Multisystem inflammatory syndrome in children (MIS-C) is a severe complication of SARS-CoV-2 infections in children. This syndrome manifests about a month after the initial viral infection and is characterized by fever, multiorgan dysfunction, and systemic inflammation. This chapter will review the emergence, epidemiology, clinical characteristics, diagnosis, pathophysiology, immunomodulatory treatment, prognosis, outcomes, and prevention of MIS-C. While the pathophysiology of MIS-C remains to be defined, it is a post-infection, hyperinflammatory syndrome of childhood with elevated inflammatory cytokines.

Infection with SARS-CoV-2 may trigger a delayed hyper-inflammatory illness in children called paediatric multisystem inflammatory syndrome temporally associated with COVID-19 (PIMS-TS). A similar syndrome is increasingly recognised in adults termed multisystem inflammatory syndrome in adults (MIS-A) and may present acutely to medical or surgical specialties with severe symptoms, such as acute abdominal pain or cardiogenic shock. No national guidelines exist in the UK for the management of MIS-A and there is limited evidence to guide treatment plans. We undertook a national Delphi process to elicit opinions from experts in hyperinflammation about the diagnosis and management of MIS-A with the dual aim of improving recognition and producing a management guideline. Colleagues in paediatrics successfully initiated a national consensus management document that facilitated regional multidisciplinary referral and follow-up pathways for children with PIMS-TS, and we propose a similar system be developed for adult patients across the UK. This would facilitate better recognition and treatment of MIS-A across the multiple specialties to which it may present as well as enable follow-up with specialty services post-discharge.

BACKGROUND: Vasculitis diseases include Kawasaki disease (KD), Kawasaki disease shock syndrome (KDSS), Multisystem Inflammatory Syndrome (MIS), Henoch-Schönlein purpura (HS), or IgA vasculitis, and additional vasculitis diseases. These diseases are often preceded by infections or immunizations. Disease incidence rates are higher in children than in adults. These diseases have been extensively studied, but understanding of the disease etiology remains to be established.
OBJECTIVE: Many studies have failed to demonstrate an association between vasculitis diseases and vaccination; this study examines possible associations.
METHODS: Herein, the Vaccine Adverse Event Reporting System (VAERS) database is retrospectively examined for associations between vasculitis diseases and immunizations.
RESULTS: For some vaccines, the number of rare cases of KD, MIS, and HS are higher than the background rates. These rare cases are predicted to occur in individuals with (1) genetic risk factors with (2) antibody titer levels above the primary immune response level. Herein, the model of humoral immune response antibodies bound to antigens (pathogen or vaccine) creating immune complexes is proposed. These immune complexes are proposed to bind Fc receptors on immune cells and platelets, resulting in cell activation and the release of inflammatory molecules including histamine and serotonin. Immune complexes and inflammatory molecules including serotonin and histamine likely trigger vasculitis. Elevated serotonin and possibly histamine drive initial vasoconstrictions, disrupting blood flow. Increased blood flow pressure from cardiac capillary vasoconstrictions is predicted to trigger coronary artery aneurysms (CAA) or lesions (CAL) in some patients. For KDSS and MIS patients, these cardiac capillary vasoconstrictions are predicted to result in ischemia followed by ventricular dysfunction. Ongoing ischemia can result in long-term cardiac damage. Cases associated with pathogens are likely to have persistent infections triggering disease onset.
CONCLUSIONS: The proposed model of immune complexes driving disease initial disease etiology by Fc receptor activation of immune cells and platelets, resulting in elevated histamine and serotonin levels, is testable and is consistent with disease symptoms and current treatments.

