Multisystem inflammatory syndrome in children

Background

• In April 2020 during the SARS-CoV-2 outbreak UK pediatricians alerted the National Health Service of a new systemic inflammatory condition similar to Kawasaki disease in children testing positive for the virus
• Cases were then reported worldwide with patients admitted to ICUs in the USA^4,5,10, Canada¹⁰Italy¹¹, and UK^2,3
• Thought to be an immunologically mediated inflammatory syndrome associated with previous SARS-CoV-2 infection¹
  • Cases occur 3-5.5 weeks after patients tested positive for SARS-CoV-2
• While Kawasaki disease has a predilection for children of Asian descent, MIS-C seems to affect African American children more often⁹
  • Compared to Kawasaki patients are generally older (median age 8.6 vs 2.5)¹ and had a predominance of GI symptoms
• Patients with MIS-C are significantly more likely to present with dyspnea, vomiting, diarrhea, lymphopenia, and elevated LDH and and D-dimer compared to patients with COVID-19 without MIS-C ⁶

Epidemiology

• Occurs in 2/100,000 persons under 21⁴
• In a systematic review published June 2020, 11/7780 (0.14%) COVID-19 positive children met the CDC’s criteria for MIS-C⁶

Clinical Features

• Fever
• Abdominal pain
• Diarrhea
• Headache
• Conjunctivitis
• Rash
• Sore throat
• Cardiac dysfunction
• Shock
• Acute kidney injury

Differential Diagnosis

• SARS-CoV-2
• Kawasaki disease
• Toxic shock syndrome
• Juvenile idiopathic arthritis
• Pneumonia (Peds)
• Sepsis
• Myocarditis
• Hemophagocytic lymphohistiocytosis
• Macrophage activation syndrome
• Rocky Mountain Spotted Fever

Evaluation

• Labs
  • CBC
    • Lymphopenia
    • Neutrophilia
  • CMP
    • Low albumin
  • Inflammatory markers (elevated)
    • CRP
    • ESR
    • Fibrinogen
    • Procalcitonin
    • D-dimer
    • Ferritin
    • LDH
    • IL-6
  • BNP
  • Troponin

• Imaging
  • Chest X-ray/CT
    • May show bilateral patchy infiltrates or ground glass opacities
  • Echocardiogram to evaluate for LV dysfunction, coronary aneurysm/dilation

Case Definition

• CDC¹²
  • An individual aged <21 years presenting with feverⁱ, 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 COVID-19 exposure within the 4 weeks prior to the onset of symptoms

• • • ⁱFever >38.0°C for ≥24 hours, or report of subjective fever lasting ≥24 hours
    • ⁱⁱIncluding, 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

• • Some individuals may fulfill full or partial criteria for Kawasaki disease but should be reported if they meet the case definition for MIS-C
  • Consider MIS-C in any pediatric death with evidence of SARS-CoV-2 infection

• WHO¹³
  • Children and adolescents 0–19 years of age with fever > 3 days
  • AND two of the following:
    • a) Rash or bilateral non-purulent conjunctivitis or muco-cutaneous inflammation signs (oral, hands or feet).
    • b) Hypotension or shock.
    • c) Features of myocardial dysfunction, pericarditis, valvulitis, or coronary abnormalities (including ECHO findings or elevated Troponin/NT-proBNP),
    • d) Evidence of coagulopathy (by PT, PTT, elevated d-Dimers).
    • e) Acute gastrointestinal problems (diarrhoea, vomiting, or abdominal pain).

• • AND
    • Elevated markers of inflammation such as ESR, C-reactive protein, or procalcitonin.
  • AND
    • No other obvious microbial cause of inflammation, including bacterial sepsis, staphylococcal or streptococcal shock syndromes.
  • AND
    • Evidence of COVID-19 (RT-PCR, antigen test or serology positive), or likely contact with patients with COVID-19.

