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A new multisystem inflammatory syndrome apparently related to infection with SARS-CoV-2 has recently been reported in older children (known as MIS-C), manifested by severe abdominal pain, cardiac dysfunction and shock. Here, I discuss the similarities and differences between MIS-C and Kawasaki disease, focusing on their epidemiology, aetiology and pathophysiological mechanisms.In this Comment, Anne Rowley discusses what we know so far about the recently described multisystem inflammatory syndrome in older children associated with SARS-CoV-2 infection and how it differs from Kawasaki disease.

Kawasaki disease is recognized as the most common cause of acquired heart disease in children in the developed world. Clinical, epidemiologic, and pathologic evidence supports an infectious agent, likely entering through the lung. Pathologic studies proposing an acute coronary arteritis followed by healing fail to account for the complex vasculopathy and clinical course. Specimens from 32 autopsies, 8 cardiac transplants, and an excised coronary aneurysm were studied by light (n=41) and transmission electron microscopy (n=7). Three characteristic vasculopathic processes were identified in coronary (CA) and non-coronary arteries: acute self-limited necrotizing arteritis (NA), subacute/chronic (SA/C) vasculitis, and luminal myofibroblastic proliferation (LMP). NA is a synchronous neutrophilic process of the endothelium, beginning and ending within the first two weeks of fever onset, and progressively destroying the wall into the adventitia causing saccular aneurysms, which can thrombose or rupture. SA/C vasculitis is an asynchronous process that can commence within the first two weeks onward, starting in the adventitia/perivascular tissue and variably inflaming/damaging the wall during progression to the lumen. Besides fusiform and saccular aneurysms that can thrombose, SA/C vasculitis likely causes the transition of medial and adventitial smooth muscle cells (SMC) into classic myofibroblasts, which combined with their matrix products and inflammation create progressive stenosing luminal lesions (SA/C-LMP). Remote LMP apparently results from circulating factors. Veins, pulmonary arteries, and aorta can develop subclinical SA/C vasculitis and SA/C-LMP, but not NA. The earliest death (day 10) had both CA SA/C vasculitis and SA/C-LMP, and an \"eosinophilic-type\" myocarditis. NA is the only self-limiting process of the three, is responsible for the earliest morbidity/mortality, and is consistent with acute viral infection. SA/C vasculitis can begin as early as NA, but can occur/persist for months to years; LMP causes progressive arterial stenosis and thrombosis and is composed of unique SMC-derived pathologic myofibroblasts.

Background Cardiac evaluations, including cardiovascular magnetic resonance (CMR) imaging and biomarker results, are needed in children during mid-term recovery after infection with SARS-CoV-2. The incidence of CMR abnormalities 1–3 months after recovery is over 50% in older adults and has ranged between 1 and 15% in college athletes. Abnormal cardiac biomarkers are common in adults, even during recovery. Methods We performed CMR imaging in a prospectively-recruited pediatric cohort recovered from COVID-19 and multisystem inflammatory syndrome in children (MIS-C). We obtained CMR data and serum biomarkers. We compared these results to age-matched control patients, imaged prior to the SARS-CoV-2 pandemic. Results CMR was performed in 17 children (13.9 years, all ≤ 18 years) and 29 age-matched control patients without SARS-CoV-2 infection. Cases were recruited with symptomatic COVID-19 (11/17, 65%) or MIS-C (6/17, 35%) and studied an average of 2 months after diagnosis. All COVID-19 patients had been symptomatic with fever (73%), vomiting/diarrhea (64%), or breathing difficulty (55%) during infection. Left ventricular and right ventricular ejection fractions were indistinguishable between cases and controls (p = 0.66 and 0.70, respectively). Mean native global T1, global T2 values and segmental T2 maximum values were also not statistically different from control patients (p ≥ 0.06 for each). NT-proBNP and troponin levels were normal in all children. Conclusions Children prospectively recruited following SARS-CoV-2 infection had normal CMR and cardiac biomarker evaluations during mid-term recovery. Trial Registration Not applicable.

Background Kawasaki Disease (KD) can cause potentially life-threatening coronary arteritis in young children, and has a likely infectious etiology. Transcriptome profiling is a powerful approach to investigate gene expression in diseased tissues. RNA sequencing of KD coronary arteries could elucidate the etiology and the host response, with the potential to improve KD diagnosis and/or treatment. Methods Deep RNA sequencing was performed on KD ( n  = 8) and childhood control ( n  = 7) coronary artery tissues, revealing 1074 differentially expressed mRNAs. Non-human RNA sequences were subjected to a microbial discovery bioinformatics platform, and microbial sequences were analyzed by Metastats for association with KD. Results T lymphocyte activation, antigen presentation, immunoglobulin production, and type I interferon response were significantly upregulated in KD arteritis, while the tumor necrosis factor α pathway was not differentially expressed. Transcripts from known infectious agents were not specifically associated with KD coronary arteritis. Conclusions The immune transcriptional profile in KD coronary artery tissues has features of an antiviral immune response such as activated cytotoxic T lymphocyte and type I interferon-induced gene upregulation. These results provide new insights into the pathogenesis of KD arteritis that can guide selection of new immunomodulatory therapies for high-risk KD patients, and provide direction for future etiologic studies.

