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Department of Pediatrics, Division of Infectious Diseases and Immunology, Guerin Children’s at Cedars-Sinai Medical Center, Los Angeles, California, USAInfectious and Immunologic Diseases Research Center (IIDRC) and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA
Department of Pediatrics, Division of Infectious Diseases and Immunology, Guerin Children’s at Cedars-Sinai Medical Center, Los Angeles, California, USAInfectious and Immunologic Diseases Research Center (IIDRC) and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USASmidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
While MIS-C and KD are considered two distinctive diseases triggered by different infectious agents, these two entities share inflammatory characteristics. They may belong to the same umbrella of inflammatory disorders but differ in many aspects of etiology, demography, epidemiology, clinical and laboratory findings, and pathology.
•
The intensity of the inflammatory response and long-term cardiovascular sequelae diverge between KD and MIS-C. Whereas MIS-C presents as a more intense inflammatory syndrome, myocardial dysfunction, and cardiogenic shock, KD vasculitis is associated with pathologic changes in the coronary arteries and long-term cardiovascular sequelae.
•
Intravenous immunoglobulin G (IVIG) is efficient in treating both MIS-C and KD patients; however, affected patients need to be followed over time to monitor the emergence or persistence of cardiovascular sequelae.
Introduction
Kawasaki disease (KD) is a febrile pediatric systemic vasculitis of unknown origin, usually affecting children younger than five years
Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association.
. KD can result in coronary artery aneurysms (CAAs) in ≈ 25% of untreated children, and it is the leading cause of acquired heart disease in children in developed countries
Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association.
. Multiple aspects of this pediatric illness are not completely understood, including the causative agent(s), the immune mechanisms underlying KD pathogenesis, and the potential long-term cardiovascular sequelae. Multisystem hyperinflammatory syndrome (MIS-C) is a novel pediatric illness that emerged during the COVID-19 pandemic
Feldstein LR, Rose EB, Horwitz SM, et al. Multisystem Inflammatory Syndrome in U.S. Children and Adolescents. N Engl J Med. Jul 23 2020;383(4):334-346. doi:10.1056/NEJMoa2021680
. While in most children SARS-CoV-2 infection is asymptomatic or results in mild symptoms, a subset of infected children develops MIS-C, which presents as fever, hypotension, gastrointestinal (GI) symptoms, and myocardial dysfunction
Feldstein LR, Rose EB, Horwitz SM, et al. Multisystem Inflammatory Syndrome in U.S. Children and Adolescents. N Engl J Med. Jul 23 2020;383(4):334-346. doi:10.1056/NEJMoa2021680
. Indeed, overlapping clinical features, including conjunctional injection, mucositis, and swelling of the hands and feet, hint that MIS-C and KD may belong to the same spectrum of inflammatory disorders. However, the observed epidemiological, pathological, inflammatory, and immunological differences between MIS-C and KD indicate that these two diseases are different entities
Feldstein LR, Rose EB, Horwitz SM, et al. Multisystem Inflammatory Syndrome in U.S. Children and Adolescents. N Engl J Med. Jul 23 2020;383(4):334-346. doi:10.1056/NEJMoa2021680
(Figure 1). Here, we review the recent advances in KD and MIS-C research.
Figure 1Divergent and overlapping features of KD and MIS-C. (A) Clinical, pathological, and immunological features specific to KD. (B) Clinical, pathological, and immunological features that overlap between KD and MIS-C. (C) Clinical, pathological, and immunological features specific to MIS-C. Created with BioRender.com.
Viral triggers as a shared etiology between MIS-C and KD.
MIS-C is a post-acute hyperinflammatory syndrome that develops after either SARS-CoV-2 infection or exposure. Most MIS-C patients have serologic evidence of previous SARS-CoV-2 infection or exposure 2 to 6 weeks before disease onset
Feldstein LR, Rose EB, Horwitz SM, et al. Multisystem Inflammatory Syndrome in U.S. Children and Adolescents. N Engl J Med. Jul 23 2020;383(4):334-346. doi:10.1056/NEJMoa2021680
Soni PR, Noval Rivas M, Arditi M. A Comprehensive Update on Kawasaki Disease Vasculitis and Myocarditis. Curr Rheumatol Rep. Feb 5 2020;22(2):6. doi:10.1007/s11926-020-0882-1
. KD patients do not respond to antibiotic treatment, often given pre-KD diagnosis during the acute phase, indicating that KD triggering agent(s) might be of viral origin rather than bacterial
Multisystem clinical findings common to MIS-C and KD, such as rash, fever, GI tract abnormalities, swollen lymph nodes, headaches, and fatigue, also overlap with clinical manifestations triggered by other pediatric viral illnesses
Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association.
