The Role of Intestinal Epithelial Permeability in Multisystem Inflammatory Syndrome in Children: A Case–Control Study
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Design
2.2. Participants
2.3. Clinical Variables and Data Sources
2.4. Blood Sample Collection
2.5. Additional Laboratory Analysis
LC-MS/MS Measurement of Protein Markers
2.6. Circulating Spike Protein Quantification
2.7. Quantification of Anti-RBD IgG, IgM, and IgA Antibodies
2.8. Statistical Methods
2.9. Patient and Public Involvement
3. Results
3.1. Cohort Description
3.2. The Effects of SARS-CoV-2 Infection on the Intestinal Epithelial Permeability of Healthy Children
3.3. Intestinal Epithelial Permeability in Children with MIS-C Compared with That of Control Groups
3.4. Circulating Levels of SARS-CoV-2 Spike Protein Following SARS-CoV-2 Infection in Children with and without MIS-C
3.5. In Silico Investigation of Markers of Intestinal Epithelial Permeability
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Shingleton, J.; Williams, H.; Oligbu, G.; Powell, A.; Cohen, J.; Arditi, M.; Watson-Koszel, T.; Kenny, S.; Gent, N.; Ladhani, S.N. The changing epidemiology of PIMS-TS across COVID-19 waves: Prospective national surveillance, January 2021 to July 2022, England. J. Infect. 2022, 85, 702–769. [Google Scholar] [CrossRef]
- Shingleton, J.; Burton, L.; Williams, H.E.; Finnie, T.J.R.; Bennett, E.; Birrell, P.; Kenny, S.; Watson-Koszel, T.; Viner, R.; Arditi, M.; et al. Risk of paediatric multisystem inflammatory syndrome (PIMS-TS) during the SARS-CoV-2 alpha and delta variant waves: National observational and modelling study, 2020–2021, England. Front. Pediatr. 2022, 10, 2166. [Google Scholar] [CrossRef] [PubMed]
- Payne, A.B.; Gilani, Z.; Godfred-Cato, S.; Belay, E.D.; Feldstein, L.R.; Patel, M.M.; Randolph, A.G.; Newhams, M.; Thomas, D.; Magleby, R.; et al. Incidence of Multisystem Inflammatory Syndrome in Children Among US Persons Infected With SARS-CoV-2. JAMA Netw. Open 2021, 4, e2116420. [Google Scholar] [CrossRef] [PubMed]
- Roarty, C.; Waterfield, T. Review and future directions for PIMS-TS (MIS-C). Arch. Dis. Child. 2022, 108, e2. [Google Scholar] [CrossRef]
- Feldstein, L.R.; Rose, E.B.; Horwitz, S.M.; Collins, J.P.; Newhams, M.M.; Son, M.B.F.; Newburger, J.W.; Kleinman, L.C.; Heidemann, S.M.; Martin, A.A.; et al. Multisystem Inflammatory Syndrome in U.S. Children and Adolescents. N. Engl. J. Med. 2020, 383, 334–346. [Google Scholar] [CrossRef] [PubMed]
- Feldstein, L.R.; Tenforde, M.W.; Friedman, K.G.; Newhams, M.; Rose, E.B.; Dapul, H.; Soma, V.L.; Maddux, A.B.; Mourani, P.M.; Bowens, C.; 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 J. Am. Med. Assoc. 2021, 325, 1074–1087. [Google Scholar] [CrossRef]
- Flood, J.; Shingleton, J.; Bennett, E.; Walker, B.; Amin-Chowdhury, Z.; Oligbu, G.; Avis, J.; Lynn, R.M.; Davis, P.; Bharucha, T.; et al. Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (PIMS-TS): Prospective, national surveillance, United Kingdom and Ireland, 2020. Lancet Reg. Health Eur. 2021, 3, 100075. [Google Scholar] [CrossRef]
