{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T16:39:46Z","timestamp":1790613586650,"version":"4.1.0"},"reference-count":149,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2024,10,24]],"date-time":"2024-10-24T00:00:00Z","timestamp":1729728000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Grigore T. Popa University of Medicine and Pharmacy of Iasi","award":["158\/2022"],"award-info":[{"award-number":["158\/2022"]}]},{"name":"Grigore T. Popa University of Medicine and Pharmacy of Iasi","award":["POC\/448\/1\/1\/127606 CENEMED project 367\/390043\/2021)"],"award-info":[{"award-number":["POC\/448\/1\/1\/127606 CENEMED project 367\/390043\/2021)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>IL-6 remains a key molecule of the cytokine storms characterizing COVID-19, exerting both proinflammatory and anti-inflammatory effects. Emerging research underscores the significance of IL-6 trans-signaling over classical signaling pathways, which has shifted the focus of therapeutic strategies. Additionally, the synergistic action of TNF-\u03b1 and IFN-\u03b3 has been found to induce inflammatory cell death through PANoptosis, further amplifying the severity of cytokine storms. Long COVID-19 patients, as well as those with cytokine storms triggered by other conditions, exhibit distinct laboratory profiles, indicating the need for targeted approaches to diagnosis and management. Growing evidence also highlights the gut microbiota\u2019s crucial role in modulating the immune response during COVID-19 by affecting cytokine production, adding further complexity to the disease\u2019s immunological landscape. Targeted intervention strategies should focus on specific cytokine cutoffs, though accurate cytokine quantification remains a clinical challenge. Current treatment strategies are increasingly focused on inhibiting IL-6 trans-signaling, which offers promise for more precise therapeutic approaches to manage hyperinflammatory responses in COVID-19. In light of recent discoveries, this review summarizes key research findings on cytokine storms, particularly their role in COVID-19 and other inflammatory conditions. It explores emerging therapeutic strategies targeting cytokines like IL-6, TNF-\u03b1, and IFN-\u03b3, while also addressing open questions, such as the need for better biomarkers to detect and manage cytokine storms. Additionally, the review highlights ongoing challenges in developing targeted treatments that mitigate hyperinflammation without compromising immune function, emphasizing the importance of continued research in this field.<\/jats:p>","DOI":"10.3390\/ijms252111411","type":"journal-article","created":{"date-parts":[[2024,10,24]],"date-time":"2024-10-24T04:11:38Z","timestamp":1729743098000},"page":"11411","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Cytokine Storm in COVID-19: Exploring IL-6 Signaling and Cytokine-Microbiome Interactions as Emerging Therapeutic Approaches"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8404-2771","authenticated-orcid":false,"given":"Tudorita Gabriela","family":"Paranga","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases (Internal Medicine II), Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"},{"name":"St. Parascheva Clinical Hospital for Infectious Diseases, 700116 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2370-3166","authenticated-orcid":false,"given":"Ivona","family":"Mitu","sequence":"additional","affiliation":[{"name":"Department of Morpho-Functional Sciences II, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2802-5993","authenticated-orcid":false,"given":"Mariana","family":"Pavel-Tanasa","sequence":"additional","affiliation":[{"name":"Department of Immunology, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"},{"name":"Laboratory of Immunology, St. Spiridon County Clinical Emergency Hospital, 700101 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel Florin","family":"Rosu","sequence":"additional","affiliation":[{"name":"St. Parascheva Clinical Hospital for Infectious Diseases, 700116 Iasi, Romania"},{"name":"Department of Preventive Medicine and Interdisciplinarity, Faculty of Medicine, University of Medicine and Pharmacy Grigore. T. Popa, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4131-1019","authenticated-orcid":false,"given":"Ionela-Larisa","family":"Miftode","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases (Internal Medicine II), Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"},{"name":"St. Parascheva Clinical Hospital for Infectious Diseases, 700116 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0732-3745","authenticated-orcid":false,"given":"Daniela","family":"Constantinescu","sequence":"additional","affiliation":[{"name":"Department of Immunology, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"},{"name":"Laboratory of Immunology, St. Spiridon County Clinical Emergency Hospital, 700101 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5807-6548","authenticated-orcid":false,"given":"Maria","family":"Obreja","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases (Internal Medicine II), Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"},{"name":"St. Parascheva Clinical Hospital for Infectious Diseases, 700116 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5704-578X","authenticated-orcid":false,"given":"Claudia Elena","family":"Plesca","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases (Internal Medicine II), Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"},{"name":"St. Parascheva Clinical Hospital for Infectious Diseases, 700116 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Egidia","family":"Miftode","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases (Internal Medicine II), Faculty of Medicine, Grigore T. 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Systemic Cytokine Release and Modulation by Corticosteroids","volume":"49","author":"Chatenoud","year":"1990","journal-title":"Transplantation"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1056\/NEJMoa063842","article-title":"Cytokine Storm in a Phase 1 Trial of the Anti-CD28 Monoclonal Antibody TGN1412","volume":"355","author":"Suntharalingam","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Paranga, T.G., Pavel-Tanasa, M., Constantinescu, D., Plesca, C.E., Petrovici, C., Miftode, I.