SaRs-Covid-2 and Multisystem-inflammatory Syndrome in Children: Should We Be Concerned?

Jennifer Harvey

PhD Student, College of Nursing

University of Utah 

Children are not little adults.  SARS CoV-2, the virus that causes COVID-19, is a new virus and multisystem-inflammatory syndrome in children (MIS-C) is a new syndrome.  What we know today is only a small thread in a long, complicated tapestry. New viruses are not a rare finding.  What is rare, is when a virus causes the majority of people’s lives to change in significant ways.  It is rare for a virus to become a pandemic on such extreme scales. We are in a time where paradigm shifts in thinking and acting are now the norm, not the exception. 

What is MIS-C?

MIS-C was first detected in late May and early April of this year after seeing children present with a multisystem inflammatory illness associated with COVID-19.  This illness appeared similar to, but not exactly like, Kawasaki Disease and/or Toxic Shock Syndrome.  Additionally, the illness appeared (and continues to appear) as a delayed immune response to the COVID-19 virus.

Not all children with MIS-C test positive for a COVID-19 infection but most do show evidence of antibodies indicating they were infected at some point in the past. 

MIS-C Related Statistics

Statistics obtained from Multisystem Inflammatory Syndrome in U.S. Children and Adolescents, (2020, Jun 29) Downloaded from nejm.org on July 31, 2020 – a CDC-authored study

• About 70% of reported cases have occurred in children who are Hispanic/Latino or Non-Hispanic Black
• 96% of cases tested positive for SARS CoV-2, the virus that causes COVID-19. The remaining 4% were around someone with COVID-19
• Most children developed MIS-C 2-4 weeks after infection with SARS-CoV-2

• Slightly more than half (55%) of reported cases were male
• Patients with Kawasaki’s disease–like features were more likely to be younger than 5 years old – similar to what is found among Kawasaki Disease

MIS-C and SARS CoV-2

Research has found that differences between COVID-19 and MIS-C can be found in viral loads. Children with MIS-C tend to have low viral loads indicating past infection while children with COVID-19 show higher loads, regardless of symptom severity.

MIS-C can present after experiencing any level of symptoms, even no reported COVID-19 symptoms.

MIS-C vs. Kawasaki Disease and Toxic Shock Syndrome

Kawasaki Disease is most common in infants and children, usually under 5 years of age.  This is an illness that involves inflammation of blood vessels, usually coronary vessels, leading to aneurysms.  Children often present with fever, rash, peeling skin.  Lymph nodes, skin, and mucous membranes are also commonly affected.

Toxic Shock Syndrome is a serious inflammatory condition resulting from complications of certain bacterial infections. TSS is often found following use of tampons, recent surgery, or open wounds but can be seen from other infections. Those inflicted often present with significant fever, hypotension, rash, nausea and vomiting. 

Like Kawasaki disease and TSS, children with MIS-C tend to present with rash, fever, cardiac dysfunction, multi-organ inflammation.  Unlike Kawasaki or TSSe, MIS-C is found in a broader age range and includes abdominal pain, diarrhea, and, frequently, a Pediatric Intensive Care Unit admission.

One of the most concerning similarities between the two illnesses is the inflammatory response in the blood vessels, notably the coronary vessels, sometimes leading to aneurysms. 

MIS-C Signs and Symptoms

As described in the Health Advisory, “Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with Coronavirus Disease 2019 (COVID-19),” the case definition for MIS-C is:

• An individual aged <21 years presenting with fever*, laboratory evidence of inflammation**, and evidence of clinically severe illness requiring hospitalization, with multisystem (>2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurological); AND
• No alternative plausible diagnoses; AND
• 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.

*Fever >38.0°C for ≥24 hours, or report of subjective fever lasting ≥24 hours
**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 and low albumin.

*Content source: National Center for Immunization and Respiratory Diseases (NCIRD), Division of Viral Diseases, Centers for Disease Control and Prevention

From: Nakra, N. A., Blumberg, D. A., Herrera-Guerra, A., & Lakshminrusimha, S. (2020). Multi-System Inflammatory Syndrome in Children (MIS-C) Following SARS-CoV-2 Infection: Review of Clinical Presentation, Hypothetical Pathogenesis, and Proposed Management. Children, 7(7), 69.

 

 MIS-C Clinical Pathway

Treatment for MIS-C starts before a child enters the hospital.  There are many clinical pathways to guide treatment.  They can be found on the sites of most hospitals, including Children’s Hospital of Philadelphia, Yale New Haven Children’s Hospital, Boston Children’s Hospital, Seattle Children’s, and Alaska Native Medical Center. (Links provided below).

 The Future of MIS-C

So where do we go from here?  How do we stay on top of studies, clinical data, changes? As more is learned, more questions will arise. 

The National Institutes of Health has posted a notice of intent to publish funding opportunities for a very important initiative that includes several projects.  The overarching initiative is the Rapid Acceleration of Diagnostics – Radical (RADx-rad) as an effort to support innovative, non-traditional approaches and applications to already existing approaches that address gaps in COVID-19 testing. One of the RADx initiatives is the Predicting Viral-Associated Inflammatory Disease Severity in Children with Laboratory Diagnostics and Artificial Intelligence (PreVAIL kIds).  PreVAIL kids aims to address critical gaps in knowledge relating to factors that contribute to increased susceptibility to MIS-C.  The project will also assess how this data can offer real-time use for risk stratification management strategies. (RADx NIH: RADx-rad initiative: www.nih.gov/research-training/medical-research-initiatives/radx/radx-programs). 