Within 6 months of the coronavirus pandemic, a new disease entity associated with a multisystem hyperinflammation syndrome as a result of a previous infection with the SARS-CoV-2 virus is increasingly being identified in children termed Multisystem Inflammatory Syndrome in Children (MIS-C) and more recently in adults(MIS-A). Due to its clinical similarity with Kawasaki Disease, some institutions have used intravenous immunoglobulins and steroids as first line agents in the management of the disease. We seek to find how effective intravenous immunoglobulin therapy is across these two disease entities. A comprehensive English literature search was conducted across PubMed, MEDLINE, and EMBASE databases using the keywords multisystem inflammatory syndrome in children/adults and treatment. All major online libraries concerning the diagnosis and treatment of MIS-C and MIS-A were searched. Relevant papers were read, reviewed, and analyzed. The use of intravenous immunoglobulins (IVIG) and steroids for the treatment of multisystemic inflammatory syndrome in children(MIS-C) is well established and recommended by multiple pediatric governing institutions. However, there is still no optimal treatment guideline or consensus on the use of IVIG in adults. The use of IVIG in both the child and adult populations may lower the risk of treatment failure and the need for adjunctive immunomodulatory therapy. Despite the promising results of IVIG use for the management of MIS-C and MIS-A, considering the pathophysiological differences between MIS-C and MIS-A, healthcare professionals need to further assess the differences in disease risk and treatment. The optimal dose, frequency, and duration of treatment are still unknown, more research is needed to establish treatment guidelines.

UNASSIGNED: The multisystem inflammatory syndrome in adults (MIS-A) has emerged, similar to those in children associated with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) [multisystem inflammatory syndrome in children (MIS-C)]. This review aimed to analyze the risk factors, clinical course, and prognosis of MIS-A.
UNASSIGNED: A comprehensive literature search was conducted using several databases for cases reporting MIS-A from 1 December 2019 till 9 September 2021. The case definitions used to identify potential cases were those recommended by the World Health Organization, Center for Disease Control, and individual country/physician classification. The meta-analysis was performed using Comprehensive Meta-Analysis (CMA) 2.2.027 and Review Manager (RevMan) 5.4.1, employing 95% confidence intervals (CI).
UNASSIGNED: Seventy studies were assessed for full-text eligibility, out of which 37 were included. The mean age of the study population was 32.52±10.29 years. The most common symptoms were fever (89.8%, 95% CI: 77.7-95.7%) and diarrhea (49%, 95% CI: 35.4-62.7%). Ventricular tachycardia (57.1%, 95% CI: 43.1-70.1%) was the most common electro-cardiac abnormality. The most common inflammatory marker was elevated C-reactive protein (89.8%, 95% CI: 77.7-95.7%). Abnormal echocardiogram was the most common imaging test result (commonly, ventricular dysfunction and arrhythmias), while steroids were the most administered treatment. Severe cases had a higher need for vasopressor and inotropic support and antibiotic therapy compared to the non-severe cases. One death was reported due to cardiovascular failure.
UNASSIGNED: Our collated findings will help clinicians identify the typical presenting symptoms and optimal management of MIS-A. Further research is required to understand the long-term prognosis and the correlation between coronavirus disease 2019 (COVID-19) and MIS-A to understand its pathogenesis and clinical spectrum.

UNASSIGNED: Multisystem inflammatory syndrome in adults (MIS-A) is a poorly understood complication of SARS-CoV-2 infection with significant morbidity and mortality.
UNASSIGNED: Identify clinical, immunological, and histopathologic features of MIS-A to improve understanding of the pathophysiology and approach to treatment.
UNASSIGNED: Three cases of MIS-A following SARS-CoV-2 infection were clinically identified between October 2021 - March 2022 using the U.S. Centers for Disease Control and Prevention diagnostic criteria. Clinical, laboratory, imaging, and tissue data were assessed.
UNASSIGNED: All three patients developed acute onset cardiogenic shock and demonstrated elevated inflammatory biomarkers at the time of hospital admission that resolved over time. One case co-occurred with new onset Type 1 diabetes and sepsis. Retrospective analysis of myocardial tissue from one case identified SARS-CoV-2 RNA. All three patients fully recovered with standard of care interventions plus immunomodulatory therapy that included intravenous immunoglobulin, corticosteroids, and in two cases, anakinra.
UNASSIGNED: MIS-A is a severe post-acute sequela of COVID-19 characterized by systemic elevation of inflammatory biomarkers. In this series of three cases, we find that although clinical courses and co-existent diseases vary, even severe presentations have potential for full recovery with prompt recognition and treatment. In addition to cardiogenic shock, glucose intolerance, unmasking of autoimmune disease, and sepsis can be features of MIS-A, and SARS-CoV-2 myocarditis can lead to a similar clinical syndrome.

The diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-associated multisystem inflammatory syndrome in adults (MIS-A) requires distinguishing it from acute coronavirus disease 2019 (COVID-19) and may affect clinical management.
In this retrospective cohort study, we applied the US Centers for Disease Control and Prevention case definition to identify adults hospitalized with MIS-A at 6 academic medical centers from 1 March 2020 to 31 December 2021. Patients MIS-A were matched by age group, sex, site, and admission date at a 1:2 ratio to patients hospitalized with acute symptomatic COVID-19. Conditional logistic regression was used to compare demographic characteristics, presenting symptoms, laboratory and imaging results, treatments administered, and outcomes between cohorts.
Through medical record review of 10 223 patients hospitalized with SARS-CoV-2-associated illness, we identified 53 MIS-A cases. Compared with 106 matched patients with COVID-19, those with MIS-A were more likely to be non-Hispanic black and less likely to be non-Hispanic white. They more likely had laboratory-confirmed COVID-19 ≥14 days before hospitalization, more likely had positive in-hospital SARS-CoV-2 serologic testing, and more often presented with gastrointestinal symptoms and chest pain. They were less likely to have underlying medical conditions and to present with cough and dyspnea. On admission, patients with MIS-A had higher neutrophil-to-lymphocyte ratio and higher levels of C-reactive protein, ferritin, procalcitonin, and D-dimer than patients with COVID-19. They also had longer hospitalization and more likely required intensive care admission, invasive mechanical ventilation, and vasopressors. The mortality rate was 6% in both cohorts.
Compared with patients with acute symptomatic COVID-19, adults with MIS-A more often manifest certain symptoms and laboratory findings early during hospitalization. These features may facilitate diagnosis and management.

Multisystem inflammatory syndrome in adults (MIS-A) is a life-threatening disease that can develop weeks after coronavirus disease 2019 (COVID-19). MIS-A symptoms include multiorgan involvement, especially gastrointestinal tract and heart involvement, and Kawasaki disease-like symptoms. We herein report a 44-year-old Japanese man with MIS-A who had contracted COVID-19 five weeks ago and went into shock after acute gastroenteritis, acute kidney injury, and Kawasaki disease-like symptoms. Methylprednisone pulse and high-dose intravenous immunoglobulin resulted in recovery of shock and his renal function, but diffuse ST-segment elevation on electrocardiography and pericardial effusion with a fever emerged after therapy. Additional granulocyte-monocyte adsorptive apheresis successfully ameliorated the cardiac involvement.

Each injection of any known vaccine results in a strong expression of pro-inflammatory cytokines. This is the result of the innate immune system activation, without which no adaptive response to the injection of vaccines is possible. Unfortunately, the degree of inflammation produced by COVID-19 mRNA vaccines is variable, probably depending on genetic background and previous immune experiences, which through epigenetic modifications could have made the innate immune system of each individual tolerant or reactive to subsequent immune stimulations.We hypothesize that we can move from a limited pro-inflammatory condition to conditions of increasing expression of pro-inflammatory cytokines that can culminate in multisystem hyperinflammatory syndromes following COVID-19 mRNA vaccines (MIS-V). We have graphically represented this idea in a hypothetical inflammatory pyramid (IP) and we have correlated the time factor to the degree of inflammation produced after the injection of vaccines. Furthermore, we have placed the clinical manifestations within this hypothetical IP, correlating them to the degree of inflammation produced. Surprisingly, excluding the possible presence of an early MIS-V, the time factor and the complexity of clinical manifestations are correlated to the increasing degree of inflammation: symptoms, heart disease and syndromes (MIS-V).

Multisystem inflammatory syndrome in adults (MIS-A) is a rare condition that can occur after an adult has been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It can occur anywhere between two and 12 weeks after the beginning of acute coronavirus disease 2019 (COVID-19) infection and is characterized by extrapulmonary multiorgan failure. It is primarily seen in young and previously healthy individuals. The exact prevalence of MIS-A is unclear. It is likely underdiagnosed due to overlapping symptoms with severe COVID-19 and difficulty in identifying the syndrome without a preceding COVID-19 infection. The pathogenesis of MIS-A is also largely unknown but is likely caused by an immune response that is dysregulated or antibody-mediated. Treatment primarily involves corticosteroids, but severe cases may require intravenous immune globulin (IVIG). The timing of starting corticosteroid therapy is crucial, as delays can result in increased complications and a longer hospital stay.