key: cord-0897621-1fx7x8af
authors: Morris, Sapna Bamrah; Schwartz, Noah G.; Patel, Pragna; Abbo, Lilian; Beauchamps, Laura; Balan, Shuba; Lee, Ellen H.; Paneth-Pollak, Rachel; Geevarughese, Anita; Lash, Maura K.; Dorsinville, Marie S.; Ballen, Vennus; Eiras, Daniel P.; Newton-Cheh, Christopher; Smith, Emer; Robinson, Sara; Stogsdill, Patricia; Lim, Sarah; Fox, Sharon E.; Richardson, Gillian; Hand, Julie; Oliver, Nora T.; Kofman, Aaron; Bryant, Bobbi; Ende, Zachary; Datta, Deblina; Belay, Ermias; Godfred-Cato, Shana
title: Case Series of Multisystem Inflammatory Syndrome in Adults Associated with SARS-CoV-2 Infection — United Kingdom and United States, March–August 2020
date: 2020-10-09
journal: MMWR Morb Mortal Wkly Rep
DOI: 10.15585/mmwr.mm6940e1
sha: 54883ec590934cc093f31f3e4870a6bcd228093c
doc_id: 897621
cord_uid: 1fx7x8af

During the course of the coronavirus disease 2019 (COVID-19) pandemic, reports of a new multisystem inflammatory syndrome in children (MIS-C) have been increasing in Europe and the United States (1-3). Clinical features in children have varied but predominantly include shock, cardiac dysfunction, abdominal pain, and elevated inflammatory markers, including C-reactive protein (CRP), ferritin, D-dimer, and interleukin-6 (1). Since June 2020, several case reports have described a similar syndrome in adults; this review describes in detail nine patients reported to CDC, seven from published case reports, and summarizes the findings in 11 patients described in three case series in peer-reviewed journals (4-6). These 27 patients had cardiovascular, gastrointestinal, dermatologic, and neurologic symptoms without severe respiratory illness and concurrently received positive test results for SARS-CoV-2, the virus that causes COVID-19, by polymerase chain reaction (PCR) or antibody assays indicating recent infection. Reports of these patients highlight the recognition of an illness referred to here as multisystem inflammatory syndrome in adults (MIS-A), the heterogeneity of clinical signs and symptoms, and the role for antibody testing in identifying similar cases among adults. Clinicians and health departments should consider MIS-A in adults with compatible signs and symptoms. These patients might not have positive SARS-CoV-2 PCR or antigen test results, and antibody testing might be needed to confirm previous SARS-CoV-2 infection. Because of the temporal association between MIS-A and SARS-CoV-2 infections, interventions that prevent COVID-19 might prevent MIS-A. Further research is needed to understand the pathogenesis and long-term effects of this newly described condition.

On October 2, 2020, this report was posted as an MMWR Early Release on the MMWR website (https://www.cdc.gov/mmwr).

During the course of the coronavirus disease 2019 (COVID-19) pandemic, reports of a new multisystem inflammatory syndrome in children (MIS-C) have been increasing in Europe and the United States (1) (2) (3) . Clinical features in children have varied but predominantly include shock, cardiac dysfunction, abdominal pain, and elevated inflammatory markers, including C-reactive protein (CRP), ferritin, D-dimer, and interleukin-6 (1). Since June 2020, several case reports have described a similar syndrome in adults; this review describes in detail nine patients reported to CDC, seven from published case reports, and summarizes the findings in 11 patients described in three case series in peer-reviewed journals (4) (5) (6) . These 27 patients had cardiovascular, gastrointestinal, dermatologic, and neurologic symptoms without severe respiratory illness and concurrently received positive test results for SARS-CoV-2, the virus that causes COVID-19, by polymerase chain reaction (PCR) or antibody assays indicating recent infection. Reports of these patients highlight the recognition of an illness referred to here as multisystem inflammatory syndrome in adults (MIS-A), the heterogeneity of clinical signs and symptoms, and the role for antibody testing in identifying similar cases among adults. Clinicians and health departments should consider MIS-A in adults with compatible signs and symptoms. These patients might not have positive SARS-CoV-2 PCR or antigen test results, and antibody testing might be needed to confirm previous SARS-CoV-2 infection. Because of the temporal association between MIS-A and SARS-CoV-2 infections interventions that prevent COVID-19 might prevent MIS-A. Further research is needed to understand the pathogenesis and long-term effects of this newly described condition.

