Multisystem Inflammatory Syndrome in Adults (MIS-A)

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Multisystem Inflammatory Syndrome in Adults (MIS-A)

Last reviewed: June 24, 2022  

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The following is a curated review of key information and literature about this topic. It is not comprehensive of all data related to this subject.

Overview  

Multisystem inflammatory syndrome is a rare but severe complication of SARS-CoV-2 that can occur around 2-12 weeks after the initial infection (Ahmad, May 2021). It was initially characterized in children (MIS-C) but later reported in adults (MIS-A) (Morris, October 2020).

CDC has developed a working case definition for MIS-A, which broadly includes:

  • Age 21 years or older;
  • Presence of a severe illness requiring hospitalization >24 hours or illness resulting in death, which meets the following clinical and laboratory criteria:
    • Clinical criteria:
      • Subjective fever or documented fever (≥38.0 °C) for ≥24 hours prior to hospitalization or within the first THREE days of hospitalization PLUS
      • At least THREE of the following clinical criteria occurring prior to hospitalization or within the first THREE days of hospitalization. At least ONE must be a primary clinical criterion:
        • Primary clinical criteria:
          • Severe cardiac illness
          • Rash AND non-purulent conjunctivitis
        • Secondary clinical criteria:
          • New-onset neurologic signs and symptoms
          • Shock or hypotension not attributable to medical therapy
          • Abdominal pain, vomiting or diarrhea
          • Thrombocytopenia
    • Laboratory criteria:
      • Recent positive test result for SARS-CoV-2 infection (PCR, antigen or antibody)
      • Elevated levels of at least TWO of the following: C-reactive protein, ferritin, IL-6, erythrocyte sedimentation rate, procalcitonin

The patient should not have a more likely alternative diagnosis for the illness (e.g., bacterial sepsis, exacerbation of a chronic medical condition). As more data about MIS-A emerge, this working case definition may be revised. 

Several case reports and series of MIS-A have been published (Chau, August 2020Magro, April 2020Oxley, April 2020). MIS-A is characterized by fever, elevated inflammatory markers, and multiple organ system involvement (usually cardiovascular and gastrointestinal manifestations). These cases series also illustrate that previous COVID-19 infection may be asymptomatic (Bastug, March 2021; Morris, October 2020). Diagnosis is particularly challenging in patients where symptoms of MIS-A overlap with those of severe COVID-19 (Davogustto, May 2021). In cases without a previously known SARS-COV-2 diagnosis, a positive serology result is required to fulfill the case definition of MIS-A, but testing has a minimal prognostic or diagnostic role due to various limiting factors (Bastug, March 2021; Hékimian, September 2020).

There are several unanswered questions related to MIS-A. The true incidence of MIS-A is not known. MIS-A is likely underdiagnosed due to overlapping symptoms with severe COVID-19, especially in patients with several comorbidities. The pathophysiology of MIS-A is also poorly understood, though it is likely due to an antibody-mediated process or dysregulated immune response. Whether MIS-A is post-infectious or antibody-mediated could have implications for vaccine safety (Tenforde, December, 2020). Additionally, there may be different presentations of MIS-A across different age groups, similar to MIS-C (Dufort, July 2020).

Guidelines  

NIH guidelines "extrapolate from MIS-C data to aid in the management of individuals with MIS-A," but emphasize "that this approach to managing MIS-A has not been studied." For now, steroids, IVIG and supportive care treatments have been suggested in the literature for MIS-A (Ahmad, May 2021; Davogustto, May 2021).

Based on current knowledge, CDC recommends COVID-19 vaccination as the best protection from MIS-A. However, there are no data on the safety and efficacy of COVID-19 vaccines in people with a history of MIS-C or MIS-A (CDC Interim Clinical Considerations for Use of COVID-19 Vaccines).

 

Key Literature  

In summary: MIS-A is a rare but important syndrome that can be difficult to distinguish from severe COVID-19, particularly in older patients with cardiac and other comorbidities. Although MIS-A may be underdiagnosed, it is reported at a much lower frequency than MIS-C. However, the evidence for MIS-A is slowly increasing.

Multisystem Inflammatory Syndrome in Adults After Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection and Coronavirus Disease 2019 (COVID-19) Vaccination (Belay, November 2021).

Study population:

  • 20 patients who met the case definition for MIS-A.
  • Median age was 35 years (range, 21-66 years), and 65% were male.
  • All patients had laboratory evidence of SARS-CoV-2 infection; 80% had a preceding COVID-19-like illness around 4 weeks before MIS-A onset.
  • Seven MIS-A patients (35%) received COVID-19 vaccine between 6 and 45 days before MIS-A onset.

Key findings:

  • Patients with MIS-A predominantly had gastrointestinal and cardiac manifestations and hypotension or shock.
  • Though there was temporal association of a few MIS-A cases with COVID-19 vaccination, all patients reported to date had evidence of prior SARS-CoV-2 infection.
  • The potential contribution of vaccination to the pathogenesis of MIS-A in these patients is unclear.
  • However, to date, no cases of MIS-A have been reported among vaccinated persons without evidence of prior SARS-CoV-2 infection despite the administration of COVID-19 vaccines to millions of recipients.

Limitations:

  • Possible underreporting as cases only reported by health departments.
  • Complications such as myocarditis were diagnosed by clinicians managing the patients.
  • Limited assessment due to absence of imaging data.

Clinical Characteristics of Multisystem Inflammatory Syndrome in Adults: A Systematic Review (Patel, September 2021).

These findings suggest that MIS-A is a serious hyperinflammatory condition in adults that presents with extrapulmonary multiorgan dysfunction approximately 4 weeks after onset of acute COVID-19 infection.

