PROINFLAMMATORY CYTOKINES AS DETERMINANTS OF ICAM-1 LEVELS IN CHILDREN WITH COVID-19 AND MULTISYSTEM INFLAMMATORY SYNDROME
DOI:
https://doi.org/10.11603/mcch.2410-681X.2026.i3.16601Keywords:
ICAM-1; IL-1β; IL-6; TNF-α; COVID-19; MIS-C; childrenAbstract
Introduction. Intercellular adhesion molecule 1 (ICAM-1) is a transmembrane glycoprotein that is widely expressed by various cell types and plays an important role in the course of infectious processes and the development of immune responses to pathogens. ICAM-1 expression increases under inflammatory conditions and is regulated by proinflammatory cytokines, particularly IL-1β, IL-6, and TNF-α. However, the relationships between these cytokines and ICAM-1 in children with SARS-CoV-2-associated diseases remain insufficiently studied. The aim of the study – to identify the key determinants of ICAM-1 levels among the proinflammatory cytokines IL-1β, IL-6, and TNF-α in children with COVID-19 and MIS-C, taking age and sex into account. Research Methods. A total of 285 children aged from 1 month to 17 years were examined: 200 with COVID-19, 40 with MIS-C, and 45 healthy children. ICAM-1, IL-1β, IL-6, and TNF-α levels were measured using enzymelinked assay. Statistical analysis included the Kruskal – Wallis test, Spearman’s rank correlation coefficient, and multiple linear regression. Results and Discussion. ICAM-1 levels in children with SARS-CoV-2-associated conditions were significantly higher than those in the control group and were 2.45 (1.91; 2.96) ng/mL in patients with COVID-19, 3.22 (2.57; 4.33) ng/mL in children with MIS-C, and 2.05 (1.81; 2.28) ng/mL in the control group (H = 33.49; p < 0.001). In the COVID-19 group, a statistically significant positive correlation was found between ICAM-1 and IL-1β levels (rs = 0.23; p = 0.032). In contrast, IL-6 and TNF-α levels were not significantly correlated with ICAM-1 (p > 0.05). According to multiple regression analysis, IL-1β showed an independent positive association with ICAM-1 levels: an increase in IL-1β concentration was accompanied by an increase in ICAM-1 levels, independently of clinical group, age, and sex. Conclusions. In children with COVID-19 and MIS-C, increased ICAM-1 levels were accompanied by proinflammatory cytokine activation, with IL-1β being an independent factor associated with ICAM-1 levels.
References
1. Qiu, Z., Wang, Y., Zhang, Z., Qin, R., Peng, Y., Tang, W., … Zhang, Y. (2022). Roles of intercellular cell adhesion molecule-1 (ICAM-1) in colorectal cancer: Expression, functions, prognosis, tumorigenesis, polymorphisms and therapeutic implications. Frontiers in Oncology, 12, 1052672. https://doi.org/10.3389/fonc.2022.1052672 DOI: https://doi.org/10.3389/fonc.2022.1052672
2. Vignarajah, M., Wood, A. J. T., Nelmes, E., Subburayalu, J., Herre, J., Nourshargh, S., & Summers, C. (2024). Regulation of ICAM-1 in human neutrophils. Journal of Leukocyte Biology, 116 (4), 901–908. https://doi.org/10.1093/jleuko/qiae090 DOI: https://doi.org/10.1093/jleuko/qiae090
3. Imani, M. M., Sadeghi, M., Gholamipour, M. A., Brühl, A. B., Sadeghi-Bahmani, D., & Brand, S. (2022). Evaluation of blood intercellular adhesion molecule-1 (ICAM-1) level in obstructive sleep apnea: A systematic review and meta-analysis. Medicina, 58 (10), 1499. https://doi.org/10.3390/medicina58101499 DOI: https://doi.org/10.3390/medicina58101499
4. Haydinger, C. D., Ashander, L. M., Tan, A. C. R., & Smith, J. R. (2023). Intercellular adhesion molecule 1: More than a leukocyte adhesion molecule. Biology, 12 (5), 743. https://doi.org/10.3390/biology12050743 DOI: https://doi.org/10.3390/biology12050743
5. Sapoznikov, A., Kozlovski, S., Levi, N., Feigelson, S. W., Regev, O., Davidzohn, N., … Alon, R. (2023). Dendritic cell ICAM-1 strengthens synapses with CD8 T cells but is not required for their early differentiation. Cell Reports, 42 (8), 112864. https://doi.org/10.1016/j.celrep.2023.112864 DOI: https://doi.org/10.1016/j.celrep.2023.112864
6. Shukla, S. D., Shastri, M. D., Vanka, S. K., Jha, N. K., Dureja, H., Gupta, G., … Walters, E. H. (2022). Targeting intercellular adhesion molecule-1 (ICAM-1) to reduce rhinovirus-induced acute exacerbations in chronic respiratory diseases. Inflammopharmacology, 30 (3), 725–735. https://doi.org/10.1007/s10787-022-00968-2 DOI: https://doi.org/10.1007/s10787-022-00968-2
7. Singh, V., Kaur, R., Kumari, P., Pasricha, C., & Singh, R. (2023). ICAM-1 and VCAM-1: Gatekeepers in various inflammatory and cardiovascular disorders. Clinica Chimica Acta, 548, 117487. https://doi.org/10.1016/j.cca.2023.117487 DOI: https://doi.org/10.1016/j.cca.2023.117487
8. Smith-Norowitz, T. A., Loeffler, J., Norowitz, Y. M., & Kohlhoff, S. (2021). Intracellular adhesion molecule-1 (ICAM-1) levels in convalescent COVID-19 serum: A case report. Annals of Clinical and Laboratory Science, 51 (5), 730–734.
