Indian Academy of Pediatrics (IAP)

STANDARD
TREATMENT
GUIDELINES 2022

Multisystem
Inflammatory
Syndrome in Children
Lead Author
Rakesh Lodha
Co-Authors
Jolly Chandran, Mahendra Jain

Under the Auspices of the IAP Action Plan 2022

Remesh Kumar R
IAP President 2022
Upendra Kinjawadekar Piyush Gupta
IAP President-Elect 2022 IAP President 2021
Vineet Saxena
IAP HSG 2022–2023
© Indian Academy of Pediatrics

IAP Standard Treatment Guidelines Committee

Chairperson
Remesh Kumar R
IAP Coordinator
Vineet Saxena
National Coordinators
SS Kamath, Vinod H Ratageri
Member Secretaries
Krishna Mohan R, Vishnu Mohan PT
Members
Santanu Deb, Surender Singh Bisht, Prashant Kariya,
Narmada Ashok, Pawan Kalyan
 Multisystem Inflammatory 163
Syndrome in Children

;; Multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease-

Introduction

2019 (COVID-19) or pediatric inflammatory multisystem syndrome (PIMS) was initially

reported in the United Kingdom and the United States in April 2020 following a surge in
COVID-19 infections in the population.
;; It has the presentation of hyperinflammatory syndrome with involvement of multiple organs,
requiring timely treatment of anti-inflammatory drugs such as steroids and intravenous
immunoglobulins.
;; It is an uncommon but potentially serious disease in children and adolescents; timely
diagnosis and treatment is associated with good outcomes.

Diagnostic Criteria

In May 2020, the World Health Organization (WHO) and the Centers for Disease Control (CDC)
issued separate diagnostic criteria based on available/published information in case reports
and case series analysis. These criteria are enlisted in Table 1.
 Multisystem Inflammatory Syndrome in Children

TABLE 1:  The WHO criteria for MIS-C.

Criteria All 6 criteria must be met
Age Age 0–19 years
Fever Fever for ≥3 days
Clinical signs ;; Rash, bilateral nonpurulent conjunctivitis, or mucocutaneous inflammation
of multisystem signs (mouth, hands, or feet)
Diagnostic Criteria

involvement (at ;; Hypotension or shock cardiac dysfunction, pericarditis, valvulitis, or

least two of the coronary abnormalities (including echocardiographic findings or elevated
following) troponin/BNP)
;; Evidence of coagulopathy (prolonged PT or PTT; elevated D-dimer)
;; Acute gastrointestinal symptoms (diarrhea, vomiting, or abdominal pain)
Elevated markers of Elevated markers of inflammation (e.g., ESR, CRP, or procalcitonin)
inflammation
Rule out other No other obvious microbial cause of inflammation, including bacterial sepsis
diagnoses and staphylococcal/streptococcal toxic shock syndromes/tropical infectious
diseases, i.e., malaria, dengue, scrub typhus, leptospirosis, and enteric fever
Recent or current ;; Any of the following tests positive:
SARS-CoV-2 −− Positive SARS-CoV-2 RT-PCR
infection or −− Positive serology
exposure −− Positive antigen test
−− Contact with an individual with COVID-19
(BNP: B-type natriuretic peptide; CRP: C-reactive protein; COVID-19: coronavirus disease-2019; ESR: erythro­
cyte sedimentation rate; MIS-C: multisystem inflammatory syndrome in children; PT: prothrombin time;
PTT: partial thromboplastin time; RT-PCR: reverse transcription–polymerase chain reaction; SARS-CoV-2:
severe acute respiratory syndrome coronavirus-2; WHO: World Health Organization)