Esper F, Shapiro ED, Weibel C, Ferguson D, Landry ML, Kahn JS. Association between a novel human coronavirus and Kawasaki disease. J Infect Dis. Feb 15 2005;191(4):499-502. doi:10.1086/428291
. For example, intracytoplasmic inclusion bodies detected in ciliated bronchial epithelium tissues from KD patients, months to years after acute KD, support the hypothesis of a viral causative agent
Quiat D, Kula T, Shimizu C, et al. High-Throughput Screening of Kawasaki Disease Sera for Antiviral Antibodies. J Infect Dis. Nov 9 2020;222(11):1853-1857. doi:10.1093/infdis/jiaa253
. The infectious agent hypothesis is further supported by the observation that KD incidence decreased in multiple areas when mitigation measures were implemented to control the spread of COVID-19 20,21.
Epidemiological differences between KD and MIS-C.
Key epidemiological differences differentiate KD and MIS-C. First, KD incidence is approximately 25 per 100,000 children under five years in the US
Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association.
, whereas a cross-sectional study of a large US cohort of MIS-C patients estimated MIS-C incidence to be ≈ 2 per 100,000 in individuals younger than 21 years
Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association.
Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association.
. In MIS-C, while the proportion of males and females is 1:1 between the ages of 0 to 4 years, it increases and reaches 2:1 for patients between 18 and 20 years
Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association.
CDC. Health Department-Reported Cases of Multisystem Inflammatory Syndrome in Children (MIS-C) in the United States. https://covidcdcgov/covid-data-tracker/#mis-national-surveillance. 2022;
. The variation in the incidence of both KD and MIS-C among ethnic groups may be at least in part related to genetic predisposition. Indeed, single-nucleotide polymorphisms (SNPs) in various genes, such as ITPKC, CASP3, FCGR2A, ORAI1, BLK, CD40, and CD40L, are associated with increased susceptibility to KD
Soni PR, Noval Rivas M, Arditi M. A Comprehensive Update on Kawasaki Disease Vasculitis and Myocarditis. Curr Rheumatol Rep. Feb 5 2020;22(2):6. doi:10.1007/s11926-020-0882-1
. Genetic analysis from a limited number of MIS-C patients identified rare variants in genes associated with autoimmunity pathways and regulation of inflammatory responses, which may potentially predispose to MIS-C
SARS-CoV-2-Specific T Cell Responses Are Stronger in Children With Multisystem Inflammatory Syndrome Compared to Children With Uncomplicated SARS-CoV-2 Infection. Original Research.
SARS-CoV-2-Specific T Cell Responses Are Stronger in Children With Multisystem Inflammatory Syndrome Compared to Children With Uncomplicated SARS-CoV-2 Infection. Original Research.
, the combination of these three HLA classes I alleles might confer increased susceptibility to MIS-C, which may explain the rarity of MIS-C and why the disease disproportionately affects specific ethnicities.
Clinical, biological, and pathological findings of KD and MIS-C.
Using data collected from retrospective cohorts of KD patients, several studies have compared the clinical, biological, and pathological characteristics of MIS-C and KD patients
Defining Kawasaki disease and pediatric inflammatory multisystem syndrome-temporally associated to SARS-CoV-2 infection during SARS-CoV-2 epidemic in Italy: results from a national, multicenter survey.
. In the absence of a specific test to identify KD, the diagnosis is based on the presence of persistent fever lasting more than five days and four of five primary clinical criteria: changes in the extremities, erythematous rash, conjunctivitis, cracked lips and strawberry tongue, and cervical lymphadenopathy
Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association.
. MIS-C patients have higher levels of C-reactive protein (CRP), ferritin, D-dimer, troponin, and N-terminal pro-brain natriuretic peptide (NT-proBNP) than KD patients, indicating hyperinflammation and potential cardiovascular involvement
Defining Kawasaki disease and pediatric inflammatory multisystem syndrome-temporally associated to SARS-CoV-2 infection during SARS-CoV-2 epidemic in Italy: results from a national, multicenter survey.