-L., Moscalu, M., Cianga, P., and Miftode, E.G. (2023). Comparison of C-Reactive Protein with Distinct Hyperinflammatory Biomarkers in Association with COVID-19 Severity, Mortality and SARS-CoV-2 Variants. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1213246"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Paranga, T.G., Pavel-tanasa, M., Constantinescu, D., Iftimi, E., Plesca, C.E., Miftode, I., Cianga, P., and Miftode, E. (2024). Distinct Soluble Immune Checkpoint pro Fi Les Characterize COVID-19 Severity, Mortality and SARS-CoV-2 Variant Infections. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1464480"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1146\/annurev-med-042921-112837","article-title":"Cytokine Storm Syndrome","volume":"74","author":"Cron","year":"2023","journal-title":"Annu. Rev. Med."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Gu, Y., Zuo, X., Zhang, S., Ouyang, Z., Jiang, S., Wang, F., and Wang, G. (2021). The Mechanism Behind Influenza Virus Cytokine Storm. Viruses, 13.","DOI":"10.3390\/v13071362"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.trsl.2021.03.002","article-title":"COVID-19 and Cytokine Storm Syndrome: Are There Lessons from Macrophage Activation Syndrome?","volume":"232","author":"Ombrello","year":"2021","journal-title":"Transl. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"107087","DOI":"10.1016\/j.intimp.2020.107087","article-title":"Toll-like Receptors in Sepsis-Associated Cytokine Storm and Their Endogenous Negative Regulators as Future Immunomodulatory Targets","volume":"89","author":"Kumar","year":"2020","journal-title":"Int. Immunopharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1007\/978-3-031-59815-9_19","article-title":"Bacteria-Associated Cytokine Storm Syndrome","volume":"1448","author":"Eloseily","year":"2024","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1007\/978-3-031-59815-9_21","article-title":"Parasitic and Fungal Triggers of Cytokine Storm Syndrome","volume":"1448","author":"Sterba","year":"2024","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1016\/j.jaci.2020.09.016","article-title":"Highways to Hell: Mechanism-Based Management of Cytokine Storm Syndromes","volume":"146","author":"Canna","year":"2020","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1007\/978-3-031-59815-9_24","article-title":"Systemic Lupus Erythematosus and Cytokine Storm","volume":"1448","author":"Caricchio","year":"2024","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Meng, J., Ma, Y., Jia, J., Wang, M., Teng, J., Shi, H., Liu, H., Su, Y., Ye, J., and Sun, Y. (2020). Cytokine Storm in Coronavirus Disease 2019 and Adult-Onset Still\u2019s Disease: Similarities and Differences. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.603389"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1007\/978-3-031-59815-9_25","article-title":"Kawasaki Disease-Associated Cytokine Storm Syndrome","volume":"1448","author":"Tsoukas","year":"2024","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1646","DOI":"10.1182\/blood-2016-10-746933","article-title":"International, Evidence-Based Consensus Diagnostic Criteria for HHV-8-Negative\/Idiopathic Multicentric Castleman Disease","volume":"129","author":"Fajgenbaum","year":"2017","journal-title":"Blood"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1080\/22221751.2021.1884503","article-title":"COVID-19-Associated Cytokine Storm Syndrome and Diagnostic Principles: An Old and New Issue","volume":"10","author":"Yongzhi","year":"2021","journal-title":"Emerg. Microbes Infect."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/s00281-024-01013-w","article-title":"Riding the Storm: Managing Cytokine-Related Toxicities in CAR-T Cell Therapy","volume":"46","author":"Hughes","year":"2024","journal-title":"Semin. Immunopathol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1016\/j.jtct.2023.03.006","article-title":"Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-like Syndrome","volume":"29","author":"Hines","year":"2023","journal-title":"Transplant. Cell. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1056\/NEJMoa1609783","article-title":"Blinatumomab Versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia","volume":"376","author":"Kantarjian","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Jarczak, D., and Nierhaus, A. (2022). Cytokine Storm-Definition, Causes, and Implications. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231911740"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.imlet.2020.09.007","article-title":"\u201cCytokine Storm\u201d, Not Only in COVID-19 Patients. Mini-Review","volume":"228","author":"Lukan","year":"2020","journal-title":"Immunol. Lett."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.psyneuen.2018.03.001","article-title":"Weathering the Storm; a Review of Pre-Pregnancy Stress and Risk of Spontaneous Abortion","volume":"92","author":"Frazier","year":"2018","journal-title":"Psychoneuroendocrinology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1089\/jir.2023.0044","article-title":"Study on the Characteristics of Early Cytokine Storm Response to Cardiac Surgery","volume":"43","author":"Zhao","year":"2023","journal-title":"J. Interf. Cytokine Res. Off. J. Int. Soc. Interf. Cytokine Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/s41379-021-00950-3","article-title":"Transcriptome and Unique Cytokine Microenvironment of Castleman Disease","volume":"35","author":"Wing","year":"2022","journal-title":"Mod. Pathol. Off. J. United States Can. Acad. Pathol. Inc."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1002\/JLB.3COVR0520-272R","article-title":"Cytokine Storm and Leukocyte Changes in Mild versus Severe SARS-CoV-2 Infection: Review of 3939 COVID-19 Patients in China and Emerging Pathogenesis and Therapy Concepts","volume":"108","author":"Wang","year":"2020","journal-title":"J. Leukoc. