An Artificial Intelligence-guided signature reveals the shared host immune response in MIS-C and Kawasaki disease
Pradipta Ghosh, Gajanan D Katkar, Chisato Shimizu, Jihoon Kim, Soni Khandelwal, Adriana H Tremoulet, John T Kanegaye, Pediatric Emergency Medicine Kawasaki Disease Research Group, Joseph Bocchini, Soumita Das, Jane C Burns, Debashis Sahoo, Naomi Abe, Lukas Austin-Page, Amy Bryl, J Joelle Donofrio-Ödmann, Atim Ekpenyong, Michael Gardiner, David J Gutglass, Margaret B Nguyen, Kristy Schwartz, Stacey Ulrich, Tatyana Vayngortin, Elise Zimmerman, Pradipta Ghosh, Gajanan D Katkar, Chisato Shimizu, Jihoon Kim, Soni Khandelwal, Adriana H Tremoulet, John T Kanegaye, Pediatric Emergency Medicine Kawasaki Disease Research Group, Joseph Bocchini, Soumita Das, Jane C Burns, Debashis Sahoo, Naomi Abe, Lukas Austin-Page, Amy Bryl, J Joelle Donofrio-Ödmann, Atim Ekpenyong, Michael Gardiner, David J Gutglass, Margaret B Nguyen, Kristy Schwartz, Stacey Ulrich, Tatyana Vayngortin, Elise Zimmerman
Abstract
Multisystem inflammatory syndrome in children (MIS-C) is an illness that emerged amidst the COVID-19 pandemic but shares many clinical features with the pre-pandemic syndrome of Kawasaki disease (KD). Here we compare the two syndromes using a computational toolbox of two gene signatures that were developed in the context of SARS-CoV-2 infection, i.e., the viral pandemic (ViP) and severe-ViP signatures and a 13-transcript signature previously demonstrated to be diagnostic for KD, and validated our findings in whole blood RNA sequences, serum cytokines, and formalin fixed heart tissues. Results show that KD and MIS-C are on the same continuum of the host immune response as COVID-19. Both the pediatric syndromes converge upon an IL15/IL15RA-centric cytokine storm, suggestive of shared proximal pathways of immunopathogenesis; however, they diverge in other laboratory parameters and cardiac phenotypes. The ViP signatures reveal unique targetable cytokine pathways in MIS-C, place MIS-C farther along in the spectrum in severity compared to KD and pinpoint key clinical (reduced cardiac function) and laboratory (thrombocytopenia and eosinopenia) parameters that can be useful to monitor severity.
Conflict of interest statement
The authors declare no competing interests.
© 2022. The Author(s).
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References
- Levin M. Childhood multisystem inflammatory syndrome - a new challenge in the pandemic. N. Engl. J. Med. 2020;383:393–395. doi: 10.1056/NEJMe2023158.
- Whittaker E, et al. Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2. JAMA. 2020;324:259–269. doi: 10.1001/jama.2020.10369.
- Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet. 2020;395:1607–1608. doi: 10.1016/S0140-6736(20)31094-1.
- Toubiana J, et al. Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in Paris, France: prospective observational study. BMJ. 2020;369:m2094. doi: 10.1136/bmj.m2094.
- Kawasaki T, Kosaki F, Okawa S, Shigematsu I, Yanagawa H. A new infantile acute febrile mucocutaneous lymph node syndrome (MLNS) prevailing in Japan. Pediatrics. 1974;54:271–276. doi: 10.1542/peds.54.3.271.
- Makino N, et al. Descriptive epidemiology of Kawasaki disease in Japan, 2011–2012: from the results of the 22nd nationwide survey. J. Epidemiol. 2015;25:239–245. doi: 10.2188/jea.JE20140089.
- Nakamura A, Ikeda K, Hamaoka K. Aetiological significance of infectious stimuli in Kawasaki disease. Front. Pediatr. 2019;7:1–9. doi: 10.3389/fped.2019.00244.
- Manlhiot C, et al. Environmental epidemiology of Kawasaki disease: linking disease etiology, pathogenesis and global distribution. PLoS ONE. 2018;13:e0191087. doi: 10.1371/journal.pone.0191087.
- Rodó, X. et al. Tropospheric winds from northeastern China carry the etiologic agent of Kawasaki disease from its source to Japan. Proc. Natl Acad. Sci. USA111, 201400380 (2014).
