An overview of MIS- C post- COVID- 19 infection in children.

1. Multisystem Inflammatory Syndrome in
Children
(MIS-C & COVID- 19)
Fatima Farid
Ped Resident Year 3
Cardiology Block

2. Contents
Basics
Case
definition
Clinical
features
Diagnosis &
evaluation
Management Outcomes
2

3. Overview
• MIS- C is a diagnosis of growing frequency, more common among pediatric rather
than adult population
• It was first recognized in April 2020 in the UK & has since been reported from
many countries world- wide
• Our information is incomplete, constantly changing and further studies are still
underway
3

4. Other Names
Pediatric multisystem
inflammatory syndrome
[PMIS]
Pediatric inflammatory
multisystem syndrome
temporally associated with
SARS-CoV-2 [PIMS-TS]
Pediatric
hyperinflammatory
syndrome
Pediatric
hyperinflammatory shock
4

5. Epidemiology
• MIS- C has been observed with greatest frequency in:
• School aged children & adolescents
• Previously healthy
• African & Hispanic ethnicity
• China and other Asian regions with high incidence of COVID- 19 at the start of the
pandemic have LOW to NO reports of MIS- C
• Studies have shown the peak of MIS- C in the population occurs 3- 4 weeks after the
spike of COVID- 19 cases, hinting to an immune mediated pathology
5

6. 6
Source: https://www.nejm.org/doi/pdf/10.1056/NEJMc2026136?articleTools=true

7. Pathogenesis
• The exact cause of MIS- C is unknown so far, but suspected to be distinct from that of
Kawasaki disease & MAS
• The likeliest mechanism is a delayed antibody- mediated dysregulated host immune
response to COVID- 19 virus infection
• Disease presentations fall on a wide spectrum of severity, some studies have shown the
risk of cardiac involvement is considerable at any degree of MIS- C
• There are several theories attempting to explain the pathogenesis of MIS- C, some are
shown in the next slides
7

8. 8
Source: UpToDate

9. 9
Source: https://www.mdpi.com/2227-9067/7/7/69#

10. 10
Source: https://www.nature.com/articles/s41577-020-0367-5

11. Pathogenesis
Heart involvement in
MIS- C may be
explained by:
• Systemic inflammation
• Acute viral myocarditis
• Hypoxia
• Stress cardiomyopathy
• Coronary artery
involvement
11

12. Subtypes (based on a limited study)
• MIS-C without concurrent acute COVID- 19 or KD picture:
• These children are more likely to develop shock, highly elevated inflammatory
markers & heart disease
• MIS- C with acute COVID- 19
• Prominent respiratory symptoms and HIGHEST mortality rate
• MIS- C with overlapping KD picture
• Younger age group, prominent mucocutaneous features
12

13. 13

14. Case Definition
14
• There are 2 guides to diagnose a child with MIS- C: CDC & WHO
• Both are similar containing these basic points:
1. Age younger than 19- 21 years
2. Clinical features consistent with MIS- C: fever + multisystem involvement (at least
2) + lab evidence of inflammation +/ - severe illness requiring hospitalization
3. No other plausible diagnosis
4. Evidence of COVID- 19 infection

15. 15
Source: UpToDate

16. MIS- C & COVID- 19
• To diagnose MIS- C, the child must have any evidence of COVID- 19 infection
(past, current & even close contact with proven cases are considered)
• Both PCR swab and blood serology for COVID- 19 are collected to diagnose MIS-C,
studies have shown:
• 60% had positive serology & negative PCR
• 34% had both positive serology & PCR
• 5% had both negative serology & PCR
16

17. Presentation
• Data has been obtained over time using different case definitions for MIS- C,
hence there is a wide spectrum of possible presentations:
17
Persistent fever
(100%)
GI symptoms
(60- 100%)
Rash
(45- 76%)
Conjunctivitis &
mucus membrane
involvement
(30- 80%)
Respiratory
symptoms
(21- 65%)
Neurocognitive
symptoms
(29- 58%)
Lymphadenopathy
(6- 16%)
Sore throat
(10- 16%)
Myalgia
(8- 17%)
Swollen hands/ feet
(9- 16%)

18. Others
• Shock, arrhythmia
• Acute kidney injury
• Encephalopathy, seizure, coma, meningoencephalitis
• Serositis, hepatitis, hepatomegaly
18