Defining Kawasaki disease and pediatric inflammatory multisystem syndrome-temporally associated to SARS-CoV-2 infection during SARS-CoV-2 epidemic in Italy: results from a national, multicenter survey.
MIS-C patients commonly present with prominent cardiac involvement manifested by left ventricular (LV) systolic and diastolic dysfunction, myocardial inflammation, and coronary artery dilations
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.
Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association.
Soni PR, Noval Rivas M, Arditi M. A Comprehensive Update on Kawasaki Disease Vasculitis and Myocarditis. Curr Rheumatol Rep. Feb 5 2020;22(2):6. doi:10.1007/s11926-020-0882-1
Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association.
Soni PR, Noval Rivas M, Arditi M. A Comprehensive Update on Kawasaki Disease Vasculitis and Myocarditis. Curr Rheumatol Rep. Feb 5 2020;22(2):6. doi:10.1007/s11926-020-0882-1
Defining Kawasaki disease and pediatric inflammatory multisystem syndrome-temporally associated to SARS-CoV-2 infection during SARS-CoV-2 epidemic in Italy: results from a national, multicenter survey.
. The prompter resolution of cardiovascular complications after the MIS-C acute phase suggests they may result from hyperinflammation associated with capillary leakage and vasodilation rather than immune infiltrations damaging the myocardium
Immunophenotyping studies have revealed that immune dysregulation, cytokine storm, and increased activation of immune cells are hallmarks of MIS-C, and these correlate with disease severity
Gruber CN, Patel RS, Trachtman R, et al. Mapping Systemic Inflammation and Antibody Responses in Multisystem Inflammatory Syndrome in Children (MIS-C). Cell. Nov 12 2020;183(4):982-995.e14. doi:10.1016/j.cell.2020.09.034
. Notably, elevated cytokines include IL-6, IL-10, TNF-α, IFN-γ, IL-1β, IL-1RA, and soluble CD25 34-36,40,50,51. While acute KD is also associated with high levels of IL-1β, TNF-α, IFN- γ, IL-10, and IL-8 36,52-54, concentrations of these cytokines appear higher during MIS-C
. IL-1β plays a crucial role in KD development. Clinical trials are currently ongoing to test the efficacy of Anakinra, an IL-1 receptor antagonist (IL-1Ra), for KD patients refractory to IVIG treatment
Rationale and study design for a phase I/IIa trial of anakinra in children with Kawasaki disease and early coronary artery abnormalities (the ANAKID trial).
Gruber CN, Patel RS, Trachtman R, et al. Mapping Systemic Inflammation and Antibody Responses in Multisystem Inflammatory Syndrome in Children (MIS-C). Cell. Nov 12 2020;183(4):982-995.e14. doi:10.1016/j.cell.2020.09.034
Gruber CN, Patel RS, Trachtman R, et al. Mapping Systemic Inflammation and Antibody Responses in Multisystem Inflammatory Syndrome in Children (MIS-C). Cell. Nov 12 2020;183(4):982-995.e14. doi:10.1016/j.cell.2020.09.034
Gruber CN, Patel RS, Trachtman R, et al. Mapping Systemic Inflammation and Antibody Responses in Multisystem Inflammatory Syndrome in Children (MIS-C). Cell. Nov 12 2020;183(4):982-995.e14. doi:10.1016/j.cell.2020.09.034
. Neutrophils from MIS-C patients exhibit higher rates of spontaneous release of neutrophil extracellular traps (NETs), which may be a driver of MIS-C vascular inflammation and endothelial damage
Boribong BP, LaSalle TJ, Bartsch YC, et al. Neutrophil Profiles of Pediatric COVID-19 and Multisystem Inflammatory Syndrome in Children. bioRxiv. Dec 20 2021;doi:10.1101/2021.12.18.473308
Gruber CN, Patel RS, Trachtman R, et al. Mapping Systemic Inflammation and Antibody Responses in Multisystem Inflammatory Syndrome in Children (MIS-C). Cell. Nov 12 2020;183(4):982-995.e14. doi:10.1016/j.cell.2020.09.034
; activated CD8+ T cells express the fractalkine receptor CX3CR1, which can interact with fractalkine-expressing vascular endothelium and may potentiate vascular endothelial damage
Gruber CN, Patel RS, Trachtman R, et al. Mapping Systemic Inflammation and Antibody Responses in Multisystem Inflammatory Syndrome in Children (MIS-C). Cell. Nov 12 2020;183(4):982-995.e14. doi:10.1016/j.cell.2020.09.034
. Nevertheless, further studies are still required to determine the specific role of autoantibodies in both MIS-C and KD.
