The challenges of multisystem inflammatory syndrome diagnosis

Multisystem inflammatory syndrome, which is MIS-C in children and MIS-A in adults, is a rare but severe condition causing an extreme immune response in patients as a result of current or recent SARS-CoV-2 infection. Both MIS-C and MIS-A continue to challenge doctors and remind us that stringent precautions for COVID-19 are still very necessary.

It is not yet known what is causing multisystem inflammatory syndrome, and more research is needed to identify risk factors (such as why there are more cases of MIS-C in African American and Latino children). The Centers for Disease Control and Prevention (CDC) and the National Institutes of Health (NIH) are working with state, local, and territorial health departments, as well as healthcare workers, scientists and researchers to utilize partnerships so they can share data and improve diagnosis and treatment of multisystem inflammatory syndrome.

Inflammation causes

MIS-C and MIS-A cause inflammation such as swelling, redness and pain throughout the body – often affecting the heart, blood vessels, kidneys, digestive system, brain, skin or eyes. Clinical features in children have primarily included shock, cardiac dysfunction, abdominal pain, and elevated inflammatory markers. According to the CDC Health Advisory, “Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with Coronavirus Disease 2019 (COVID-19),” the current case definition of MIS-C includes multiple elements.

The disease involves an individual younger than 21 years old, presenting with fever (Fever >38.0°C for ≥24 hours, or report of subjective fever lasting ≥24 hours) and laboratory evidence of inflammation, including, but not limited to, one or more of the following: an elevated C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), fibrinogen, procalcitonin, d-dimer, ferritin, lactic acid dehydrogenase (LDH), or interleukin 6 (IL-6), elevated neutrophils, reduced lymphocytes or low albumin. There also should be evidence of clinically severe illness requiring hospitalization, with multisystem organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurological). In addition, these conditions should be met:

1. No alternative plausible diagnoses.

2. Positive for current or recent SARS-CoV-2 infection by RT-PCR, serology, or antigen test; or exposure to a suspected or confirmed COVID-19 case within the 4 weeks prior to the onset of symptoms.¹

On October 9, 2020, CDC researchers published a case series in the Morbidity and Mortality Weekly Report (MMWR), detailing their findings about MIS-A thus far through various studies conducted from March through June in both the United States and United Kingdom. In about one third of the 27 cases, antibody testing was needed to identify SARS-CoV-2 infection. Similarly, 45 percent of 440 children with MIS-C reported to the CDC through July 29, 2020, had negative PCR and positive SARS-CoV-2 antibody test results. This leads some experts to believe MIS-A and MIS-C might be post-infectious processes and they propose that antibody results might be invaluable for clinical recognition and treatment. Gregory Poland, MD, of the Vaccine Research Group at Mayo Clinic said, “Even after infection in what appears to be recovery mode, people can develop this multisystem inflammatory syndrome weeks later. And that’s a very unusual thing for a viral infection like this. So we’re learning every week about the incredible harm that this virus is capable of doing.”²

Also mentioned in the October 9th edition of MMWR, is that the 27 individuals with MIS-A presented with cardiovascular, gastrointestinal, dermatologic, and neurologic symptoms without severe respiratory illness. Their working case definition for MIS-A included five criteria:

1. A severe illness requiring hospitalization in a person at least 21 years old.

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).

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.³

Although hyperinflammation and extrapulmonary organ dysfunction have also been noted in severe COVID-19 cases, these conditions are usually accompanied by respiratory failure. “The typical case, as we understand it right now, is somebody who comes in with rapidly deteriorating multiorgan failure with very little or no respiratory symptoms. And the reason for that is they’ve been infected in the past two to six weeks, but are not infected now. They have antibodies but negative swabs. So it appears to be something related to the ongoing immune response or the antibodies that were created,” Poland said.²

All patients included in the MMWR case series had 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).³

Identifying laboratory evidence of inflammation as listed in the case definition is key. Screening for systemic inflammation, hypercoagulability, and organ damage (e.g., CRP, ESR, ferritin, d-dimer, cardiac enzymes, liver enzymes, and creatinine) might also assist in the early identification and management of multisystem inflammatory syndrome. Cardiac testing is also being performed due to the prevalence of cardiac symptoms in multisystem inflammatory syndrome patients, often revealing electrocardiogram abnormalities such as arrhythmias, elevated troponin levels, or echocardiographic evidence.⁴