- Hoste, L.; Van Paemel, R.; Haerynck, F. Multisystem inflammatory syndrome in children related to COVID-19: A systematic review. Eur. J. Pediatr. 2021, 180, 2019–2034. [Google Scholar] [CrossRef]
- Porritt, R.A.; Paschold, L.; Rivas, M.N.; Cheng, M.H.; Yonker, L.M.; Chandnani, H.; Lopez, M.; Simnica, D.; Schultheiß, C.; Santiskulvong, C.; et al. HLA class I–associated expansion of TRBV11-2 T cells in multisystem inflammatory syndrome in children. J. Clin. Investig. 2021, 131, e146614. [Google Scholar] [CrossRef]
- Vella, L.A.; Giles, J.R.; Baxter, A.E.; Oldridge, D.A.; Diorio, C.; Kuri-Cervantes, L.; Alanio, C.; Pampena, M.B.; Wu, J.E.; Chen, Z.; et al. Deep immune profiling of MIS-C demonstrates marked but transient immune activation compared to adult and pediatric COVID-19. Sci. Immunol. 2021, 6, eabf7570. [Google Scholar] [CrossRef] [PubMed]
- Ramaswamy, A.; Brodsky, N.N.; Sumida, T.S.; Comi, M.; Asashima, H.; Hoehn, K.B.; Li, N.; Liu, Y.; Shah, A.; Ravindra, N.G.; et al. Immune dysregulation and autoreactivity correlate with disease severity in SARS-CoV-2-associated multisystem inflammatory syndrome in children. Immunity 2021, 54, 1083–1095.e7. [Google Scholar] [CrossRef] [PubMed]
- Kouo, T.; Chaisawangwong, W. SARS-CoV-2 as a superantigen in multisystem inflammatory syndrome in children. J. Clin. Investig. 2021, 131, e149327. [Google Scholar] [CrossRef] [PubMed]
- 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. 2022, 13, 3480. [Google Scholar] [CrossRef] [PubMed]
- Hongying Cheng, M.; Zhang, S.; Porritt, R.A.; Noval Rivas, M.; Paschold, L.; Willscher, E.; Binder, M.; Arditi, M.; Bahar, I. Superantigenic character of an insert unique to SARS-CoV-2 spike supported by skewed TCR repertoire in patients with hyperinflammation. Proc. Natl. Acad. Sci. USA 2020, 117, 25254–25262. [Google Scholar] [CrossRef] [PubMed]
- Yonker, L.M.; Gilboa, T.; Ogata, A.F.; Senussi, Y.; Lazarovits, R.; Boribong, B.P.; Bartsch, Y.C.; Loiselle, M.; Noval Rivas, M.; Porritt, R.A.; et al. Multisystem inflammatory syndrome in children is driven by zonulin-dependent loss of gut mucosal barrier. J. Clin. Investig. 2021, 131, e149633. [Google Scholar] [CrossRef]
- Swann, O.V.; Holden, K.A.; Turtle, L.; Pollock, L.; Fairfield, C.J.; Drake, T.M.; Seth, S.; Egan, C.; Hardwick, H.E.; Halpin, S.; et al. Clinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: Prospective multicentre observational cohort study. BMJ 2020, 370, 5. [Google Scholar] [CrossRef]
- Whittaker, E.; Bamford, A.; Kenny, J.; Kaforou, M.; Jones, C.E.; Shah, P.; Ramnarayan, P.; Fraisse, A.; Miller, O.; Davies, P.; et al. Clinical Characteristics of 58 Children with a Pediatric Inflammatory Multisystem Syndrome Temporally Associated with SARS-CoV-2. JAMA J. Am. Med. Assoc. 2020, 324, 259–269. [Google Scholar] [CrossRef]