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"156287","DOI":"10.1016\/j.cyto.2023.156287","article-title":"Emerging Aspects of Cytokine Storm in COVID-19: The Role of Proinflammatory Cytokines and Therapeutic Prospects","volume":"169","author":"Dharra","year":"2023","journal-title":"Cytokine"},{"key":"ref_29","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_30","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_31","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.cca.2020.06.017","article-title":"Cytokine Storm Induced by SARS-CoV-2","volume":"509","author":"Song","year":"2020","journal-title":"Clin. Chim. Acta"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Wang, X., Tang, G., Liu, Y., Zhang, L., Chen, B., Han, Y., Fu, Z., Wang, L., Hu, G., and Ma, Q. (2022). The Role of IL-6 in Coronavirus, Especially in COVID-19. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.1033674"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Grebenciucova, E., and VanHaerents, S. (2023). Interleukin 6: At the Interface of Human Health and Disease. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1255533"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"101697","DOI":"10.1016\/j.arr.2022.101697","article-title":"The Hormetic and Hermetic Role of IL-6","volume":"80","author":"Forcina","year":"2022","journal-title":"Ageing Res. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1038\/s41577-023-00856-y","article-title":"Targeting IL-6 Trans-Signalling: Past, Present and Future Prospects","volume":"23","author":"Jenkins","year":"2023","journal-title":"Nat. Rev. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1111\/cns.14041","article-title":"Contemplating IL-6, a Double-Edged Sword Cytokine: Which Side to Use for Stroke Pathology?","volume":"29","author":"Monsour","year":"2023","journal-title":"CNS Neurosci. Ther."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.7150\/ijms.53564","article-title":"Role of IL-6 Inhibitor in Treatment of COVID-19-Related Cytokine Release Syndrome","volume":"18","author":"Du","year":"2021","journal-title":"Int. J. Med. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1007\/s10787-022-00992-2","article-title":"COVID-19 and the Role of Cytokines in This Disease","volume":"30","author":"Hasanvand","year":"2022","journal-title":"Inflammopharmacology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1007\/s10517-024-06106-y","article-title":"Factors of Interleukin-6 Signaling in COVID-19 Patients with Lung Damage of Varying Degrees: A Pilot Study","volume":"176","author":"Korotaeva","year":"2024","journal-title":"Bull. Exp. Biol. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1007\/s10456-024-09916-w","article-title":"Interleukin-6 Drives Endothelial Glycocalyx Damage in COVID-19 and Bacterial Sepsis","volume":"27","author":"Drost","year":"2024","journal-title":"Angiogenesis"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"156420","DOI":"10.1016\/j.cyto.2023.156420","article-title":"Cytokine Storm in COVID-19 and Malaria: Annals of pro-Inflammatory Cytokines","volume":"173","author":"Qidwai","year":"2024","journal-title":"Cytokine"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"100745","DOI":"10.1016\/j.blre.2020.100745","article-title":"Coagulation Dysfunction in COVID-19: The Interplay between Inflammation, Viral Infection and the Coagulation System","volume":"46","author":"Lazzaroni","year":"2021","journal-title":"Blood Rev."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s13613-020-00798-x","article-title":"Elevated Plasma IL-6 and CRP Levels Are Associated with Adverse Clinical Outcomes and Death in Critically Ill SARS-CoV-2 Patients: Inflammatory Response of SARS-CoV-2 Patients","volume":"11","author":"Lavillegrand","year":"2021","journal-title":"Ann. Intensive Care"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"109130","DOI":"10.1016\/j.intimp.2022.109130","article-title":"Interleukin-6 Cytokine: An Overview of the Immune Regulation, Immune Dysregulation, and Therapeutic Approach","volume":"111","author":"Aliyu","year":"2022","journal-title":"Int. Immunopharmacol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Carlini, V., Noonan, D.M., Abdalalem, E., Goletti, D., Sansone, C., Calabrone, L., and Albini, A. (2023). The Multifaceted Nature of IL-10: Regulation, Role in Immunological Homeostasis and Its Relevance to Cancer, COVID-19 and Post-COVID Conditions. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1161067"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Al-Qahtani, A.A., Alhamlan, F.S., and Al-Qahtani, A.A. (2024). Pro-Inflammatory and Anti-Inflammatory Interleukins in Infectious Diseases: A Comprehensive Review. Trop. Med. Infect. Dis., 9.","DOI":"10.3390\/tropicalmed9010013"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Dhawan, M., Rabaan, A.A., Alwarthan, S., Alhajri, M., Halwani, M.A., Alshengeti, A., Najim, M.A., Alwashmi, A.S.S., Alshehri, A.A., and Alshamrani, S.A. (2023). Regulatory T Cells (Tregs) and COVID-19: Unveiling the Mechanisms, and Therapeutic Potentialities with a Special Focus on Long COVID. Vaccines, 11.","DOI":"10.3390\/vaccines11030699"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Nara, H., and Watanabe, R. (2021). Anti-Inflammatory Effect of Muscle-Derived Interleukin-6 and Its Involvement in Lipid Metabolism. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22189889"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2003006","DOI":"10.1183\/13993003.03006-2020","article-title":"Confronting the Controversy: Interleukin-6 and the COVID-19 Cytokine Storm Syndrome","volume":"56","author":"Chen","year":"2020","journal-title":"Eur. Respir. J."