19. 19
Source: https://www.mdpi.com/2227-9067/7/7/69#

20. DDx
Sepsis
Kawasaki disease
Toxic shock
syndrome
Appendicitis
Viral infections: EBV,
CMV, adenovirus &
enterovirus
Hemophagocytic
lymphohistiocytosis
Macrophage
activation syndrome
20

21. Investigations
• For mild presentation, the following labs are collected:
• CBC
• CRP
• Urea electrolytes
• Renal function testing
• If these are abnormal, then to proceed for more extensive investigations
21

22. 22
Source: UpToDate

23. Investigations
• If a child has moderate to severe presentation, labs can be prioritized as below:
23
Core Additional
• FBC, renal function, LFT
• Blood group & save
• CRP, ESR, Procalcitonin
• Blood and urine cultures
• Ferritin, triglycerides, LDH
• Interleukin 6
• Troponin T, NT- proBNP, CK
• PT/ PTT, fibrinogen, D- dimer
• Immunoglobulin level
• Chest x- ray
• Consider abdominal x- ray if clinically relevant
• COVID- 19 virus PCR on nasopharyngeal
secretions
• COVID- 19 serology test
• Standard respiratory viral panel
• Respiratory culture
• Serum EBV, CMV and Adenovirus DNA PCR
• Blood film
• Vitamin D
• Amylase
Source: National Guidelines for Clinical Management and Treatment of COVID-19 (Version 5.1, February 18th, 2021)

24. Imaging
• Chest x- ray, abdomen USS and CT chest may be indicated & reported abnormal
depending on the clinical indication
• CXR: consolidation, effusion, atelectasis
• Abdomen USS: ascites, mesenteric lymphadenitis, bowel inflammation
• CT chest: similar to CXR & rarely ground glass appearance
• The most important imaging in proven MIS- C is echocardiography
24

25. Cardiac assessment
In children with MIS- C, a full
cardiac assessment is crucial
Components include:
• Blood tests: troponin, NT- pro BNP
• 12 lead ECG
• Echocardiography
25

26. Heart involvement
• ECG may show arrhythmia or heart block
• Echocardiography features:
• LV/ biventricular impairment
• Diastolic dysfunction
• Pericardial effusion
• Mitral or tricuspid valve dysfunction
• Coronary artery dilation, including giant coronary artery aneurysms
26

27. Treatment – 4 main components
Infection control
(prevent spread to
others)
Stabilization &
monitoring as per
usual
Medications
specific for MIS- C
Echocardiographic
re- assessments
27

28. Initial Management
• Examination:
• Exclude potential septic foci
• Careful cardiac examination: liver, JVP, cardio- thoracic ratio on CXR
• Resuscitation:
• If signs of shock: fluid resuscitation (10 ml/kg NS) with re- evaluation after each bolus, discuss with PICU
• If no improvement with fluids: start inotropes (Dopamine 5- 10 mcg/kg/min) until central line access obtained
(then consider Epinephrine infusion)
• Ceftriaxone and Clindamycin as sepsis is impossible to exclude. Add broader spectrum antibiotic (i.e
Vancomycin) if hospital- acquired/ drug resistant organisms suspected. Keep Clindamycin to reverse toxins
release.
• Early IVIG 2 g/kg once over 10- 12 hours, max dose 100 grams
28
Source: National Guidelines for Clinical Management and Treatment of COVID-19 (Version 5.1, February 18th, 2021)

29. Classification of Clinical Severity
• Mild:
1. No vasoactive requirement
2. Minimal to no respiratory support
3. Minimal organ injury
• Moderate:
1. Vasoactive- inotrope score (VIS) </= 10
2. Significant supplemental oxygen requirement
3. Mild or isolated organ injury
29
Source: National Guidelines for Clinical Management and Treatment of COVID-19 (Version 5.1, February 18th, 2021)

30. Classification of Clinical Severity
• Severe:
1. VIS > 10
2. Non- invasive or invasive ventilator support
3. Moderate or severe organ injury, including moderate to severe ventricular
dysfunction
30
Source: National Guidelines for Clinical Management and Treatment of COVID-19 (Version 5.1, February 18th, 2021)

31. 31
Source: National Guidelines for Clinical Management and Treatment of COVID-19 (Version 5.1, February 18th, 2021)

32. 32
Source: National Guidelines for Clinical Management and Treatment of COVID-19 (Version 5.1, February 18th, 2021)