- Waterfield, T.; Watson, C.; Moore, R.; Ferris, K.; Tonry, C.; Watt, A.; McGinn, C.; Foster, S.; Evans, J.; Lyttle, M.D.; et al. Seroprevalence of SARS-CoV-2 antibodies in children: A prospective multicentre cohort study. Arch. Dis. Child. 2020, 106, 680–686. [Google Scholar] [CrossRef]
- Yonker, L.M.; Swank, Z.; Gilboa, T.; Senussi, Y.; Kenyon, V.; Papadakis, L.; Boribong, B.P.; Carroll, R.W.; Walt, D.R.; Fasano, A. Zonulin Antagonist, Larazotide (AT1001), As an Adjuvant Treatment for Multisystem Inflammatory Syndrome in Children: A Case Series. Crit. Care Explor. 2022, 10, e0641. [Google Scholar] [CrossRef]
- Henderson, L.A.; Canna, S.W.; Friedman, K.G.; Gorelik, M.; Lapidus, S.K.; Bassiri, H.; Behrens, E.M.; Kernan, K.F.; Schulert, G.S.; Seo, P.; et al. American College of Rheumatology Clinical Guidance for Multisystem Inflammatory Syndrome in Children Associated With SARS–CoV-2 and Hyperinflammation in Pediatric COVID-19: Version 3. Arthritis Rheumatol. 2022, 74, e1–e20. [Google Scholar] [CrossRef]
- Harwood, R.; Allin, B.; Jones, C.E.; Whittaker, E.; Ramnarayan, P.; Ramanan, A.V.; Kaleem, M.; Tulloh, R.; Peters, M.J.; Almond, S.; et al. A national consensus management pathway for paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS): Results of a national Delphi process. Lancet Child. Adolesc. Health 2020, 5, 133–141. [Google Scholar] [CrossRef]
- Corr, M.; Christie, S.; Watson, C.; Maney, J.; Fairley, D.; Ladhani, S.N.; Lyttle, M.D.; McFetridge, L.; Mitchell, H.; Shields, M.D.; et al. Seroprevalence of SARS-CoV-2 antibodies in children of United Kingdom healthcare workers: A prospective multicentre cohort study protocol. BMJ Open 2020, 10, e041661. [Google Scholar] [CrossRef] [PubMed]
- Roarty, C.; Mills, C.; Tonry, C.; Cosgrove, P.; Norman-Bruce, H.; Groves, H.; Watson, C.; Waterfield, T. Study protocol: Medium throughput, deep proteomic characterization of children with PIMS-TS, and identification of candidate diagnostic biomarkers. medRxiv 2022. [Google Scholar] [CrossRef]
- Consortium, T.U.; Bateman, A.; Martin, M.J.; Orchard, S.; Magrane, M.; Ahmad, S.; Alpi, E.; Bowler-Barnett, E.H.; Britto, R.; Bye-A-Jee, H.; et al. UniProt: The Universal Protein Knowledgebase in 2023. Nucleic Acids Res. 2022, 51, D523–D531. [Google Scholar] [CrossRef] [PubMed]
- Sacco, K.; Castagnoli, R.; Vakkilainen, S.; Liu, C.; Delmonte, O.M.; Oguz, C.; Kaplan, I.M.; Alehashemi, S.; Burbelo, P.D.; Bhuyan, F.; et al. Immunopathological signatures in multisystem inflammatory syndrome in children and pediatric COVID-19. Nat. Med. 2022, 28, 1050–1062. [Google Scholar] [CrossRef]
- Amanat, F.; Stadlbauer, D.; Strohmeier, S.; Nguyen, T.H.O.; Chromikova, V.; McMahon, M.; Jiang, K.; Arunkumar, G.A.; Jurczyszak, D.; Polanco, J.; et al. A serological assay to detect SARS-CoV-2 seroconversion in humans. Nat. Med. 2020, 26, 1033–1036. [Google Scholar] [CrossRef]