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s40265-022-01803-2","article-title":"Should We Interfere with the Interleukin-6 Receptor During COVID-19: What Do We Know So Far?","volume":"83","author":"Plocque","year":"2023","journal-title":"Drugs"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"156445","DOI":"10.1016\/j.cyto.2023.156445","article-title":"Impact of IL-6 Rs1800795 and IL-17A Rs2275913 Gene Polymorphisms on the COVID-19 Prognosis and Susceptibility in a Sample of Iranian Patients","volume":"174","author":"Khafaei","year":"2024","journal-title":"Cytokine"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1007\/s44197-024-00204-w","article-title":"Impacts of Inflammatory Cytokines Variants on Systemic Inflammatory Profile and COVID-19 Severity","volume":"14","author":"Deng","year":"2024","journal-title":"J. Epidemiol. Glob. Health"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Noureddine, R., Baba, H., Aqillouch, S., Abounouh, K., Laazaazia, O., Elmessaoudi-Idrissi, M., Bahmani, F.Z., Tanouti, I.A., Ouladlahsen, A., and Sarih, M. (2024). The Interleukin-6 Gene Variants May Protect against SARS-CoV-2 Infection and the Severity of COVID-19: A Case-Control Study in a Moroccan Population. BMC Med. Genom., 17.","DOI":"10.1186\/s12920-024-01911-w"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Zawawi, Z.M., Kalyanasundram, J., Zain, R.M., Thayan, R., Basri, D.F., and Yap, W.B. (2023). Prospective Roles of Tumor Necrosis Factor-Alpha (TNF-\u03b1) in COVID-19: Prognosis, Therapeutic and Management. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24076142"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1038\/s41577-022-00792-3","article-title":"Death by TNF: A Road to Inflammation","volume":"23","author":"Bertrand","year":"2023","journal-title":"Nat. Rev. Immunol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1708","DOI":"10.3389\/fimmu.2020.01708","article-title":"Cytokine Storm in COVID-19: The Current Evidence and Treatment Strategies","volume":"11","author":"Tang","year":"2020","journal-title":"Front Immunol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1636","DOI":"10.1038\/s41591-020-1051-9","article-title":"An Inflammatory Cytokine Signature Predicts COVID-19 Severity and Survival","volume":"26","author":"Huang","year":"2020","journal-title":"Nat. Med."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Halim, C., Mirza, A.F., and Sari, M.I. (2022). The Association between TNF-\u03b1, IL-6, and Vitamin D Levels and COVID-19 Severity and Mortality: A Systematic Review and Meta-Analysis. Pathogens, 11.","DOI":"10.3390\/pathogens11020195"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1093\/cid\/ciaa415","article-title":"Obesity in Patients Younger Than 60 Years Is a Risk Factor for COVID-19 Hospital Admission","volume":"71","author":"Lighter","year":"2020","journal-title":"Clin. Infect. Dis."},{"key":"ref_60","first-page":"154244","article-title":"Letter to the Editor: Obesity as a Risk Factor for Greater Severity of COVID-19 in Patients with Metabolic Associated Fatty Liver Disease","volume":"108","author":"Zheng","year":"2020","journal-title":"Microorganism"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/S2213-2600(20)30079-5","article-title":"Clinical Course and Outcomes of Critically Ill Patients with SARS-CoV-2 Pneumonia in Wuhan, China: A Single-Centered, Retrospective, Observational Study","volume":"8","author":"Yang","year":"2020","journal-title":"Lancet Respir. Med."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Balzanelli, M.G., Distratis, P., Lazzaro, R., Cefalo, A., Catucci, O., Aityan, S.K., Dipalma, G., Vimercati, L., Inchingolo, A.D., and Maggiore, M.E. (2021). The Vitamin D, IL-6 and the EGFR Markers a Possible Way to Elucidate the Lung-Heart-Kidney Cross-Talk in COVID-19 Disease: A Foregone Conclusion. Microorganisms, 9.","DOI":"10.3390\/microorganisms9091903"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/s10875-020-00899-z","article-title":"Circulating Levels of Interleukin-6 and Interleukin-10, But Not Tumor Necrosis Factor-Alpha, as Potential Biomarkers of Severity and Mortality for COVID-19: Systematic Review with Meta-Analysis","volume":"41","author":"Udomsinprasert","year":"2021","journal-title":"J. Clin. Immunol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.cell.2020.11.025","article-title":"Synergism of TNF-\u03b1 and IFN-\u03b3 Triggers Inflammatory Cell Death, Tissue Damage, and Mortality in SARS-CoV-2 Infection and Cytokine Shock Syndromes","volume":"184","author":"Karki","year":"2021","journal-title":"Cell"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Eldesouki, R.E., Kishk, R.M., Abd El-Fadeal, N.M., Mahran, R.I., Kamel, N., Riad, E., Nemr, N., Kishk, S.M., and Mohammed, E.A.-M. (2024). Association of IL-10-592 C\u2009>\u2009A \/-1082 A\u2009>\u2009G and the TNF\u03b1 -308 G\u2009>\u2009A with Susceptibility to COVID-19 and Clinical Outcomes. BMC Med. Genom., 17.","DOI":"10.1186\/s12920-023-01793-4"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Pyrillou, K., Burzynski, L.C., and Clarke, M.C.H. (2020). Alternative Pathways of IL-1 Activation, and Its Role in Health and Disease. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.613170"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1007\/s00011-022-01596-w","article-title":"The Role of IL-1 Family of Cytokines and Receptors in Pathogenesis of COVID-19","volume":"71","author":"Makaremi","year":"2022","journal-title":"Inflamm. Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1089\/jir.2022.0185","article-title":"The Role of Inflammatory Cytokines (Interleukin-1 and Interleukin-6) as a Potential Biomarker in the Different Stages of COVID-19 (Mild, Severe, and Critical)","volume":"43","author":"Nezhad","year":"2023","journal-title":"J. Interferon Cytokine Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.4049\/jimmunol.2200844","article-title":"Intestinal IL-1\u03b2 Plays a Role in Protecting against SARS-CoV-2 Infection","volume":"211","author":"Heinrich","year":"2023","journal-title":"J. Immunol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"e28751","DOI":"10.1002\/jmv.28751","article-title":"The Roles of Critical Pro-inflammatory Cytokines in the Drive of Cytokine Storm During SARS-CoV-2 Infection","volume":"95","author":"Qudus","year":"2023","journal-title":"J. Med. Virol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.cytogfr.2020.06.001","article-title":"SARS-CoV-2 Infection: The Role of Cytokines in COVID-19 Disease","volume":"54","author":"Ruiz","year":"2020","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"100663","DOI":"10.1016\/j.xcrm.2022.100663","article-title":"The IL-1\u03b2, IL-6, and TNF Cytokine Triad Is Associated with Post-Acute Sequelae of COVID-19","volume":"3","author":"Willscher","year":"2022","journal-title":"Cell Rep. Med."