Introduction

Throughout the worldwide pandemic of COVID, the general understanding became that pediatric patients were not only less susceptible to the virus but also to the clinical symptoms that accompany it. Albeit rare, Multisystem Inflammatory Syndrome in Children (MIS-C) is a relatively new differential diagnosis that does not necessarily need positive COVID testing and in fact presents with non-specific symptoms likely requiring hospitalization with possible ICU level care. 

Definition of MIS-C

Multisystem Inflammatory Syndrome in Children has been defined as a full body inflammatory response likely secondary to COVID infection. Although COVID is largely considered the source of MIS-C with almost 87% of patients testing positive through serology, a direct causation has yet to be defined. Patients with MIS-C will persistently present with >4 days of fever, gastrointestinal symptoms, rash, mucous membrane involvement, possibly lethargy and more. The CDC has provided criteria for diagnosis covered by Nakra 2020 et. al:

Pathophysiology

The pathophysiology behind MIS-C is thought to be a three phase process in which the first stage in pediatric patients is infection with an asymptomatic or mild COVID course. The respiratory failure from COVID infection is thought to be secondary to immune dysregulation rather than direct cell injury. As a result, the second phase differs between pediatrics and adults in which adults with a critical disease course will experience respiratory failure, whereas pediatrics will not. At a molecular level, this is thought to be secondary to pediatric patients lacking ACE receptors in their lung tissue. 

Phase three is the inflammatory stage in which macrophages will activate T cells, leading to interleukin activation, and a cytokine release/storm. With this, there is an activation of leukocytes as well as plasma cells/antibodies leading to a hyperimmune response. 

This response then leads to the clinical signs then seen including but not limited to meningeal irritation, pulmonary edema, mucosal inflammation, shock, acute kidney injury, skin changes, pericholecystic edema, mesenteric adenitis, ileitis, colitis, and ascites. 

Clinical Presentation

Clinical presentation is noted to include fever, fatigue, two or more organ system involvements with inflammation and evidence of COVID infection. Although Multi-System Inflammatory Syndrome is a newer diagnosis, this should be kept in mind in the presence of a sick pediatric patient with no obvious source of infection as they have a high likelihood of rapid decompensation. 

Similar to Kawasaki’s Disease, Toxic shock syndrome or secondary hemophagocytic lymphohistiocytosis (SHLH)/macrophage activation syndrome, it appears that MIS-C has a similar post viral immune dysregulation. 

In a case series that evaluated 70 children between 2-16 years old from the UK, Italy, France and Switzerland it was found that 84% had gastrointestinal symptoms including abdominal pain, vomiting, diarrhea and several mucocutaneous symptoms similar to Kawasaki. 74% developed hypotension with 11% requiring extracorporeal membrane oxygen (ECMO). 

Interestingly enough, these patients were found to have a myriad of signs/symptoms of inflammation including elevated C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), procalcitonin and ferritin. 

Classically not ordered in the pediatric population, these patients were also found to have an 81% rate of elevated troponin and 70% rate of elevated proBNP. 

Although described hand in hand with kawasaki, toxic shock syndrome and SHLH, there does appear to be several differences: 

Kawasaki Disease

Patients with MIS-C will tend to have higher rates of cardiac dysfunction, hypotension, whereas coronary artery abnormalities tend to be seen in Kawasaki

Toxic Shock Syndrome (TSS)

Presentation can be similar to TSS in which patients will have hypotension, diffuse rash, mucous involvement, multiorgan dysfunction with the predominant difference in pathophysiology. In TSS the inflammatory response is secondary to bacterial exotoxins functioning 

Lab workup

Important concept to keep in mind is that these patients may test negative for COVID, however their serology may present positively. Interestingly enough, patients with MIS-C were noted to test positive to RT-PCR Nasopharyngeal testing only 32% of the time, however positive for serology testing 87% of the time, lending to the fact this may predominantly present as a post infectious state. 