33. PICU Care
• Patient to be managed as COVID positive even if PCR negative (full PPE and room in appropriate area)
• Central line access: femoral line preferred in awake, self- ventilating patients (as most would require
Epinephrine)
• Temperature control: regular paracetamol & active cooling if ventilated
• Ensure IVIG was administered, otherwise give dose as mentioned, monitor for fluid overload during
infusion
• Methylprednisolone as detailed previously
• Proton pump inhibitor: Esomeprazole 1 mg/kg/day, max dose 40 mg/day
• Aspirin & anticoagulation as detailed previously
33
Source: National Guidelines for Clinical Management and Treatment of COVID-19 (Version 5.1, February 18th, 2021)

34. Cardiac Management
• Clinical course is unpredictable with rapid deterioration observed in some
• 12- lead ECG required – arrhythmias reported in some
• Urgent echocardiogram
• Low threshold for Milrinone infusion
• Severe cases consider Levosimendan
• VA ECMO for refractory shock
34
Source: National Guidelines for Clinical Management and Treatment of COVID-19 (Version 5.1, February 18th, 2021)

35. Immunomodulatory Therapy
• Severe refractory cases should be discussed with a pediatric rheumatologist/ specialist
prior to starting higher treatment modalities
• Medications:
• Repeat IVIG dose
• Pulse steroid therapy
• Anakinra (IL- 1 receptor antagonist)
• Infliximab (monoclonal antibody)
• Tocilizumab (IL- 6 receptor antibody)
35
Source: National Guidelines for Clinical Management and Treatment of COVID-19 (Version 5.1, February 18th, 2021)

36. Recommended Doses for Biologics
36
Source: National Guidelines for Clinical Management and Treatment of COVID-19 (Version 5.1, February 18th, 2021)

37. Monitoring
Urgent echo upon
admission to PICU, then
repeat as clinically
indicated
12- lead ECG at
admission, repeat
daily or if clinical
concerns
If oxygen requirement,
repeat CXR
Regular blood gas -
measure lactate
Repeat core
investigations 12
hourly – if rising
inflammatory markers,
discuss with ID team
37
Source: National Guidelines for Clinical Management and Treatment of COVID-19 (Version 5.1, February 18th, 2021)

38. Therapy Complications
• Fluid overload: risk with IVIG infusion, consider diuretic administration
• Hypertension: high dose methylprednisolone is associated with severe hypertension and PRESS
(posterior reversible encephalopathy syndrome). Treatment with calcium channel blockade or
SNP if severe cardiac dysfunction.
• Hyperglycemia: may require insulin infusion
• Gastritis: patient should all receive a high dose PPI
• Salicylate complications: acute kidney injury, respiratory alkalosis
38
Source: National Guidelines for Clinical Management and Treatment of COVID-19 (Version 5.1, February 18th, 2021)

39. Good Treatment Response
Normalization
of vital signs
Improvement in
inflammatory
markers
Resolution of
symptoms and
signs
39
Source: National Guidelines for Clinical Management and Treatment of COVID-19 (Version 5.1, February 18th, 2021)

40. Continuity of Care
40
Source: National Guidelines for Clinical Management and Treatment of COVID-19 (Version 5.1, February 18th, 2021)

41. Outcomes
• The prognosis of MIS-C is uncertain, given that it is a relatively new clinical entity and
long-term follow-up studies are lacking
• Though MIS-C has many similarities to Kawasaki disease and toxic shock syndrome, the
disease course in MIS-C can be more severe, with many children requiring intensive care
interventions
• Most children survive, but there have been several deaths reported
• The nature and frequency of long-term complications from MIS-C are unknown as post-
discharge follow-up data are not yet available
41

42. References
• UpToDate:
• Coronavirus disease 2019 (COVID-19): Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation,
and diagnosis
• Coronavirus disease 2019 (COVID-19): Multisystem inflammatory syndrome in children (MIS-C) management and outcome
• National Guidelines for Clinical Management and Treatment of COVID-19 (Version 5.1, February 18th, 2021)
• 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.
2020; 7(7):69. https://doi.org/10.3390/children7070069
• Rowley, A.H. Understanding SARS-CoV-2-related multisystem inflammatory syndrome in children. Nat Rev Immunol 20, 453–454
(2020). https://doi.org/10.1038/s41577-020-0367-5
• https://www.nejm.org/doi/pdf/10.1056/NEJMc2026136?articleTools=true
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43. Thank you
43