Investigation in MIS-C depends upon severity of disease. Approach to a child with features
suggestive of MIS-C:
;; Tier-1 tests: Complete blood count (CBC), C-reactive protein (CRP), erythrocyte sedimentation
rate (ESR), liver function test (LFT), kidney function test (KFT), blood sugar, blood gas, and severe
Investigations
acute respiratory syndrome coronavirus-2 (SARS-COV-2) serology/reverse transcription–
polymerase chain reaction (RT-PCR).
;; Tier-2 tests: Electrocardiogram (ECG), echocardiogram, B-type natriuretic peptide (BNP),
troponin-T, ferritin, lactate dehydrogenase (LDH), procalcitonin, interleukin 6 (IL-6),
prothrombin time (PT), activated partial thromboplastin time (aPTT), D-dimer, and fibrinogen.
Positive tier 1 screen (both of these should be present):
1. CRP > 5 mg/dL and/or ESR > 40 mm/hour
2. At least one of these: Absolute lymphocyte count (ALC) < 1,000/µL, platelet count
< 150,000/µL, Na < 135 mEq/L, neutrophilia, and hypoalbuminemia
Isolated increased COVID-19 antibodies are not synonymous with MIS-C. For diagnosis of
MIS-C, it is mandatory to rule out common tropical infections including malaria, dengue, enteric
4 fever, rickettsial illness (scrub typhus), etc.
 Multisystem Inflammatory Syndrome in Children

Multisystem inflammatory syndrome in children associated with COVID-19 can present as

critical illness. There can be a spectrum of presentations from mild symptoms to multiorgan
dysfunction syndrome.

;; Stabilize the patient (airway stabilization and adequate perfusion)

;; Treat organ dysfunction and prevent further progression (beware of organ
dysfunction)
;; Control of systemic inflammation by choosing the right immunosuppression
;; Close monitoring for disease progression
;; Long-term follow-up for complications.

ABCD: Airway stabilization and Adequate perfusion, Beware of organ

dysfunction, Control systemic inflammation, and close monitoring for Disease
progression

Management
Steps of Management

Clinical Types
Multisystem inflammatory syndrome in children for management purposes can be
grouped into four categories (Flowchart 1):
1. MIS-C without shock: Any child who fulfills the WHO criteria for MIS-C and stable
without any feature of shock
2. MIS-C with shock/multiple organ dysfunction syndrome (MODS): Any child who
fulfills the WHO criteria for MIS-C and having features of shock in the form of
tachycardia, hypotension, requiring fluid bolus ≥ 30 mL/kg, or inotropic support.
MODS: Any child who fulfills the WHO criteria for MIS-C and has two or more organ
involvement [respiratory/cardiac/central nervous system (CNS)/liver/renal]
3. MIS-C with Kawasaki phenotype: Children who meet complete or incomplete
Kawasaki disease criteria as defined by the American Heart Association (Kawasaki
diagnosis is established by fever lasting 5 or more days and at least four of the
following five clinical criteria: Polymorphous rash (excluding bullous or vesicular
eruptions); Conjunctival injection; Oropharyngeal mucous membrane changes;
Extremity changes; and Lymphadenopathy)
4. MIS-C with refractory disease: Any child who fulfills the WHO criteria for MIS-C and
has not responded to first tier therapy [intravenous immunoglobulin (IVIg) and
low-dose steroids) after 48 hours.

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 Multisystem Inflammatory Syndrome in Children

Flowchart 1:  Management of MIS-C.

(IV: intravenous; IVIg: intravenous immunoglobulin; MIS-C: multisystem inflammatory syndrome in

children; MODS: multiple organ dysfunction syndrome)
Management

Steps of Management

;; Airway stabilization and adequate perfusion:

•• These children should preferably be monitored in intensive care unit (ICU). Shock
can be vasodilatory/cardiogenic.
•• Judicious fluid resuscitation 10–20 mL/kg over 30–60 minutes and aggressive
hemodynamic support with prompt initiation of vasoactive agents.
•• Epinephrine can be used if there is hypotension with cardiac involvement,
norepinephrine if there is vasodilatory shock aiming good mean arterial pressure for
adequate organ perfusion.
•• In extreme cases with catecholamine, refractory shock vasopressin is advised.
;; Treat organ dysfunction and prevent further progression (beware of organ dysfunction):
•• Antibiotics in first hour after obtaining blood cultures as per local hospital antibiotic
guidelines
•• Prevent organ dysfunction by maintaining good organ perfusion
•• Avoid fluid overload.