The Superantigen hypothesis and expansion of TRBV11-2 T cell clonotypes in MIS-C.
Superantigens (SAgs) are microbial proteins able to activate large fractions of T cells non-specifically by cross-linking major histocompatibility complex (MHC) class II molecules at the surface of antigen-presenting cells (APCs) with T cell Receptor (TCR) β-chains (Vβ) at their variable domain
Hongmin Li, Andrea Llera, Emilio L. Malchiodi, Mariuzza RA. THE STRUCTURAL BASIS OF T CELL ACTIVATION BY SUPERANTIGENS. Annu Rev Immunol. 1999;17(1):435-466. doi:10.1146/annurev.immunol.17.1.435
Hongmin Li, Andrea Llera, Emilio L. Malchiodi, Mariuzza RA. THE STRUCTURAL BASIS OF T CELL ACTIVATION BY SUPERANTIGENS. Annu Rev Immunol. 1999;17(1):435-466. doi:10.1146/annurev.immunol.17.1.435
. Over-activation of T cells by SAg results in an uncontrolled release of chemokines and proinflammatory cytokines and underlies toxic shock syndrome (TSS). KD shares some clinical features with SAg-mediated diseases, including fever, desquamating rash, and SAgs have been considered as potential KD triggers. While a few studies reported the expansion of different Vβ T cell populations during acute KD, this has not been confirmed by follow-up studies on independent cohorts of KD patients
Characterization of CD4+ T helper cells in patients with Kawasaki disease (KD): preferential production of tumour necrosis factor-alpha (TNF-alpha) by V beta 2- or V beta 8- CD4+ T helper cells.
Pietra BA, De Inocencio J, Giannini EH, Hirsch R. TCR V beta family repertoire and T cell activation markers in Kawasaki disease. J Immunol. Aug 15 1994;153(4):1881-1888.
Feldstein LR, Rose EB, Horwitz SM, et al. Multisystem Inflammatory Syndrome in U.S. Children and Adolescents. N Engl J Med. Jul 23 2020;383(4):334-346. doi:10.1056/NEJMoa2021680
COVID-19-associated multisystem inflammatory syndrome in children (MIS-C): A novel disease that mimics toxic shock syndrome-the superantigen hypothesis.
Computational studies comparing SARS-CoV-2 with bacterial toxins revealed the presence of a motif in SARS-CoV-2 Spike protein subunit S1 that harbors high sequence and structural similarities with a segment of staphylococcal enterotoxin B (SEB), a bacterial SAg
COVID-19-associated multisystem inflammatory syndrome in children (MIS-C): A novel disease that mimics toxic shock syndrome-the superantigen hypothesis.
COVID-19-associated multisystem inflammatory syndrome in children (MIS-C): A novel disease that mimics toxic shock syndrome-the superantigen hypothesis.
. Further supporting the potential involvement of the SAg-like motif in SARS-CoV-2 pathogenesis, incubation of SARS-CoV-2 with the 6D3 anti-SEB mAb inhibited cellular viral infection in vitro
TCR repertoire sequencing performed on independent cohorts of MIS-C patients indicate TCRVβ skewing and expansion of TRBV11-2 (Vβ21.3+) T cell clonotypes, suggestive of superantigenic stimulation
. Severe MIS-C patients with TRBV11-2 T cell expansion also exhibit more robust autoantibodies responses, a solid imprint of antigenic selection in their BCR repertoires, and increased usage of autoantibody-associated IGHV genes
. In silico modeling indicates that TRBV11-2 engages in a CDR3-independent interaction with the polybasic insert “PRRA” in the SARS-CoV-2 SAg-like motif
Autopsy studies of fatal MIS-C cases indicate the sustained presence of SARS-CoV-2 in multiple tissues, including lung, heart, brain, and intestinal tissues
Multisystem inflammatory syndrome in children (MIS-C) showing disseminated aspergillosis, cytomegalovirus reactivation and persistent SARS-COV-2: Case report with autopsy review.
