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.
1. Parasher A, COVID-19: Current understanding of its pathophysiology, clinical presentation and treatment: Postgrad Med J, 2021; 97(1147); 312-20
2. Nature News, COVID research: a year of scientific milestones: Nature May 5, 2021; 2021, doi: 10.1038/d41586-020-00502-w Epub ahead of print. Available from: https://www.nature.com/articles/d41586-020-00502-w
3. Siemieniuk RA, Bartoszko JJ, Ge L, Drug treatments for COVID-19: living systematic review and network meta-analysis: BMJ, 2020; 370; m2980
4. Malone B, Campbell EA, Molnupiravir: Coding for catastrophe: Nat Struct Mol Biol, 2021; 28(9); 706-8
5. Li X, Zhong X, Wang Y, Clinical determinants of the severity of COVID-19: A systematic review and meta-analysis: PLoS One, 2021; 16(5); e0250602
6. National Institutes of Health (NIH), COVID-19 treatment guidelines: Clinical spectrum of SARS-CoV-2 infection, 2021 Available from: https://www.covid19treatmentguidelines.nih.gov/overview/clinical-spectrum/
7. Weatherhead JE, Clark E, Vogel TP, Inflammatory syndromes associated with SARS-CoV-2 infection: dysregulation of the immune response across the age spectrum: J Clin Invest, 2020; 130(12); 6194-97
8. Choudhary S, Sharma K, Silakari O, The interplay between inflammatory pathways and COVID-19: A critical review on pathogenesis and therapeutic options: Microb Pathog, 2021; 150; 104673
9. Webb BJ, Peltan ID, Jensen P, Clinical criteria for COVID-19-associated hyperinflammatory syndrome: A cohort study: Lancet Rheumatol, 2020; 2(12); e754-63
10. Parums DV, Editorial: Long COVID, or post-COVID syndrome, and the global impact on health care: Med Sci Monit, 2021; 27; e933446
11. Parums DV, Editorial: COVID-19 and multisystem inflammatory syndrome in children (MIS-C): Med Sci Monit, 2021; 27; e933369
12. Morris SB, Schwartz NG, Patel P, Case series of multisystem inflammatory syndrome in adults associated with SARS-CoV-2 infection – United Kingdom and United States, March–August 2020: MMWR Morb Mortal Wkly Rep, 2020; 69(40); 1450-56
13. Davogustto GE, Clark DE, Hardison E, Characteristics associated with multisystem inflammatory syndrome among adults with SARS-CoV-2 infection: JAMA Netw Open, 2021; 4(5); e2110323
14. Dufort EM, Koumans EH, Chow EJNew York State and Centers for Disease Control and Prevention Multisystem Inflammatory Syndrome in Children Investigation Team, Multisystem inflammatory syndrome in children in New York State: N Engl J Med, 2020; 383(4); 347-58
15. Patel P, DeCuir J, Abrams J, Clinical characteristics of multisystem inflammatory syndrome in adults: A systematic review: JAMA Netw Open, 2021; 4(9); e2126456
16. Chow EJ, The multisystem inflammatory syndrome in adults with SARS-CoV-2 infection – another piece of an expanding puzzle: JAMA Netw Open, 2021; 4(5); e2110344
17. Hanson KE, Caliendo AM, Arias CA: Infectious Diseases Society of America guidelines on the diagnosis of COVID-19: Serologic testing, Infectious Diseases Society of America (IDSA) Available from: https://www.idsociety.org/practice-guideline/covid-19-guideline-serology/
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