Abstract
Background
Multisystem inflammatory syndrome in children (MIS-C) represents a hyperinflammatory state that can result in multi-organ dysfunction and death. Myeloid-derived suppressor cells (MDSC) are an immunosuppressive cell population that expands under inflammatory conditions and suppresses T cell function. We hypothesized that MDSC would be increased in children with MIS-C and that MDSC expansion would be associated with T cell lymphopenia.
Methods
We conducted a prospective, observational study. Initial blood samples were collected within 48 h of admission. Age-matched healthy controls underwent sampling once. MDSC and T cell populations were identified by flow cytometric methods.
Results
We enrolled 22 children with MIS-C (12 ICU, 10 ward) and 21 healthy controls (HC). Children with MIS-C demonstrated significantly higher MDSC compared to HC, and MDSC expansion persisted for >3 weeks in the ICU group. Children with MIS-C admitted to the ICU demonstrated significantly lower absolute numbers of T cells and natural killer cells. There were no significant associations between MDSC and cardiac dysfunction, duration of hospitalization, or vasoactive inotrope score.
Conclusions
Our study suggests that children critically ill with MIS-C have expansion of MDSC and associated decreased T cell and NK cell populations. Our results did not demonstrate associations between MDSC and clinical outcomes.
Impact
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Multisystem inflammatory syndrome in children (MIS-C) is a dysregulated immune response occurring several weeks after SARS-CoV-2 infection that can result in multi-organ dysfunction and death.
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Children severely ill with MIS-C demonstrated increased myeloid-derived suppressor cells and decreased absolute numbers of CD4+ and CD8 + T cells and NK cells compared to healthy controls.
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There was no significant association between MDSC numbers and clinical outcomes; including cardiac dysfunction, length of stay, or requirement of vasoactive support, in children with MIS-C.
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Data availability
The datasets generated during and/or analyzed during the current study are available form the corresponding author on reasonable request.
References
Feldstein, L. R. et al. Characteristics and outcomes of US children and adolescents with multisystem inflammatory syndrome in children (MIS-C) compared with severe acute COVID-19. JAMA 325, 1074–1087 (2021).
Greene, A. G., Saleh, M., Roseman, E. & Sinert, R. Toxic shock-like syndrome and COVID-19: multisystem inflammatory syndrome in children (MIS-C). Am. J. Emerg. Med. 38, 2492.e5–2492.e6 (2020).
Wessels, P. A. & Bingler, M. A. A comparison of Kawasaki disease and multisystem inflammatory syndrome in children. Prog. Pediatr. Cardiol. 65, 101516 (2022).
Sperotto, F. et al. Cardiac manifestations in SARS-CoV-2-associated multisystem inflammatory syndrome in children: a comprehensive review and proposed clinical approach. Eur. J. Pediatr. 180, 307–322 (2021).
Kwak, J. H., Lee, S.-Y. & Choi, J.-W. Clinical features, diagnosis, and outcomes of multisystem inflammatory syndrome in children associated with coronavirus disease 2019. Clin. Exp. Pediatr. 64, 68–75 (2020).
Whittaker, E. et al. Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2. JAMA 324, 259–269 (2020).
Vella, L. A. et al. Deep immune profiling of MIS-C demonstrates marked but transient immune activation compared with adult and pediatric COVID-19. Sci. Immunol. https://www.science.org/doi/10.1126/sciimmunol.abf7570. Accessed 3 May 2023.
Consiglio, C. R. et al. The immunology of multisystem inflammatory syndrome in children with COVID-19. Cell 183, 968–981.e7 (2020).
Bronte, V. et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat. Commun. 7, 12150 (2016).
Kolahian, S. et al. The emerging role of myeloid-derived suppressor cells in lung diseases. Eur. Respir. J. 47, 967–977 (2016).
Glover, A., Zhang, Z. & Shannon-Lowe, C. Deciphering the roles of myeloid derived suppressor cells in viral oncogenesis. Front. Immunol. 14, 1161848 (2023).
Bline, K. et al. Myeloid-derived suppressor cells and clinical outcomes in children with COVID-19. Front. Pediatr. 10, 893045. https://www.frontiersin.org/article/10.3389/fped.2022.893045 (2022).
Bline, K. E. et al. Novel Identification of Myeloid-Derived Suppressor Cells in Children With Septic Shock. Pediatr. Crit. Care Med. J. Soc. Crit. Care Med. World Fed. Pediatr. Intensive Crit. Care Soc. 23, e555–e563 (2022).
Porritt, R. A. et al. The autoimmune signature of hyperinflammatory multisystem inflammatory syndrome in children. J. Clin. Investig. 131, e151520 (2021).
CDC. Multisystem Inflammatory Syndrome (MIS). Centers for Disease Control and Prevention, https://www.cdc.gov/mis/mis-c/hcp/index.html (2020).
Pollack, M. M., Patel, K. M. & Ruttimann, U. E. PRISM III: an updated pediatric risk of mortality score. Crit. Care Med. 24, 743–752 (1996).
