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.

A non-immunocompromised patient developed life-threatening soft-tissue infection with Trichosporon asahii, Fusarium, and Saksenaea that progressed despite maximum anti-fungal therapies and aggressive debridement. IL-7 immunotherapy resulted in clinical improvement, fungal clearance, reversal of lymphopenia, and improved T-cell function. Immunoadjuvant therapies to boost host immunity may be efficacious in life-threatening fungal infections.

BACKGROUND: Immunotherapy treatment for coronavirus disease 2019 combined with antiviral therapy and supportive care remains under intense investigation. However, the capacity to distinguish patients who would benefit from immunosuppressive or immune stimulatory therapies remains insufficient. Here, we present a patient with severe coronavirus disease 2019 with a defective immune response, treated successfully with interleukin-7 on compassionate basis with resultant improved adaptive immune function. CASE SUMMARY: A previously healthy 43-year-old male developed severe acute respiratory distress syndrome due to the severe acute respiratory syndrome coronavirus 2 virus with acute hypoxemic respiratory failure and persistent, profound lymphopenia. Functional analysis demonstrated depressed lymphocyte function and few antigen-specific T cells. Interleukin-7 administration resulted in reversal of lymphopenia and improved T-cell function. Respiratory function and clinical status rapidly improved, and he was discharged home. Whole exome sequencing identified a deleterious autosomal dominant mutation in TICAM1 , associated with a dysfunctional type I interferon antiviral response with increased severity of coronavirus disease 2019 disease. CONCLUSIONS: Immunoadjuvant therapies to boost host immunity may be efficacious in life-threatening severe coronavirus disease 2019 infections, particularly by applying a precision medicine approach in selecting patients expressing an immunosuppressive phenotype.

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