{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T05:08:29Z","timestamp":1788930509519,"version":"build-2803163510"},"reference-count":31,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The Center of Competence in Molecular Diagnostics (CEKOM) project","award":["KK.01.2.2.03.006"],"award-info":[{"award-number":["KK.01.2.2.03.006"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Severe COVID-19 is characterized by immune dysregulation, yet reliable biomarkers associated with adverse outcomes remain limited. Immunoglobulin G (IgG) N-glycosylation modulates antibody effector function and reflects the immune system\u2019s inflammatory state. In this study, we investigated whether specific IgG glycosylation profiles are associated with COVID-19 severity, mortality, and clinical course in patients without known prior SARS-CoV-2 infection. Of the 806 admitted COVID-19 patients included in the study, 377 hospitalized patients were longitudinally monitored, and 2001 serum samples were analyzed. Significant alterations in IgG N-glycome composition were observed in patients with severe disease and those who died. The most prominent changes included increased agalactosylation and decreased mono- and digalactosylation, features associated with a more pro-inflammatory IgG glycosylation profile. Nosocomial infections were associated with a more pro-inflammatory IgG glycosylation profile. No statistically significant differences in IgG N-glycome composition were observed between vaccinated and unvaccinated patients, although the small number of vaccinated patients limited this analysis. The observed glycomic profiles likely reflect immune responses characteristic of the early phase of the COVID-19 pandemic. Whether similar glycosylation changes occur in other infectious or inflammatory diseases remains to be established. IgG glycosylation analysis holds promise for personalized risk stratification and early therapeutic intervention in COVID-19 and other severe infectious diseases.<\/jats:p>","DOI":"10.3390\/v18090960","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T15:08:43Z","timestamp":1788275323000},"page":"960","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Longitudinal Changes in IgG N-glycome Are Associated with Disease Severity and Mortality in COVID-19 Patients"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-7887-7246","authenticated-orcid":false,"given":"Martina","family":"Vinicki","sequence":"first","affiliation":[{"name":"Genos Glycoscience Research Laboratory, 10 000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frano","family":"Vu\u010dkovi\u0107","sequence":"additional","affiliation":[{"name":"Genos Glycoscience Research Laboratory, 10 000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1212-3302","authenticated-orcid":false,"given":"Kristian","family":"Boduli\u0107","sequence":"additional","affiliation":[{"name":"University Hospital for Infectious Diseases, 10 000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alemka","family":"Markoti\u0107","sequence":"additional","affiliation":[{"name":"University Hospital for Infectious Diseases, 10 000 Zagreb, Croatia"},{"name":"Faculty of Medicine, Catholic University of Croatia, 10 000 Zagreb, Croatia"},{"name":"Faculty of Medicine, University of Rijeka, 51 000 Rijeka, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoran","family":"Baru\u0161i\u0107","sequence":"additional","affiliation":[{"name":"University Hospital for Infectious Diseases, 10 000 Zagreb, Croatia"},{"name":"Faculty of Medicine, Catholic University of Croatia, 10 000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renata","family":"La\u0161kaj","sequence":"additional","affiliation":[{"name":"University Hospital for Infectious Diseases, 10 000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9536-1009","authenticated-orcid":false,"given":"Ivan Christian","family":"Kurolt","sequence":"additional","affiliation":[{"name":"University Hospital for Infectious Diseases, 10 000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanja","family":"Zember","sequence":"additional","affiliation":[{"name":"University Hospital for Infectious Diseases, 10 000 Zagreb, Croatia"},{"name":"Faculty of Medicine, Catholic University of Croatia, 10 000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8766-7438","authenticated-orcid":false,"given":"Rok","family":"\u010civljak","sequence":"additional","affiliation":[{"name":"University Hospital for Infectious Diseases, 10 000 Zagreb, Croatia"},{"name":"School of Medicine, University of Zagreb, 10 