Potential MIS-A patients were identified from several sources: reports from clinicians and health departments, published case reports, and published case series. Clinicians and health departments in the United States voluntarily reported adult patients with suspected MIS-A to CDC using the case report form* developed for MIS-C after a Health Advisory was published on May 14, 2020, calling for reporting of MIS-C cases. The case report form included information on patient demographics, underlying medical conditions, clinical findings, complications, laboratory test results including those from SARS-CoV-2 testing, imaging findings, treatments, and outcomes. Two clinician reviewers selected patients who fulfilled the working MIS-A case definition used in this report, which included the following five criteria: 1) a severe illness requiring hospitalization in a person aged ≥21 years; 2) a positive test result for current or previous SARS-CoV-2 infection (nucleic acid, antigen, or antibody) during admission or in the previous 12 weeks; 3) severe dysfunction of one or more extrapulmonary organ systems (e.g., hypotension or shock, cardiac dysfunction, arterial or venous thrombosis or thromboembolism, or acute liver injury); 4) laboratory evidence of severe inflammation (e.g., elevated CRP, ferritin, D-dimer, or interleukin-6); and 5) absence of severe respiratory illness (to exclude patients in which inflammation and organ dysfunction might be attributable simply to tissue hypoxia). Patients with mild respiratory symptoms who met these criteria were included. Patients were excluded if alternative diagnoses such as bacterial sepsis were identified.

To identify potential published cases, a literature search was performed on August 20, 2020, and 355 publications were identified. † Abstracts were screened by one reviewer to determine whether cases met the working MIS-A case definition; when no abstract was available, the full paper was examined. The references were reviewed to identify additional relevant articles. Data were obtained from published reports; authors were contacted to confirm published data and, when necessary, to provide data not included in the original articles.

Demographic characteristics and underlying conditions. Cases in nine patients reported to CDC (Table 1) and seven  published case reports (Table 2) , originating from seven U.S. jurisdictions and the United Kingdom, met the working case definition. The 16 patients ranged in age from 21 to 50 years and included seven men and nine women. Five were reported as Hispanic, nine as African American, one as Asian, and one as a United Kingdom-born man of African ethnicity. Nine patients had no reported underlying medical conditions; six were obese, one had poorly controlled diabetes mellitus type 2 (hemoglobin A1C >9.0%), two had hypertension, and one had obstructive sleep apnea. Eight patients had documented respiratory illness before developing symptoms of MIS-A, and eight did not.

Initial signs and symptoms. Twelve of 16 patients had fever (≥100.4°F [38.0°C] for ≥24 hours or report of subjective fever lasting ≥24 hours) at the time of presentation. Six patients were initially evaluated for possible cardiac symptoms such as chest pain or palpitations; all 16 had evidence of cardiac effects, including electrocardiogram abnormalities such as arrhythmias, elevated troponin levels, or echocardiographic evidence of left or right ventricular dysfunction. Thirteen patients had gastrointestinal symptoms on admission; five had dermatologic manifestations on admission, including three with mucositis. Despite minimal respiratory symptoms, 10 patients had pulmonary ground glass opacities, and six had pleural effusions identified on chest imaging.

Inflammatory markers. All patients had markedly elevated laboratory markers of inflammation, including CRP (range of peak values = 84-580 mg/L; upper limit of normal [ULN] = 10 mg/L) and ferritin (196 to >100,000 ng/mL; ULN = 150 ng/mL for women, 300 ng/mL for men), as well as markers of coagulopathy including D-dimer (275-8691 ng/mL; ULN = 500 ng/mL). Ten patients had absolute lymphocyte counts lower than normal range (range of nadir values 120-2120 cells/µL; lower limit of normal = 1000 cells/µL).

SARS-CoV-2 test results. Ten patients received positive SARS-CoV-2 PCR test results at the time of initial assessment for MIS-A, seven of whom also had serologic evidence of infection (positive antibody test results) at that time. Six patients received negative SARS-CoV-2 PCR test results; of those, four had positive anti-SARS-CoV-2 antibody test results when first evaluated. Two patients had positive SARS-CoV-2 PCR test results 14 and 37 days before admission, negative PCR results at the time of admission, and no known antibody testing. Three additional patients had positive SARS-CoV-2 PCR test results 25-41 days before admission and continued positive PCR test results at the time of admission.

