Previous reports suggested that COVID-19 may be a systemic endothelial disease or a multi-organ disease including endothliitis, hypercoagulability, and cytokine storm, thereby therapeutic strategy is complicated especially in severe stage [1-3]. With respect to the SARS-CoV-2 Omicron variant, the author emphasizes that it is important to assess endothelial function because this strain exhibited more efficient transduction of ACE2-expressing target cells, leading to endothelial dysfunction [4]. Whereas SARS-CoV-2 infection shows mild and asymptomatic features in children. A rare post-infectious hyperinflammatory disease associated with SARS-CoV-2, so called MIS-C has emerged [5]. Center for Disease Control and Prevention (CDC) and the World Health Organization (WHO) have published case definition of multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 [6, 7]. In this article, current knowledge of characteristic clinical and immunological manifestations in MIS-C along with endothelial cell damage has been reviewed. Additionally, the therapeutic strategy and efficacy of COVID-19 mRNA vaccination in patients with MIS-C have been also summarized.

Endothelial Dysfunction in COVID-19

The expression of ACE2 was recognized in the respiratory epithelium, vascular endothelium, and other cell types and considered as a primary mechanism of the SARS-CoV-2 entry and infection processes. It is also known that SARS-CoV-2 infection depends on ACE2 and TMPRSS2 as host cell factors [8]. The position paper recommended that the endothelial biomarkers and function such as flow-mediated vasodilation (FMD) should be assessed for their usefulness of the risk stratification in patients with COVID-19 [9]. The author has previously suggested that COVID-19 may be a systemic endothelial disease or a multi-organ disease due to endothliitis, hypercoagulability, and cytokine storm, thereby therapeutic strategy is complicated especially in severe stage [1-3]. Regarding the SARS-CoV-2 Omicron variant, the author emphasizes that it is important to estimate endothelial function because this strain exhibited more efficient transduction of ACE2-expressing target cells, leading to endothelial dysfunction [4]. It has been established that flow-mediated vasodilation (FMD) and nitroglycerin-mediated vasodilation (NMD) in the brachial artery are promising procedures for assessing vascular endothelial and vascular smooth muscle cell (VSMC) function in atherosclerosis status [10]. The previous reports on the diseases of migraine, cardiovascular disease (CVD), chronic kidney disease (CKD), dyslipidemia, aging liver, NAFLD, hypertension, and COVID-19 using FMD and NMD teats have been provided [11-24]. With respect to FMD examinations in COVID-19, several reports have been reported as previously described [4, 25-30]. Similar to FMD study, the position statements recommend that arterial stiffness should be monitored in studies of COVID-19 outcome and therapy efficacy [9]. Regarding to PWV test, previous reports suggested that the patients with COVID-19 appeared to be associated with an increased PWV reflecting arterial stiffness [4, 31-35].

Immunology of SARS-CoV-2 infection in pediatric population

The previous studies support the notion that fewer ACE2 receptors in children account for decreased viral entry [36]. It is thought that TMPRSS2 expression in the airway epithelium has increased with age [36, 37]. With respect to development of pediatric immune response to viral infection, it is known that innate cell function including IFN, IL-12, and IL-10 reaches adult level in early childhood between 2 and 5 years of age. Both B cell and T cell functions continue to develop throughout childhood. Whereas it is thought that regulatory T cell function wanes along with age [36, 37]. The report indicated the factors including fewer comorbidities, innate immunity, and T cell immunity that decreased the severity of SARS-CoV-2 infection in children. It is suggested that children tend to have fewer comorbidities including obesity, type 2 diabetes mellitus (T2DM), cerebrovascular disease, chronic liver disease (CLD), chronic lung disease, and chronic kidney disease (CKD) and have protective innate immune factors including less ACE2 expression and robust IFN response. Regarding T cell immunity, due to the status of the greater thymus output, T cells show specific for non-structural viral proteins and less T cell exhaustion [36].