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Gomes, S.M.R., de Brito, A.C.S., Manfro, W.F.P., Ribeiro-Alves, M., de Ribeiro, R.S.A., da Cal, M.S., da Lisboa, V.C., de Abreu, D.P.B., Castilho, L.D.R., and de Porto, L.C.M.S. (2023). High Levels of Pro-Inflammatory SARS-CoV-2-Specific Biomarkers Revealed by In Vitro Whole Blood Cytokine Release Assay (CRA) in Recovered and Long-COVID-19 Patients. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0283983"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Alonso-Dom\u00ednguez, J., Gallego-Rodr\u00edguez, M., Mart\u00ednez-Barros, I., Calder\u00f3n-Cruz, B., Leiro-Fern\u00e1ndez, V., P\u00e9rez-Gonz\u00e1lez, A., and Poveda, E. (2023). High Levels of IL-1\u03b2, TNF-\u03b1 and MIP-1\u03b1 One Month after the Onset of the Acute SARS-CoV-2 Infection, Predictors of Post COVID-19 in Hospitalized Patients. Microorganisms, 11.","DOI":"10.3390\/microorganisms11102396"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Chen, Y., and Chen, C. (2024). Gut Microbiota, Inflammatory Proteins and COVID-19: A Mendelian Randomisation Study. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1406291"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Giovanetti, M., Pannella, G., Altomare, A., Rocchi, G., Guarino, M., Ciccozzi, M., Riva, E., and Gherardi, G. (2024). Exploring the Interplay between COVID-19 and Gut Health: The Potential Role of Prebiotics and Probiotics in Immune Support. Viruses, 16.","DOI":"10.3390\/v16030370"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1038\/mi.2011.55","article-title":"Pulmonary-Intestinal Cross-Talk in Mucosal Inflammatory Disease","volume":"5","author":"Keely","year":"2012","journal-title":"Mucosal Immunol."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Ancona, G., Alagna, L., Alteri, C., Palomba, E., Tonizzo, A., Pastena, A., Muscatello, A., Gori, A., and Bandera, A. (2023). Gut and Airway Microbiota Dysbiosis and Their Role in COVID-19 and Long-COVID. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1080043"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Rizzello, F., Viciani, E., Gionchetti, P., Filippone, E., Imbesi, V., Melotti, L., Dussias, N.K., Salice, M., Santacroce, B., and Padella, A. (2024). Signatures of Disease Outcome Severity in the Intestinal Fungal and Bacterial Microbiome of COVID-19 Patients. Front. Cell. Infect. Microbiol., 14.","DOI":"10.3389\/fcimb.2024.1352202"},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Essex, M., Pascual-Leone, B.M., L\u00f6ber, U., Kuhring, M., Zhang, B., Br\u00fcning, U., Fritsche-Guenther, R., Krzanowski, M., Vernengo, F.F., and Brumhard, S. (2024). Gut Microbiota Dysbiosis Is Associated with Altered Tryptophan Metabolism and Dysregulated Inflammatory Response in COVID-19. NPJ Biofilms Microbiomes, 10.","DOI":"10.1038\/s41522-024-00538-0"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1038\/s41575-022-00698-4","article-title":"Gut Microbiota in COVID-19: Key Microbial Changes, Potential Mechanisms and Clinical Applications","volume":"20","author":"Zhang","year":"2023","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1136\/gutjnl-2020-323020","article-title":"Gut Microbiota Composition Reflects Disease Severity and Dysfunctional Immune Responses in Patients with COVID-19","volume":"70","author":"Yeoh","year":"2021","journal-title":"Gut"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Giron, L.B., Dweep, H., Yin, X., Wang, H., Damra, M., Goldman, A.R., Gorman, N., Palmer, C.S., Tang, H.-Y., and Shaikh, M.W. (2021). Plasma Markers of Disrupted Gut Permeability in Severe COVID-19 Patients. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.779064"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1053\/j.gastro.2022.09.024","article-title":"Human Gut Microbiota and Its Metabolites Impact Immune Responses in COVID-19 and Its Complications","volume":"164","author":"Nagata","year":"2023","journal-title":"Gastroenterology"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1053\/j.gastro.2021.10.013","article-title":"Prolonged Impairment of Short-Chain Fatty Acid and L-Isoleucine Biosynthesis in Gut Microbiome in Patients With COVID-19","volume":"162","author":"Zhang","year":"2022","journal-title":"Gastroenterology"},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Liu, S., Wang, B., Chen, T., Wang, H., Liu, J., Zhao, X., and Zhang, Y. (2024). Two New and Effective Food-Extracted Immunomodulatory Agents Exhibit Anti-Inflammatory Response Activity in the HACE2 Acute Lung Injury Murine Model of COVID-19. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1374541"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Cione, E., Siniscalchi, A., Gangemi, P., Cosco, L., Colosimo, M., Longhini, F., Luciani, F., De Sarro, G., Berrino, L., and D\u2019Agostino, B. (2021). Neuron-Specific Enolase Serum Levels in COVID-19 Are Related to the Severity of Lung Injury. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0251819"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Shen, Y., Cheng, C., Zheng, X., Jin, Y., Duan, G., Chen, M., and Chen, S. (2021). Elevated Procalcitonin Is Positively Associated with the Severity of COVID-19: A Meta-Analysis Based on 10 Cohort Studies. Medicina, 57.","DOI":"10.3390\/medicina57060594"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"SB, M.J., Chacko, B., Selvarajan, S., Peter, J.V., Geevar, T., Dave, R.G., Georgy, J.T., Zachariah, A., George, T., and Sathyendra, S. (2024). Biomarkers of Coagulation, Endothelial, Platelet Function, and Fibrinolysis in Patients with COVID-19: A Prospective Study. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-51908-9"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1161\/CIRCULATIONAHA.120.050543","article-title":"Myocardial Injury in Severe COVID-19 Compared with Non-COVID-19 Acute Respiratory Distress Syndrome","volume":"143","author":"Metkus","year":"2021","journal-title":"Circulation"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1001\/jamacardio.2020.0950","article-title":"Association of Cardiac Injury with Mortality in Hospitalized Patients with COVID-19 in Wuhan, China","volume":"5","author":"Shi","year":"2020","journal-title":"JAMA Cardiol."