11 October 2021: Editorial
Med Sci Monit 2021; 27:e935005
ABSTRACT: Recent studies on the pathogenesis and clinical spectrum of human disease following infection with the new human pathogen, SARS-CoV-2, have identified the varied presentations and sequelae of COVID-19. Acute ‘cytokine storm’ in severe COVID-19 results in multiorgan damage due to vascular hyperpermeability, edema, and hypercoagulation. The long-term consequences of infection from SARS-CoV-2 include long COVID. or post-COVID syndrome, and multisystem inflammatory syndrome in children (MIS-C). Several case reports of multisystem inflammatory syndrome in adults (MIS-A) have shown the presentation at more than four weeks after initial infection with SARS-CoV-2 in adults more than 21 years of age. In September 2021, a published systematic review of the literature identified 221 patients with MIS-A, representing the most comprehensive clinical study to date. MIS-A occurs in the post-acute COVID-19 period. The pathogenesis may involve a dysregulated antibody-mediated immune response, similar to MIS-C. Therefore, patients with MIS-A may respond to supportive therapies that control hyperinflammation. This Editorial aims to describe MIS-A and discuss COVID-19 as a spectrum of hyperinflammatory disease in terms of severity, extent, duration, and patient age.
Keywords: Editorial, Multisystem Inflammatory Disease, Adults, MIS-A, SARS-CoV-2, COVID-19, COVID-19, cytokine release syndrome, Humans, Systemic Inflammatory Response Syndrome
Recent studies on the pathogenesis and clinical spectrum of human disease following infection with the new human pathogen, SARS-CoV-2, have begun to identify and define the varied presentations and sequelae of COVID-19 [1,2]. Understanding the mechanisms of diseases such as COVID-19 is the basis for diagnosis and prevention [1,2]. Ongoing studies based on current knowledge of the pathogenesis of COVID-19 underpin the development of new approaches to treatment, including antiviral agents and anti-inflammatory agents [3,4]. Some patients with COVID-19 are asymptomatic, some have a moderate or severe respiratory illness, and some require hospitalization and ventilatory support . The classification of disease severity and the risk factors for developing severe COVID-19 have been studied to identify clinical risk factors for disease severity, hospitalization, and mortality [5,6]. However, there is a range of systemic and organ-specific inflammatory events associated with SARS-CoV-2 infection in different age groups and at different stages of infection that remains, as yet, both enigmatic and unpredictable [7,8].
Patients with severe acute COVID-19 pneumonia may develop ‘cytokine storm,’ or activation of the innate immune response, including inflammatory signaling pathways and cytokines . The ‘cytokine storm’ results in acute respiratory distress syndrome (ARDS) and is also associated with the downregulation of angiotensin-converting enzyme 2 (ACE2), which results in dysfunction of the renin-angiotensin system (RAS) . The acute ‘cytokine storm’ that occurs in patients with severe COVID-19 results in multiorgan damage due to vascular hyperpermeability, edema, and hypercoagulation [8,9].
The long-term consequences of infection from SARS-CoV-2 include long COVID. or post-COVID syndrome, and multisystem inflammatory syndrome in children (MIS-C) [10,11]. Long COVID occurs in between 10% and 30% of adult patients who recover from initial acute infection with SARS-CoV-2 . Long COVID includes pulmonary, hematologic, cardiovascular, renal, neuropsychiatric, renal, hepatobiliary, gastrointestinal, and dermatologic clinical complications . MIS-C was first identified in April 2020 and is also a form of long COVID in children and adolescents . The US Centers for Disease Control and Surveillance (CDC) criteria for the diagnosis of MIS-C include age <21 years and a clinical presentation requiring hospitalization, and positive laboratory for current or recent SARS-CoV-2 infection, or SARS-CoV-2 exposure, within the past four weeks . Both long COVID in adults and MIS-C in children may be due to the systemic effects of inflammatory tissue damage [10,11].
