Mechanisms of Immune Dysregulation in COVID-19 Are Different From SARS and MERS: A Perspective in Context of Kawasaki Disease and MIS-C

Abstract

Coronaviruses have led to three major outbreaks to date-Severe Acute Respiratory Syndrome (SARS; 2002), Middle East Respiratory Syndrome (MERS; 2012) and the ongoing pandemic, Coronavirus Disease (COVID-19; 2019). Coronavirus infections are usually mild in children. However, a few children with MERS had presented with a severe phenotype in the acute phase resulting in progressive pneumonic changes with increasing oxygen dependency and acute respiratory distress requiring ventilatory support. A subset of children with a history of SARS-CoV-2 infection develops a multisystem hyper-inflammatory phenotype known as Multisystem Inflammatory Syndrome in Children (MIS-C). This syndrome occurs 4-6 weeks after infection with SARS-CoV-2 and has been reported more often from areas with high community transmission. Children with MIS-C present with high fever and often have involvement of cardiovascular, gastrointestinal and hematologic systems leading to multiorgan failure. This is accompanied by elevation of pro-inflammatory cytokines such as IL-6 and IL-10. MIS-C has several similarities with Kawasaki disease (KD) considering children with both conditions present with fever, rash, conjunctival injection, mucosal symptoms and swelling of hands and feet. For reasons that are still not clear, both KD and MIS-C were not reported during the SARS-CoV and MERS-CoV outbreaks. As SARS-CoV-2 differs from SARS-CoV by 19.5% and MERS by 50% in terms of sequence identity, differences in genomic and proteomic profiles may explain the varied disease immunopathology and host responses. Left untreated, MIS-C may lead to severe abdominal pain, ventricular dysfunction and shock. Immunological investigations reveal reduced numbers of follicular B cells, increased numbers of terminally differentiated CD4+T lymphocytes, and decreased IL-17A. There is still ambiguity about the clinical and immunologic risk factors that predispose some children to development of MIS-C while sparing others. Host-pathogen interactions in SARS, MERS and COVID-19 are likely to play a crucial role in the clinical phenotypes that manifest. This narrative review focuses on the immunological basis for development of MIS-C syndrome in the ongoing SARS-CoV-2 pandemic. To the best of our knowledge, these aspects have not been reviewed before.

Celiac Disease and Targeting the Molecular Mechanisms of Autoimmunity in COVID Pandemic

“…They pointed out that SARS-CoV-2 is characterized by a modified spike polypeptide (S1) with a higher binding affinity to host NRP1 receptors, being responsible for high infectivity and tissue tropism in SARS-CoV-2 infections. The molecular mechanisms of COVID-19 appear to have delayed IFN responses, which are responsible for the high secretion of IL-6, IL-7 and TNF-α, hyperinflammation and worsening of clinical status, with the release of the following autoantibodies to dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2), and to the casein kinase family (Casein kinase 1, alpha 1 (CSNK1A1), Casein kinase 2, alpha 1 (CSNK2A1) and Casein kinase 1, epsilon 1 (CSNK1E1)), found exclusively in MIS-C [ 120 ].…”

Ophthalmic Manifestations of Multisystem Inflammatory Syndrome in Children

“…Immune dysregulation triggered by COVID-19 infection, hyperinflammation as a result of cytokine storm, endothelial dysfunction, and microangiopathy is responsible for systemic multiorgan involvement. [30][31][32] Elevation of at least two inflammation markers is required for the diagnosis. 11 Among the inflammatory markers, CRP, procalcitonin, ESR, ferritin, IL-6, and D-dimer levels showed remarkable increases.…”

“…Cardiac involvement was found in 67 to 80% of the children with MIS-C, including ventricular dysfunction, arrhythmias, conduction abnormalities, and coronary artery aneurysms (33–50%, 28–67%, and 13–26%, respectively). 32 Recently, Dhaliwal et al 30 reported that 42.3% of patients with MIS-C had low ejection fraction, 20.8% had coronary aneurysm, 23% had pericardial effusion, and 23% had mitral regurgitation. Abrams et al 35 evaluated 1,080 patients with MIS-C and found that 303 had cardiac involvements such as shock, decreased cardiac function, myocarditis, and coronary artery abnormality (36, 28, 18, and 17%, respectively).…”

Anakinra treatment in multisystemic inflammatory syndrome in children (MIS-C) associated with COVID-19

“…The median resolution day of the fever was 3 (1-10) days after anakinra treatment. The lymphocyte counts, BNP, CRP, and D-dimer values of the patients became normal on the median day of 5 (1-18), 8.5 (5-53), 10 (1-33), and 11.5 (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20), respectively. The pattern of improvement in EF…”

“…The underlying pathogenesis has not yet been fully elucidated and an abnormal immune response is blamed as the main factor in the pathogenesis of MIS-C. Various cytokines are thought to cause hyperinflammation, including, interleukin-1 (IL-1), interferon-gama (IFNγ), IL-18, IL-6, IL-8, and IL-10 ( 3 , 4 ). While intravenous immunoglobulin (IVIG) and corticosteroids are used in the first line of treatment, anakinra is recommended as a therapeutic option in resistant cases ( 5 ).…”