MIS-C

Learning objectives

• When to suspect MIS-C

• Clinical features of MIS-C
• Step-wise evaluation for MIS-C
• Criteria for diagnosis of MIS-C
• Management of MIS-C
 MIS-C

• What is MIS-C?

• A novel multisystem hyperinflammatory syndrome that

follows exposure to SARS- CoV-2 by 3-6 weeks and affects
children and adolescents

• First reported from the UK in April 2020 as a Kawasaki Disease

like illness, the surge of which followed that of Covid19 by a
month!
• No of cases of MIS-C started rising later than covid 19 peak.

• There is gap of around 3 to 6 wks between covid 19 peak and surge in

MIS-C cases

How common is MIS-C ?

• Overall uncommon: <1% of all COVID-19 in children and adolescents

• <10% of children hospitalized with COVID-19/ related conditions

 When to suspect MIS-C

suspect MISC whenever there is a

1. Child presenting with fever > 3 day

2. Multisystem involvement with or without external features of KD , +/-shock or

hemodynamic compromise is present

3. Link with COVID 19- proven, suggestive history in patient or close contacts or

hailing from area of high prevalence, positivity on PCR, antigen or antibody

testing.

The importance of suspicion and early recognition is key because early

immunomodulation can be life saving in these patients.
 Pathogenesis of MIS-C

• Incompletely understood
• Diagnosed in children who had Covid infection previously and also among
those with active infection

• Possible mechanism of inflammation:

• Immune dysregulation
• Antibody enhancement
• T-cell mediated damage or enhancement
 Pathogenesis of MIS-C: a hypothesis

Low viral High viral

load load

Nature Reviews Immunology. 2020; 20: 453–454

 Clinical features MIS-C
MIS-C

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
 Mucocutaneous manifestations

Rash may be maculopapular, petechial but not vesicular

• MIS-C with Kawasaki Disease (KD) phenotype is characterised by fever,

conjunctival redness, oropharyngeal findings (red and/or cracked lips,

strawberry tongue), rash, swollen and/or erythematous hands and feet

and cervical lymphadenopathy

 Clinical spectrum of MIS-C

Spectrum of disease is mild to severe

Class I (35%) Class II (30%) Class III (35%)

• Hyperinflammation • Respiratory • KD/ Atypical KD

with MODS – ARDS , • Age ≈ 6 years
>6 organs (50%) myocarditis
cytokine storm • Serology positive -
GI , CVS ( 100%) 63%
• Serology and RT-
• Serology positive- • RT-PCR positive- PCR positive- 34%
98% 84%
• Mortality-0%
• Mortality-0.5 % • Mortality –
highest (5%)

Godfred-Cato S United States, March–July 2020. MMWR Morb Mortal Wkly Rep 2020;69:1074–1080.
MIS-C: How to investigate ?
 Evaluation of suspected MIS-C

Evaluation
3

1. Unremitting fever ≥38 °C Ye

Ye Tier
Shock / Life s
2. Clinical features s 1
suggestive of MIS- threatening
C condition Tier
3. Epidemiological link to (No alternative 2
SARS-CoV-2 Dx)
No
No Tier
1
Evaluate for
Negative
alternate Positive
diagnosis Monitor
for features of
Tier
MIS-C
2
 2 out of 5 must be present

1. Rash or bilateral non- purulent conjunctivitis or muco-

cutaneous inflammation (oral, hands or feet)
2. Hypotension or shock
3. Myocardial dysfunction, pericarditis ,valvulitis or coronary
abnormalities (Echo findings or elevated Trop T, BNP)
4. Evidence of coagulopathy (PT, APTT, d- Dimer)
5. Acute GI problems (Diarrhea / Vomiting / Abdominal pain)
 Tier 1- Evaluation

1. CBC
2. Complete metabolic profile:
(LFT / RFT/ ABG (serum Na) / BGL
/serum albumin )
3. CRP and / or ESR
4. SARS-CoV-2 Serology and/or PCR
 Tier 1- Positive screen

Both +
 CRP > 5 mg/dL and/or ESR > 40 mm per
hour
 At
i. least
ALCone of these < 1000/µL
ii. Platelet < 150,000/µL
iii. Serum Na < 135 mEq/L
iv. Neutrophilia
v. Hypoalbuminemia <3 g/dl
 Tier 2- Evaluation

1. Cardiac
 ECG
 Echocardiogram
 NT- pro BNP, Trop T
2. Inflammatory markers
 Procalcitonin
 PT, PTT, D-dimer,
Fibrinogen
 LDH
 Triglyceride
 Cytokine panel
3. Blood Smear
 Tier 2 - Positive screen