Treatment. Seven patients were treated with intravenous immunoglobulin, 10 with corticosteroids, and two with the interleukin-6 inhibitor, tocilizumab. Ten patients required intensive care; seven required inotropes or vasopressors, and one required mechanical circulatory support (extracorporeal membrane oxygenation followed by temporary left and right ventricular assist devices). Three patients required endotracheal intubation and mechanical ventilation, and two patients died.

Three published case series were identified describing adult patients with manifestations consistent with MIS-A (4-6). One series describes seven previously healthy, young adult men aged 20-42 years who experienced mixed cardiogenic and vasoplegic shock and hyperinflammation along with high SARS-CoV-2 immunoglobulin G antibody titers indicating active or previous infection (4) . Two of the patients identified as African American, two as Hispanic, two as Middle Eastern, and one as White. Four of the seven patients had negative PCR test results for SARS-CoV-2 at the time of admission, all had markedly elevated inflammatory markers and required inotropes or vasopressors, and three required intraaortic balloon pumps. All were treated with corticosteroids and therapeutic anticoagulation. All seven patients recovered and were discharged home after 7 to 18 days of hospitalization with improved cardiovascular function.

A second case series describes two patients aged 21 and 50 years who came to medical attention because of large-vessel strokes associated with positive SARS-CoV-2 tests (5). Information on race/ethnicity of these patients was not reported. These patients had elevated inflammatory markers and minimal respiratory symptoms, consistent with MIS-A. The authors proposed endothelial dysfunction and coagulopathy related to SARS-CoV-2 infection as potential etiologies. Incidence of large-vessel stroke among young adults during this same time the previous year was statistically significantly lower (5) .

A third case series describes the pathologic findings of endothelialitis and complement deposition in the vessels of two patients with illness resembling MIS-A (cardiac dysfunction, abdominal signs and symptoms, and rash) associated with positive SARS-CoV-2 test results (6) . Information on race/ ethnicity of these patients was not reported. One of these two patients had no underlying medical conditions and recovered; the other had multiple underlying conditions at higher risk for severe COVID-19 and died hours after seeking care. Pathologic findings in this case series were similar to autopsy findings for those of patient 14 (Table 2) . 

Findings indicate that adult patients of all ages with current or previous SARS-CoV-2 infection can develop a hyperinflammatory syndrome resembling MIS-C. Although hyperinflammation and extrapulmonary organ dysfunction have been described in hospitalized adults with severe COVID-19, these conditions are generally accompanied by respiratory failure (7) . In contrast, the patients described here had minimal respiratory symptoms, hypoxemia, or radiographic abnormalities in accordance with the working case definition, which was meant to distinguish MIS-A from severe COVID-19; only eight of 16 patients had any documented respiratory symptoms before onset of MIS-A.

The pathophysiology of MIS in both children and adults is currently unknown. Eight of 27 (30%) adults described in this report and 45% of 440 children with MIS-C reported to CDC through July 29, 2020, (1) had negative PCR and positive SARS-CoV-2 antibody test results, suggesting MIS-A and MIS-C might represent postinfectious processes. However, in some patients, persistent infection outside the upper respiratory tract is possible; SARS-CoV-2 has been identified in US Department of Health and Human Services/Centers for Disease Control and Prevention 

multiple organs including the heart, liver, brain, kidneys, and gastrointestinal tract (7) . Additional proposed mechanisms for extrapulmonary dysfunction in COVID-19 include endothelial damage and thromboinflammation, dysregulated immune responses, and dysregulation of the renin-angiotensinaldosterone system (7) . The interval between infection and development of MIS-A is unclear, adding to uncertainty regarding whether MIS-A represents a manifestation of acute infection or an entirely postacute phenomenon. In patients with COVID-19, dyspnea is typically experienced a median of 5-8 days and critical illness 10-12 days after onset of symptoms. § In patients who reported typical COVID-19 symptoms before MIS-A onset, MIS-A was experienced approximately 2-5 weeks later. However, eight MIS-A patients reported no preceding respiratory symptoms, making it difficult to estimate when initial infection occurred.

Given the high proportion of MIS-C patients with negative PCR testing, clinical guidelines recommend the use of both antibody and viral testing to assist with diagnosis (8) (9) (10) . In patients with atypical or late manifestations of SARS-CoV-2 infection, including MIS-A, positive antibody results might be crucial to augment clinical recognition of this condition and guide treatment. In addition, the use of a panel of laboratory tests for inflammation, hypercoagulability, and organ damage (e.g., CRP, ferritin, D-dimer, cardiac enzymes, liver enzymes, and creatinine) might assist in the early identification and management of this COVID-19-associated condition.