6
 Multisystem Inflammatory Syndrome in Children

;; Control of systemic inflammation by choosing the right immunosuppression: This therapy

is mainly targeted to reduce tissue inflammation or prevent progression of coronary
artery aneurysm/myocardial dysfunction. Initial combined treatment with IVIg and
corticosteroids may be beneficial.
•• IVIg: Dose: 2 g/kg (based on ideal body weight with maximum dose of 100 g) IV. This
can be given as a single infusion over 8–12 hours or 12–24 hours based on patient’s
clinical status and cardiac function. In children who fail to respond, second dose may
be considered.
•• Methylprednisolone: Should be administered simultaneously with IVIg at low dose of
2 mg/kg/day; however in children with coronary artery changes or refractory disease,
pulsed dose of 10–30 mg/kg (maximum of 1,000 mg) may be administered. This is
slowly transitioned to oral prednisolone which is tapered over 2–3 weeks with clinical
and CRP monitoring.
•• Anakinra: In children with refractory disease despite glucocorticoid treatment or in
patients with contraindications to steroids, anakinra at dose of >4 mg/kg/day IV or SC
should be considered after expert consult.
•• Infliximab/tocilizumab: Currently not recommended for use in children.

Management
Steps of Management

;; Close monitoring and disease progression:

•• Vigilant clinical monitoring for progression into hemodynamic instability or organ
involvement should be done.
•• Laboratory monitoring of inflammatory markers is recommended till patient is stable.
•• ECG and echocardiogram have to be repeated after 48 hours as per clinician’s
discretion, subsequent echocardiogram at 1–2 weeks, 4–6 weeks, and 1 year if initial
echocardiogram abnormal.
•• If child appears unwell or deteriorates after 24–48 hours of treatment, consider expert
consult.
;; Anticoagulation:
•• MIS-C with documented thrombosis/ejection fraction < 35%/coronary artery Z score
≥ 10/giant aneurysm with diameter > 8 mm: Enoxaparin 1 mg/kg (0.75 mg/kg/dose in
<2 months) SC for 2 weeks after discharge.
•• Low-dose aspirin (3–5 mg/kg/day; maximum 80 mg/day) should be used if platelets
>80,000/µL and continued till normal coronary arteries are confirmed at ≥4 weeks
after diagnosis.
In patients with aneurysm or risk of thrombosis, it is desirable to continue antiplatelet
and anticoagulation as per their risk/need with clinicians’ judgment.
;; Long-term follow-up for complications: Mortality is reported in 1–2% of affected patients;
higher figures are often reported with delayed presentations. Coronary artery aneurysm
occurs in 25%, cardiac dysfunction in 50–60%, respiratory failure in 30%, renal involvement
in 12%, CNS in 3%, and systemic thrombosis in 3–6%.

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 Multisystem Inflammatory Syndrome in Children

;; Centers for Disease Control and Prevention. (2020). Multisystem Inflammatory Syndrome in Children
(MIS-C) associated with Coronavirus Disease 2019 (COVID-19). [online] Available from: https://
emergency.cdc.gov/han/2020/han00432.asp. [Last accessed June, 2022].
;; Elsevier.health. (2022). Multisystem Inflammatory Syndrome in children (MIS-C). [online] Available
from:  https://elsevier.health/en-US/preview/multisystem-inflammatory-syndrome-in-children-
mis-c. [Last accessed June, 2022].
;; Henderson LA, Canna SW, Friedman KG, Gorelik M, Lapidus SK, Bassiri H, et al. American College of
Further Reading

Rheumatology Clinical Guidance for Multisystem Inflammatory Syndrome in Children Associated

With SARS-CoV-2 and Hyperinflammation in Pediatric COVID-19: Version 2. Arthritis Rheumatol.
2021;73(4):e13-29.
;; McMurray JC, May JW, Cunningham MW, Jones OY. Multisystem inflammatory syndrome in children
(MIS-C), a post-viral myocarditis and systemic vasculitis—a critical review of its pathogenesis and
treatment. Front Pediatr. 2020;8:626182.
;; Ministry of Health and Family Welfare. (2022). Revised Comprehensive Guidelines for Management
of COVID-19 in Children and Adolescents (below 18 years). [online] Available from: https://www.
mohfw.gov.in/pdf/RevisedComprehensiveGuidelinesforManagementofCOVID19inChildren
andAdolescents below18years.pdf. [Last accessed June, 2022].
;; 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;7(7):69.
;; World Health Organization (2020). Multisystem inflammatory syndrome in children and adolescents
with COVID-19: Scientific Brief. [online] Available from: https://www.who.int/publications-detail/
multisystem-inflammatory-syndrome-in-children-and-adolescents-with-covid-19. [Last accessed
June, 2022].