Leteurtre, S. et al. PELOD-2: an update of the pediatric logistic organ dysfunction score. Crit. Care Med. 41, 1761–1773 (2013).
Feldstein, L. R. et al. Multisystem inflammatory syndrome in U.S. children and adolescents. N. Engl. J. Med. 383, 334–346 (2020).
Apodaca, M. C. et al. Characterization of a whole blood assay for quantifying myeloid-derived suppressor cells. J. Immunother. Cancer 7, 230 (2019).
Diaz-Montero, C. M. et al. Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin–cyclophosphamide chemotherapy. Cancer Immunol. Immunother. 58, 49–59 (2009).
Thiele, C. & Hirschfeld, G. cutpointr: improved estimation and validation of optimal cutpoints in R. J. Stat. Softw. 98, 1–27, www.jstatsoft.org (2021).
R: The R Project for Statistical Computing. https://www.r-project.org/. Accessed 18 July 2023.
Quintero, A. M. et al. Differences in SARS-CoV-2 clinical manifestations and disease severity in children and adolescents by infecting variant. Emerg. Infect. Dis. 28, 2270–2280 (2022).
Corwin, D. J. et al. Distinguishing multisystem inflammatory syndrome in children from Kawasaki disease and benign inflammatory illnesses in the SARS-CoV-2 pandemic. Pediatr. Emerg. Care 36, 554–558 (2020).
Noval Rivas, M., Porritt, R. A., Cheng, M. H., Bahar, I. & Arditi, M. Multisystem inflammatory syndrome in children and long COVID: the SARS-CoV-2 viral superantigen hypothesis. Front. Immunol. 13, 941009 (2022).
Carter, M. J. et al. Peripheral immunophenotypes in children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection. Nat. Med. 26, 1701–1707 (2020).
Rajamanickam, A. et al. Unique cellular immune signatures of multisystem inflammatory syndrome in children. PLoS Pathog. 18, e1010915 (2022).
Boribong, B. P. et al. Neutrophil profiles of pediatric COVID-19 and multisystem inflammatory syndrome in children. Cell Rep. Med. 3, 100848 (2022).
Ruan, W.-S. et al. Early activation of myeloid-derived suppressor cells participate in sepsis-induced immune suppression via PD-L1/PD-1 Axis. Front. Immunol. 11, 1299 (2020).
Köstlin-Gille, N. & Christian, G. Myeloid-derived suppressor cells in pregnancy and the neonatal period. Front. Immunol. 11, 584712 (2020).
Passive transfer of tumour‐derived MDSCs inhibits asthma‐related airway inflammation. Scand. J. Immunol. Wiley Online Library. https://onlinelibrary.wiley.com/doi/full/10.1111/sji.12140. Accessed 7 Sept. 2022.
van Geffen, C. et al. Myeloid-derived suppressor cells dampen airway inflammation through prostaglandin E2 receptor 4. Front. Immunol. 12, 695933 (2021).
Yang, F. et al. The effect of immunosuppressive drugs on MDSCs in transplantation. J. Immunol. Res. 3, 5414808 (2018).
Simón-Fuentes, M. et al. Intravenous immunoglobulins promote an expansion of monocytic myeloid-derived suppressor cells (MDSC) in CVID patients. J. Clin. Immunol. 42, 1093–1105 (2022).
Cheng, R. et al. Periodontal inflammation recruits distant metastatic breast cancer cells by increasing myeloid-derived suppressor cells. Oncogene 39, 1543–1556, www.nature.com (2020).
Acknowledgements
We would like to thank the patients and their families for their participation in this study. We also want to express our gratitude for Nationwide Children’s Hospital Clinical Research Services and nursing staff for their efforts in patient recruitment and sample collection.
Funding
This project was made possible by funding from the Thrasher Research Fund.
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K.B., A.M., and O.R. contributed substantially to conception and design. A.W., A.A., S.M., F.Y., L.S., and A.W. contributed to acquisition of data. K.B. and R.A. contributed to analysis and interpretation of data. K.B. drafted the article. All authors gave final approval of the published version.
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A.M. has received fees for participation in Advisory Boards from Janssen, Merck, Pfizer, AstraZeneca and Sanofi-Pasteur, grants from NIH, Merck, and Janssen to institutions. O.R. has received research grants to institution from Janssen, Merck, NIH, and the Bill & Melinda Gates Foundation; and fees for participation in Advisory Boards from Sanofi-Pasteur, Merck, and Pfizer and for lectures from Pfizer, Sanofi-Pasteur, Merck, and AstraZeneca.
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Bline, K.E., Wilt, A.L., Alexander, R.N. et al. Myeloid-derived suppressor cells and T cell populations in children with Multisystem Inflammatory Syndrome. Pediatr Res 95, 1288–1294 (2024). https://doi.org/10.1038/s41390-023-02919-1
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DOI: https://doi.org/10.1038/s41390-023-02919-1