Role of inflammatory cytokines (IL-1, IL-6 and TNF-alfa) in the prognosis of COVID-19: A systematic review
DOI:
https://doi.org/10.33448/rsd-v14i11.49986Keywords:
COVID-19, Cytokines, SARS-CoV-2.Abstract
Introduction: Elevated levels of pro-inflammatory cytokines (IL-1, IL-6, and TNF-alpha) have been implicated in the severity of COVID-19, but their prognostic value remains heterogeneous. Objective: To assess the association between IL-1, IL-6, and TNF-alpha and clinical outcomes in COVID-19. Methods: Systematic review following PRISMA guidelines. Searches were performed in PubMed using combinations of “Covid,” “interleukin,” and “inflammatory cytokines.” Studies in English or Portuguese involving adults/elderly with COVID-19, serum cytokine levels, and clinical evolution were included; reviews, coinfections, and unavailable full texts were excluded. Of 94 records, 11 met eligibility criteria. Results: Most studies showed elevated IL-6 in severe cases, associated with oxygen demand, mechanical ventilation, higher severity scores, and mortality. IL-6–based algorithms showed high sensitivity for predicting oxygen need. Longitudinal cohorts demonstrated persistently high IL-6 in non-survivors and a rapid decline in mild cases. TNF-alpha increased in severe disease and sometimes progressively in non-survivors. IL-1 evidence was scarce. One study linked IL-6 to thrombosis via alpha-defensin release. Conclusion: IL-6 emerges as the most consistent prognostic marker of COVID-19, useful for early risk stratification. TNF-alpha may complement prediction, while IL-1 requires further evidence. Standardized studies are needed to define cutoff values and integrate cytokines into clinical scoring.
References
Abdeen, S., et al. (2021). Alpha-defensins: Risk factor for thrombosis in COVID-19 infection. British Journal of Haematology, 194(1), 44–52. https://doi.org/10.1111/bjh.17442
Blot, M., et al. (2020). The dysregulated innate immune response in severe COVID-19 pneumonia that could drive poorer outcome. Journal of Translational Medicine, 18(1). https://doi.org/10.1186/s12967-020-02594-2
Casella, I. B. (2020). Physiopathology of SARS-CoV-2-infection-associated thrombosis. Jornal Vascular Brasileiro. Sociedade Brasileira de Angiologia e Cirurgia Vascular. https://doi.org/10.1590/1677-5449.200105
Huang, C., et al. (2020). Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet, 395(10223), 497–506. https://doi.org/10.1016/S0140-6736(20)30183-5
Ji, P., et al. (2020). Association of elevated inflammatory markers and severe COVID-19: A meta-analysis. Medicine, 99(47), e23315. https://doi.org/10.1097/MD.0000000000023315
Jøntvedt Jørgensen, M., et al. (2020). Increased interleukin-6 and macrophage chemoattractant protein-1 are associated with respiratory failure in COVID-19. Scientific Reports, 10(1). https://doi.org/10.1038/s41598-020-78466-9
Le Bert, N., et al. (2021). Highly functional virus-specific cellular immune response in asymptomatic SARS-CoV-2 infection. Journal of Experimental Medicine, 218(5). https://doi.org/10.1084/jem.20202617
Lenoir, C., et al. (2021). Impact of SARS-CoV-2 infection (COVID-19) on cytochromes P450 activity assessed by the Geneva cocktail. Clinical Pharmacology and Therapeutics, 110(5), 1358–1367. https://doi.org/10.1002/cpt.2412
Moher, D., et al. (2016). Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Revista Española de Nutrición Humana y Dietética, 20(2), 148–160. https://doi.org/10.14306/renhyd.20.2.164
Mojtabavi, H., Saghazadeh, A., & Rezaei, N. (2020). Interleukin-6 and severe COVID-19: A systematic review and meta-analysis. European Cytokine Network. John Libbey. https://doi.org/10.1684/ecn.2020.0459
Oliveira Lima, C. M. A. (2020). Information about the new coronavirus disease (COVID-19). Radiologia Brasileira. Colégio Brasileiro de Radiologia. https://doi.org/10.1590/0100-3984.2020.53.2e1
Oliveira, C. M. B., et al. (2019). Citocinas e dor. Brazilian Journal of Anesthesiology, 61(2), 260–265. https://doi.org/10.1016/j.bjan.2018.06.006
Pecly, I. M. D., et al. (2021). A review of COVID-19 and acute kidney injury: From pathophysiology to clinical results. Brazilian Journal of Nephrology, 43, 551–571. https://doi.org/10.1590/2175-8239-JBN-2020-0179
Pereira, A. S. et al. (2018). Metodologia da pesquisa científica. [e-book]. Ed. UAB/NTE/UFSM.
Petrey, A. C., et al. (2021). Cytokine release syndrome in COVID-19: Innate immune, vascular, and platelet pathogenic factors differ in severity of disease and sex. Journal of Leukocyte Biology, 109(1), 55–66. https://doi.org/10.1002/JLB.3COV0820-466R
Pirabe, A., et al. (2021). Age related differences in monocyte subsets and cytokine pattern during acute COVID-19: A prospective observational longitudinal study. Cells, 10(12). https://doi.org/10.3390/cells10123567
Santa Cruz, A., et al. (2021). Interleukin-6 is a biomarker for the development of fatal severe acute respiratory syndrome coronavirus 2 pneumonia. Frontiers in Immunology, 12. https://doi.org/10.3389/fimmu.2021.613422
Snyder, H. (2019). Literature review as a research methodology: An overview and guidelines. Journal of Business Research. 104, 333-9. https://doi.org/10.1016/j.jbusres.2019.07.039.
Van Singer, M., et al. (2021). COVID-19 risk stratification algorithms based on sTREM-1 and IL-6 in emergency department. Journal of Allergy and Clinical Immunology, 147(1), 99–106.e4. https://doi.org/10.1016/j.jaci.2020.09.018
Varchetta, S., et al. (2021). Unique immunological profile in patients with COVID-19. Cellular and Molecular Immunology, 18(3), 604–612. https://doi.org/10.1038/s41423-020-00557-9
Venet, F., et al. (2021). Longitudinal assessment of IFN-I activity and immune profile in critically ill COVID-19 patients with acute respiratory distress syndrome. Critical Care, 25(1). https://doi.org/10.1186/s13054-021-03780-6
Yan, Q., et al. (2021a). Longitudinal peripheral blood transcriptional analysis reveals molecular signatures of disease progression in COVID-19 patients. The Journal of Immunology, 206(9), 2146–2159. https://doi.org/10.4049/jimmunol.2001393
Yan, W., et al. (2021b). Differences of blood cells, lymphocyte subsets and cytokines in COVID-19 patients with different clinical stages: A network meta-analysis. BMC Infectious Diseases, 21(1). https://doi.org/10.1186/s12879-021-06687-3
Yonas, E., et al. (2020). Elevated interleukin levels are associated with higher severity and mortality in COVID-19: A systematic review, meta-analysis, and meta-regression. Diabetes and Metabolic Syndrome: Clinical Research and Reviews, 14(6), 2219–2230. https://doi.org/10.1016/j.dsx.2020.11.011
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Copyright (c) 2025 Bruno Coelho Duarte Oliveira, Alessandra Braga Macedo, Rodrigo Abrantes Jacinto, Isabelle Braga Macedo, Gabriel Cerqueira Santos, Luiz Alberto Ferreira Cunha da Câmara, Catarina Piva Mattos
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