Multisystem Inflammatory Syndrome in Children

SARS-CoV-2 infection presents with mild and asymptomatic manifestations in children. A rare post-infectious hyperinflammatory disease associated with SARS-CoV-2, so called MIS-C have emerged [5]. A novel hyperinflammatory disorder associated with COVID-19 presenting severe Kawasaki disease-like features in children and adolescent in the UK, Italy, and USA has been reported [38-41]. CDC and the WHO developed case definition of MIS-C associated with COVID-19 [6, 7]. The cardiovascular disorders such as arrhythmias and myocardial injury have been regarded as important complications in patients with COVID-19 [35]. It is thought that results of the direct cytotoxic effect of the virus and the cytokine storm may induce left heart failure and mitral insufficiency [42]. Regarding endothelial dysfunction in MIS-C, the study provided that patients with MIS-C showed endothelial dysfunction assessed by FMD and arterial stiffness evaluated by aortic strain and aortic distensibility values, indicating the correlation between the endothelial dysfunction and decreased ejection fractions [35]. Ciftel et al. also concluded that characteristic manifestation of hyperinflammation in MIS-C plays a crucial role in arterial stiffness [35]. With regard to other disorders in MIS-C, Feldstein et al. described major manifestations including gastrointestinal: GI (92%), cardiovascular (80%), mucocutaneous (74%), and respiratory (70%) disorders in patients with MIS-C [40].

Comparison between MIS-C and Kawasaki Disease Manifestations

MIS-C patients have shown a severe hyperinflammatory syndrome approximately 2-6 weeks after recovery from COVID-19 infection, suggesting that post-infectious immune dysregulation serves as a crucial role in the pathogenesis of MIS-C rather than a response to the acute viral infection [42]. Previous study suggested that even after the amelioration of systolic heart function, diastolic heart function decline has been shown [43]. The study by Chang et al. revealed that myocardial function is globally decreased in MIS-C, suggesting that cardiac dysfunction may be driven by the skewed cytokine responses toward IL-6 and IL-8 pathways than the magnitude of the cytokine storm [44]. Cytokine storm, acute stress cardiomyopathy, direct immune-mediated tissue injury, hypoperfusion from shock, and microvascular injury as etiology of cardiac dysfunction have been presumed [44]. It is known that the inflammatory response in MIS-C differed from the cytokine storm of SARS-CoV-2 and presented with severe Kawasaki Disease (KD) like features [45]. Whereas KD is a systemic vasculitis affecting medium-size arteries such as coronary arteries in children [5]. This entity was first described by Tomisaku Kawasaki in Japan [46]. The patients with KD predispose to develop coronary artery aneurysms, rash, conjunctivitis, oral mucosal changes such as strawberry tongue in children younger than 5 years old [5]. Similar to MIS-C, patients with Kawasaki Disease Shock Syndrome (KDSS) representing KD associated with manifestations of hypotension and shock, tend to present thrombocytopenia, coagulopathy, hyponatremia, hypoalbuminemia, and elevated CRP [5, 47]. Previous study revealed elevated IL-1β, IL-6, IL-8, IL-10, IL-17, IFN-γ levels and decreased T and B cell subsets in patients with MIS-C [48]. Recent study indicated an anti-IL-1Ra in a high proportion of MIS-C patients, suggesting that these antibodies impair interleukin-1 receptor antagonist (IL-1Ra) and might contribute to increase IL-1β- signaling in MIS-C patients [49]. Whereas Consiglio et al. revealed that the inflammatory response in MIS-C differs from the cytokine storm of COVID-19. Furthermore the result indicated the elevated IL-6 and IL-17A levels in patient with KD, suggesting the different pathogenesis between two entities that IL 17A drives KD but not MIS-C hyperinflammation [45]. MIS-C occurs 6-8 weeks after COVID-19 onset and characteristic manifestations of MIS-C represented fever, hyperinflammation, and multi-organ involvement. It is also known that MIS-C have more severe lymphopenia, neutropenia, and thrombocytopenia compared to patients with KD [36]. Additionally, increased circulating proteins levels associated with endothelial damage were observed in KD patients than in MIS-C patients [45]. The difference of recovery of coronary artery aneurysms between two entities may be attributed to these immune cell activation [36]. Based on evidence of IFN, inflammasome signaling, T cell activation, and broad humoral response to common viruses as well as SARS-CoV-2, they suggested that children with MIS-C exhibit activated multilineage immune cell [36]. According to Ramaswamy’s repot, the analysis data of serum proteomics showed elevated endothelial E-selectin reflecting inflamed endothelial cells in MIS-C [50]. They also revealed that patient with severe MIS-C exhibited a potential autoantibodies response as measured by IgG binding to cultured human cardiac microvascular endothelial cells (HCMEC). These evidence including elevated endothelium E-selectin and autoantibody binding to endothelial cells provided that endothelial cell damage and endothelium- reactive IgG may be characteristic features in patients with severe MIS-C. The author suggests that it may be important to estimate endothelial function assessed by FMD test for risk stratification, follow-up of convalescence, and prediction of autoimmune disease in MIS-C patients, because endothelial cell damage and endothelium- reactive IgG were shown in patients with severe MIS-C. They also demonstrated that the alarmin, cytotoxicity, TCR repertoire, and plasmablast signatures predict disease severity MIS-C [50].

