":"147","author":"Nitschke","year":"2022","journal-title":"Analyst"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"11962","DOI":"10.1021\/acs.analchem.8b02412","article-title":"Quantitative Lipoprotein Subclass and Low Molecular Weight Metabolite Analysis in Human Serum and Plasma by 1H NMR Spectroscopy in a Multilaboratory Trial","volume":"90","author":"Holmes","year":"2018","journal-title":"Anal. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"W652","DOI":"10.1093\/nar\/gkp356","article-title":"MetaboAnalyst: A web server for metabolomic data analysis and interpretation","volume":"37","author":"Xia","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"3050","DOI":"10.1002\/elps.201500352","article-title":"Missing value imputation strategies for metabolomics data","volume":"36","author":"Armitage","year":"2015","journal-title":"Electrophoresis"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the False Discovery Rate\u2014A Practical and Powerful Approach to Multiple Testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J. R. Stat. Soc. Ser. B-Stat. Methodol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.arcmed.2020.12.002","article-title":"Hypertension, Diabetes and Obesity, Major Risk Factors for Death in Patients with COVID-19 in Mexico","volume":"52","author":"Rasc","year":"2021","journal-title":"Arch. Med. Res."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Landstra, C.P., and de Koning, E.J.P. (2021). COVID-19 and Diabetes: Understanding the Interrelationship and Risks for a Severe Course. Front. Endocrinol., 12.","DOI":"10.3389\/fendo.2021.649525"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2127","DOI":"10.2337\/dc18-0287","article-title":"Glycemic Control and Risk of Infections Among People With Type 1 or Type 2 Diabetes in a Large Primary Care Cohort Study","volume":"41","author":"Critchley","year":"2018","journal-title":"Diabetes Care"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Liu, S.P., Zhang, Q., Wang, W., Zhang, M., Liu, C., Xiao, X.F., Liu, Z.D., Hu, W.M., and Jin, P. (2020). Hyperglycemia is a strong predictor of poor prognosis in COVID-19. Diabetes Res. Clin. Pract., 167.","DOI":"10.1016\/j.diabres.2020.108338"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1111\/dom.14099","article-title":"Newly diagnosed diabetes is associated with a higher risk of mortality than known diabetes in hospitalized patients with COVID-19","volume":"22","author":"Li","year":"2020","journal-title":"Diabetes Obes. Metab."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/s41574-020-00435-4","article-title":"COVID-19 and diabetes mellitus: From pathophysiology to clinical management","volume":"17","author":"Lim","year":"2021","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1016\/j.cmet.2021.05.013","article-title":"SARS-CoV-2 infects human pancreatic \u03b2 cells and elicits \u03b2 cell impairment","volume":"33","author":"Wu","year":"2021","journal-title":"Cell Metab."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"45777","DOI":"10.1074\/jbc.M301977200","article-title":"Interleukin-6 (IL-6) induces insulin resistance in 3T3-L1 adipocytes and is, like IL-8 and tumor necrosis factor-\u03b1, overexpressed in human fat cells from insulin-resistant subjects","volume":"278","author":"Rotter","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Schultz, O., Oberhauser, F., Saech, J., Rubbert-Roth, A., Hahn, M., Krone, W., and Laudes, M. (2010). Effects of Inhibition of Interleukin-6 Signalling on Insulin Sensitivity and Lipoprotein (A) Levels in Human Subjects with Rheumatoid Diseases. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0014328"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/j.cmet.2020.07.007","article-title":"Elevated Glucose Levels Favor SARS-CoV-2 Infection and Monocyte Response through a HIF-1\u03b1\/Glycolysis-Dependent Axis","volume":"32","author":"Codo","year":"2020","journal-title":"Cell Metab."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.biochi.2020.11.010","article-title":"The key role of Warburg effect in SARS-CoV-2 replication and associated inflammatory response","volume":"180","author":"Icard","year":"2021","journal-title":"Biochimie"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.drup.2016.09.003","article-title":"The reduced concentration of citrate in cancer cells: An indicator of cancer aggressiveness and a possible therapeutic target","volume":"29","author":"Icard","year":"2016","journal-title":"Drug Resist. Updat."