All but one of the patients with MIS-A described in this report belonged to racial or ethnic minority groups. Longstanding health and social inequities have resulted in increased risk for infection and severe outcomes from COVID-19 in communities of color. ¶ MIS-C has also been reported disproportionately in these communities (1). Because patients described in this review represent a convenience sample from a small number of jurisdictions, conclusions cannot be made regarding the true burden or determinants of MIS-A in different groups; further research is needed. § https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidancemanagement-patients.html. ¶ https://www.cdc.gov/coronavirus/2019-ncov/community/health-equity/raceethnicity.html. The majority (24 of 27) of patients with MIS-A survived, similar to those with MIS-C, associated with receiving care in acute, often intensive, health care settings. Because of the potential therapies that might benefit these patients as described in these case reports, clinicians should consider MIS-A within a broader differential diagnosis when caring for adult patients with clinical and laboratory findings consistent with the working MIS-A case definition.

The findings in this report are subject to at least three limitations. First, cases described here were voluntarily reported or published and therefore are not representative of the true clinical spectrum or racial/ethnic distribution of this emerging Clinicians and health departments should consider MIS-A in adults with signs and symptoms compatible with the current working MIS-A case definition. Antibody testing for SARS-CoV-2 might be needed to confirm previous COVID-19 infection in patients who do not have positive SARS-CoV-2 PCR or antigen test results. Findings in this convenience sample emphasize the importance of collecting race/ethnicity data on case reports at the jurisdictional level. As with children, it is important that multidisciplinary care be considered to ensure optimal treatment. In the process of learning more

What is already known about this topic?

Multisystem inflammatory syndrome in children (MIS-C) is a rare but severe complication of SARS-CoV-2 infection in children and adolescents. Since June 2020, several case reports and series have been published reporting a similar multisystem inflammatory syndrome in adults (MIS-A).

What is added by this report?

Cases reported to CDC and published case reports and series identify MIS-A in adults, who usually require intensive care and can have fatal outcomes. Antibody testing was required to identify SARS-CoV-2 infection in approximately one third of 27 cases.

What are the implications for public health practice?

Clinical suspicion and indicated SARS-CoV-2 testing, including antibody testing, might be needed to recognize and treat adults with MIS-A. Further research is needed to understand the pathogenesis and long-term effects of this condition. Ultimately, the recognition of MIS-A reinforces the need for prevention efforts to limit spread of SARS-CoV-2.

from MIS-A cases, the working case definition might need to be revised in order to systematically conduct a call for cases. Further research is needed to understand the pathogenesis and long-term effects of this newly described condition. Ultimately, the recognition of MIS-A reinforces the need for prevention efforts to limit spread of SARS-CoV-2.

CDC COVID-19 Response Team; 2 Epidemic Intelligence

Maine Center for Disease Control and Prevention

Minnesota Department of Health; 11 Lousiana State University Health Sciences Center

Oak Ridge Institute for Science and Education

California MIS-C Response Team. COVID-19-associated multisystem inflammatory syndrome in children-United States

SARS-CoV-2-related paediatric inflammatory multisystem syndrome, an epidemiological study

Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2

Cardiogenic shock and hyperinflammatory syndrome in young males with COVID-19. Circ Heart Fail

Large-vessel stroke as a presenting feature of Covid-19 in the young

Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases

Extrapulmonary manifestations of COVID-19

American College of Rheumatology clinical guidance for pediatric patients with multisystem inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2 and hyperinflammation in COVID-19. version 1

Infectious Diseases Society of America guidelines on the diagnosis of COVID-19: serologic testing

Information for healthcare providers about multisystem inflammatory syndrome in children (MIS-C)

All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Lilian Abbo reports personal fees from Pfizer, Merck/MSD, Nabriva Therapeutics, Roche Diagnostics, Paratek, and Achaogen, outside the submitted work. Sharon E. Fox reports personal fees from Boehringer Ingelheim, outside the submitted work. Christopher Newton-Cheh reports grants from the National Institutes of Health, and personal fees from GE Healthcare, and Novartis, outside the submitted work. No other potential conflicts of interest were disclosed.