Therapeutic strategies in MIS-C

Current treatment guidelines recommended intravenous immunoglobulins (IVIG) and glucocorticoid in patients with MIS-C. Additionally, IL-1Ra or IL-6 inhibitor were treated in MIS-C patients [5]. According to Gruber‘s report, MIS-C also showed potential autoantibodies that may link organ systems [51]. They suggested that patients with MIS-C were treated with anti-IL-6R antibody and/or IVIG, leading to disease recovery [51]. Whereas Abdei-Heg et al. concluded that supportive care, IVIG, and second-line treatment with infliximab were associated with an excellent outcome [52]. Though the evidence revealed that patients with KD developed approximately 25% risk of coronary artery aneurysms, therapeutics using IVIG and aspirin within the first 10 days of symptoms showed a 5% risk of developing them [5].

Gastrointestinal disorders in MIS-C

Previous study indicated that gastrointestinal (GI) manifestations were presenting symptoms in 84% of cases accompanied by fever and rash in 100% and 71% of cases respectively [53]. Recent study showed that GI appearances are identified predominantly in patient with MIS-C [5]. The abdominal image features including ultrasonography (US) and computed tomography (CT) showed abdominal lymph node swelling, hepatosplenomegaly, mesenteric adenitis, pancreatitis, cholecystitis, ascites, and bowel wall thickness and inflammation [52]. Due to the multilineage immune activation, patients with MIS-C showed tissue inflammation including increased GI permeability, elevated complement C5b9 level, troponin, and natriuretic peptides [36]. The affinity of the SARS-CoV-2 for ACE2 located in enterocyte such as the ileum ad colon is regarded as a plausible physiological mechanism of GI involvement [54]. The report by Younker et al. showed that GI sources of SARS-CoV-2 viral antigenemia may drive MIS-C [55].

Efficacy of Mrna Vaccination in Children

The BNT162b2 mRNA is a lipid nanoparticle-formulated nucleoside-modified RNA vaccine manufactured by Pfizer-BioNTech [56]. The vaccine of which use the original wild-type SARS-CoV-2 spike protein first identified in Wuhan, China in 2019 have been approved by FDA [57]. Previous study revealed immunization against SARS-CoV-2 infection with BNT162b2 vaccine in children 5 to11 years of age and demonstrated the safety, efficacy, and immunogenicity for COVID-19 mRNA vaccine [58]. Receipt of 2 doses of the BNT162b2 (Pfizer-BioNTech) vaccine is associated with a high level of protection against MIS-C among individuals aged 12-18 years, suggesting the importance of vaccination [59]. Yousai et al. described 21 cases with MIS-C aged 12-20 years who had received one or more doses of a COVID-19 mRNA vaccination before onset of disease, suggesting that MIS-C after COVID-19 vaccination is rare. They also indicated the continued surveillance for MIS-C disease after COVID-19 vaccination [60]. Wangu et al. reported a case of MIS-C possibly secondary to COVID-19 mRNA vaccination suggesting that it may be considered as a significant trigger for MIS-C illness after having received two doses of vaccine 12 weeks prior [61]. The study provided that very few cases with MIS-C developed following COVID-19 mRNA vaccination in individuals aged 12-17 years, compared to the post-SARS-CoV-2 MIS-C, suggesting that these findings support the mRNA vaccination [62]. Regarding the cardiac outcomes, the risks for cardiac complications were higher after SARS-CoV-2 infection than after mRNA vaccination for all other groups, indicating that these results support mRNA COVID-19 vaccination among eligible individuals aged >5 years [63]. 