Although Kawasaki disease (KD) is the most common cause of acquired heart disease in children in the developed world, its aetiology remains unknown. In this Opinion, Anne Rowley and colleagues discuss evidence, including recently identified cytoplasmic inclusion bodies, which suggests that KD is caused by an infectious agent. Kawasaki disease (KD) has emerged as the most common cause of acquired heart disease in children in the developed world. The cause of KD remains unknown, although an as-yet unidentified infectious agent might be responsible. By determining the causative agent, we can improve diagnosis, therapy and prevention of KD. Recently, identification of an antigen-driven IgA response that was directed at cytoplasmic inclusion bodies in KD tissues has provided new insights that could unlock the mysteries of KD.

order=\"0\" lang=\"eng\">When cases of severe acute respiratory syndrome coronavirus 2-associated multisystem inflammatory syndrome in children (MIS-C) were initially reported from Europe, the predominant clinical findings were persistent fever, marked abdominal symptoms, cytokine storm, myocardial dysfunction, and cardiogenic shock with left ventricular dysfunction in the setting of multisystem inflammation, reminiscent of toxic shock syndrome (TSS) or Kawasaki disease shock syndrome (KDSS) and requiring ICU care. Other clinical findings included those commonly observed in children with a variety of different infections and noninfectious illnesses, such as conjunctival injection, oral mucosal changes, and rash, features that are overlapping with TSS and incomplete Kawasaki disease. Because mucocutaneous findings are present in children with Kawasaki disease, and because patients with MIS-C sometimes developed mild coronary artery dilation, diagnostic confusion initially led some clinicians to conclude that the two conditions were the same. Here, Rowley et al discuss the importance of distinguishing MIS-C and Kawasaki disease.

Key Points Epidemiologic data strongly suggest an infectious aetiology for Kawasaki disease, which is the leading cause of acquired heart disease among children in developed countries Necrotizing arteritis, subacute chronic vasculitis, and luminal myofibroblastic proliferation are three linked processes underlying the arteriopathy associated with Kawasaki disease Genetic susceptibility is indicated by the strikingly high rate of Kawasaki disease in children of Asian ethnicity and by its increased incidence in first-degree relatives of affected patients Timely diagnosis and treatment of Kawasaki disease with intravenous immunoglobulin (IVIg) and aspirin substantially decreases the risk of developing coronary artery abnormalities Adjunctive therapy with corticosteroids is of value in Japanese patients at particularly high risk of coronary complications, but identification of such high-risk patients is difficult in ethnically diverse populations Management of patients who do not respond to standard therapy is challenging; options include pulsed steroids, additional IVIg, and infliximab or other immunomodulatory agents Considerable progress has been made in understanding the pathologic processes and pathophysiology of Kawasaki disease. This article also discusses genetic susceptibility to Kawasaki disease and describes current approaches to treatment of the acute stage of the disease. This Review summarizes recent advances in understanding of the pathologic processes and pathophysiologic mechanisms leading to coronary arteritis in Kawasaki disease, and describes current approaches to its treatment. Kawasaki disease is the most common cause of acquired heart disease among children in developed countries, in whom the resulting coronary artery abnormalities can cause myocardial ischaemia, infarction and even death. Epidemiologic data strongly suggest an infectious aetiology, although the causative agent has yet to be identified. Genetic factors also increase susceptibility to Kawasaki disease, as indicated by its strikingly high incidence rate in children of Asian ethnicity and by an increased incidence in first-degree family members. The treatment of Kawasaki disease is based on timely administration of intravenous immunoglobulin and aspirin. However, the management of patients who do not respond to this standard therapy remains challenging; although several options are available, comparative data on which to base treatment decisions are scarce. The added value of adjunctive therapy with corticosteroids in patients at particularly high risk of coronary complications has been demonstrated in Japanese populations, but identification of high-risk patients has proven to be difficult in ethnically diverse populations.

Kawasaki Disease (KD) is the most common cause of acquired heart disease in children in developed nations. The KD etiologic agent is unknown but likely to be a ubiquitous microbe that usually causes asymptomatic childhood infection, resulting in KD only in genetically susceptible individuals. KD synthetic antibodies made from prevalent IgA gene sequences in KD arterial tissue detect intracytoplasmic inclusion bodies (ICI) resembling viral ICI in acute KD but not control infant ciliated bronchial epithelium. The prevalence of ICI in late-stage KD fatalities and in older individuals with non-KD illness should be low, unless persistent infection is common. Lung tissue from late-stage KD fatalities and non-infant controls was examined by light microscopy for the presence of ICI. Nucleic acid stains and transmission electron microscopy (TEM) were performed on tissues that were strongly positive for ICI. ICI were present in ciliated bronchial epithelium in 6/7 (86%) late-stage KD fatalities and 7/27 (26%) controls ages 9-84 years (p = 0.01). Nucleic acid stains revealed RNA but not DNA within the ICI. ICI were also identified in lung macrophages in some KD cases. TEM of bronchial epithelium and macrophages from KD cases revealed finely granular homogeneous ICI. These findings are consistent with a previously unidentified, ubiquitous RNA virus that forms ICI and can result in persistent infection in bronchial epithelium and macrophages as the etiologic agent of KD.

The pathogenesis of coronary arterial inflammation in acute Kawasaki disease (KD) is unclear. To test the hypothesis that the KD vascular lesion is an activated T lymphocyte–dependent process, immunohistochemical studies were done on coronary artery aneurysms from 8 fatal acute KD cases by using antibodies to CD45RO (activated or memory T lymphocyte), CD8 (cytotoxic T lymphocyte), CD4 (helper T lymphocyte), HAM56 (macrophage), and CD20 (B lymphocyte). Acute KD coronary arteritis was characterized by transmural infiltration of CD45RO T lymphocytes with CD8 T lymphocytes predominating over CD4 T lymphocytes. Macrophages were present primarily in the adventitial layer; B lymphocytes were notably absent. These data lend support to the hypotheses that KD results from infection with an intracellular pathogen, such as a virus, whose antigens are presented by major histocompatibility complex class I molecules, and that CD8 T lymphocytes and macrophages are important in the pathogenesis of KD coronary aneurysms