Recently, there has been further clinical support that the pathogenesis of COVID-19 involves a spectrum of mild and severe, acute and chronic, respiratory and multisystem inflammatory syndromes that affect all age groups [13–15]. Multisystem inflammatory syndrome in adults (MIS-A) has recently been described [12–15]. MIS-A presents more than four weeks after initial infection with SARS-CoV-2 in young adults more than 21 years of age [12–15]. Although there have been several case reports of MIS-A in young adults, it was not until August 2021 that Davogustto and colleagues described 15 adult patients with MIS-A who had a recent infection with SARS-CoV-2, confirmed by laboratory testing . This study compared patients with MIS-A with young adult patients presenting with acute COVID-19 . Compared with acute SARS-positive patients with acute COVID-19, patients with MIS-A were younger and had positive SARS-CoV-2 serology, and 33.3% required admission to the intensive care (ICU) . As with cases of MIS-C, none of the cases of MIS-A were fatal . These investigators noted an overlap between the symptoms of acute COVID-19 and MIS-A in 60% of cases studied .
Currently, there are several unknowns regarding the diagnosis and pathogenesis of MIS-A. The clinical overlap between MIS-A and acute COVID-19 is likely to make it difficult to diagnose. This diagnostic difficulty is less likely in children who mainly have an asymptomatic infection or mild COVID-19 symptoms before presenting with symptomatic MIS-C [11,13,15]. Also, there may be a diversity of individual and age-related phenotypes for MIS-A [13,15]. Children with MIS-C in younger cohorts more commonly present with mucocutaneous symptoms and signs [11,14]. Children in older cohorts present with gastrointestinal symptoms and myocarditis [11,14].
A systematic review of the literature on reported cases and studies, published in September 2021, represents the most comprehensive clinical information in MIS-A to date . Patel and colleagues reviewed 221 patients with MIS-A from the published literature and cases reported to the US Centers for Disease Control and Prevention (CDC) between May 2020 to May 2021 . The review identified 221 patients with MIS-A worldwide . Patients presented with MIS-A approximately four weeks after an initial diagnosis of acute COVID-19 . The median age of the 221 patients with MIS-A was 21 years (range, 19–34 years), 70% were men, 58% had no underlying comorbidity, and 68% reported a previous symptomatic COVID-19-like illness at a median of 28 days previously . The main presenting symptoms of MIS-A were fever (96%), hypotension (60%), cardiac dysfunction (54%), shortness of breath (52%), and diarrhea (52%) . This review showed that in patients with MIS-A, the median number of organ systems involved was five, the median hospital stay was 8 days (range, 5–12 days) . Also, 57% of patients were admitted to the ICU, 47% required respiratory support, and 7% of patients with MIS-A died following hospital admission . Most patients with MIS-A [90%) had increased coagulopathy or inflammatory markers, and 72% had a positive serological test for SARS-CoV-2 . The authors concluded that MIS-A with extrapulmonary multiorgan involvement was difficult to discern from both acute biphasic COVID-19 and post-acute sequelae of SARS-CoV-2 infection . The findings from this review supported that MIS-A is a post-acute COVID-19 syndrome with a heterogeneous clinical presentation due to a dysregulated immune response [15,16]. Also, identifying post-acute COVID-19 syndromes, including MIS-C and MIS-A, highlights the importance of accurate serological testing for SARS-CoV antibodies .
Currently, there are insufficient studies on patients with MIS-A to identify different clinical presentations of MIS-A with age. Currently, there is no evidence to support the optimal treatment strategy for MIS-A, which is likely to require symptomatic or supportive care. Children with MIS-C are treated with intravenous immunoglobulin (IVIG) and glucocorticoids [11,14]. However, there is no evidence to support whether these treatments will be effective in patients with MIS-A.
There remain many questions regarding the presentation, pathogenesis, and outcome of MIS-A. Until more is known about the clinical presentation of MIS-A and its diagnosis, future cases are likely to be unrecognized. Because cases of MIS-A occur in the post-acute COVID-19 period, the pathogenesis may involve a dysregulated antibody-mediated immune response, similar to MIS-C. Therefore, patients with MIS-A may respond to supportive therapies that control hyperinflammation. Although the incidence of MIS-A is unknown, as with MIS-C in children, MIS-A is likely to be an uncommon complication of SARS-CoV-2 infection in adults.
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