It is putative that MIS-C as a post-infectious hyperinflammatory disease differs from the cytokine storm of COVID-19. The evidence including elevated endothelium E-selectin and autoantibody binding to endothelial cells provided that endothelial cell damage and endothelium- reactive IgG may be characteristic features in patients with severe MIS-C. The author suggests that it may be important to estimate endothelial function assessed by FMD test for risk stratification, follow-up of convalescence, and prediction of autoimmune disease in MIS-C patients, because endothelial cell damage and endothelium- reactive IgG were shown in patients with severe MIS-C. The skewed cytokine response to IL-6 and IL-8 pathways may induce characteristic cardiac outcomes in MIS-C patients. The different pathogenesis between these entities provided that IL-17A drives KD but not MIS-C hyperinflammation. It is plausible that the risks for cardiac involvements were higher after SARS-CoV-2 infection than after mRNA vaccination for all other groups. Based on the evidence, it is putative that MIS-C development after COVID-19 mRNA vaccination, compared to post-SARS-CoV-2 MIS-C, may be a rare disorder, thereby the continued use of mRNA COVID-19 vaccination among all eligible individuals is supported.

• The inflammatory response in MIS-C so called post-infectious hyperinflammatory diseases may differ from the cytokine storm of COVID-19.
• The author suggests that it may be important to estimate endothelial function for risk stratification, follow-up of convalescence, and prediction of autoimmune disease in MIS-C patients.
• It is putative that cardiac dysfunction may be driven by the skewed cytokine responses toward IL-6 and IL-8 pathways than the magnitude of the cytokine storm in MIS-C patients.
• Based on the evidence for mRNA vaccination status, the continued use of recommended mRNA vaccine among all eligible individuals is supported.