- Dufort EM, et al. Multisystem inflammatory syndrome in children in New York state. N. Engl. J. Med. 2020;383:347–358. doi: 10.1056/NEJMoa2021756.
- Kanegaye JT, et al. Recognition of a Kawasaki disease shock syndrome. Pediatrics. 2009;123:e783–e789. doi: 10.1542/peds.2008-1871.
- Gruber CN, et al. Mapping systemic inflammation and antibody responses in multisystem inflammatory syndrome in children (MIS-C) Cell. 2020;183:982–995.e914. doi: 10.1016/j.cell.2020.09.034.
- Consiglio CR, et al. The immunology of multisystem inflammatory syndrome in children with COVID-19. Cell. 2020;183:968–981.e967. doi: 10.1016/j.cell.2020.09.016.
- Vella LA, et al. Deep immune profiling of MIS-C demonstrates marked but transient immune activation compared to adult and pediatric COVID-19. Sci. Immunol. 2021;6:1–18. doi: 10.1126/sciimmunol.abf7570.
- Ramaswamy A, 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.e1087. doi: 10.1016/j.immuni.2021.04.003.
- Carter MJ, et al. Peripheral immunophenotypes in children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection. Nat. Med. 2020;26:1701–1707. doi: 10.1038/s41591-020-1054-6.
- Henderson LA, Yeung RSM. MIS-C: early lessons from immune profiling. Nat. Rev. Rheumatol. 2021;17:75–76. doi: 10.1038/s41584-020-00566-y.
- Sahoo D, et al. AI-guided discovery of the invariant host response to viral pandemics. EBioMedicine. 2021;68:103390. doi: 10.1016/j.ebiom.2021.103390.
- Dabydeen SA, Desai A, Sahoo D. Unbiased Boolean analysis of public gene expression data for cell cycle gene identification. Mol. Biol. Cell. 2019;30:1770–1779. doi: 10.1091/mbc.E19-01-0013.
- Schoggins JW, et al. A diverse range of gene products are effectors of the type I interferon antiviral response. Nature. 2011;472:481–485. doi: 10.1038/nature09907.
- Zhang W, et al. Inhibition of respiratory syncytial virus infection with intranasal siRNA nanoparticles targeting the viral NS1 gene. Nat. Med. 2005;11:56–62. doi: 10.1038/nm1174.
- Ogata S, et al. Clinical score and transcript abundance patterns identify Kawasaki disease patients who may benefit from addition of methylprednisolone. Pediatr. Res. 2009;66:577–584. doi: 10.1203/PDR.0b013e3181baa3c2.
- Ben Tsutomu Saji JWN, Jane C, Burns MT. Guidelines for diagnosis and management of cardiovascular sequelae in Kawasaki disease (JCS 2013). Digest version. Circ. J. 2014;78:2521–2562. doi: 10.1253/circj.CJ-66-0096.
- Eleftheriou D, et al. Management of Kawasaki disease. Arch. Dis. Child. 2014;99:74–83. doi: 10.1136/archdischild-2012-302841.
- Yanagawa H, et al. Update of the epidemiology of Kawasaki disease in Japan—from the results of 1993–94 nationwide survey. J. Epidemiol. 1996;6:148–157. doi: 10.2188/jea.6.148.
- McCrindle BW, et al. Coronary artery involvement in children with Kawasaki disease: risk factors from analysis of serial normalized measurements. Circulation. 2007;116:174–179. doi: 10.1161/CIRCULATIONAHA.107.690875.
- Manlhiot C, Millar K, Golding F, McCrindle BW. Improved classification of coronary artery abnormalities based only on coronary artery z-scores after Kawasaki disease. Pediatr. Cardiol. 2010;31:242–249. doi: 10.1007/s00246-009-9599-7.
- Burns JC, et al. Temporal clusters of Kawasaki disease cases share distinct phenotypes that suggest response to diverse triggers. J. Pediatr. 2021;229:48–53.e41. doi: 10.1016/j.jpeds.2020.09.043.
- Rypdal M, et al. Clustering and climate associations of Kawasaki Disease in San Diego County suggest environmental triggers. Sci. Rep. 2018;8:16140. doi: 10.1038/s41598-018-33124-4.