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Ceperuelo-Mallafr\u00e9, V., Revert\u00e9, L., Peraire, J., Madeira, A., Maym\u00f3-Masip, E., L\u00f3pez-Dupla, M., Gutierrez-Valencia, A., Ruiz-Mateos, E., Buz\u00f3n, M.J., and Jorba, R. (2022). Circulating pyruvate is a potent prognostic marker for critical COVID-19 outcomes. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.912579"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1042\/CS20110520","article-title":"Glutamine and glutathione at ICU admission in relation to outcome","volume":"122","author":"Rodas","year":"2012","journal-title":"Clin. Sci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"3199","DOI":"10.1038\/s41418-021-00892-y","article-title":"Comorbidity-associated glutamine deficiency is a predisposition to severe COVID-19","volume":"28","author":"Matsuyama","year":"2021","journal-title":"Cell Death Differ."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2515S","DOI":"10.1093\/jn\/131.9.2515S","article-title":"Why Is L-Glutamine Metabolism Important to Cells of the Immune System in Health, Postinjury, Surgery or Infection?","volume":"131","author":"Newsholme","year":"2001","journal-title":"J. Nutr."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Cruzat, V., Macedo Rogero, M., Noel Keane, K., Curi, R., and Newsholme, P. (2018). Glutamine: Metabolism and Immune Function, Supplementation and Clinical Translation. Nutrients, 10.","DOI":"10.20944\/preprints201809.0459.v1"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"e492","DOI":"10.1097\/HS9.0000000000000492","article-title":"Hypoferremia is Associated With Increased Hospitalization and Oxygen Demand in COVID-19 Patients","volume":"4","author":"Hippchen","year":"2020","journal-title":"HemaSphere"},{"key":"ref_78","first-page":"1","article-title":"COVID-19: Captures iron and generates reactive oxygen species to damage the human immune system","volume":"54","author":"Liu","year":"2021","journal-title":"Autoimmunity"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.canlet.2008.07.002","article-title":"Serum phenylalanine concentrations in patients with ovarian carcinoma correlate with concentrations of immune activation markers and of isoprostane-8","volume":"272","author":"Neurauter","year":"2008","journal-title":"Cancer Lett."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1515\/pterid-2013-0001","article-title":"Immune activation and inflammation increase the plasma phenylalanine-to-tyrosine ratio","volume":"24","author":"Geisler","year":"2013","journal-title":"Pteridines"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/j.it.2021.03.007","article-title":"Enemy or ally? Fasting as an essential regulator of immune responses","volume":"42","author":"Wilhelm","year":"2021","journal-title":"Trends Immunol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.medj.2020.06.008","article-title":"Investigating Ketone Bodies as Immunometabolic Countermeasures against Respiratory Viral Infections","volume":"1","author":"Stubbs","year":"2020","journal-title":"Med"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1038\/s41586-022-05128-8","article-title":"Impaired ketogenesis ties metabolism to T cell dysfunction in COVID-19","volume":"609","author":"Karagiannis","year":"2022","journal-title":"Nature"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2020\/6401341","article-title":"COVID-19: Proposing a Ketone-Based Metabolic Therapy as a Treatment to Blunt the Cytokine Storm","volume":"2020","author":"Bradshaw","year":"2020","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Hirschberger, S., Gellert, L., Effinger, D., Muenchhoff, M., Herrmann, M., Briegel, J.M., Zwi\u00dfler, B., and Kreth, S. (2022). Ketone Bodies Improve Human CD8(+) Cytotoxic T-Cell Immune Response During COVID-19 Infection. Front. Med., 9.","DOI":"10.3389\/fmed.2022.923502"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1194\/jlr.R300019-JLR200","article-title":"Effects of infection and inflammation on lipid and lipoprotein metabolism: Mechanisms and consequences to the