9. Abd, M., Abd, A., & Ali, H. A. (2022). Plasma ICAM-1 level is highly associated with disease severity and predicts the progression of COVID-19. Sapporo Medical Journal, 56 (8), 1–21.
10. World Health Organization. (2020). Multisystem inflammatory syndrome in children and adolescents temporally related to COVID-19. Retrieved July 20, 2025, from https://www.who.int/news-room/commentaries/detail/multisystem-inflammatory-syndrome-in-childrenand-adolescents-with-covid-19
11. Roarty, C., Mills, C., Tonry, C., Groves, H. E., Watson, C., & Waterfield, T. (2024). The role of intestinal epithelial permeability in multisystem inflammatory syndrome in children: A case–control study. COVID, 4 (9), 1355–1367. https://doi.org/10.3390/covid4090096 DOI: https://doi.org/10.3390/covid4090096
12. Raj, R., Katragadda, R., Iyer, A., Anupama, C. P., Govidarajan, V. K., Priya, L., … Krishnasamy, K. (2025). An analysis of novel endothelial biomarkers to ascertain their role as prognostic indicators in severe COVID-19 illness. Indian Journal of Medical Research, 161 (3), 298–305. https://doi.org/10.25259/ijmr_915_2024 DOI: https://doi.org/10.25259/IJMR_915_2024
13. Albarzanji, Z. N. M., Wahid, N. M., Shaker, N. B., & Al-Bayati, Z. M. (2024). Relation of ICAM-1 and VCAM-1 markers in COVID-19 patients in Kirkuk province. Human Antibodies, 32 (4), 213–220. https://doi.org/10.3233/hab-240027 DOI: https://doi.org/10.3233/HAB-240027
14. Trofin, F., Nastase, E. V., Vâță, A., Iancu, L. S., Luncă, C., Buzilă, E. R., … Dorneanu, O. S. (2023). The immune, inflammatory and hematological response in COVID-19 patients, according to the severity of the disease. Microorganisms, 11 (2), 319. https://doi.org/10.3390/microorganisms11020319 DOI: https://doi.org/10.3390/microorganisms11020319
15. Butters, C., Benede, N., Moyo-Gwete, T., Richardson, S. I., Rohlwink, U., Shey, M., … Webb, K. (2024). Comparing the immune abnormalities in MIS-C to healthy children and those with inflammatory disease reveals distinct inflammatory cytokine production and a monofunctional T cell response. Clinical Immunology, 259, 109877. https://doi.org/10.1016/j.clim.2023.109877 DOI: https://doi.org/10.1016/j.clim.2023.109877
16. Montazersaheb, S., Hosseiniyan Khatibi, S. M., Hejazi, M. S., Tarhriz, V., Farjami, A., Ghasemian Sorbeni, F., … Rezaei, N. (2022). COVID-19 infection: An overview on cytokine storm and related interventions. Virology Journal, 19 (1), 92. https://doi.org/10.1186/s12985-022-01814-1 DOI: https://doi.org/10.1186/s12985-022-01814-1
17. Jia, F., Wang, G., Xu, J., Long, J., Deng, F., & Jiang, W. (2021). Role of tumor necrosis factor-α in the mortality of hospitalized patients with severe and critical COVID-19 pneumonia. Aging, 13 (21), 23895–23912. https://doi.org/10.18632/aging.203663 DOI: https://doi.org/10.18632/aging.203663
18. Mohd Zawawi, Z., Kalyanasundram, J., Mohd Zain, R., Thayan, R., Basri, D. F., & Yap, W. B. (2023). Prospective roles of tumor necrosis factor-alpha (TNF-α) in COVID-19: Prognosis, therapeutic and management. International Journal of Molecular Sciences, 24 (7), 6142. https://doi.org/10.3390/ijms24076142 DOI: https://doi.org/10.3390/ijms24076142
19. Sacco, K., Castagnoli, R., Vakkilainen, S., Liu, C., Delmonte, O. M., Oguz, C., … Notarangelo, L. D. (2022). Immunopathological signatures in multisystem inflammatory syndrome in children and pediatric COVID-19. Nature Medicine, 28 (5), 1050–1062. https://doi.org/10.1038/s41591-022-01724-3 DOI: https://doi.org/10.1038/s41591-022-01724-3
20. Jain, S., He, F., Brown, K., Burns, J. C., & Tremoulet, A. H. (2023). Multisystem inflammatory syndrome therapies in children (MISTIC): A randomized trial. Contemporary Clinical Trials Communications, 32, 101060. https://doi.org/10.1016/j.conctc.2023.101060 DOI: https://doi.org/10.1016/j.conctc.2023.101060
21. Lin, J., Harahsheh, A. S., Raghuveer, G., Jain, S., Choueiter, N. F., Garrido-Garcia, L. M., … McCrindle, B. W. (2023). Emerging insights into the pathophysiology of multisystem inflammatory syndrome associated with COVID-19 in children. Canadian Journal of Cardiology, 39 (6), 793–802. https://doi.org/10.1016/j.cjca.2023.01.002 DOI: https://doi.org/10.1016/j.cjca.2023.01.002