- Rigante D. Kawasaki disease as the immune-mediated echo of a viral infection. Mediterr. J. Hematol. Infect. Dis. 2020;12:e2020039. doi: 10.4084/mjhid.2020.039.
- Jordan-Villegas A, Chang ML, Ramilo O, Mejías A. Concomitant respiratory viral infections in children with Kawasaki disease. Pediatr. Infect. Dis. J. 2010;29:770–772. doi: 10.1097/INF.0b013e3181dba70b.
- Chang LY, et al. Viral infections associated with Kawasaki disease. J. Formos. Med Assoc. 2014;113:148–154. doi: 10.1016/j.jfma.2013.12.008.
- Belhadjer Z, et al. Acute heart failure in multisystem inflammatory syndrome in children in the context of global SARS-CoV-2 pandemic. Circulation. 2020;142:429–436. doi: 10.1161/CIRCULATIONAHA.120.048360.
- Friedman KG, Harrild DM, Newburger JW. Cardiac dysfunction in multisystem inflammatory syndrome in children: a call to action. J. Am. Coll. Cardiol. 2020;76:1962–1964. doi: 10.1016/j.jacc.2020.09.002.
- Matsubara D, et al. Echocardiographic findings in pediatric multisystem inflammatory syndrome associated with COVID-19 in the United States. J. Am. Coll. Cardiol. 2020;76:1947–1961. doi: 10.1016/j.jacc.2020.08.056.
- Jang GC, Kim HY, Ahn SY, Kim DS. Raised serum interleukin 15 levels in Kawasaki disease. Ann. Rheum. Dis. 2003;62:264–266. doi: 10.1136/ard.62.3.264.
- Wright VJ, et al. Diagnosis of Kawasaki disease using a minimal whole-blood gene expression signature. JAMA Pediatr. 2018;172:e182293. doi: 10.1001/jamapediatrics.2018.2293.
- de Cevins C, et al. A monocyte/dendritic cell molecular signature of SARS-CoV-2-related multisystem inflammatory syndrome in children with severe myocarditis. Medicine (N. Y.) 2021;2:1072–1092 e1077.
- Harley JB, et al. Transcription factors operate across disease loci, with EBNA2 implicated in autoimmunity. Nat. Genet. 2018;50:699–707. doi: 10.1038/s41588-018-0102-3.
- McInnes IB, Gracie JA. Interleukin-15: a new cytokine target for the treatment of inflammatory diseases. Curr. Opin. Pharm. 2004;4:392–397. doi: 10.1016/j.coph.2004.04.003.
- Dinarello CA, Simon A, van der Meer JW. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat. Rev. Drug Discov. 2012;11:633–652. doi: 10.1038/nrd3800.
- Del Valle DM, et al. An inflammatory cytokine signature predicts COVID-19 severity and survival. Nat. Med. 2020;26:1636–1643. doi: 10.1038/s41591-020-1051-9.
- Robinson PC, et al. The potential for repurposing anti-TNF as a therapy for the treatment of COVID-19. Medicine (N. Y.) 2020;1:90–102.
- Feldmann M, et al. Trials of anti-tumour necrosis factor therapy for COVID-19 are urgently needed. Lancet. 2020;395:1407–1409. doi: 10.1016/S0140-6736(20)30858-8.
- Zong X, Gu Y, Yu H, Li Z, Wang Y. Thrombocytopenia is associated with COVID-19 severity and outcome: an updated meta-analysis of 5637 patients with multiple outcomes. Lab. Med. 2021;52:10–15. doi: 10.1093/labmed/lmaa067.
- Martincic Z, et al. Severe immune thrombocytopenia in a critically ill COVID-19 patient. Int. J. Infect. Dis. 2020;99:269–271. doi: 10.1016/j.ijid.2020.08.002.
- Iba T, Levy JH, Levi M, Thachil J. Coagulopathy in COVID-19. J. Thromb. Haemost. 2020;18:2103–2109. doi: 10.1111/jth.14975.
- Xu P, Zhou Q, Xu J. Mechanism of thrombocytopenia in COVID-19 patients. Ann. Hematol. 2020;99:1205–1208. doi: 10.1007/s00277-020-04019-0.
- Bhattacharjee, S. & Banerjee, M. Immune thrombocytopenia secondary to COVID-19: a systematic review. SN Compr. Clin. Med. 2, 1–11 (2020).