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Ochoa-Ram\u00edrez, L.A., De la Herr\u00e1n Arita, A.K., Sanchez-Zazueta, J.G., R\u00edos-Burgue\u00f1o, E., Murillo-Llanes, J., De Jes\u00fas-Gonz\u00e1lez, L.A., Farfan-Morales, C.N., Cordero-Rivera, C.D., Del \u00c1ngel, R.M., and Romero-Utrilla, A. (2024). Association between Lipid Profile and Clinical Outcomes in COVID-19 Patients. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-62899-y"},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Sarkar, A., Sanyal, S., Majumdar, A., Tewari, D.N., Bhattacharjee, U., Pal, J., Chakrabarti, A.K., and Dutta, S. (2022). Development of Lab Score System for Predicting COVID-19 Patient Severity: A Retrospective Analysis. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0273006"},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Antunez Mui\u00f1os, P.J., L\u00f3pez Otero, D., Amat-Santos, I.J., L\u00f3pez Pa\u00eds, J., Aparisi, A., Cacho Antonio, C.E., Catal\u00e1, P., Gonz\u00e1lez Ferrero, T., Cabez\u00f3n, G., and Otero Garc\u00eda, O. (2021). The COVID-19 Lab Score: An Accurate Dynamic Tool to Predict in-Hospital Outcomes in COVID-19 Patients. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-88679-6"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"e044500","DOI":"10.1136\/bmjopen-2020-044500","article-title":"Prediction of COVID-19 Severity Using Laboratory Findings on Admission: Informative Values, Thresholds, ML Model Performance","volume":"11","author":"Statsenko","year":"2021","journal-title":"BMJ Open"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"101188","DOI":"10.1016\/j.imu.2023.101188","article-title":"Machine Learning Models for Predicting Severe COVID-19 Outcomes in Hospitals","volume":"37","author":"Wendland","year":"2023","journal-title":"Inform. Med. Unlocked"},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Laatifi, M., Douzi, S., Ezzine, H., El Asry, C., Naya, A., Bouklouze, A., Zaid, Y., and Naciri, M. (2023). Explanatory Predictive Model for COVID-19 Severity Risk Employing Machine Learning, Shapley Addition, and LIME. Sci. Rep., 13.","DOI":"10.1038\/s41598-023-31542-7"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Rashidi, H.H., Ikram, A., Dang, L.T., Bashir, A., Zohra, T., Ali, A., Tanvir, H., Mudassar, M., Ravindran, R., and Akhtar, N. (2024). Comparing Machine Learning Screening Approaches Using Clinical Data and Cytokine Profiles for COVID-19 in Resource-Limited and Resource-Abundant Settings. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-63707-3"},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Cabaro, S., D\u2019Esposito, V., Di Matola, T., Sale, S., Cennamo, M., Terracciano, D., Parisi, V., Oriente, F., Portella, G., and Beguinot, F. (2021). Cytokine Signature and COVID-19 Prediction Models in the Two Waves of Pandemics. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-00190-0"},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Hawerkamp, H.C., Dyer, A.H., Patil, N.D., McElheron, M., O\u2019Dowd, N., O\u2019Doherty, L., Mhaonaigh, A.U., George, A.M., O\u2019Halloran, A.M., and Reddy, C. (2023). Characterisation of the Pro-Inflammatory Cytokine Signature in Severe COVID-19. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1170012"},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Kalinina, O., Golovkin, A., Zaikova, E., Aquino, A., Bezrukikh, V., Melnik, O., Vasilieva, E., Karonova, T., Kudryavtsev, I., and Shlyakhto, E. (2022). Cytokine Storm Signature in Patients with Moderate and Severe COVID-19. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23168879"},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Maa\u00df, H., Ynga-Durand, M., Milo\u0161evi\u0107, M., Krstanovi\u0107, F., Mate\u0161i\u0107, M.P., \u017du\u017ea, I., Jonji\u0107, S., Brizi\u0107, I., \u0160usti\u0107, A., and Bloos, F. (2024). Serum Cytokine Dysregulation Signatures Associated with COVID-19 Outcomes in High Mortality Intensive Care Unit Cohorts across Pandemic Waves and Variants. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-64384-y"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"5174","DOI":"10.1182\/bloodadvances.2020002592","article-title":"Diagnostic Biomarkers to Differentiate Sepsis from Cytokine Release Syndrome in Critically Ill Children","volume":"4","author":"Diorio","year":"2020","journal-title":"Blood Adv."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.1002\/art.41763","article-title":"Discrimination of COVID-19 From Inflammation-Induced Cytokine Storm Syndromes Using Disease-Related Blood Biomarkers","volume":"73","author":"Kessel","year":"2021","journal-title":"Arthritis Rheumatol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"e283","DOI":"10.1111\/bjh.16934","article-title":"Secondary HLH Is Uncommon in Severe COVID-19","volume":"190","author":"Wood","year":"2020","journal-title":"Br. J. Haematol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1177\/1535370220962043","article-title":"Secondary Hemophagocytic Lymphohistiocytosis versus Cytokine Release Syndrome in Severe COVID-19 Patients","volume":"246","author":"Hakim","year":"2021","journal-title":"Exp. Biol. Med."},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Onuk, S., Sipahio\u011flu, H., Karahan, S., Ye\u015filtepe, A., Kuzug\u00fcden, S., Karabulut, A., Dursun, Z.B., and Ak\u0131n, A. (2023). Cytokine Levels and Severity of Illness Scoring Systems to Predict Mortality in COVID-19 Infection. Healthcare, 11.","DOI":"10.3390\/healthcare11030387"},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Ruytinx, P., Vandormael, P., Fraussen, J., Pieters, Z., Thonissen, S., Hellings, N., Stinissen, P., Callebaut, I., Penders, J., and Vanhove, K. (2023). Comprehensive Antibody and Cytokine Profiling in Hospitalized COVID-19 Patients in Relation to Clinical Outcomes in a Large Belgian Cohort. Sci. Rep., 13.","DOI":"10.1038\/s41598-023-46421-4"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1016\/j.jaci.2020.07.001","article-title":"The Role of IL-6 and Other Mediators in the Cytokine Storm Associated with SARS-CoV-2 Infection","volume":"146","author":"Copaescu","year":"2020","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1002\/jmv.25770","article-title":"Diagnostic Utility of Clinical Laboratory Data Determinations for Patients with the Severe COVID-19","volume":"92","author":"Gao","year":"2020","journal-title":"J. Med. Virol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"e2004433","DOI":"10.1002\/advs.202004433","article-title":"Cytokines: From Clinical Significance to Quantification","volume":"8","author":"Liu","year":"2021","journal-title":"Adv. Sci."