Management

• ASA
• IVIG
• Corticosteroids (shock or risk of coronary aneurysm)¹
• Antibiotics for sepsis or pneumonia
• Mechanical ventilation
• Vasopressors
• Biologics (unresponsive to IVIG and steroids)¹
• ECMO

Complications

'	Study	Capone et al.1	Davies et al.3	Dufort et al.4	Fields et al.5	Lee et al.7	Shekerdemian et al.10
Complication (%)	ICU admission	79	100%i	80	80	61	100%i
	Invasive mechanical ventilation	18	46	10	20	0	38
	Vasopressor support	76	83	62	48	25	25
	Coronary artery abnormalities	24	36	9	8	21	N/A
	LV dysfunction	19	N/A	52	38	39	N/A
	Acute kidney injury	70	N/A	10	5	21	N/A
	RRT	N/A	1	N/A	N/A	N/A	0
	ECMO	N/A	4	4	4	0	2
	Death	0	3	2	2	0	4

ⁱStudy contained only patients admitted to pediatric ICUs.

Disposition

• Admission
• Varied reports on proportion requiring ICU level of care (21-80)^1,4

See Also

COVID-19

External Links

• NY Webinar
• https://www.cdc.gov/mis-c/hcp/
• https://www.who.int/news-room/commentaries/detail/multisystem-inflammatory-syndrome-in-children-and-adolescents-with-covid-19

References

1. Capone CA et al. Characteristics, cardiac involvement, and outcomes of multisystem inflammatory disease of childhood (MIS-C) associated with SARS-CoV-2 infection. J Pediatr. 2020. (Epub ahead of print).
2. Chiotos K et al. Multisystem Inflammatory Syndrome in Children During the Coronavirus 2019 Pandemic: A Case Series. J Pediatric Infect Dis Soc. 2020;9(3):393-398.
3. Davies P et al. Intensive care admissions of children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) in the UK: a multicenter observational study. doi: 10.1016/S2352-4642(20)30215-7
4. Dufort EM et al. Multisystem Inflammatory Syndrome in Children in New York State. N Eng J Med. 2020;383(4):347-358.
5. Feldstein LR et al. Multisystem Inflammatory Syndrome in U.S. Children and Adolescents. N Eng J Med. 2020;383(4):334-346.
6. Hoang et al. COVID-19 in 7780 pediatric patients: A systemic review. EClinicalMedicine. 2020;24. Accessed August 1, 2020. DOI: https://doi.org/10.1016/j.eclinm.2020.100433
7. Levin M. Childhood Multisystem Inflammatory Syndrome – A New Challenge in the Pandemic. N Eng J Med. 2020;383(4):393-395.
8. Lee PY et al. Distinct clinical and immunological features of SARS-COV-2-induced multisystem inflammatory syndrome in children. J Clin Invest. 2020. https://doi.org/10.1172/JCI141113
9. Miller J et al. Gastrointestinal symptoms as a major presentation component of a novel multisystem inflammatory syndrome in children (MIS-C) that is related to COVID-19: a single center experience of 44 cases. Gastroenterology. 2020. (Epub ahead of print). doi: 10.1053/j.gastro.2020.05.079
10. Rowley A. Understanding SARS-CoV-2 related multisystem inflammatory syndrome in children. Nat Rev Immunol. 2020;20(453-454). https://doi.org/10.1038/s41577-020-0367-5
11. Shekerdemian LS et al. Characteristics and Outcomes of Children With Coronavirus Disease 2019 (COVID-19) Infection Admitted to US and Canadian Pediatric Intensive Care Units. JAMA Pediatr. 2020. doi:10.1001/jamapediatrics.2020.1948
12. Verdoni L et al. An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study. Lancet 2020; 395: 1771-8.
13. Center for Disease Control and Prevention. Health Alert Network (HAN). Multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease 2019 (COVID-19). Accessed July 2020. https://emergency.cdc.gov/han/2020/han00432.asp
14. https://www.who.int/news-room/commentaries/detail/multisystem-inflammatory-syndrome-in-children-and-adolescents-with-covid-19