MIS-C is a serious condition that appears to be associated with COVID-19 in children. Symptoms include persistent fever, inflammatory reactions and evidence of multiple organ dysfunction or shock. Contents: - Introduction - Risk factors - Pathophysiology - Clinical features - Diagnostic criteria according to CDC, WHO, RCPCH - Investigations - Management - Ddx of Kawasaki disease - References

1. FENTY THOMAS
THOMAS FENTY
MULTISYSTEM
INFLAMMATORY
SYNDROME IN
CHILDREN

2. FENTY THOMAS
INTRODUCTION
❑ In April 2020, a new syndrome. of severe
multisystem inflammation with features like
Kawasaki disease has emerged in children, first
reported in Europe.
❑ At the same time, children with similar
symptomatology were identified in NY
❑ The syndrome is now known as MIS-C-
multisystem inflammatory syndrome in children.
By the end of May, 176 children were reported in
NYS

3. FENTY THOMAS
INTRODUCTION
❑ Multisystem inflammatory syndrome in children (MIS-C) is a condition among pediatric
patients with coronavirus disease of 2019 (COVID-19), resulting in inflammation of a variety
of organ systems, including the heart, lungs, brain, kidneys, gastrointestinal system, skin, and
eyes.
❑ 80-100% patients have positive SARS-CoV-2 antibodies (2-4 weeks after infection or
exposure)
❑ It is characterized by severe, febrile inflammatory Kawasaki-like illness
❑ School-age children (mean 6-10 years)
❑ Risk factors: Overweight (BMI>25), asthma

4. FENTY THOMAS
PATHOPHYSIOLOGY
❑ The pathophysiology of MIS-C is not well
understood.
❑ Early infection (Stage I) with SARS-CoV-2 is likely
to be asymptomatic or mildly symptomatic in
children.
❑ The pulmonary phase (Stage II) is severe in adults
but is mild or absent in many children.
❑ The early infection appears to trigger macrophage
activation followed by the stimulation of T-helper
cells. This in turn leads to cytokine release, the
stimulation of macrophages, neutrophils, and
monocytes, along with B-cell and plasma cell
activation with the production of antibodies
leading to a hyperimmune response (Stage III).
This immune dysregulation is associated with the
inflammatory syndrome in affected children.
Direct infection with SARS-CoV-2 is less likely to
play a role in MIS-C. ACE2-angiotensin converting
enzyme 2 receptors; TNF-β-tumor necrosis factor
β; IL-interleukins.

5. FENTY THOMAS
PATHOPHYSIOLOGY
❑ Immune dysregulation – It has been suggested that the syndrome results from an abnormal
immune response to the virus, with some clinical similarities to Kawasaki disease (KD), macrophage
activation syndrome (MAS), and cytokine release syndrome. However, based on the available studies,
MIS-C appears to have an immunophenotype that is distinct from KD and MAS. The exact mechanisms
by which SARS-CoV-2 triggers the abnormal immune response are unknown.
❑ Preliminary studies suggest that patients with severe MIS-C have persistent immunoglobulin G (IgG)
antibodies with enhanced ability to activate monocytes, persistent cytopenia (particularly T cell
lymphopenia), and greater activation of CD8+ T cells that differ from findings in acute COVID-19
infection. The certainty of these findings is limited due to the small number of patients in these
studies.

6. FENTY THOMAS
PATHOPHYSIOLOGY
❑ SARS-CoV-2 virus – Many affected children have negative polymerase chain reaction (PCR)
testing for SARS-CoV-2 but have positive serology, a finding that further supports the hypothesis
that MIS-C is related to immune dysregulation occurring after acute infection has passed.
However, some children do have positive PCR testing.
❑ A study examining SARS-CoV-2 viral sequences from 11 children with MIS-C did not detect any
differences compared with the viral sequences from children with acute COVID-19 without MIS-
C. These preliminary data suggest that viral factors are less likely to explain why some children
develop multisystem inflammation following SARS-CoV-2 infection, while others do not. It is
more likely that host factors are responsible for the abnormal inflammatory response in MIS-C.