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"987","DOI":"10.2217\/bmm-2020-0770","article-title":"Pre-Analytical Sample Handling Effects on Blood Cytokine Levels: Quality Control of a COVID-19 Biobank","volume":"15","author":"Verberk","year":"2021","journal-title":"Biomark. Med."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.clinbiochem.2019.01.001","article-title":"Impact of Clinical Sample Handling and Processing on Ultra-Low Level Measurements of Plasma Cytokines","volume":"65","author":"Cohen","year":"2019","journal-title":"Clin. Biochem."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"e2101508","DOI":"10.1002\/smll.202101508","article-title":"An Intelligent Graphene-Based Biosensing Device for Cytokine Storm Syndrome Biomarkers Detection in Human Biofluids","volume":"17","author":"Hao","year":"2021","journal-title":"Small"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"7593","DOI":"10.1038\/s41467-022-35278-2","article-title":"Ultrasensitive Rapid Cytokine Sensors Based on Asymmetric Geometry Two-Dimensional MoS(2) Diodes","volume":"13","author":"Fawzy","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_116","doi-asserted-by":"crossref","unstructured":"Calvo-Alvarez, E., D\u2019Alessandro, S., Zanotta, N., Basilico, N., Parapini, S., Signorini, L., Perego, F., Maina, K.K., Ferrante, P., and Modenese, A. (2024). Multiplex Array Analysis of Circulating Cytokines and Chemokines in COVID-19 Patients during the First Wave of the SARS-CoV-2 Pandemic in Milan, Italy. BMC Immunol., 25.","DOI":"10.1186\/s12865-024-00641-z"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.clicom.2023.02.003","article-title":"de D.L.-G. Predictors of Mortality in Patients with COVID-19 by Flow Cytometry","volume":"3","author":"Izquierdo","year":"2023","journal-title":"Clin. Immunol. Commun."},{"key":"ref_118","doi-asserted-by":"crossref","unstructured":"Liu, J., Li, S., Liu, J., Liang, B., Wang, X., Wang, H., Li, W., Tong, Q., Yi, J., and Zhao, L. (2020). Longitudinal Characteristics of Lymphocyte Responses and Cytokine Profiles in the Peripheral Blood of SARS-CoV-2 Infected Patients. EBioMedicine, 55.","DOI":"10.1016\/j.ebiom.2020.102763"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"2620","DOI":"10.1172\/JCI137244","article-title":"Clinical and Immunological Features of Severe and Moderate Coronavirus Disease 2019","volume":"130","author":"Chen","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1016\/j.medcli.2020.07.002","article-title":"Anti-IL-6 Receptor Antibody Treatment for Severe COVID-19 and the Potential Implication of IL-6 Gene Polymorphisms in Novel Coronavirus Pneumonia","volume":"155","author":"Ulhaq","year":"2020","journal-title":"Med. Clin."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1016\/j.medmal.2020.04.002","article-title":"Interleukin-6 as a Potential Biomarker of COVID-19 Progression","volume":"50","author":"Ulhaq","year":"2020","journal-title":"Med. Mal. Infect."},{"key":"ref_122","doi-asserted-by":"crossref","unstructured":"Balzanelli, M.G., Distratis, P., Lazzaro, R., Pham, V.H., Tran, T.C., Dipalma, G., Bianco, A., Serlenga, E.M., Aityan, S.K., and Pierangeli, V. (2022). Analysis of Gene Single Nucleotide Polymorphisms in COVID-19 Disease Highlighting the Susceptibility and the Severity towards the Infection. Diagnostics, 12.","DOI":"10.3390\/diagnostics12112824"},{"key":"ref_123","first-page":"171","article-title":"Clinical and Diagnostic Findings in COVID-19 Patients: An Original Research from SG Moscati Hospital in Taranto Italy","volume":"35","author":"Balzanelli","year":"2021","journal-title":"J. Biol. Regul. Homeost. Agents"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2174\/1871530321666210127141945","article-title":"An Alternative \u201cTrojan Horse\u201d Hypothesis for COVID-19: Immune Deficiency of IL-10 and SARS-CoV-2 Biology","volume":"22","author":"Balzanelli","year":"2022","journal-title":"Endocr. Metab. Immune Disord. Drug Targets"},{"key":"ref_125","doi-asserted-by":"crossref","unstructured":"Cron, R.Q., and Behrens, E.M. (2024). COVID-19 Pneumonia and Cytokine Storm Syndrome. Cytokine Storm Syndrome, Springer International Publishing.","DOI":"10.1007\/978-3-031-59815-9"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1186\/s12967-020-02423-8","article-title":"The Timeline and Risk Factors of Clinical Progression of COVID-19 in Shenzhen, China","volume":"18","author":"Wang","year":"2020","journal-title":"J. Transl. Med."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"e250","DOI":"10.1093\/cid\/ciac724","article-title":"Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients With COVID-19 (September 2022)","volume":"78","author":"Bhimraj","year":"2024","journal-title":"Clin. Infect. Dis."},{"key":"ref_128","doi-asserted-by":"crossref","unstructured":"Gentilotti, E., Savoldi, A., Compri, M., G\u00f3rska, A., De Nardo, P., Visentin, A., Be, G., Razzaboni, E., Soriolo, N., and Meneghin, D. (2021). Assessment of COVID-19 Progression on Day 5 from Symptoms Onset. BMC Infect. Dis., 21.","DOI":"10.1186\/s12879-021-06596-5"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"2333","DOI":"10.1056\/NEJMoa2028836","article-title":"Efficacy of Tocilizumab in Patients Hospitalized with COVID-19","volume":"383","author":"Stone","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1001\/jamainternmed.2020.6615","article-title":"Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial","volume":"181","author":"Salvarani","year":"2021","journal-title":"JAMA Intern. Med."