1. Fujioka K. A link between endothelial dysfunction and SARS-CoV-2 infection in patients with COVID-19. CPQ Medicine. 2021: 11: 01-08.
2. Fujioka K. Cutaneous manifestation and vasculitis of COVID-19 in dermatology. Acta Scientific Medical Sciences. 2021; 5: 16-19.
3. Fujioka K. Clinical manifestation of endotheliitis in COVID-19 along with flow-mediated vasodilation study. J Clin Trials. 2021; 11: 1000469.
4. Fujioka K. Endothelial dysfunction in COVID-19 along with SARS-CoV-2 Omicron variant. Int J Case Rep Clin Image. 2022; 4: 174.
5. Patel JM. Multisystem inflammatory syndrome in children (MIS-C). Curr Allergy Asthma Rep. 2022; 22: 53-60.
6. World Health Organization. 2022. https://www.who.int/emergencies/diseases/novel-coronavirus-2019.
7. Center for Disease Control and Prevention. Multisystem inflammatory syndrome in children (MIS-C) 2021. https://www.cdc.gov/mis-c/cases.
8. Hoffmann M, Kleine- Weber H, Schroeder S, Kruger N, Herrier T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020; 181: 271-280.
9. Evans PC, Rainger GE, Mason JC, Guzik TJ, Osto E, Stamataki Z, et al. Endothelial dysfunction in COVID-19: a position paper of the ESC Working Group for Atherosclerosis and Vascular Biology, and the ESC Council of Basic Cardiovascular Science. Cardiovasc Res. 2020; 116: 2177-2184.
10. Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, et al. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol. 2002; 39: 257-265.
11. Fujioka K, Oishi M, Fujioka A, Nakayama T. Increased nitroglycerin-mediated vasodilation in migraineurs without aura in the interictal period. J Med Ultrason. 2018; 45: 605-610.
12. Fujioka K. Reply to: Endothelium-dependent and -independent functions in migraineurs. J Med Ultrason. 2019; 46: 169-170.
13. Fujioka K, Oishi M, Nakayama T, Fujioka A. Association of brachial artery measures with estimated GFR>60mL/min/1.73m² in a cross-sectional study of the community-based women. Angiology Open Access. 2019; 7: 231.
14. Fujioka K. Propensity to the vascular smooth muscle cell abnormality in migraine without aura and vasospastic angina along with a genome-wide association studies. J Carcinog Mutagen. 2019; 10: 334.
15. Fujioka K, Oishi M, Fujioka A, Nakayama T, Okada M. Interrelationship among lipid profiles, arterial stiffness, and nitroglycerin-mediated vasodilation in the community-based setting of the Japanese women. Angiology Open Access. 2019 7: 235.
16. Fujioka K. Effect on microRNA-92a in atherosclerosis along with flow-mediated vasodilation study. J Cancer Oncol. 2020; 4: 000153.
17. Fujioka K. A novel biomarker microRNA 92a-3p as a link between cardiovascular disease and chronic kidney disease. J Carcinog Mutagen. 2020; 11: 1000345.
18. Fujioka K. Association between chronic liver disease and atherosclerosis: an inflammation as common pathway. J Clin Trials 2021; 11: 444.
19. Fujioka K, Oishi M, Nakayama T, Fujioka A. Correlation between vascular failure (endothelial dysfunction) and fibrosis markers. Jpn J Med Ultrsonics. 2016; 43: S458.
20. Fujioka K. Association between endothelial function and aspartate aminotransferase to platelet ratio index in patients without hepatic-associated disease. Int J Case Rep Clin Image. 2021; 3: 1-10.
21. Fujioka K. NAFLD/NASH-related hepatocellular carcinoma: along with the role of genetics. J Cancer Oncol. 2020; 4: 000165.
22. Fujioka K. Current genetic advances in NAFLD/NASH: Related hepatocellular carcinoma along with characteristic clinical manifestations. J Carcinog Mutagen. 2021; 12: 1000001.
23. Fujioka K. Polygenic risk score in NAFLD/NASH-associated hepatocellular carcinoma along with multifactorial process. J Carcinog Mutagen. 2021; 12: 1000370.
24. Fujioka K. Link between non-alcoholic fatty liver disease and hypertension: non-alcoholic fatty liver disease as a multisystem disease. International Journal of Clinical Case Reports and Reviews. 2022; 10: 203.