. Yonker et al. observed the prolonged presence of SARS-CoV-2 RNA in the GI tract of MIS-C patients weeks after initial exposure and elevated levels of Zonulin and other markers indicative of increased intestinal permeability
. This suggests that the GI tract may act as a viral reservoir for SARS-CoV-2. Increased intestinal permeability might be permissive for SARS-CoV-2 antigens to breach the intestinal barrier and enter the systemic circulation
. Indeed, MIS-C patients with a severe clinical phenotype and TBRV11-2 expansion have higher levels of circulating S1, which contains the SARS-CoV-2 SAg-like motif
Soni PR, Noval Rivas M, Arditi M. A Comprehensive Update on Kawasaki Disease Vasculitis and Myocarditis. Curr Rheumatol Rep. Feb 5 2020;22(2):6. doi:10.1007/s11926-020-0882-1
. Up to ≈7% of IVIG-treated children with KD will develop coronary artery abnormalities, which may progress to stenosis, occlusion and/or thrombosis over time
. Long-term KD complications include coronary artery stenosis and calcification, myocardial infarction, fibrosis, and long-term systolic or diastolic dysfunction, and may predispose to premature atherosclerosis
Soni PR, Noval Rivas M, Arditi M. A Comprehensive Update on Kawasaki Disease Vasculitis and Myocarditis. Curr Rheumatol Rep. Feb 5 2020;22(2):6. doi:10.1007/s11926-020-0882-1
While the cardiovascular manifestations of acute MIS-C improve rapidly, little is known regarding the long-term outcomes, and myocardial inflammation could lead to long-term sequelae such as fibrosis and scaring
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.
6-month multidisciplinary follow-up and outcomes of patients with paediatric inflammatory multisystem syndrome (PIMS-TS) at a UK tertiary paediatric hospital: a retrospective cohort study.
. A multicenter follow-up study of US children that developed MIS-C indicates that some symptoms, such as fatigue, weakness, activity impairment, and headache may persist beyond two months after hospitalization
. In another cohort of MIS-C patients, six months after acute disease, markers of systemic inflammation returned to baseline, electrocardiograms were normal, GI symptoms were absent, and minimal functional neurological impairment was observed
6-month multidisciplinary follow-up and outcomes of patients with paediatric inflammatory multisystem syndrome (PIMS-TS) at a UK tertiary paediatric hospital: a retrospective cohort study.
. However, in this study, 18 of the 40 patients exhibited a reduced functional exercise capacity six months post-MIS-C. Whether this resulted from MIS-C or involved other factors, such as a sedentary lifestyle, remains unclear
6-month multidisciplinary follow-up and outcomes of patients with paediatric inflammatory multisystem syndrome (PIMS-TS) at a UK tertiary paediatric hospital: a retrospective cohort study.
. Additional and extended studies are still required to determine the long-term impacts of MIS-C on cardiovascular function, and a multicenter observational cohort study (COVID MUSIC study) is currently ongoing
. Omicron, which exhibits more than 30 amino acid substitutions, quickly became the dominant circulating variant in 2022, raising potential concerns about increased MIS-C incidence. However, MIS-C severity and incidence dramatically decreased during the Omicron wave compared with Alpha and Delta waves
CDC. Health Department-Reported Cases of Multisystem Inflammatory Syndrome in Children (MIS-C) in the United States. https://covidcdcgov/covid-data-tracker/#mis-national-surveillance. 2022;
. Multiple parameters may account for such a decrease in MIS-C frequency, including children's vaccination and the efficiency of SARS-CoV-2 vaccines in preventing MIS-C
Effectiveness of BNT162b2 (Pfizer-BioNTech) mRNA Vaccination Against Multisystem Inflammatory Syndrome in Children Among Persons Aged 12-18 Years - United States, July-December 2021.
. Indeed, mutations in SARS-CoV-2 Spike may explain disease severity differences between variants. The highly pathogenic Delta harbors a Spike mutation, P681R, which becomes more polybasic in nature and is further cleaved by the acidic motif furin, releasing higher amounts of the shed S1 subunit
. On the other hand, the relatively less pathogenic Omicron harbors several mutations in Spike that result in inefficient use of TMPRSS2, suboptimal S1/S2 cleavage, and reduced levels of shed S1 95. Since the SAg-like motif is in the S1 SARS-CoV-2 subunit, these findings may potentially support the superantigen hypothesis of MIS-C and may explain the significant reduction of MIS-C incidence during the Omicron wave, in addition to vaccines-induced protection.