• Left ventricular (LV) dysfunction

1. Cardiac (20–55% of cases), ejection
 ECG fraction
 Echocardiogram <35%
• Coronary artery dilation or
 BNP (>400 ,
aneurysm
Trop pg/ml)
T ~20% ( 2-2.5 z score ; > 2.5 z score)
2. Inflammatory markers • Valvular dysfunction and pericardial
 Procalcitonin effusion (less frequent)
 PT , PTT, D- (>2 , •Fibrinogen (>400 mg/dl)
Electrical conduction abnormalities
dimer mg/L)*
 LDH
 Triglyceride
 Cytokine panel
3. Blood smear (schistocytes, Burr
cells)
* > 5times normal

Henderson LA et al Arthritis Rheumatol.2020 Nov : 1791-1805

 WHO criteria for diagnosis

• Children and adolescents 0–19 years of age with fever > 3 days

• AND two of the following:  

                                                
• Rash or bilateral non-purulent conjunctivitis or muco-cutaneous inflammation signs
(oral, hands or feet).

• Hypotension or shock.

• Features of myocardial dysfunction, pericarditis, valvulitis, or coronary

abnormalities (including ECHO findings or elevated Troponin/NT-proBNP),

• Evidence of coagulopathy (by PT, PTT, elevated d-Dimers).

• Acute gastrointestinal problems (diarrhoea, vomiting, or abdominal pain).

 WHO criteria for diagnosis

AND
• Elevated markers of inflammation such as
ESR (>40mm),
C-reactive protein(>5mg/l),
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.
 WHO criteria for diagnosis

•Alternative diagnoses that must be excluded before making a diagnosis of

MIS-C

 Tropical fevers (malaria, dengue, scrub typhus,enteric fever)

 Toxic shock syndrome (staphylococcal or streptococcal)

 Bacterial sepsis
No single diagnostic laboratory test for
diagnosis of MIS-C !
MIS-C: Management
 Management of MIS-C

1. Management of hyperinflammatory state

Immunomodulators:
- IV Immunoglobulin
-Corticosteroids
Biological agents (Anakinra)
2. Management of procoagulant state :
Antiplatelet drugs:
Aspirin
Anticoagulants:
Low Molecular Weight Heparin
3.Supportive care
 Guidelines for Management of COVID-19 in Children

Management of MIS-C

MIS-C with shock or MODS Kawasaki phenotype MIS-C without shock

IVIG 2 gm/kg over 12-16 hours (max. 100 g), and IVIG 2 gm/kg over 12-16 hours (max. 100 g), and
IV methylprednisolone 2 mg/kg/day, and IV methylprednisolone 1-2 mg/kg/day
IV methylprednisolone 1-2 mg/kg/day
Empirical antimicrobials as per hospital antibiogram

If symptoms persist for 48-72 hours of If symptoms persist for 48-72 hours of If symptoms persist for 48-72 hours of
treatment, or if early worsening treatment, or if early worsening treatment, or if early worsening

Increase IV MPS to 10 mg/kg/day (max. 1 g) Treat as per the phenotype

Consult specialist/expert for biologicals
Consult specialist/expert for biologicals to which evolution occurs

 Appropriate supportive care is needed preferably in ICU for treatment of cardiac dysfunction, coronary involvement, shock or multi-organ dysfunction syndrome (MODS)
Use biologicals only after expert consultation
 IVIG to be given slower (over up to 48 hours) in children with cardiac failure/ fluid overload
and at tertiary care only
 Taper steroids over 2-3 weeks with clinical and CRP monitoring
 Aspirin 3-5 mg/kg/day, maximum 75 mg/day in all children for 4-6 weeks (with platelet count >80,000/µL) for at least 4-6 weeks or longer for those with coronary aneurysms
 Low molecular weight heparin (Enoxaparin) 1 mg/kg/dose twice daily s/c in >2 months (0.75mg/kg/dose in <2 months) if patient has thrombosis or giant aneurysm with absolute coronary diameter ≥8 mm or Z score ≥10 or LVEF <30%
 For children with cardiac involvement, repeat ECG 48 hourly & repeat ECHO at 7-14 days and between 4 to 6 weeks, and after 1 year if initial ECHO was abnormal

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 Outcome
• Favorable outcomes are reported in the majority with low-mortality rates
(1-2%) even though most children require intensive care and
immunomodulatory therapies.

• The nature and frequency of long-term complications is unknown since

few post-discharge follow-up data are not available
 Take home message

• MIS-C is not common

• Think of common conditions first

• Investigate judiciously if high index of suspicion for MIS-C

• Provide good supportive care

• Ensure judicious use of medications

• Outcome is usually favorable

 MIS-C vs Kawasaki disease
MIS-C as compared to KD
1. Broader age range 1.Lower platelet counts
2. More prominent GI and 2. Lower absolute lymphocyte counts
neurologic symptoms 3. Higher CRP levels
3. May be without mucocutaneous
manifestations
4.Present more frequently in shock
5.More likely to display cardiac
dysfunction (arrhythmias and
ventricular dysfunction)

MIS-C patients without KD features can develop coronary artery aneurysm

It is not known if incidence CAA is different in MISC and KD