7. FENTY THOMAS
CLINICAL PRESENTATION
❑ Fever
❑ In addition to fever, children with MIS-C commonly present with abdominal pain, vomiting, diarrhea, rash,
conjunctivitis, mucocutaneous lesions and in severe cases, with hypotension and shock.
❑ Children should be evaluated by a medical provider immediately if these symptoms appear, especially in a child
who had, or was exposed to someone with, COVID-19, within the prior 2–6 weeks.
❑ Gastrointestinal symptoms – Gastrointestinal symptoms (abdominal pain, vomiting, diarrhea) are particularly
common and prominent, with the presentation in some children mimicking appendicitis. Some children have
been noted to have terminal ileitis on abdominal imaging and/or colitis on colonoscopy.
❑ Cardiorespiratory symptoms – Cardiac involvement is common. Respiratory symptoms (tachypnea, labored
breathing), when present, may be due to shock or cardiogenic pulmonary edema. Cough is uncommon. Though
some children require supplemental oxygen or positive pressure ventilation for cardiovascular stabilization,
severe pulmonary involvement (eg, acute respiratory distress syndrome) is not a prominent feature.
❑ Neurocognitive symptoms – Neurocognitive symptoms are common and may include headache, lethargy,
confusion, or irritability. A minority of patients present with more severe neurologic manifestations, including
encephalopathy, seizures, coma, stroke, meningoencephalitis, muscle weakness, and brainstem and/or
cerebellar signs. Life-threatening neurologic conditions including severe encephalopathy, central nervous system
demyelination, stroke, acute fulminant cerebral edema, and Guillain-Barré syndrome.

8. FENTY THOMAS
CLINICAL PRESENTATION
Presenting symptoms Frequenc
y (%)
• Persistent fevers (median duration 4 to 6 days) 100
• Gastrointestinal symptoms (abdominal pain,
vomiting, diarrhea)
60 to 100
• Rash 45 to 76
• Conjunctivitis 30 to 81
• Mucous membrane involvement 27 to 76
• Neurocognitive symptoms (headache, lethargy,
confusion)
29 to 58
• Respiratory symptoms (tachypnea, labored
breathing)
21 to 65
• Sore throat 10 to 16
• Myalgias 8 to 17
• Swollen hands/feet 9 to 16
• Lymphadenopathy 6 to 16

9. FENTY THOMAS
DIAGNOSTIC CRITERIA
CRITERIA CDC WHO RCPCH
• Age <21 years <19 years All children (age not
defined)
• Fever ≥38C for ≥24 h or
subjective fever lasting ≥
24 h
Fever ≥ 3 days Persistent fever ≥ 38.5C
• Clinical Evidence of clinically
severe illness requiring
hospitalization, with
multisystem organ
involvement (≥2 of the
following: cardiac, renal,
respiratory, hematologic,
GI, dermatologic, or
neurologic)
At least 2 of the following:
1) Rash, conjunctivitis,
mucocutaneous
inflammation
2) Hypotension or shock
3) Cardiac involvement⁎
4) Coagulopathy
5) Acute GI symptoms
Single or multiorgan
dysfunction and additional
features

10. FENTY THOMAS
DIAGNOSTIC CRITERIA
CRITERIA CDC WHO RCPCH
• Inflammation At least one of the following:
elevated CRP, ESR, fibrinogen,
procalcitonin, D-dimer, ferritin,
lactic acid dehydrogenase, IL-6,
elevated neutrophils, reduced
lymphocytes, low albumin
Elevated CRP, ESR,
procalcitonin
Neutrophilia, elevated
CRP, and lymphopenia
• SARS-CoV-2 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 symptom onset
Positive for current or
recent SARS-CoV-2
infection by RT-PCR,
serology, or antigen test,
or likely COVID-19
exposure
Positive or negative
RT-PCR
• Exclusion No alternative diagnosis No obvious microbial
cause
Exclusion of other
infections

11. FENTY THOMAS
INVESTIGATIONS
❑ Laboratory tests recommended for the initial diagnosis and monitoring of disease progression include
complete blood count (CBC), kidney and liver function markers, cardiac function biomarkers,
and coagulation parameters.
❑ CBC: lymphopenia, neutrophilia, mild anemia, and thrombocytopenia in patients with moderate or
severe symptoms.
❑ Serum electrolytes and renal function have been reported as abnormal even in patients with mild
symptoms.
❑ Myocardial injury is one of the main clinical manifestations of MIS-C. Therefore, close monitoring of the
levels of markers of myocardial function such as troponin, N-terminal pro-BNP (NT-pro-BNP) and
BNPs are an essential part of the MIS-C workup.
❑ Inflammatory markers whose levels have been shown to correlate with disease severity include C-
reactive protein (CRP), which has been reported as critically elevated in majority of patients;
erythrocyte sedimentation rate (ESR); and interleukin 6 (IL-6).
❑ Coagulopathy resulting in high fibrinogen, D-dimer, partial thromboplastin time
(PTT), prothrombin time (PT), and factor VIII levels has been observed in MIS-C patients
experiencing moderate to severe symptoms. Ferritin is also elevated in MIS-C, being higher in 55-76%
of patients.
❑ PCR and serology for SARS COV2