Conclusions
Several clinical features overlap between MIS-C and KD. These two entities share inflammatory characteristics, indicating that MIS-C and KD may belong to the same broad umbrella of inflammatory disorders involving the master cytokine IL-1β
, but differ in many aspects of etiology, demography, epidemiology, clinical and laboratory findings, as well as pathology. The intensity of the inflammatory response and long-term cardiovascular sequelae diverge between KD and MIS-C. Whereas MIS-C presents with a more intense inflammatory syndrome, KD vasculitis is associated with pathologic changes in the coronary arteries and associated with long-term cardiovascular sequelae. The 2 to 6 weeks delay between SARS-CoV-2 exposure and MIS-C development may account for the development of the autoinflammatory response involving dysregulated B and T cell responses, plasmablast differentiation, and autoantibody production
. While the general hypothesis is that KD is triggered by a viral infectious agent(s), the causative agents remain unidentified, and whether KD can be considered a post-infectious syndrome, like MIS-C, remains unclear. In conclusion, the data available so far support the hypothesis that MIS-C and KD belong to the same broad spectrum of inflammatory disorders but with clearly distinct etiopathology, presentation, and long-term consequences.
Clinical Care Points:
•
MIS-C and KD are considered two distinctive diseases triggered by different infectious agents. However, these two entities share inflammatory characteristics. It is, therefore, not surprising that both diseases respond well to IVIG +/- steroids. Furthermore, anti-IL-1 receptor therapies, such as Anakinra, are expected to treat these two conditions efficiently.
•
KD is associated with the development of coronary artery aneurysms and later coronary remodeling with luminal myofibroblast proliferation that leads to coronary stenosis, ischemia, and myocardial fibrosis as long-term sequelae. Children with MIS-C should also be followed longitudinally to determine if any long-term complications will emerge.
•
COVID-19 vaccinations have significantly decreased MIS-C incidence and should be encouraged among all eligible age groups.
Kang J-M, Kim Y-E, Huh K, et al. Reduction in Kawasaki Disease After Nonpharmaceutical Interventions in the COVID-19 Era: A Nationwide Observational Study in Korea. Circulation. 2021;143(25):2508-2510. doi:doi:10.1161/CIRCULATIONAHA.121.054785
Burney JA, Roberts SC, DeHaan LL, et al. Epidemiological and Clinical Features of Kawasaki Disease During the COVID-19 Pandemic in the United States. JAMA Network Open. 2022;5(6):e2217436-e2217436. doi:10.1001/jamanetworkopen.2022.17436
Lapp SA, Abrams J, Lu AT, et al. Serologic and Cytokine Signatures in Children With Multisystem Inflammatory Syndrome and Coronavirus Disease 2019. Open Forum Infectious Diseases. 2022;9(3)doi:10.1093/ofid/ofac070
Lin CY, Lin CC, Hwang B, Chiang BN. The changes of interleukin-2, tumour necrotic factor and gamma-interferon production among patients with Kawasaki disease. Eur J Pediatr. Jan 1991;150(3):179-182. doi:10.1007/bf01963561
Meng B, Abdullahi A, Ferreira I, et al. Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity. Nature. Mar 2022;603(7902):706-714. doi:10.1038/s41586-022-04474-x
Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association.
