Case: An 8-year-old female with no significant past medical history presented to the Emergency Department due to fever and abdominal pain. She was otherwise well until 2 days beforehand when she developed high fever (40oC), nausea, vomiting, and abdominal pain. In the local ED, she received an abdominal CT to evaluate for appendicitis, which demonstrated a normal appendix and nonspecific mesenteric adenitis. She had a positive rapid Streptococcal pharyngitis test, and she was noted to have bilateral conjunctival injection. However, she quickly began to decompensate with oxygen requirement and hypotension requiring intravenous fluid resuscitation, and she received broad-spectrum antibiotics with concern for sepsis and toxic shock syndrome. Laboratory markers were significant for elevated CRP (35 mg/dL), ESR (27 mm/hr), ferritin (1395 ng/mL), procalcitonin (30 ng/mL), B natriuretic peptide (191 pg/mL), fibrinogen (504 mg/dL), and D-dimer (> 20 mcg/mL), along with transaminitis (ALT 52 and AST 76 IU/L), leukopenia (WBC 3.8), neutrophilia (85%), lymphopenia (7%), thrombocytopenia (platelets 114), and hypoalbuminemia (3.3 g/dL).

Her father had COVID-19 about 1 month before her illness, but her SARS-CoV-2 PCR was negative in the ED. After starting norepinephrine and escalating her respiratory support to BiPAP, she was transferred to the Children’s Hospital of Philadelphia PICU.

Discussion: In late April 2020, there were reports from the United Kingdom of otherwise healthy children presenting with a severe inflammatory disease similar to Kawasaki disease in the setting of COVID-19. There have been several case definitions since then, and in May 2020, the U.S. Centers for Disease Control and Prevention (CDC) defined this condition as the multi-system inflammatory syndrome in children (MIS-C), which was the diagnosis for our patient.

The CDC defines MIS-C as a disease that affects individuals younger than 21 years old who present with fever (≥ 38oC or subjective) for at least 24 hours, laboratory evidence of inflammation, severe illness requiring hospitalization, multi-system (≥ 2) organ involvement, and no alternative plausible diagnosis (except for Kawasaki disease). Patients with MIS-C must also be positive for current or recent SARS-CoV-2 infection or have a clear exposure to SARS-CoV-2 within 4 weeks prior to symptom onset.

Compared to the overall SARS-CoV-2 infections in children, MIS-C is relatively rare, with the incidence surpassing 2 617 in the United States on March 1, 2021, equivalent to less than 0.1% of all SARS-CoV-2 infections in this age range. With the ongoing pandemic though, MIS-C admissions at CHOP occur regularly, and the CDC provides national data regularly online: www.cdc.gov/mis-c/cases/index.html.

MIS-C is felt to be a delayed immune response to a prior COVID-19 infection rather than a syndrome from the acute viral infection, and several institutions have identified different immunologic and antibody profiles in MIS-C compared to acute COVID-19 infection. Patients typically present around 2 to 6 weeks after the initial COVID-19 infection with positive SARS-CoV-2 antibodies.

There is characteristically a slight male predominance, and it is found most commonly in children 5 to 9 years old, although infants and older adolescents may be affected as well. Similar to COVID-19, there is a higher incidence of MIS-C in patients of African-American or Hispanic race and ethnicity. Most children are otherwise healthy, but obesity is frequently reported.

Patients may present quite ill in shock and can decompensate quickly. In addition to fever, they may initially present with Kawasaki disease- like mucocutaneous symptoms, such as rash and conjunctival injection. Gastrointestinal symptoms, such as abdominal pain, vomiting, and diarrhea, are common.

The laboratory markers are markedly abnormal, including significantly elevated inflammatory markers, such as CRP, ESR, and ferritin. There are commonly abnormal coagulation markers such as fibrinogen and D-dimer levels, with hyponatremia, hypoalbuminemia, thrombocytopenia, and lymphopenia. B-natriuretic peptide and troponin levels are frequently elevated as well.

MIS-C’s cardiac connection

Cardiac involvement in MIS-C is common. Approximately 50% of patients develop acute left ventricular systolic dysfunction, and less often coronary artery dilation and/or aneurysms and arrhythmias, including various degrees of heart block.

The treatment for MIS-C includes the acute management of shock, anti- inflammatory treatment, and thromboprophylaxis. While there is practice variation among institutions, the vast majority of patients fortunately respond quickly. In the largest case series published by the CDC, the median length of stay was 6 days, although the published mortality rate is currently around 1% to 2%.

Anti-inflammatory treatment typically involves intravenous immunoglobulin (IVIG), similar to the regimen used to treat Kawasaki disease, despite the differences between MIS-C and Kawasaki disease. Various steroid regimens are common, in conjunction with IVIG, and additional agents are available for refractory cases. Thromboprophylaxis includes low-dose aspirin and additional anticoagulation in certain inpatient situations, such as those deemed to be high risk for venous thromboembolism.

There are a variety of specialties involved in the management of patients with MIS-C, and CHOP’s multidisciplinary clinical pathway for the evaluation of possible MIS-C can be located online: www.chop.edu/misc-pathway. We are actively evaluating the long-term cardiac manifestations of children with MIS-C and are a participating center in the National Heart, Lung, and Blood Institute (NHLBI) study through the Pediatric Heart Network: Long-Term Outcomes after the Multi-system Inflammatory Syndrome In Children (MUSIC).

Our patient in the above case presentation was treated with IVIG and methylprednisolone on admission. She had slightly elevated BNP and troponin levels, but normal echocardiograms with no ventricular dysfunction and normal coronary arteries. She clinically improved quickly and remains asymptomatic at home with her family, with ongoing cardiology follow-up.

References and suggested readings

Elias M, McCrindle B, Larios G., et al. Management of multi-system inflammatory syndrome in children associated with COVID-19: a survey from the International Kawasaki Disease Registry. CJC Open. 2020;2(6):632-640.

Vella LA, Giles JR, Baxter AE, et al. Deep immune profiling of MIS-C demonstrates marked but transient immune activation compared to adult and pediatric COVID-19. Sci Immunol. 2021;6(57):eabf7570.

Matsubara D, Kauffman HL, Wang Y, et al. Echocardiographic findings in pediatric multi-system inflammatory syndrome associated with COVID-19 in the United States. J Am Coll Cardiol. 2020;76(17):1947-1961.

Godfred-Cato S, Bryant B, Leung J, et al. COVID-19-associated multi-system inflammatory syndrome in children – United States, March-July 2020. MMWR Morb Mortal Wkly Rep. 2020;69:1074-80.

Henderson LA, Canna SW, Friedman KG, et al. American College of Rheumatology Clinical Guidance for multi-system inflammatory syndrome in children associated with SARS-CoV-2 and hyperinflammation in pediatric COVID-19: Version 2. [Published online ahead of print, December 5, 2020.] Arthritis Rheumatol.