Study population:

  • 219 patients with data available; 70% were men.
  • Patients’ median age was 21. 
  • Black and Hispanic patients also made up a higher proportion of cases. 
  • Most patients who developed MIS-A had no underlying comorbidity.
  • 57% were admitted to the intensive care unit; 7% died. 

Key findings:

  • The syndrome typically developed about 4 weeks after a COVID-19 infection. 
  • The symptoms included fever, low blood pressure, cardiac dysfunction, shortness of breath and diarrhea.
  • The median number of organ systems involved was five. 
  • Treatment of MIS-A included anticoagulants, corticosteroids, IVIG and immune modulators.
  • Patients with MIS-A (compared to MIS-C) were more likely to report a previous COVID-19 infection and to present with myocarditis, cardiac dysfunction, arterial thrombosis, pulmonary embolism or deep venous thrombosis. Patients with MIS-C were more likely to have dermatologic and mucocutaneous manifestations.
  • The findings suggest that MIS-A can be more severe than MIS-C, with longer hospital stays and a more frequent need for ventilation. 

Limitations:

  • Descriptive study, combines data from many sources.
  • Using data from the MIS-C surveillance system may have contributed to selection bias.
  • Inability to report specifics of SARS-CoV-2 testing.

Characteristics Associated with Multisystem Inflammatory Syndrome Among Adults With SARS-CoV-2 Infection (Davogustto, May 2021).  

Overall, in this single-center retrospective cohort study, patients with MIS-A exhibited a heterogenous presentation. MIS-A is commonly underdiagnosed due to presence of overlapping symptoms with acute severe COVID-19 infection.  

Study population: 

  • Single-center, retrospective cohort study of 7,196 patients with SARS-CoV-2 infection by RT-PCR or serologic testing. 
  • Inclusion criteria: All adults 21 years or older with a positive SARS-CoV-2 test result and a subsequent admission 14 and 84 days after positive PCR result or 15 days before or after positive serology result. 

Primary endpoint: 

Key findings: 

  • 15 of 698 patients analyzed met criteria for MIS-A. 
  • The median interval between acute COVID-19 admission and MIS-A admission was 23 days. 
  • At least 4 organ systems were most commonly affected, including gastrointestinal, hematologic and renal systems. 
  • Among the MIS-A group, 33.3% required intensive care unit admission and 20% were diagnosed with shock.  
  • None of the 15 patients died in the hospital, similar to what was seen in cases of MIS-C. 
  • Patients with MIS-A were significantly younger (45.1 vs 56.5 years) and more likely to have detectable SARS-CoV-2 serology (9 vs none), compared to those with acute COVID-19. 

Limitations: 

  • Single center study limits generalizability. 
  • Overlapping symptoms of acute COVID-19 and MIS-A make differentiating the two diagnoses difficult.  
  • Data likely underestimate the incidence of MIS-A. It is likely that among those diagnosed with severe COVID-19, some were cases of MIS-A.

Coronavirus Disease 2019 Acute Myocarditis and Multisystem Inflammatory Syndrome in Adult Intensive and Cardiac Care Units (Hékimian, September 2020).

Overall, this case series describes the clinical presentation, characteristics and management of patients over 16 years of age with COVID-19 who were admitted for suspected acute or fulminant myocarditis and MIS-A.

Study population:

  • Case series of 20 patients admitted for clinically suspected acute or fulminant myocarditis.
  • 11 patients had a confirmed positive PCR or serology test result for SARS-CoV-2.
  • Age between 16 and 40 years; five were women, and none had severe comorbidities.

Primary endpoint:

  • Patients with clinically suspected acute or fulminant myocarditis with a history of confirmed SARS-CoV-2 infection based on RT-PCR or serology.

Key findings:

  • All the patients presented with an acute nonischemic left ventricular dysfunction and a troponin elevation at admission.
  • Radiographic evidence of edematous myocarditis was seen on cardiac MRI in all six patients who underwent imaging.
  • Negative RT-PCR test result and positive antibody test result in the setting of a suggestive clinical history and presentation may be helpful.

Limitations:

  • Findings from case reports limit generalizability.
  • Limitations of testing: RT-PCR may stay positive for several weeks; antibody assays may represent remote exposure to SARS-CoV-2.

Case Series of Multisystem Inflammatory Syndrome in Adults Associated with SARS-CoV-2 Infection — United Kingdom and United States, March–August 2020 (Morris, October 2020).

Overall, this CDC MMWR review of physician-reported cases, published case reports and case series indicates that adults of any age can develop a hyperinflammatory syndrome after SARS-CoV-2 infection similar to MIS-C.

Study population:

  • 16 patients: Nine patients from the cases reported to CDC and seven from published case reports from the U.S. and U.K. met the CDC working case definition.
  • Patients ranged in age from 21 to 50 years; 43% were men.
  • Five were reported as Hispanic, nine as African American, one as Asian and one as a U.K.-born man of African ethnicity.
  • Nine patients had no reported underlying medical conditions.
  • Eight patients had a history of documented respiratory illness.
  • Fever, cardiac and gastrointestinal symptoms were most common. Few patients had dermatologic manifestations.

Primary endpoint:

  • Patients that met CDC’s working case definition of MIS-A from reported cases and published case reports.

Key findings:

  • All patients had markedly elevated laboratory markers of inflammation.
  • 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.
  • Seven patients were treated with intravenous immunoglobulin, 10 with corticosteroids and two with tocilizumab.

Limitations:

  • Cases described here were voluntarily reported or published, which limits representation of the true spectrum of disease.
  • Working case definition excludes patients with severe respiratory dysfunction, which may exclude patients in which the two conditions overlap.

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