Feldstein LR, Rose EB, Horwitz SM, et al. Multisystem Inflammatory Syndrome in U.S. Children and Adolescents. N Engl J Med. Jul 23 2020;383(4):334-346. doi:10.1056/NEJMoa2021680
Soni PR, Noval Rivas M, Arditi M. A Comprehensive Update on Kawasaki Disease Vasculitis and Myocarditis. Curr Rheumatol Rep. Feb 5 2020;22(2):6. doi:10.1007/s11926-020-0882-1
Esper F, Shapiro ED, Weibel C, Ferguson D, Landry ML, Kahn JS. Association between a novel human coronavirus and Kawasaki disease. J Infect Dis. Feb 15 2005;191(4):499-502. doi:10.1086/428291
Quiat D, Kula T, Shimizu C, et al. High-Throughput Screening of Kawasaki Disease Sera for Antiviral Antibodies. J Infect Dis. Nov 9 2020;222(11):1853-1857. doi:10.1093/infdis/jiaa253
Kang J-M, Kim Y-E, Huh K, et al. Reduction in Kawasaki Disease After Nonpharmaceutical Interventions in the COVID-19 Era: A Nationwide Observational Study in Korea. Circulation. 2021;143(25):2508-2510. doi:doi:10.1161/CIRCULATIONAHA.121.054785
Burney JA, Roberts SC, DeHaan LL, et al. Epidemiological and Clinical Features of Kawasaki Disease During the COVID-19 Pandemic in the United States. JAMA Network Open. 2022;5(6):e2217436-e2217436. doi:10.1001/jamanetworkopen.2022.17436
CDC. Health Department-Reported Cases of Multisystem Inflammatory Syndrome in Children (MIS-C) in the United States. https://covidcdcgov/covid-data-tracker/#mis-national-surveillance. 2022;
SARS-CoV-2-Specific T Cell Responses Are Stronger in Children With Multisystem Inflammatory Syndrome Compared to Children With Uncomplicated SARS-CoV-2 Infection. Original Research.
Defining Kawasaki disease and pediatric inflammatory multisystem syndrome-temporally associated to SARS-CoV-2 infection during SARS-CoV-2 epidemic in Italy: results from a national, multicenter survey.
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.
Gruber CN, Patel RS, Trachtman R, et al. Mapping Systemic Inflammation and Antibody Responses in Multisystem Inflammatory Syndrome in Children (MIS-C). Cell. Nov 12 2020;183(4):982-995.e14. doi:10.1016/j.cell.2020.09.034
Lapp SA, Abrams J, Lu AT, et al. Serologic and Cytokine Signatures in Children With Multisystem Inflammatory Syndrome and Coronavirus Disease 2019. Open Forum Infectious Diseases. 2022;9(3)doi:10.1093/ofid/ofac070
Lin CY, Lin CC, Hwang B, Chiang BN. The changes of interleukin-2, tumour necrotic factor and gamma-interferon production among patients with Kawasaki disease. Eur J Pediatr. Jan 1991;150(3):179-182. doi:10.1007/bf01963561
Rationale and study design for a phase I/IIa trial of anakinra in children with Kawasaki disease and early coronary artery abnormalities (the ANAKID trial).
Boribong BP, LaSalle TJ, Bartsch YC, et al. Neutrophil Profiles of Pediatric COVID-19 and Multisystem Inflammatory Syndrome in Children. bioRxiv. Dec 20 2021;doi:10.1101/2021.12.18.473308
Hongmin Li, Andrea Llera, Emilio L. Malchiodi, Mariuzza RA. THE STRUCTURAL BASIS OF T CELL ACTIVATION BY SUPERANTIGENS. Annu Rev Immunol. 1999;17(1):435-466. doi:10.1146/annurev.immunol.17.1.435
Characterization of CD4+ T helper cells in patients with Kawasaki disease (KD): preferential production of tumour necrosis factor-alpha (TNF-alpha) by V beta 2- or V beta 8- CD4+ T helper cells.
Pietra BA, De Inocencio J, Giannini EH, Hirsch R. TCR V beta family repertoire and T cell activation markers in Kawasaki disease. J Immunol. Aug 15 1994;153(4):1881-1888.
COVID-19-associated multisystem inflammatory syndrome in children (MIS-C): A novel disease that mimics toxic shock syndrome-the superantigen hypothesis.
Multisystem inflammatory syndrome in children (MIS-C) showing disseminated aspergillosis, cytomegalovirus reactivation and persistent SARS-COV-2: Case report with autopsy review.
6-month multidisciplinary follow-up and outcomes of patients with paediatric inflammatory multisystem syndrome (PIMS-TS) at a UK tertiary paediatric hospital: a retrospective cohort study.
Effectiveness of BNT162b2 (Pfizer-BioNTech) mRNA Vaccination Against Multisystem Inflammatory Syndrome in Children Among Persons Aged 12-18 Years - United States, July-December 2021.
Meng B, Abdullahi A, Ferreira I, et al. Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity. Nature. Mar 2022;603(7902):706-714. doi:10.1038/s41586-022-04474-x
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