25. Guervilly C, Burtey S, Sabatiler F, Cauchois R, Lano G, Abdili E, et al. Circulating endothelial cells as a marker of endothelial injury in severe COVID-19. J Infect Dis. 2020; 222: 1789-1793.
26. Khider L, Gendron N, Goudot G, Chocron R, Hauw-Berlemont C, Cheng C, et al. Curative anticoagulation prevents endothelial lesion in COVID-19 patients. J Thromb Haemost. 2020; 18: 2391-2399.
27. Sega FVD, Fortini F, Spadaro S, Ronzoni L, Zucchetti O, Manfrini M, et al. Time course of endothelial dysfunction markers and mortality in COVID-19 patients: a pilot study. Clin Trans Med. 2021; 11: e283.
28. Riou M, Oulehri W, Momas C, Rouyer O, Lebourg F, Meyer A, et al. Reduced flow-mediated dilatation is not related to COVID-19 severity three months after hospitalization for SARS-CoV-2 infection. J Clin Med. 2021; 10: 1318.
29. Jud P, Kessier HH, Brodmann M. Case report: changes of vascular reactivity and arterial stiffness in a patient with COVID-19 infection. Front Cardiovasc Med. 2021; 8: 671669.
30. Ergul E, Yilmaz AS, Ogutveren MM, Emlek N, Kostakoglu U, Cetin M. COVID 19 disease independently predicted endothelial dysfunction measured by flow-mediated dilatation. Int J Cardiovasc Imaging. 2021; 20: 1-8.
31. Schnaubelt S, Oppenauer J, Tihanyi D, Mueller M, Maldonado-Gonzalez E, Zejnilovic S, et al. Arterial stiffness in acute COVID-19 and potential associations with clinical outcome. J Intern Med. 2021; 290: 437-443.
32. Jud P, Gressenberger P, Muster V, Avian A, Meinitzer A, Srohmaier H, et al. Evaluation of endothelial dysfuntion and inflammatory vasculopathy after SARS-CoV-2 infection-a cross-sectional study. Front Cardiovasc Med. 2021; 8. 750887.
33. Rodilla E, Lopez-Carmona MD, Cortes X, Cobos-Palacios L, Canales S, Saez MC, et al. Impact of arterial stiffness on all-cause mortality in patients hospitalized with COVID-19 in Spain. Hypertension. 2021; 77: 856-867.
34. Ratchford SM, Stickford JL, Province VM, Stute N, Augenreich MA, Koontz LK, et al. Vacular alterations among young adults with SARS-CoV-2. Am J Physiol Heart Circ Physiol. 2021; 320: H404-H410.
35. Ciftel M, Ates N, Yilmaz O. Investigation of endothelial dysfunction and arterial stiffness in multisystem inflammatory syndrome in children. Eur J Pediatr. 2022; 181: 91-97.
36. Chou J, Thomas PG, Randolph AG. Immunology of SARS-CoV-2 infection in children. Nat Immunol. 2022; 23: 177-185.
37. Schuler BA, Habermann AC, Plosa EJ, Tayler CJ, Jetter C, Negretti NM, et al. Age-determined expression of priming protease TMPRSS2 and localization of SARS-CoV-2 in lung epithelium. J Clin Invest. 2021; 131: e140766.
38. Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet. 2020; 395: 1607-1608.
39. Verdoni L, Mazza A, Gervasoni A, Martelli L, Ruggeri M, Ciuffreda M, et al. An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study. Lancet. 2020; 395: 1771-1778.
40. Feldstein LR, Rose E, Horwitz SM, Collins JP, Newhams MM, Son MB, et al. Multisystem inflammatory syndrome in U.S. children and adolescents. N Engl J Med. 2020; 383: 334-346.
41. Dufort EM, Koumans EH, Chow EJ, Rosenthal EM, Muse A, Rowlands J, et al. Multisystem inflammatory syndrome in children in New York State. N Engl J Med. 2020; 383: 347-358.
42. Chan JF, Yuan S, Kok K, To KK, Chu H, Yang J, et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet. 2020; 395: 514-523.
43. Matsubara D, Kauffman HL, Wang Y, Calderon-Anyosa R, Nadaraj S, Elias M, 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.
44. Chang JC, Matsubara D, Morgan RW, Diorio C, Nadaraj S, Teachey DT, et al. Skewed cytokine responses rather than the magnitude of the cytokine storm may drive cardiac dysfunction in multisystem inflammatory syndrome in children. J Am Heart Assoc. 2021; 10: e021428.
45. Consiglio CR, Cotugno N, Sardh F, Pou C, Amodio D, Rodriguez L, et al. The immunology of multisystem inflammatory syndrome in children with COVID-19. Cell. 2020; 183: 968-981.e7.
46. Suga K, Inoue M, Ono A, Terada T, Kawahito M, Mori K, et al. Early combined treatment with steroid and immunoglobulin is effective for serious Kawasaki disease complicated by myocarditis and encephalopathy. J Med Invest. 2016; 63: 140-143.