- Porritt, R.A.; Binek, A.; Paschold, L.; Rivas, M.N.; McArdle, A.; Yonker, L.M.; Alter, G.; Chandnani, H.K.; Lopez, M.; Fasano, A.; et al. The autoimmune signature of hyperinflammatory multisystem inflammatory syndrome in children. J. Clin. Investig. 2021, 131, e151520. [Google Scholar] [CrossRef]
- Diorio, C.; Shraim, R.; Vella, L.A.; Giles, J.R.; Baxter, A.E.; Oldridge, D.A.; Canna, S.W.; Henrickson, S.E.; McNerney, K.O.; Balamuth, F.; et al. Proteomic profiling of MIS-C patients indicates heterogeneity relating to interferon gamma dysregulation and vascular endothelial dysfunction. Nat. Commun. 2021, 12, 7222. [Google Scholar] [CrossRef]
- Giron, L.B.; Dweep, H.; Yin, X.; Wang, H.; Damra, M.; Goldman, A.R.; Gorman, N.; Palmer, C.S.; Tang, H.Y.; Shaikh, M.W.; et al. Plasma Markers of Disrupted Gut Permeability in Severe COVID-19 Patients. Front. Immunol. 2021, 12, 686240. [Google Scholar]
- Hoel, H.; Heggelund, L.; Reikvam, D.H.; Stiksrud, B.; Ueland, T.; Michelsen, A.E.; Otterdal, K.; Muller, K.E.; Lind, A.; Muller, F.; et al. Elevated markers of gut leakage and inflammasome activation in COVID-19 patients with cardiac involvement. J. Intern. Med. 2021, 289, 523–531. [Google Scholar] [CrossRef]
- Messner, C.B.; Demichev, V.; Wendisch, D.; Michalick, L.; White, M.; Freiwald, A.; Textoris-Taube, K.; Vernardis, S.I.; Egger, A.S.; Kreidl, M.; et al. Ultra-High-Throughput Clinical Proteomics Reveals Classifiers of COVID-19 Infection. Cell Syst. 2020, 11, 11–24.e4. [Google Scholar] [CrossRef] [PubMed]
- Viner, R.M.; Mytton, O.T.; Bonell, C.; Melendez-Torres, G.J.; Ward, J.; Hudson, L.; Waddington, C.; Thomas, J.; Russell, S.; Van Der Klis, F.; et al. Susceptibility to SARS-CoV-2 Infection Among Children and Adolescents Compared With Adults: A Systematic Review and Meta-analysis. JAMA Pediatr. 2021, 175, 143–156. [Google Scholar] [CrossRef] [PubMed]
- Rhedin, S.; Lundholm, C.; Horne, A.C.; Smew, A.I.; Osvald, E.C.; Haddadi, A.; Alfvén, T.; Kahn, R.; Król, P.; Brew, B.H.; et al. Risk factors for multisystem inflammatory syndrome in children—A population-based cohort study of over 2 million children. Lancet Reg. Health Eur. 2022, 19, 100443. [Google Scholar] [CrossRef] [PubMed]
- Abrams, J.Y.; Oster, M.E.; Godfred-Cato, S.E.; Bryant, B.; Datta, S.D.; Campbell, A.P.; Leung, J.W.; Tsang, C.A.; Pierce, T.J.; Kennedy, J.L.; et al. Factors linked to severe outcomes in mul-tisystem inflammatory syndrome in children (MIS-C) in the USA: A retrospective surveillance study. Lancet Child. Adolesc. Health 2021, 5, 323–331. [Google Scholar] [CrossRef]
- Mayordomo-Colunga, J.; Vivanco-Allende, A.; López-Alonso, I.; López-Martínez, C.; Fernández-Vega, I.; Gil-Peña, H.; Rey, C. SARS-CoV-2 Spike Protein in Intestinal Cells of a Patient with Coronavirus Disease 2019 Multisystem Inflammatory Syn-drome. J. Pediatr. 2022, 243, 214–218.e5. [Google Scholar] [CrossRef] [PubMed]