000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Puljiz","sequence":"additional","affiliation":[{"name":"University Hospital for Infectious Diseases, 10 000 Zagreb, Croatia"},{"name":"School of Medicine, University of Zagreb, 10 000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gordan","family":"Lauc","sequence":"additional","affiliation":[{"name":"Genos Glycoscience Research Laboratory, 10 000 Zagreb, Croatia"},{"name":"Department of Biochemistry and Molecular Biology, Faculty of Pharmacy and Biochemistry, University of Zagreb, 10 000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tea","family":"Pribi\u0107","sequence":"additional","affiliation":[{"name":"Genos Glycoscience Research Laboratory, 10 000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Khan, M., Adil, S.F., Alkhathlan, H.Z., Tahir, M.N., Saif, S., Khan, M., and Khan, S.T. (2020). COVID-19: A Global Challenge with Old History, Epidemiology and Progress So Far. Molecules, 26.","DOI":"10.3390\/molecules26010039"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.ajem.2022.01.028","article-title":"Clinical update on COVID-19 for the emergency clinician: Presentation and evaluation","volume":"54","author":"Long","year":"2022","journal-title":"Am. J. Emerg. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1002\/jmv.26232","article-title":"The cytokine storm and COVID-19","volume":"93","author":"Hu","year":"2021","journal-title":"J. Med. Virol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"R229","DOI":"10.1016\/j.cub.2019.01.003","article-title":"Protein glycosylation","volume":"29","author":"Eichler","year":"2019","journal-title":"Curr. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Jay, J.W., Bray, B., Qi, Y., Igbinigie, E., Wu, H., Li, J., and Ren, G. (2018). IgG Antibody 3D Structures and Dynamics. Antibodies, 7.","DOI":"10.3390\/antib7020018"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Vidarsson, G., Dekkers, G., and Rispens, T. (2014). IgG Subclasses and Allotypes: From Structure to Effector Functions. Front. Immunol., 5.","DOI":"10.3389\/fimmu.2014.00520"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"108169","DOI":"10.1016\/j.biotechadv.2023.108169","article-title":"IgG glycans in health and disease: Prediction, intervention, prognosis, and therapy","volume":"67","author":"Shkunnikova","year":"2023","journal-title":"Biotechnol. Adv."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1002\/eji.202149491","article-title":"Altered IgG glycosylation at COVID-19 diagnosis predicts disease severity","volume":"52","author":"Vicente","year":"2022","journal-title":"Eur. J. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"eabc8378","DOI":"10.1126\/science.abc8378","article-title":"Afucosylated immunoglobulin G responses are a hallmark of enveloped virus infections and show an exacerbated phenotype in COVID-19","volume":"371","author":"Larsen","year":"2021","journal-title":"Science"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1038\/s41590-020-00828-7","article-title":"Proinflammatory IgG Fc structures in patients with severe COVID-19","volume":"22","author":"Chakraborty","year":"2021","journal-title":"Nat. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"eabm7853","DOI":"10.1126\/scitranslmed.abm7853","article-title":"Early non-neutralizing, afucosylated antibody responses are associated with COVID-19 severity","volume":"14","author":"Chakraborty","year":"2022","journal-title":"Sci. Transl. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"103957","DOI":"10.1016\/j.ebiom.2022.103957","article-title":"Immunoglobulin G1 Fc glycosylation as an early hallmark of severe","volume":"78","author":"Pongracz","year":"2022","journal-title":"EBioMedicine"},{"key":"ref_13","first-page":"372","article-title":"Composition of the immunoglobulin G glycome associates with the severity of COVID-19","volume":"31","author":"Alves","year":"2021","journal-title":"Glycobiology"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Vilibic-Cavlek, T., Stevanovic, V., Brlek-Gorski, D., Ferencak, I., Ferenc, T., Ujevic-Bosnjak, M., Tabain, I., Janev-Holcer, N., Perkovic, I., and Anticevic, M. (2021). Emerging Trends in the Epidemiology of COVID-19: The Croatian \u2018One Health\u2019 Perspective. Viruses, 13.","DOI":"10.3390\/v13122354"},{"key":"ref_15","first-page":"1","article-title":"High throughput isolation and glycosylation analysis of IgG-variability and heritability of the IgG N-glycome in three isolated human populations","volume":"10","author":"Adamczyk","year":"2011","journal-title":"Mol. Cell Proteom."