host","volume":"45","author":"Khovidhunkit","year":"2004","journal-title":"J. Lipid Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1016\/j.jhep.2020.04.006","article-title":"COVID-19: Abnormal liver function tests","volume":"73","author":"Cai","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"377","DOI":"10.3748\/wjg.v27.i5.377","article-title":"Liver injury in the era of COVID-19","volume":"27","author":"Michalak","year":"2021","journal-title":"World J. Gastroenterol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"2005","DOI":"10.4254\/wjh.v13.i12.2005","article-title":"Liver dysfunction as a cytokine storm manifestation and prognostic factor for severe COVID-19","volume":"13","author":"Taneva","year":"2021","journal-title":"World J. Hepatol."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Gray, N., Lawler, N., Zeng, A., Ryan, M., Bong, S., Boughton, B., Bizkarguenaga, M., Bruzzone, C., Embade, N., and Wist, J. (2021). Diagnostic Potential of the Plasma Lipidome in Infectious Disease: Application to Acute SARS-CoV-2 Infection. Metabolites, 11.","DOI":"10.3390\/metabo11070467"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1002\/biof.1205","article-title":"The dual nature of HDL: Anti-Inflammatory and pro-Inflammatory","volume":"41","author":"Gao","year":"2015","journal-title":"BioFactors"},{"key":"ref_92","first-page":"274629","article-title":"Friend turns foe: Transformation of anti-inflammatory HDL to proinflammatory HDL during acute-phase response","volume":"2011","author":"Rao","year":"2011","journal-title":"Cholesterol"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2291","DOI":"10.1038\/s41598-021-81638-1","article-title":"Altered high-density lipoprotein composition and functions during severe COVID-19","volume":"11","author":"Begue","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1373\/clinchem.2004.032763","article-title":"Sex and Age Differences in Lipoprotein Subclasses Measured by Nuclear Magnetic Resonance Spectroscopy: The Framingham Study","volume":"50","author":"Freedman","year":"2004","journal-title":"Clin. Chem."},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Lucero, D., Islam, P., Freeman, L.A., Jin, X., Pryor, M., Tang, J., Kruth, H.S., and Remaley, A.T. (2020). Interleukin 10 promotes macrophage uptake of HDL and LDL by stimulating fluid-phase endocytosis. Biochim. Biophys. Acta (BBA)\u2014Mol. Cell Biol. Lipids, 1865.","DOI":"10.1016\/j.bbalip.2019.158537"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"15670","DOI":"10.18632\/aging.103770","article-title":"Elevated Lactate Dehydrogenase (LDH) level as an independent risk factor for the severity and mortality of COVID-19","volume":"12","author":"Li","year":"2020","journal-title":"Aging"},{"key":"ref_97","unstructured":"Schienkiewitz, A., Mensink, G.B.M., Kuhnert, R., and Lange, C. (2017). \u00dcbergewicht und Adipositas bei Erwachsenen in Deutschland. J. Health Monit."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1706","DOI":"10.1038\/s41591-022-01909-w","article-title":"Symptoms and risk factors for long COVID in non-hospitalized adults","volume":"28","author":"Subramanian","year":"2022","journal-title":"Nat. Med."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1186\/s12931-020-01364-6","article-title":"Increased mortality of acute respiratory distress syndrome was associated with high levels of plasma phenylalanine","volume":"21","author":"Xu","year":"2020","journal-title":"Respir. Res."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Luporini, R.L., Pott-Junior, H., Di Medeiros Leal, M.C.B., Castro, A., Ferreira, A.G., Cominetti, M.R., and De Freitas Anibal, F. (2021). Phenylalanine and COVID-19: Tracking disease severity markers. Int. Immunopharmacol., 101.","DOI":"10.1016\/j.intimp.2021.108313"},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Malo, A.