- Lehmann, M.; Allers, K.; Heldt, C.; Meinhardt, J.; Schmidt, F.; Rodriguez-Sillke, Y.; Kunkel, D.; Schumann, M.; Böttcher, C.; Stahl-Hennig, C.; et al. Human small intestinal infection by SARS-CoV-2 is characterized by a mucosal infiltration with activated CD8+ T cells. Mucosal Immunol. 2021, 14, 1381–1392. [Google Scholar] [CrossRef] [PubMed]
- Lamers, M.M.; Beumer, J.; Vaart, J.; Van Der Knoops, K.; Puschhof, J.; Breugem, T.I.; Ravelli, R.B.G.; Schayck, J.P.; Van Mykytyn, A.Z.; Duimel, H.Q.; et al. SARS-CoV-2 productively infects human gut enterocytes. Science 2020, 369, 50–54. [Google Scholar] [CrossRef]
- Gruber, C.N.; Patel, R.S.; Trachtman, R.; Lepow, L.; Amanat, F.; Krammer, F.; Wilson, K.M.; Onel, K.; Geanon, D.; Tuballes, K.; et al. Mapping Systemic Inflammation and Antibody Responses in Multisystem Inflammatory Syndrome in Children (MIS-C). Cell 2020, 183, 982–995.e14. [Google Scholar] [CrossRef]
- Bartsch, Y.C.; Wang, C.; Zohar, T.; Fischinger, S.; Atyeo, C.; Burke, J.S.; Kang, J.; Edlow, A.G.; Fasano, A.; Baden, L.R.; et al. Humoral signatures of protective and pathological SARS-CoV-2 infection in children. Nat. Med. 2021, 27, 454–462. [Google Scholar] [CrossRef]
- Leroy, O.; Gangneux, J.P.; Montravers, P.; Mira, J.P.; Gouin, F.; Sollet, J.P.; Carlet, J.; Reynes, J.; Rosenheim, M.; Regnier, B.; et al. Epidemiology, management, and risk factors for death of invasive Candida infections in critical care: A multicenter, prospective, observational study in France (2005–2006). Crit. Care Med. 2009, 37, 1612–1618. [Google Scholar] [CrossRef]
- Young, P.J.; Bellomo, R.; Bernard, G.R.; Niven, D.J.; Schortgen, F.; Saxena, M.; Beasley, R.; Weatherall, M. Fever control in critically ill adults. An individual patient data meta-analysis of randomised controlled trials. Intensiv. Care Med. 2019, 45, 468–476. [Google Scholar] [CrossRef]
- Pires, W.; Veneroso, C.E.; Wanner, S.P.; Pacheco, D.A.S.; Vaz, G.C.; Amorim, F.T.; Tonoli, C.; Soares, D.D.; Coimbra, C.C. Association Between Exercise-Induced Hyperthermia and Intestinal Permeability: A Systematic Review. Sports Med. 2016, 47, 1389–1403. [Google Scholar] [CrossRef]
- Dokladny, K.; Moseley, P.L.; Ma, T.Y. Physiologically relevant increase in temperature causes an increase in intestinal epithelial tight junction permeability. Am. J. Physiol. Liver Physiol. 2006, 290, G204–G212. [Google Scholar] [CrossRef]
- Stanley, D.; Mason, L.J.; MacKin, K.E.; Srikhanta, Y.N.; Lyras, D.; Prakash, M.D.; Nurgali, K.; Venegas, A.; Hill, M.D.; Moore, R.J.; et al. Translocation and dissemination of commensal bacteria in post-stroke infection. Nat. Med. 2016, 22, 1277–1284. [Google Scholar] [CrossRef]
- Wang, J.; Li, F.; Wei, H.; Lian, Z.X.; Sun, R.; Tian, Z. Respiratory influenza virus infection induces intestinal immune injury via mi-crobiotamediated Th17 cell-dependent inflammation. J. Exp. Med. 2014, 211, 2397–2410. [Google Scholar] [CrossRef] [PubMed]