},{"key":"ref_16","first-page":"1062","article-title":"Robustness and repeatability of GlycoWorks RapiFluor-MS IgG N-glycan profiling in a long-term high-throughput glycomic study","volume":"31","author":"Lauber","year":"2021","journal-title":"Glycobiology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fchem.2018.00324","article-title":"Comparison of 2-aminobenzamide, procainamide and RapiFluor-MS as derivatizing agents for high-throughput HILIC-UPLC-FLR-MS N-glycan analysis","volume":"6","author":"Keser","year":"2018","journal-title":"Front. Chem."},{"key":"ref_18","unstructured":"(2025, March 15). R: The R Project for Statistical Computing. Available online: https:\/\/www.r-project.org\/."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.eng.2022.08.007","article-title":"Differences in Immunoglobulin G Glycosylation Between Influenza and COVID-19 Patients","volume":"26","author":"Radovani","year":"2023","journal-title":"Engineering"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3081","DOI":"10.1002\/art.23865","article-title":"Initiation of the alternative pathway of murine complement by immune complexes is dependent on N -glycans in IgG antibodies","volume":"58","author":"Banda","year":"2008","journal-title":"Arthritis Rheum."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1038\/nm0395-237","article-title":"Glycosylation changes of IgG associated with rheumatoid arthritis can activate complement via the mannose-binding protein","volume":"1","author":"Malhotra","year":"1995","journal-title":"Nat. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"104101","DOI":"10.1016\/j.ebiom.2022.104101","article-title":"IgG N-glycome changes during the course of severe COVID-19: An observational study","volume":"81","author":"Vijay","year":"2022","journal-title":"EBioMedicine"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Hou, H., Yang, H., Liu, P., Huang, C., Wang, M., Li, Y., Zhu, M., Wang, J., Xu, Y., and Wang, Y. (2021). Profile of Immunoglobulin G N-Glycome in COVID-19 Patients: A Case-Control Study. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.748566"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1093\/glycob\/cwaa018","article-title":"Understanding the role of antibody glycosylation through the lens of severe viral and bacterial diseases","volume":"30","author":"Edward","year":"2020","journal-title":"Glycobiology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/S0140-6736(20)30183-5","article-title":"Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China","volume":"395","author":"Huang","year":"2020","journal-title":"Lancet"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Lee, A.J., and Ashkar, A.A. (2018). The Dual Nature of Type I and Type II Interferons. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.02061"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1038\/nm.2862","article-title":"Anti-inflammatory activity of IgG1 mediated by Fc galactosylation and association of Fc\u03b3RIIB and dectin-1","volume":"18","author":"Karsten","year":"2012","journal-title":"Nat. Med."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Yakovlieva, L., F\u00fclleborn, J.A., and Walvoort, M.T.C. (2021). Opportunities and Challenges of Bacterial Glycosylation for the Development of Novel Antibacterial Strategies. Front. Microbiol., 12.","DOI":"10.3389\/fmicb.2021.745702"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1016\/j.tim.2015.07.003","article-title":"Sweet Talk: Protein Glycosylation in Bacterial Interaction With the Host","volume":"23","author":"Lu","year":"2015","journal-title":"Trends Microbiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"541","DOI":"10.5483\/BMBRep.2021.54.11.129","article-title":"Remodeling of host glycoproteins during bacterial infection","volume":"54","author":"Kim","year":"2021","journal-title":"BMB Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e00176","DOI":"10.1002\/edm2.176","article-title":"The impact of obesity on severe disease and mortality in people with SARS-CoV-2: A systematic review and meta-analysis","volume":"4","author":"Seidu","year":"2020","journal-title":"Endocrinol. Diabetes Metab."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/18\/9\/960\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T04:29:53Z","timestamp":1788928193000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/18\/9\/960"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,1]]},"references-count":31,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["v18090960"],"URL":"https:\/\/doi.org\/10.3390\/v18090960","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,1]]}}}