-I., Rull, A., Girona, J., Domingo, P., Fuertes-Mart\u00edn, R., Amig\u00f3, N., Rodr\u00edguez-Borjabad, C., Mart\u00ednez-Micaelo, N., Leal, M., and Peraire, J. (2020). Glycoprotein Profile Assessed by 1H-NMR as a Global Inflammation Marker in Patients with HIV Infection. A Prospective Study. J. Clin. Med., 9.","DOI":"10.3390\/jcm9051344"},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Rodr\u00edguez-Carrio, J., Alperi-L\u00f3pez, M., L\u00f3pez, P., P\u00e9rez-\u00c1lvarez, \u00c1.I., Gil-Serret, M., Amig\u00f3, N., Ulloa, C., Benavente, L., Ballina-Garc\u00eda, F.J., and Su\u00e1rez, A. (2020). GlycA Levels during the Earliest Stages of Rheumatoid Arthritis: Potential Use as a Biomarker of Subclinical Cardiovascular Disease. J. Clin. Med., 9.","DOI":"10.3390\/jcm9082472"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1177\/0961203315617842","article-title":"GlycA, a novel marker of inflammation, is elevated in systemic lupus erythematosus","volume":"25","author":"Chung","year":"2016","journal-title":"Lupus"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1093\/ecco-jcc\/jjy162","article-title":"GlycA, a Nuclear Magnetic Resonance Spectroscopy Measure for Protein Glycosylation, is a Viable Biomarker for Disease Activity in IBD","volume":"13","author":"Dierckx","year":"2019","journal-title":"J. Crohn\u2019s Colitis"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1007\/s10753-014-0107-8","article-title":"GlycA is a Novel Marker of Inflammation Among Non-Critically Ill Hospitalized Patients with Type 2 Diabetes","volume":"38","author":"Dungan","year":"2015","journal-title":"Inflammation"},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Gruppen, E.G., Riphagen, I.J., Connelly, M.A., Otvos, J.D., Bakker, S.J.L., and Dullaart, R.P.F. (2015). GlycA, a Pro-Inflammatory Glycoprotein Biomarker, and Incident Cardiovascular Disease: Relationship with C-Reactive Protein and Renal Function. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0139057"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1111\/eci.12481","article-title":"A novel protein glycan biomarker and LCAT activity in metabolic syndrome","volume":"45","author":"Gruppen","year":"2015","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"4038","DOI":"10.1021\/acs.jproteome.9b00528","article-title":"Glycoprotein A and B Height-to-Width Ratios as Obesity-Independent Novel Biomarkers of Low-Grade Chronic Inflammation in Women with Polycystic Ovary Syndrome (PCOS)","volume":"18","author":"Moncayo","year":"2019","journal-title":"J. Proteome Res."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1111\/j.1600-065X.1992.tb01407.x","article-title":"IL-6 and NF-IL6 in acute-phase response and viral infection","volume":"127","author":"Akira","year":"1992","journal-title":"Immunol. Rev."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.cels.2015.09.007","article-title":"The Biomarker GlycA Is Associated with Chronic Inflammation and Predicts Long-Term Risk of Severe Infection","volume":"1","author":"Ritchie","year":"2015","journal-title":"Cell Syst."},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Fischer, K., Kettunen, J., W\u00fcrtz, P., Haller, T., Havulinna, A.S., Kangas, A.J., Soininen, P., Esko, T., Tammesoo, M.-L., and M\u00e4gi, R. (2014). Biomarker Profiling by Nuclear Magnetic Resonance Spectroscopy for the Prediction of All-Cause Mortality: An Observational Study of 17,345 Persons. PLoS Med., 11.","DOI":"10.1371\/journal.pmed.1001606"},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"Julkunen, H., Cicho\u0144ska, A., Slagboom, P.E., and W\u00fcrtz, P. (2021). Metabolic biomarker profiling for identification of susceptibility to severe pneumonia and COVID-19 in the general population. eLife, 10.","DOI":"10.7554\/eLife.63033"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1021\/acs.analchem.1c04576","article-title":"J-Edited DIffusional Proton Nuclear Magnetic Resonance Spectroscopic Measurement of Glycoprotein and Supramolecular Phospholipid Biomarkers of Inflammation in Human Serum","volume":"94","author":"Nitschke","year":"2022","journal-title":"Anal. Chem."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1007\/s11481-020-09974-z","article-title":"Is COVID-19 Gender-sensitive?","volume":"16","author":"Mukherjee","year":"2021","journal-title":"J. Neuroimmune Pharmacol."}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/12\/12\/1277\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:42:46Z","timestamp":1760146966000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/12\/12\/1277"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,16]]},"references-count":114,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["metabo12121277"],"URL":"https:\/\/doi.org\/10.3390\/metabo12121277","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,16]]}}}