47. Taddio A, Rossi ED, Monasta L, Pastore S, Tommasini A, Lepore L, et al. Describing Kawasaki shock syndrome: results from a retrospective study and literature review. Clin Rheumatol. 2017; 36: 223-228.
48. Carter MJ, Fish M, Jennings A, Doores KJ, Wellman P, Seow J, et al. Peripheral immunophenotypes in children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection. Nat Med. 2020; 26: 1701-1707.
49. Pfeifer J, Thurner B, Kessel C, Fadle N, Kheiroddin P, Regitz E, et al. Autoantibodies against interleukin-1 receptor antagonist in multisystem inflammatory syndrome in children: a multicentre, retrospective, cohort study. Lancet Rheumatol. 2022; 4: e329-e337.
50. Ramaswamy A, Brodsky NN, Sumida TS, Comi M, Asashima H, Hoehn KB, et al. Immune dysregulation and autoreactivity correlate with dsease severity in SARS-CoV-2-associated multisystem inflammatory syndromes in children. Immunity. 2021; 54: 1083-1095.e7.
51. Gruber CN, Patel RS, Trachtman R, Lepow L, Amanat F, Krammer F, et al. Mapping systemic inflammation and antibody responses in multisystem inflammatory syndrome in children (MIS-C). Cell. 2020; 183: 982-995.e14.
52. Abdei-Haq N, Asmar BI, Leon MPD, McGrath EJ, Arora HS, Cashen K, et al. SARS-CoV-2-associated multisystem inflammatory syndrome in children: clinical manifestations and the role of infliximab treatment. Eur J Pediatr. 2021; 180: 1581-1591.
53. Miller J, Cantor A, Zachariah P, Ahn D, Martinez M, Margolis KG. Gastrointestinal symptoms as a major presentation component of a novel multisystem inflammatory syndrome in children that is related to coronavirus disease 2019: a single center experience of 44 cases. Gastroenterology. 2020; 159: 1571-1574.e2.
54. Agarwal A, Chen A, Ravindran N, To C, Thuluvath PJ. Gastrointestinal and liver manifestations of COVID-19. J Clin Exp Hepatol. 2020; 10: 263-265.
55. Yonker LM, Gilboa T, Ogata A, Senussi Y, Lazarovits R, Boribong BP, et al. Multisystem inflammatory syndrome in children is driven by zonulin-dependent loss of gut mucosal barrier. J Clin Invest. 2021; 131: e149633.
56. Polack FP, Thomas SJ, Kitchin N, Absalon J, Gurtman A, Lockhart S, et al. Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine. N Engl J Med. 2020; 383: 2603-2615.
57. Garcia-Beltran WF, Denis KJS, Hoelzemer A, Lam EC, Nitido AD, Sheehan ML, et al. mRNA-based COVID-19 vaccine boosters induce neutralizing immunity against SARS-CoV-2 Omicron variant. Cell. 2022; 185: 1-10.
58. Walter EB, Talaat KR, Sabharwal C, Gurtman A, Lockhart S, Paulsen GC, et al. Evaluation of the BNT162b2 COVID-19 vaccine in children 5 to 11 years of age. N Engl J Med. 2022; 386; 35-46.
59. Zambrano LD, Newhams MM, Olson SM, Halasa NB, Price AM, Boom JA, et al. Effectiveness of BNT162b2 (Pfizer-BioNTech) mRNA vaccination against multisystem inflammatory syndrome in children among persons aged 12-18 years- United States, July-December 2021. MMWR Morb Mortal Wkly Rep. 2022; 71: 52-58.
60. Yousaf A, Cortese MM, Taylor AW, Broder K, Oster ME, Wong JM, et al. Reported cases of multisystem inflammatory syndrome in children aged 12-20 years in the USA who received a COVID-19 vaccine, December, 2020, through August, 2021: a surveillance investigation. Lancet Child Adolesc Health. 2022; 6: 303-312.
61. Wangu Z, Swartz H, Doherty M. Multisystem inflammatory syndrome in children (MIS-C) possibly secondary to COVID-19 mRNA vaccination. BMJ Case Rep. 2022; 15: e247176.
62. Ouldali N, Bagheri H, Salvo F, Antona D, Pariente A, Leblanc C, et al. Hyper inflammatory syndrome following COVID-19 mRNA vaccine in children: a national post-authorization pharmacovigilance study. Lancet Reg Health Eur. 2022; 17: 100393.
63. Block JP, Boehmer TK, Forrest CB, Carton TW, Lee GM, Ajani UA, et al. Cardiac complications after SARS-CV-2 infection and mRNA COVID-19 vaccination-PCORnet, United States, January 2021-January 2022. MMWR Morb Mortal Wkly Rep. 2022; 71: 517-523.