One question that has been mentioned by experts is related to vaccines.  If MIS-C is, in fact, an immune mediated response, will a vaccine then increase risk?  We must continue thinking outside of the box.

Last Words

As we are experiencing life with COVID-19, things change daily.  One of the reasons pediatric medicine is so special is that, unlike adults, there are no “usual cases.”  Children can survive things we adults would surrender to in a second.  Strength aside, children can change at any moment. Children are my boss, not the other way around.  As a result, providers on all levels must have a keen sense of assessment, be on our toes looking for any minute changes, and ALWAYS trust a child when they say something is really wrong. 

What is currently known may look nothing like what we know in 2 weeks, 2 months, a year, or more.  Each child is different but knowing the signs and symptoms is important to ensure prompt diagnosis with initiation of life-saving and protecting interventions.

If children do not contract the illness as severely as adults or at the rates of adults, then why should we care of MIS-C? Because of how it presents. Because of how severe it can be.  Because our children deserve it.

 

References

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.

Boston Children’s Hospital. (2020, June 17). Boston Children’s Hospital COVID-19 and MIS-C Treatment Guidelines. Retrieved from: https://www.openpediatrics.org/assets/document/boston-childrens-hospital-covid-19-and-mis-c-treatment-guidelines

Children’s Hospital of Philadelphia.(rev. 2020, July 8). Emergency Department, ICU and Inpatient Clinical Pathway for Evaluation of Possible Multisystem Inflammatory Syndrome in Children (MIS-C).

Dufort EM, Koumans EH, Chow EJ, et al. Multisystem inflammatory syndrome in children in New York state. Published online ahead of print, June 29, 2020 Jun 29. N Engl J Med. 2020;10.1056/NEJMoa2021756. doi:10.1056/NEJMoa2021756.

Feldstein LR, Rose EB, Horwitz SM, et al. Multisystem Inflammatory Syndrome in U.S. Children and Adolescents [published online ahead of print, 2020 Jun 29]. N Engl J Med. 2020;10.1056/NEJMoa2021680. doi:10.1056/NEJMoa2021680

Levin Michael. (2020) Childhood Multisystem Inflammatory Syndrome — A New Challenge in the Pandemic. N Engl J Med 383:4, 393-395.

Nakra, N. A., Blumberg, D. A., Herrera-Guerra, A., & Lakshminrusimha, S. (2020). Multi-System Inflammatory Syndrome in Children (MIS-C) Following SARS-CoV-2 Infection: Review of Clinical Presentation, Hypothetical Pathogenesis, and Proposed Management. Children, 7(7), 69.

National Center for Immunization and Respiratory Diseases (NCIRD), Division of Viral Diseases. (2020, July 22). Information for Healthcare Professionals about Coronavirus (COVID-19). Centers for Disease Control and Prevention. Retrieved from: https://www.cdc.gov/coronavirus/2019-nCoV/hcp/index.html

National Center for Immunization and Respiratory Diseases (NCIRD), Division of Viral Diseases. (2020, July 16).  Multisystem-Inflammatory Syndrome (MIS-C). Centers for Disease Control and Prevention. Multisystem Inflammatory Syndrome (MIS-C).

Seattle Children’s Hospital, Kazmier K, Albert J, de la Morena M, Eckart C, Fenstermacher S, Hartford E, Hayward K, Kemna M, Nutman S, Portman M, Sushan D, Valdivia H, Vora S, Waghmare A, Migita D. (2020, July). COVID-19 Pathway. Available from: http://www.seattlechildrens.org/pdf/covid-19-pathway.pdf

Shafer, Emily. (2020, July 30). CHOP Researchers Elucidate Clinical, Immune-related Features of MIS-C. Children’s Hospital of Philadelphia Cornerstone Blog. Retrieved from: https://www.research.chop.edu/cornerstone-blog/chop-researchers-elucidate-clinical-immune-related-features-of-mis-c

Yale Medical Center Pediatric Covid Treatment Team, Oliveira, Carlos, Cappello, Michael, Murray, Tom, Paintsil, Elijah, Zirinsky, Elissa, Campbell, Melissa, Rychalsky, Michelle, Ferguson, Ian, Berkwitt, Adam, Loyal, Jaspreet, Faustina, Vince, Pnisello, Josep, Emerson, Beth, Faherty, Erin, Asnes, Jeremy, Grossman, Matthew, Ciaburri, Rebecca, Yale NewHaven Health, Yale New Haven Children’s Hospital, Yale School of Medicine. (2020). Clinical Pathways Program. Retrieved from: https://www.ynhh.org/childrens-hospital/medical-professionals/clinical-pathways.aspx

Yale Medicine. (2020). Multi-inflammatory Syndrome in Children (MIS-C). Retrieved from:

https://www.yalemedicine.org/conditions/multisystem-inflammatory-syndrome-in-children-mis-c/