12. FENTY THOMAS
INVESTIGATIONS
❑ ECG findings : In children with MIS-C, baseline ECGs may be nonspecific (eg, repolarization changes with
abnormal ST- or T-wave segments), though arrhythmia and heart block have been described
❑ Echocardiogram: Depressed LV function, Coronary artery dilation/aneurysm, Other findings can include
mitral regurgitation and pericardial effusion
❑ Chest radiograph: Normal in many patients, Abnormal findings included small pleural effusions, patchy
consolidations, focal consolidation, and atelectasis.
❑ Computed tomography (CT) of chest :Chest CT (when obtained) generally had findings similar to those
on chest radiograph. Ground-glass opacification was a common finding.
❑ Abdominal imaging (ultrasound and/or CT): Findings are nonspecific, including free fluid, ascites, bowel
and mesenteric inflammation, including terminal ileitis, mesenteric adenopathy/adenitis, and
pericholecystic edema
Testing for other pathogens — Testing for other viral and bacterial pathogens includes.
❑ Blood culture, Urine culture, Throat culture, Stool culture, Nasopharyngeal aspirate or throat swab for
respiratory viral panel, Epstein-Barr virus serology and PCR, Cytomegalovirus serology and PCR,
Enterovirus PCR, Adenovirus PCR

13. FENTY THOMAS
MANAGEMENT
Treatments have consisted
primarily of supportive care
and directed care against the
underlying inflammatory
process. Supportive measures
have included:
❑ fluid resuscitation;
❑ inotropic support;
❑ respiratory support; and
❑ in rare cases,
extracorporeal
membranous oxygenation
(ECMO).

14. FENTY THOMAS
MANAGEMENT
❑ Shock — Children presenting with shock should be resuscitated. Some children with MIS-C may present with vasodilatory
shock that is refractory to volume expansion. Epinephrine or norepinephrine are the preferred vasoactive agents for the
management of fluid-refractory shock in children. Epinephrine is preferred when there is evidence of left ventricular (LV)
dysfunction. In children presenting with severe LV dysfunction, the addition of intravenous diuretics and inotropic agents,
such as dopamine, and dobutamine and milrinone may be helpful
❑ Antibiotic therapy — MIS-C can present with signs and symptoms that mimic those of septic shock and toxic shock
syndrome. Thus, patients presenting with severe multisystem involvement and shock should receive prompt empiric
broad-spectrum antibiotic therapy pending culture results. An appropriate empiric regimen consists of ceftriaxone plus
vancomycin. Ceftaroline plus piperacillin-tazobactam is an alternative regimen, particularly for children with acute kidney
injury. Clindamycin is added if there are features consistent with toxin-mediated illness (eg, diffuse erythroderma).
Antibiotics should be discontinued once bacterial infection has been excluded if the child's clinical status has stabilized.

15. FENTY THOMAS
❑ Patients who meet criteria for incomplete or
complete Kawasaki disease (KD) should receive
standard therapies for KD, including intravenous
immune globulin (IVIG), aspirin, and, if there are
persistent signs of inflammation or coronary
artery (CA) dilation/aneurysm, glucocorticoids. It
will be increasingly difficult to distinguish
patients with incident KD who have
seroconverted from prior SARS Co-V2 infections
from patients with MIS-C who meet KD criteria.
Thus, it is important to intensify treatment if KD
high-risk criteria are present.

16. FENTY THOMAS
REFERENCES
❑ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185530/table/t0005/?report=objectonly
❑ https://www.uptodate.com/contents/covid-19-multisystem-inflammatory-syndrome-in-children-mis-c-
clinical-features-evaluation-and-diagnosis#H2589496221
❑ https://www.researchgate.net/figure/Pathogenesis-of-MIS-C-Early-infection-phase-I-with-SARS-CoV-2-
is-likely-to-be_fig2_342627263
❑ https://www.medscape.com/viewarticle/968803#vp_2

17. FENTY THOMAS
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