},{"key":"ref_131","first-page":"23247096211019556","article-title":"Tocilizumab for the Treatment of COVID-19-Induced Cytokine Storm and Acute Respiratory Distress Syndrome: A Case Series From a Rural Level 1 Trauma Center in Western Pennsylvania","volume":"9","author":"Suresh","year":"2021","journal-title":"J. Investig. Med. High Impact Case Rep."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1056\/NEJMoa2030340","article-title":"Tocilizumab in Patients Hospitalized with COVID-19 Pneumonia","volume":"384","author":"Salama","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1001\/jama.2021.11330","article-title":"Association between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-Analysis","volume":"326","author":"Vale","year":"2021","journal-title":"JAMA"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"100459","DOI":"10.1016\/j.eclinm.2020.100459","article-title":"Early Use of Low Dose Tocilizumab in Patients with COVID-19: A Retrospective Cohort Study with a Complete Follow-Up","volume":"25","author":"Scarpazza","year":"2020","journal-title":"EClinicalMedicine"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/S0140-6736(22)01109-6","article-title":"Baricitinib in Patients Admitted to Hospital with COVID-19 (RECOVERY): A Randomised, Controlled, Open-Label, Platform Trial and Updated Meta-Analysis","volume":"400","author":"Allen","year":"2022","journal-title":"Lancet"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1016\/j.cmi.2022.10.015","article-title":"Tocilizumab versus Baricitinib in Hospitalized Patients with Severe COVID-19: An Open Label, Randomized Controlled Trial","volume":"29","author":"Karampitsakos","year":"2023","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"ofad426","DOI":"10.1093\/ofid\/ofad426","article-title":"Comparison of Tocilizumab vs Baricitinib in Clinical Outcomes Among Hospitalized Patients with COVID-19: Experience From a Public Hospital System in New York City","volume":"10","author":"Sunny","year":"2023","journal-title":"Open Forum Infect. Dis."},{"key":"ref_138","doi-asserted-by":"crossref","unstructured":"Zhang, J., Fan, X., Zhang, X., Jiang, F., Wu, Y., Yang, B., Li, X., and Liu, D. (2023). Efficacy and Safety of Tocilizumab and Baricitinib among Patients Hospitalized for COVID-19: A Systematic Review and Meta-Analysis. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1293331"},{"key":"ref_139","doi-asserted-by":"crossref","unstructured":"Dastan, F., Jamaati, H., Barati, S., Varmazyar, S., Yousefian, S., Niknami, E., and Tabarsi, P. (2023). The Effects of Combination-Therapy of Tocilizumab and Baricitinib on the Management of Severe COVID-19 Cases: A Randomized Open-Label Clinical Trial. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1265541"},{"key":"ref_140","doi-asserted-by":"crossref","unstructured":"Miftode, E., Miftode, L., Coman, I., Prepeliuc, C., Obreja, M., St\u0103m\u0103teanu, O., P\u0103r\u00e2ng\u0103, T.G., Leca, D., and Ple\u015fca, C.E. (2021). Diabetes Mellitus-A Risk Factor for Unfavourable Outcome in COVID-19 Patients-The Experience of an Infectious Diseases Regional Hospital. Healthcare, 9.","DOI":"10.3390\/healthcare9070788"},{"key":"ref_141","first-page":"852","article-title":"Drugs that aggravate the course of COVID-19: Really?","volume":"16","author":"Rothuizen","year":"2020","journal-title":"Rev. Med. Suisse"},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"1477","DOI":"10.1007\/s10787-020-00755-x","article-title":"ACEIs, ARBs, Ibuprofen Originally Linked to COVID-19: The Other Side of the Mirror","volume":"28","author":"Kelleni","year":"2020","journal-title":"Inflammopharmacology"},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1007\/s10787-020-00745-z","article-title":"A Narrative Review of the Potential Pharmacological Influence and Safety of Ibuprofen on Coronavirus Disease 19 (COVID-19), ACE2, and the Immune System: A Dichotomy of Expectation and Reality","volume":"28","author":"Smart","year":"2020","journal-title":"Inflammopharmacology"},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"2147","DOI":"10.1007\/s10787-023-01309-7","article-title":"Ibuprofen, Other NSAIDs and COVID-19: A Narrative Review","volume":"31","author":"Laughey","year":"2023","journal-title":"Inflammopharmacology"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1038\/s41533-022-00300-z","article-title":"The Use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) in COVID-19","volume":"32","author":"Kushner","year":"2022","journal-title":"NPJ Prim. Care Respir. Med."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"e25734","DOI":"10.1016\/j.heliyon.2024.e25734","article-title":"Evaluating NSAIDs in SARS-CoV-2: Immunomodulatory Mechanisms and Future Therapeutic Strategies","volume":"10","author":"Moshawih","year":"2024","journal-title":"Heliyon"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"10-1128","DOI":"10.1128\/JVI.00014-21","article-title":"Non-Steroidal Anti-Inflammatory Drugs Dampen the Cytokine and Antibody Response to SARS-CoV-2 Infection","volume":"95","author":"Chen","year":"2021","journal-title":"J. Virol."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1056\/NEJMoa2021436","article-title":"Dexamethasone in Hospitalized Patients with COVID-19","volume":"384","author":"Horby","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_149","doi-asserted-by":"crossref","unstructured":"Rodr\u00edguez-Hern\u00e1ndez, M.\u00c1., Baena-Bustos, M., Carneros, D., Zurita-Palomo, C., Mu\u00f1oz-Pinillos, P., Mill\u00e1n, J., Padillo, F.J., Smerdou, C., von Kobbe, C., and Rose-John, S. (2024). Targeting IL-6 Trans-Signalling by Sgp130Fc Attenuates Severity in SARS-CoV-2 -Infected Mice and Reduces Endotheliopathy. EBioMedicine, 103.","DOI":"10.1016\/j.ebiom.2024.105132"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/21\/11411\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:19:06Z","timestamp":1760113146000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/21\/11411"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,24]]},"references-count":149,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2024,11]]}},"alternative-id":["ijms252111411"],"URL":"https:\/\/doi.org\/10.3390\/ijms252111411","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,24]]}}}