Phenotype, Susceptibility, Autoimmunity, and Immunotherapy Between Kawasaki Disease and Coronavirus Disease-19 Associated Multisystem Inflammatory Syndrome in Children

Abstract

Coronavirus disease-19 (COVID-19) in children is usually mild but some are susceptible to a Kawasaki disease (KD)-like multisystem inflammatory syndrome in children (MIS-C) in the convalescent stage, posing a need to differentiate the phenotype, susceptibility, autoimmunity, and immunotherapy between KD and MIS-C, particularly in the upcoming mass vaccination of COVID-19. Patients with MIS-C are prone to gastrointestinal symptoms, coagulopathy, and shock in addition to atypical KD syndrome with fever, mucocutaneous lesions, lymphadenopathy, and/or cardiovascular events. MIS-C manifests KD-like symptoms that alert physicians to early recognize and adopt the KD treatment regimen for patients with MIS-C. MIS-C linked to COVID-19 teaches us infection-associated autoimmune vasculitis and vice versa. Studies on genetic susceptibility have identified certain human leukocyte antigen (HLA) locus and toll-like receptor (TLR) associated with KD and/or COVID-19. Certain HLA subtypes, such as HLA-DRB1 and HLA-MICA A4 are associated with KD. HLA-B*46:01 is proposed to be the risk allele of severe COVID-19 infection, and blood group O type is a protective factor of COVID-19. The autoimmune vasculitis of KD, KD shock syndrome (KDSS), or MIS-C is mediated by a genetic variant of HLA, FcγR, and/or antibody-dependent enhancement (ADE) resulting in hyperinflammation with T helper 17 (Th17)/Treg imbalance with augmented Th17/Th1 mediators: interleukin-6 (IL-6), IL-10, inducible protein-10 (IP-10), Interferon (IFNγ), and IL-17A, and lower expression of Treg-signaling molecules, FoxP3, and transforming growth factor (TGF-β). There are certain similarities and differences in phenotypes, susceptibility, and pathogenesis of KD, KDSS, and MIS-C, by which a physician can make early protection, prevention, and precision treatment of the diseases. The evolution of immunotherapies for the diseases has shown that intravenous immunoglobulin (IVIG) alone or combined with corticosteroids is the standard treatment for KD, KDSS, and MIS-C. However, a certain portion of patients who revealed a treatment resistance to IVIG or IVIG plus corticosteroids, posing a need to early identify the immunopathogenesis, to protect hosts with genetic susceptibility, and to combat Th17/Treg imbalance by anti-cytokine or pro-Treg for reversal of the hyperinflammation and IVIG resistance. Based on physiological and pathological immunity of the diseases under genetic susceptibility and host milieu conditions, a series of sequential regimens are provided to develop a so-called “Know thyself, enemy (pathogen), and ever-victorious” strategy for the prevention and immunotherapy of KD and/or MIS-C.

Immunopathogenesis of Different Emerging Viral Infections: Evasion, Fatal Mechanism, and Prevention

“…Early administration of MoAbs or convalescent plasma has also shown effectiveness on the limitation of disease progression in Ebola ( 140), SARS-CoV-1 (141), MERS-CoV (142), and SARS-CoV-2 (154,(175)(176)(177). It is also postulated that a combination of neutralizing MoAbs and anti-virus agent may induce a synergistic effect (178). The early diagnosis followed by early treatment with MoAbs or convalescent plasma in 72 hours has been shown to reduce viral load, hospitalization and disease progression of COVID-19 (175)(176)(177).…”

“…Different emerging infections may induce variant types of cytokine storm (87,92,97,120,158) to which immunotherapies with anticytokine and/or immune regulatory therapies have been proposed to rescue the patients with cytokine storm (114,(159)(160)(161). It is, however, postulated that aiming at a single target of one cytokine action may be ineffective, and sequential targeting may be required for eliminating the cytokine storm (178). A combined regimen with circulating supports by ECMO and eliminating cytokines by CRRT (156,157,162) may be beneficial.…”

Perspective of Immunopathogenesis and Immunotherapies for Kawasaki Disease

“…The fact that MIS-C occurs after SARS-CoV-2 infection presenting a KD-like disorder suggests that both KD and MIS-C have similar pathogenesis of autoimmune etiology induced by certain viral infection ( 25 ). Therefore, the algorithm for diagnosis and treatment of typical and atypical (incomplete) KD in children has been adopted for the early recognition and management of the MIS-C, such as treatment with IVIG and corticosteroids ( 26 ). Interestingly, the MIS-C cases are mostly reported from Italy, France, UK, and USA but not found in Asia, where the incidence of KD is 10 times higher than that in Western countries ( 24 , 27 ).…”

“…Ferritin (>500–1,000 ng/ml) and D-dimer (>1,000–4,000 ng/ml) are also significantly higher in children with KDSS ( 52 – 54 ). The inflammatory mediators, phagocyte activation and coagulopathy profiles are very similar between KDSS and MIS-C ( 26 ). In general, hyperferritinemia in KDSS is thought to originate from macrophage activation syndrome (MAS), and thus is concurrent with hypertriglyceridemia, anemia, and hypercytokinemia.…”

The Role of Exosomes in the Treatment, Prevention, Diagnosis, and Pathogenesis of COVID-19

“…17,25,[53][54][55][56][57] Some authors have speculated that MSC-derived exosomes could be of use in the most severe cases of the Kawasaki-like multisystem inflammatory syndrome. 17,58 The rationale behind their employment is that MSC-exosomes are able to attenuate severe inflammatory responses and promote regeneration of the damaged tissues. Exosomes are also emerging as ideal biological nanocarriers for drug delivery in multiple clinical applications.…”