Severe COVID-19, multisystem inflammatory syndrome in children, and Kawasaki disease: immunological mechanisms, clinical manifestations and management

Abstract

Multisystem inflammatory syndrome (MIS-C) is a pediatric hyperinflammation disorder caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). It has now been reported from several countries the world over. Some of the clinical manifestations of MIS-C mimic Kawasaki disease (KD) shock syndrome. MIS-C develops 4-6 weeks following SARS-CoV-2 infection, and is presumably initiated by adaptive immune response. Though it has multisystem involvement, it is the cardiovascular manifestations that are most prominent. High titres of anti-SARS-CoV-2 antibodies are seen in these patients. As this is a new disease entity, its immunopathogenesis is not fully elucidated. Whether it has some overlap with KD is still unclear. Current treatment guidelines recommend use of intravenous immunoglobulin and high-dose corticosteroids as first-line treatment. Mortality rates of MIS-C are lower compared to adult forms of severe COVID-19 disease. Keywords Multisystem inflammatory syndrome (MIS-C) • Kawasaki disease (KD) • Hyperinflammation • Coronavirus disease 2019 • Kawasaki-like disease Background Kawasaki disease (KD) is a medium vessel vasculitis of undetermined etiology usually affecting children below 5 years [1-3]. Rowley et al. had hypothesized as far back as 2004 that an unidentified respiratory infectious agent with tropism to vascular tissue, likely a virus, could be linked to the etiology of KD [4]. This putative RNA virus, presumably a ubiquitous one, resulted in persistent infection in bronchial epithelium and macrophages and was associated with intracytoplasmic inclusions [5, 6]. Rheumatology INTERNATIONAL Jayakanthan Kabeerdoss and Rakesh Kumar Pilania are the joint first authors and they contributed equally. Disclaimer We hereby state that this manuscript is original and no part of the manuscript has either been published before, or is under consideration of publication elsewhere. The definition of scientific term alluded to, in the manuscript have been duly cited.

Public interest in musculoskeletal symptoms and disorders during the COVID-19 pandemic

“…As myalgia is among the common symptoms of COVID-19 [23,24], this observation was not unexpected. Furthermore, the increase in toe swelling was probably related to media coverage of chilblains associated with COVID-19, called as "COVID toe" [25][26][27]. In the second pandemic period, internet searches for toe swelling was not statistically significantly different compared to prior years, which might be due to that public accessed the information on this condition in the early pandemic and reduced their information intake after this period.…”

<strong>Long COVID, A Comprehensive Systematic Scoping Review</strong>

“…Predominantly in children and recently found few cases in adults, the SARS-COV-2 has resulted in a hyperinflammatory state called multisystem inflammatory syndrome (MIS), which was later divided into MIS in Children (MIS-C) and MIS in adults (MIS-A). The disease resembled acute rheumatic fever, toxic shock syndrome and Kawasaki disease that was misdiagnosed in the beginning (169)(170)(171); however, later, it was found to be a post-infectious state of the SARS-COV-2 primarily following 4-6 weeks after infection. In general, the syndrome may present with a combination of fever, abdominal pain, dermatologic manifestations, diarrhea, nausea, and organ failure (170).…”

“…The disease resembled acute rheumatic fever, toxic shock syndrome and Kawasaki disease that was misdiagnosed in the beginning (169)(170)(171); however, later, it was found to be a post-infectious state of the SARS-COV-2 primarily following 4-6 weeks after infection. In general, the syndrome may present with a combination of fever, abdominal pain, dermatologic manifestations, diarrhea, nausea, and organ failure (170). Among the presentation sign/symptoms, the cardiovascular symptoms are more prominent: up to 80% of the patients may have symptomatic myocarditis, 9-24% may present with coronary artery abnormalities and valvular regurgitation, pericarditis, and pericardial effusion (170).…”

“…In general, the syndrome may present with a combination of fever, abdominal pain, dermatologic manifestations, diarrhea, nausea, and organ failure (170). Among the presentation sign/symptoms, the cardiovascular symptoms are more prominent: up to 80% of the patients may have symptomatic myocarditis, 9-24% may present with coronary artery abnormalities and valvular regurgitation, pericarditis, and pericardial effusion (170). The prognosis and long-term complications of the MIS are currently unclear.…”

COVID-19: from an acute to chronic disease? Potential long-term health consequences

“…This is supported by the association of SARS-CoV-2 infection with cardiac complications and long-term follow-up studies of SARS-CoV-1 [39] and pneumonia [40] suggesting increased CVD risk. Interestingly, children infected with SARS-CoV-2 have been reported to have a syndrome resembling Kawasaki disease [50], which has subsequently been named as multisystem inflammatory syndrome in children (MIS-C) and has been reviewed in detail elsewhere [51][52][53][54][55]. Briefly, MIS-C often develops 4-6 weeks after SARS-CoV-2 infection and exhibits multisystem involvement with clinical features, including fever, a hyperinflammatory state, cutaneous manifestations, abdominal pain, diarrhea, vomiting, and organ dysfunction [52].…”