- Arora K, Guleria S, Jindal AK, Rawat A, Singh S. Platelets in Kawasaki disease: is this only a numbers game or something beyond. Genes Dis. 2020;7:62–66. doi: 10.1016/j.gendis.2019.09.003.
- Tanni, F. et al. Eosinopenia and COVID-19. J. Am. Osteopath. Assoc. (2020).
- Huang PY, Huang YH, Guo MM, Chang LS, Kuo HC. Kawasaki disease and allergic diseases. Front. Pediatr. 2020;8:614386. doi: 10.3389/fped.2020.614386.
- Tsai CM, et al. A novel score system of blood tests for differentiating Kawasaki disease from febrile children. PLoS ONE. 2021;16:e0244721. doi: 10.1371/journal.pone.0244721.
- Liu XP, et al. A nomogram model identifies eosinophilic frequencies to powerfully discriminate Kawasaki disease from febrile infections. Front. Pediatr. 2020;8:559389. doi: 10.3389/fped.2020.559389.
- Lin LY, et al. Comparison of the laboratory data between Kawasaki disease and enterovirus after intravenous immunoglobulin treatment. Pediatr. Cardiol. 2012;33:1269–1274. doi: 10.1007/s00246-012-0293-9.
- Kuo HC, et al. Association of lower eosinophil-related T helper 2 (Th2) cytokines with coronary artery lesions in Kawasaki disease. Pediatr. Allergy Immunol. 2009;20:266–272. doi: 10.1111/j.1399-3038.2008.00779.x.
- Lindsley AW, Schwartz JT, Rothenberg ME. Eosinophil responses during COVID-19 infections and coronavirus vaccination. J. Allergy Clin. Immunol. 2020;146:1–7. doi: 10.1016/j.jaci.2020.04.021.
- Guo L, et al. Role of interleukin-15 in cardiovascular diseases. J. Cell. Mol. Med. 2020;24:7094–7101. doi: 10.1111/jcmm.15296.
- Yeghiazarians Y, et al. IL-15: a novel prosurvival signaling pathway in cardiomyocytes. J. Cardiovasc. Pharm. 2014;63:406–411. doi: 10.1097/FJC.0000000000000061.
- Yonker LM, et al. Multisystem inflammatory syndrome in children is driven by zonulin-dependent loss of gut mucosal barrier. J. Clin. Investig. 2021;131:1–12. doi: 10.1172/JCI149633.
- Hsieh, L. E. et al. Characterization of SARS-CoV-2 and common cold coronavirus-specific T-cell responses in MIS-C and Kawasaki disease children. Eur. J. Immunol.131, 1–15 (2021).
- Abdel-Haq, N. et al. SARS-CoV-2-associated multisystem inflammatory syndrome in children: clinical manifestations and the role of infliximab treatment. Eur. J. Pediatr. 180, 1–11 (2021).
- Henderson LA, 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 2. Arthritis Rheumatol. 2021;73:e13–e29.
- Speth C, Löffler J, Krappmann S, Lass-Flörl C, Rambach G. Platelets as immune cells in infectious diseases. Future Microbiol. 2013;8:1431–1451. doi: 10.2217/fmb.13.104.
- Assinger A. Platelets and infection—an emerging role of platelets in viral infection. Front. Immunol. 2014;5:649. doi: 10.3389/fimmu.2014.00649.
- Seyoum M, Enawgaw B, Melku M. Human blood platelets and viruses: defense mechanism and role in the removal of viral pathogens. Thromb. J. 2018;16:16. doi: 10.1186/s12959-018-0170-8.
- Venkata C, Kashyap R, Farmer JC, Afessa B. Thrombocytopenia in adult patients with sepsis: incidence, risk factors, and its association with clinical outcome. J. Intensive Care. 2013;1:9. doi: 10.1186/2052-0492-1-9.
- Tsirigotis P, et al. Thrombocytopenia in critically ill patients with severe sepsis/septic shock: prognostic value and association with a distinct serum cytokine profile. J. Crit. Care. 2016;32:9–15. doi: 10.1016/j.jcrc.2015.11.010.
- Bashash D, et al. The prognostic value of thrombocytopenia in COVID-19 patients; a Systematic Review and Meta-Analysis. Arch. Acad. Emerg. Med. 2020;8:e75.