Lab evaluation includes CBC with diff, CMP, cardiac markers including troponin/BNP, urinalysis, blood gas, inflammatory markers (ESR, CRP, procalcitonin, ferritin, triglycerides), coagulation panels, creatinine kinase, LDH, blood cultures. Imaging includes chest xray, abdominal ultrasound/CT as needed, echocardiogram and EKG

Treatment

As MIS-C appears to have a similar presentation to several immunological dysregulated syndromes, initial treatment is centered around intravenous immune globulin (IVIG), and high dose steroids. With the limited numbers provided, several also required immunological antagonists (anakinra as noted by Nakra 2021) with high dose aspirin in the event of cardiac involvement. 

Patients with mild disease should be placed in step down, with moderate to severe disease placed into PICU. Along with a high level of care, early consultation to cardiology, rheumatology, infectious disease is recommended with transfer to higher level of care as needed. 

Disposition

A systematic review of 16 case series described 655 patients with 11 noted deaths (1.7%). As pediatric patients may present with mild symptoms and have a rapid decline, the index of suspicion should remain high. These patients can progress rapidly to critical illness with hypotension, and as a result should be managed in pediatric ICU settings. 

Take home points

• MIS-C is an emerging diagnosis in the field of pediatric infectious disease that requires rapid identification and close management
• 34% were found to have a positive nasopharyngeal COVID testing, however 87% noted to have positive COVID serology
• There are similarities between MIS-C and Kawasaki, Toxic Shock syndrome and SHLH, with a similar treatment taking place with IVIG and glucocorticoids. 
• Patients with mild disease should be admitted with moderate/severe being managed at tertiary care facility and likely PICU admission. 
• Degree of end organ damage will dictate treatment as well as hospital management of these patients

Written by: Hakkam Zaghmout, MD

Peer Reviewed and Edited by: Michael Witt, MD

References:

1. Nakra NA, Blumberg DA, Herrera-Guerra A, Lakshminrusimha S. Multi-System Inflammatory Syndrome in Children (MIS-C) Following SARS-CoV-2 Infection: Review of Clinical Presentation, Hypothetical Pathogenesis, and Proposed Management. Children (Basel). 2020 Jul 1;7(7):69. doi: 10.3390/children7070069. PMID: 32630212; PMCID: PMC7401880.
2. Son, Mary Beth, and Kevin Friedman. “COVID-19: Multisystem Inflammatory Syndrome in Children (MIS-C) Management and Outcome.” UptoDate, 24 May 2021, http://www.uptodate.com/contents/covid-19-multisystem-inflammatory-syndrome-in-children-mis-c-management-and-outcome?search=mis%20c&source=search_result&selectedTitle=1~91&usage_type=default&display_rank=1. 
3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7401880/pdf/children-07-00069.pdf
4. CDC COVID-19 Response Team. Coronavirus disease 2019 in children—United States, February 12–April 2, 2020. Morb. Mortal. Wkly. Rep. 2020, 69, 422–426.
5. Parri, N.; Lenge, M.; Buonsenso, D. Children with Covid-19 in Pediatric Emergency Departments in Italy. N. Engl. J. Med. 2020
6. Shulman, S.T. Pediatric COVID-associated Multi-system Inflammatory Syndrome (PMIS). J. Pediatr. Infect. Dis. Soc. 2020
7. Statement by pediatric intensive care society (PICS) noted at https://picsociety.uk/wp-content/uploads/2020/04/PICS-statement-re-novel-KD-C19-presentation-v2-27042020.pdf 
8. Kaushik A, et al. “A Systematic Review of Multisystem Inflammatory Syndrome in Children Associated With SARS-CoV-2 Infection.” Pediatric Infectious Disease Journal 39.11 (2020): e340-e346. Ovid MEDLINE(R). Web. 18 May. 2021. http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=reference&D=med17&NEWS=N&AN=32925547.