- Bruewer, M.; Luegering, A.; Kucharzik, T.; Parkos, C.A.; Madara, J.L.; Hopkins, A.M.; Nusrat, A. Proinflammatory Cytokines Disrupt Epithelial Barrier Function by Apoptosis-Independent Mechanisms 1 [Internet]. J. Immunol. 2003, 171, 6164–6172. [Google Scholar] [CrossRef]
- Heller, F.; Florian, P.; Bojarski, C.; Richter, J.; Christ, M.; Hillenbrand, B.; Mankertz, J.; Gitter, A.H.; Bürgel, N.; Fromm, M.; et al. Interleukin-13 Is the Key Effector Th2 Cytokine in Ulcerative Colitis That Affects Epithelial Tight Junctions, Apoptosis, and Cell Restitution. Gastroenterology 2005, 129, 550–564. [Google Scholar] [CrossRef] [PubMed]
- Capaldo, C.T.; Nusrat, A. Cytokine regulation of tight junctions. Biochim. Biophys. Acta BBA Biomembr. 2008, 1788, 864–871. [Google Scholar] [CrossRef]
- Sturgeon, J.P.; Bourke, C.D.; Prendergast, A.J. Children with Noncritical Infections Have Increased Intestinal Permeability, Endotoxemia and Altered Innate Immune Responses. Pediatr. Infect. Dis. J. 2019, 38, 741–748. [Google Scholar] [CrossRef] [PubMed]
- Yonker, L.M.; Swank, Z.; Bartsch, Y.C.; Burns, M.D.; Kane, A.; Boribong, B.P.; Davis, J.P.; Loiselle, M.; Novak, T.; Senussi, Y.; et al. Circulating Spike Protein Detected in Post–COVID-19 mRNA Vaccine Myocarditis. Circulation 2023, 147, 867–876. [Google Scholar] [CrossRef]
MIS-C (N = 25) | Febrile Controls (N = 33) | Seropositive Healthy Controls (N = 25) | p-Value | |
---|---|---|---|---|
Male, n (%) | 13 (52%) | 14 (42.4%) | 14 (56%) | 0.564 |
Age, months, Median (IQR) | 119 (85, 163) | 58 (30, 125) | 112(85 to 158) | 0.065 |
GI symptoms reported, n (%) | 21 (84%) | NA | 7 (38.9%) | 0.0001 |
MIS-C (N = 25) | Febrile Controls (N = 33) | p-Value | |
---|---|---|---|
Pre-existing health condition, n (%) | 6(14%) | 18(56%) | 0.014 |
Steroid administered, n (%) | 18 (72%) | 11 (33%) | 0.004 |
Antibiotic administered, n (%) | 9 (41%) | 28 (85%) | <0.001 |
Inotrope administered, n (%) | 10 (40%) | 5 (15%) | 0.032 |
Respiratory support, n (%) | 6 (27%) | 21 (64%) | 0.008 |
ICU admission, n (%) | 11 (44%) | 16 (50%) | 0.65 |
Length of hospital stay, median (IQR) | 8.0 (6.0, 9.0) | 7.0 (5.0, 13.5) | 0.88 |
Deceased, n (%) | 0(0%) | 3(9.1%) | 0.25 |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Roarty, C.; Mills, C.; Tonry, C.; Groves, H.E.; Watson, C.; Waterfield, T. The Role of Intestinal Epithelial Permeability in Multisystem Inflammatory Syndrome in Children: A Case–Control Study. COVID 2024, 4, 1355-1367. https://doi.org/10.3390/covid4090096
Roarty C, Mills C, Tonry C, Groves HE, Watson C, Waterfield T. The Role of Intestinal Epithelial Permeability in Multisystem Inflammatory Syndrome in Children: A Case–Control Study. COVID. 2024; 4(9):1355-1367. https://doi.org/10.3390/covid4090096
Chicago/Turabian StyleRoarty, Cathal, Clare Mills, Claire Tonry, Helen E. Groves, Chris Watson, and Thomas Waterfield. 2024. "The Role of Intestinal Epithelial Permeability in Multisystem Inflammatory Syndrome in Children: A Case–Control Study" COVID 4, no. 9: 1355-1367. https://doi.org/10.3390/covid4090096