- Liao D, et al. Haematological characteristics and risk factors in the classification and prognosis evaluation of COVID-19: a retrospective cohort study. Lancet Haematol. 2020;7:e671–e678. doi: 10.1016/S2352-3026(20)30217-9.
- Jesenak M, et al. Immune parameters and COVID-19 infection—associations with clinical severity and disease prognosis. Front. Cell. Infect. Microbiol. 2020;10:1–10. doi: 10.3389/fcimb.2020.00364.
- Jesenak M, Schwarze J. Lung eosinophils—a novel “virus sink” that is defective in asthma? Allergy. 2019;74:1832–1834. doi: 10.1111/all.13811.
- Bass DA. Reproduction of the eosinopenia of acute infection by passive transfer of a material obtained from inflammatory exudate. Infect. Immun. 1977;15:410–416. doi: 10.1128/iai.15.2.410-416.1977.
- Bass DA, et al. Eosinopenia of acute infection: production of eosinopenia by chemotactic factors of acute inflammation. J. Clin. Investig. 1980;65:1265–1271. doi: 10.1172/JCI109789.
- Abidi K, et al. Eosinopenia is a reliable marker of sepsis on admission to medical intensive care units. Crit. Care. 2008;12:R59. doi: 10.1186/cc6883.
- Shaaban H, Daniel S, Sison R, Slim J, Perez G. Eosinopenia: Is it a good marker of sepsis in comparison to procalcitonin and C-reactive protein levels for patients admitted to a critical care unit in an urban hospital? J. Crit. Care. 2010;25:570–575. doi: 10.1016/j.jcrc.2010.03.002.
- Abidi K, et al. Eosinopenia, an early marker of increased mortality in critically ill medical patients. Intensive Care Med. 2011;37:1136–1142. doi: 10.1007/s00134-011-2170-z.
- Du H, et al. Clinical characteristics of 182 pediatric COVID-19 patients with different severities and allergic status. Allergy. 2021;76:510–532. doi: 10.1111/all.14452.
- Kim YH, et al. Prognostic usefulness of eosinopenia in the pediatric intensive care unit. J. Korean Med. Sci. 2013;28:114–119. doi: 10.3346/jkms.2013.28.1.114.
- McCrindle BW, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association. Circulation. 2017;135:e927–e999. doi: 10.1161/CIR.0000000000000484.
- Barrett T, et al. NCBI GEO: mining millions of expression profiles—database and tools. Nucleic Acids Res. 2005;33:D562–D566. doi: 10.1093/nar/gki022.
- Barrett T, et al. NCBI GEO: archive for functional genomics data sets–update. Nucleic Acids Res. 2013;41:D991–D995. doi: 10.1093/nar/gks1193.
- Edgar R, Domrachev M, Lash AE. Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 2002;30:207–210. doi: 10.1093/nar/30.1.207.
- Irizarry RA, et al. Summaries of Affymetrix GeneChip probe level data. Nucleic Acids Res. 2003;31:e15. doi: 10.1093/nar/gng015.
- Irizarry RA, et al. Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics. 2003;4:249–264. doi: 10.1093/biostatistics/4.2.249.
- Li B, Dewey CN. RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinforma. 2011;12:323. doi: 10.1186/1471-2105-12-323.
- Pachter, L. Models for transcript quantification from RNA-Seq. Genomics (); Methodology ()1, 1–28 (2011).
- Sahoo D, Dill DL, Tibshirani R, Plevritis SK. Extracting binary signals from microarray time-course data. Nucleic Acids Res. 2007;35:3705–3712. doi: 10.1093/nar/gkm284.
- Sahoo D, Dill DL, Gentles AJ, Tibshirani R, Plevritis SK. Boolean implication networks derived from large scale, whole genome microarray datasets. Genome Biol. 2008;9:R157. doi: 10.1186/gb-2008-9-10-r157.
- Fabregat A, et al. The reactome pathway knowledgebase. Nucleic Acids Res. 2018;46:D649–D655. doi: 10.1093/nar/gkx1132.
- Sahoo, D. & Vo, T. D. Artificial intelligence guided discovery of a barrier-protective therapy in inflammatory bowel disease. GitHub/sahoo00/BoNE (2021).
- Sahoo, D. Artificial intelligence guided discovery of a barrier-protective therapy in inflammatory bowel disease. GitHub/sahoo00/Hegemon (2021).
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