Expanded laboratory tests may also include pro-BNP, triglycerides, amylase, urine culture, prothrombin time/partial thromboplastin time (PT/PTT), INR, LDH, as well as a comprehensive metabolic panel. In all cases, COVID-19 testing should be performed with RT-PCR and serologic testing, which must be done prior to administration of intravenous immunoglobulin (IVIG).⁵

While more research is needed to identify the best treatment protocols, supportive care and directed care against the underlying inflammatory process continue. These include: fluid resuscitation, inotropic support, respiratory support and, in rare cases, extracorporeal membranous oxygenation (ECMO). IVIG and steroids are also in frequent use. Aspirin has commonly been used for coronary artery involvement, and antibiotics are routinely prescribed to treat potential sepsis while awaiting bacterial cultures. Thrombotic prophylaxis is often used given the hypercoagulable state typically associated with MIS-C.⁴ The American College of Rheumatology has developed clinical guidance specifically regarding the management of MIS-C.

Conclusion

The majority of patients with MIS-A and MIS-C survive when receiving care in acute, intensive, healthcare settings. Early intervention with SARS-CoV-2 testing, including antibody testing, might be needed to recognize and treat patients. Further research is needed to understand the pathogenesis and long-term effects of these conditions, but clinicians and health departments should consider MIS-A in adults with signs and symptoms compatible with the current working MIS-A case definition and continue with efforts to limit spread of SARS-CoV-2.³

REFERENCES 

1. HAN Archive - 00432. Centers for Disease Control and Prevention. https://emergency.cdc.gov/han/2020/han00432.asp. Published March 27, 2020. Accessed December 9, 2020.
2. Stiepan, DeeDee. Pediaitric Inflammatory Syndrome linked to COVID-19 also discovered in adults. Mayo Clinic News Network. https://services.aap.org/en/pages/2019-novel-coronavirus-covid-19-infections/clinical-guidance/multisystem-inflammatory-syndrome-in-children-mis-c-interim-guidance/. Accessed December 8, 2020.
3. Morris SB, Schwartz NG, Patel P, et al. Case Series of Multisystem Inflammatory Syndrome in Adults Associated with SARS-CoV-2 Infection — United Kingdom and United States, March–August 2020. Morb Mortal Wkly Rep 2020;69:1450–1456. doi:10.15585/mmwr.mm6940e1
4. Information for Healthcare Providers about Multisystem Inflammatory Syndrome in Children (MIS-C). Centers for Disease Control and Prevention. https://www.cdc.gov/mis-c/hcp/index.html. Published August 28, 2020. Accessed December 9, 2020.
5. American Academy of Pediatrics. Multisystem Inflammatory Syndrome in Children (MIS-C) Interim Guidance.services.aap.org. https://services.aap.org/en/pages/2019-novel-coronavirus-covid-19-infections/clinical-guidance/multisystem-inflammatory-syndrome-in-children-mis-c-interim-guidance/. Updated November 17, 2020. Accessed December 9, 2020. 
6. Henderson, L. A., Canna, S. W., Friedman, K. G., Gorelik, M., Lapidus, S. K., Bassiri, H., Mehta, J. J. American College of Rheumatology Clinical Guidance for Multisystem Inflammatory Syndrome in Children Associated With SARS–CoV‐2 and Hyperinflammation in Pediatric COVID‐19: Version 1. Arthritis & Rheumatol, 72(11), 1791–1805. doi:10.1002/art.41454
7. Mayo Clinic Staff. Multisystem inflammatory syndrome in children (MIS-C) and COVID-19. Mayo Clinic. December 1, 2020. https://www.mayoclinic.org/diseases-conditions/mis-c-in-kids-covid-19/symptoms-causes/syc-20502550. Accessed December 8, 2020.
8. Multisystem Inflammatory Syndrome in Adults (MIS-A). Centers for Disease Control and Prevention. https://www.cdc.gov/mis-c/mis-a.html. Published November 13, 2020. Accessed December 9, 2020. 
9. Weiss C. Mayo Clinic Q and A: COVID-19 and multisystem inflammatory syndromes in children and adults. Mayo Clinic. https://newsnetwork.mayoclinic.org/discussion/mayo-clinic-q-and-a-covid-19-and-multisystem-inflammatory-syndromes-in-children-and-adults/. Published November 26, 2020. Accessed December 9, 2020.