Multisystem Inflammatory Syndrome in Children: Host Immunologic Responses

Abstract

Several weeks into the COVID-19 pandemic, a new syndrome causing sudden critical illness in children was identified (1)(2)(3)(4). Multisystem inflammatory syndrome in children (MIS-C), also called Pediatric Inflammatory Multisystem Syndrome Temporally associated with Severe acute respiratory syndrome coronavirus 2 (5), is a clinical syndrome of systemic inflammation, strongly associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, that has some similarities to, but is clinically and biologically distinct from, Kawasaki disease shock, macrophage activation syndrome, and toxic shock syndrome (TSS) (6-8). MIS-C typically afflicts infected (and often asymptomatic) children 4-6 weeks after exposure to SARS-CoV-2 and can cause multiple organ involvement affecting the heart, lungs, kidneys, brain, skin, and gastrointestinal system (1). These patients often present with cardiogenic or distributive shock and/or with severe abdominal pathology requiring admission to the PICU (9). Feldstein et al (1) studied a cohort of 539 MIS-C patients throughout the United States and demonstrated a nearly 75% ICU admission rate, 45% vasopressor requirement with less than 2% mortality, with the majority of patients achieving a complete recovery. Although MIS-C is a rare new clinical entity, formative studies are shaping the basic immunopathologic mechanisms behind the syndrome (2). The focus of this review is to synthesize the currently published immunologic profiles of patients with MIS-C into a robust mechanistic schema, which will identify future areas of study to complete the identification of the immunologic pathophysiology of MIS-C and to create a template that can be applied to several other autoinflammatory and post-infectious processes. A PATHOLOGIC IMMUNE RESPONSE, DIRECT SARS-COV-2 EFFECT, OR POST-INFECTIOUS SYNDROME?The prevailing (nonmutually exclusive) hypotheses for the pathogenic etiology of MIS-C include: 1) a post-infectious autoimmune-mediated inflammatory process, 2) a cytokine storm instigated by a superantigen response, and 3) a dysregulated immune response to chronic exposure to SARS-CoV-2 viral antigens. There are data to support all three theories in the literature and the underlying etiology is likely complex and multifactorial.

Intestinal microbiota composition of children with infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and multisystem inflammatory syndrome (MIS-C)

“…Although genetic and immune system-related risk factors are thought to play a role in the pathogenesis of MIS-C, they have not been fully elucidated and the underlying etiology appears to be multifactorial. An autoimmune-mediated inflammatory process after infection, a cytokine storm initiated by a superantigen response, and a dysregulated immune response to exposure to SARS-CoV-2 viral antigens have been proposed as theories to explain its pathogenesis [ 11 , 12 ]. Immunological mechanisms, such as humoral and cellular adaptive immunity and innate response, play roles in the development of systemic inflammatory syndrome [ 11 ].…”

“…An autoimmune-mediated inflammatory process after infection, a cytokine storm initiated by a superantigen response, and a dysregulated immune response to exposure to SARS-CoV-2 viral antigens have been proposed as theories to explain its pathogenesis [ 11 , 12 ]. Immunological mechanisms, such as humoral and cellular adaptive immunity and innate response, play roles in the development of systemic inflammatory syndrome [ 11 ]. Recent studies have also suggested that specific HLA haplotypes could be more frequently associated with the presence of this disease [ 13 ].…”

Cardiac Complications Associated with COVID-19, MIS-C, and mRNA COVID-19 Vaccination

“…Yonker et al have shown that weeks after acute infection, SARS-CoV-2 antigen can still be found in the gastrointestinal tract of patients who developed MIS-C [ 31 ]. Finally, similar to patients with toxic shock syndrome, a third theory suggests “superantigen-like activity of the SARS-CoV-2 spike protein” → incites a dysregulated immune response with cytokine storm [ 30 ]. As it pertains to cardiovascular dysfunction, the release of cytokines (TNF-⍺ IL-1β, IL-2, IL-6, and IFN-γ) is the known cause for left ventricular dysfunction, affecting both the extracellular matrix and myocyte contractility [ 32 ].…”

“…Patients with MIS-C present several weeks after acute infection, have low viral load, low immunoglobulin M (IgM), and high IgG and IgA expression [29]. It is therefore plausible that like other viral triggers of autoimmunity, SARS-CoV-2 activates an autoimmune response resulting in tissue damage [20,30]. A second theory is that there is an uncontrolled immune response to prolonged presence of SARS-CoV-2 antigen.…”

Intestinal Microbiota Composition of Children with Infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-COV-2) and Multisystem Inflammatory Syndrome (MIS-C)

“…[11; 12] Immunological mechanisms, such as humoral and cellular adaptive immunity and innate response, play roles in the development of systemic in ammatory syndrome. [11] Recent studies have also suggested that speci c HLA haplotypes could be more frequently associated with the presence of this disease. [13] It has been shown that infections, especially of the gastrointestinal and respiratory systems, have effects on microbiota composition.…”