MULTISYSTEM

INFLAMMATORY SYNDROME
IN CHILDREN (MIS-C)

PREPARE BY: Mohmmad Maher Mezead

OUTLINES; MULTISYSTEM INFLAMMATORY
SYNDROME IN CHILDREN (MIS-C)

 INTRODUCTION
 Epidemiology 
 Pathophysiology 
 Clinical presentation
 Evaluation 
 Case definition
 Differential diagnosis
 management and outcome
INTRODUCTION
 A novel coronavirus was identified in late 2019 that rapidly
reached pandemic proportions. 
 In children, COVID-19 is usually mild. However, in rare cases,
children can be severely affected
 In April of 2020, reports from the United Kingdom documented a
presentation in children similar to incomplete Kawasaki disease or
toxic shock syndrome .
 The condition has been termed multisystem inflammatory
syndrome in children (MIS-C); also referred to as

-pediatric multisystem inflammatory syndrome [PMIS],

-pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-
2 [PIMS-TS],
-pediatric hyperinflammatory syndrome,
-pediatric hyperinflammatory shock).
EPIDEMIOLOGY
EPIDEMIOLOGY 
 MIS-C appears to be a relatively rare complication of
COVID-19 in children.
 MIS-C can occur at any age from infancy through late
adolescence, but most cases have occurred in previously
healthy children between the ages of 6 to 12 years.
 Cases of MIS-C typically peak several weeks after surges
of COVID-19 in the community. ?!
PATHOPHYSIOLOGY
PATHOPHYSIOLOGY 
 The pathophysiology of MIS-C is not well understood.
 It is thought to result from an abnormal immune response to the
virus, with some clinical similarities to Kawasaki disease (KD),
macrophage activation syndrome (MAS), and cytokine release
syndrome(CKS).
 MIS-C appears to have an immunophenotype that is distinct from
KD and MAS.
 Most affected children have positive serology for SARS-CoV-2 with
negative polymerase chain reaction (PCR), 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. 
CLINICAL PRESENTATION
CLINICAL PRESENTATION
 The clinical presentation of MIS-C may include persistent fevers,
gastrointestinal symptoms (abdominal pain, vomiting, diarrhea),
rash, and conjunctivitis.

 Patients typically present with three to five days of fever, followed

by development of shock and/or multisystem involvement.

 Onset of symptoms — In children who have a known history of documented

or suspected COVID-19, the usual duration between acute infection and onset of
MIS-C symptoms is two to six weeks. However, rare cases of MIS-C occurring
>6 weeks after the acute SARS-CoV-2 infection have been reported.
 PRESENTING SYMPTOMS 
●Fever, usually persistent (median duration four to six days) – 100 percent
●Gastrointestinal (abdominal pain, vomiting, diarrhea ) – 60 to100 %
●Conjunctivitis – 30 to 81 %
●Mucous membrane involvement (red or swollen lips, strawberry tongue)
– 27 to 76 percent
●Neurocognitive symptoms (headache, lethargy, confusion) – 29 to 58%
●Cardiorespiratory symptoms –65 %
●Sore throat , Myalgia, Swollen hands &feet, Lymphadenopathy 5-10%.
 Common presenting symptoms include:

●Fever – Most patients present with three to five days of fever

●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.

●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
LABORATORY,  INFLAMMATORY MARKERS, IMAGING MODALITIES
 Laboratory markers of inflammation appear to correlate with severity of
illness .For example, in one series, children who developed shock had higher
CRP values mean 32.1 higher neutrophil counts (16 *109/L), lower
lymphocyte counts (0.7 *109/L), and lower serum albumin (2.2 g/Dl). In
addition, children with shock more commonly had elevated cardiac markers.
 Echocardiography :
 Chest radiograph – Many patients had normal chest radiographs. Abnormal
findings included 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 – Findings on abdominal ultrasound or CT included free
fluid, ascites, and bowel and mesenteric inflammation including terminal
ileitis, mesenteric adenopathy/adenitis, and pericholecystic edema
EVALUATION
 The clinician should also assess for other common causes of fever (eg,
streptococcal pharyngitis, mononucleosis, influenza, respiratory syncytial
virus), particularly with children and adolescents back to in-person school
and common childhood infections circulating widely. Having an alternative
diagnosis essentially excludes MIS-C, particularly in an otherwise well-
appearing child.
 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
CASE DEFINITION
CASE DEFINITION

 Mild symptoms – For patients presenting with fever for ≥3

days and who are well-appearing (ie, normal vital signs and
reassuring physical examination) with only mild symptoms
suggestive of MIS-C, we suggest a more limited evaluation
initially. We typically start with the following:
 •CBC with differential
 •CRP,ESR
 •Serum electrolytes and kidney function tests
 If these results are abnormal, additional testing is performed
CASE DEFINITION

 Moderate to severe (MOST COMMON ) :

For children with moderate to severe symptoms, who are LOOK ILL,

•Complete blood count (CBC) with differential

•C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR; procalcitonin
is optional)
•Serum electrolytes and kidney function tests
•Ferritin
•Liver function tests and lactate dehydrogenase
•Coagulation studies (prothrombin time/international normalized ratio,
activated partial thromboplastin time, D-dimer, fibrinogen)
•Troponin
•Brain natriuretic peptide (BNP) or N-terminal pro-BNP (NT-pro-BNP)
  ECG findings :

-may be nonspecific 
-though arrhythmia and heart block have been described
-First-degree atrioventricular block occurs in approximately 20
percent of hospitalized patients
 Echocardiographic findings may include:

-Depressed LV function
-Coronary artery (CA) abnormalities, including dilation or aneurysm
-Mitral regurgitation
-Pericardial effusion
*Follow-up echocardiography Very important.
 CA assessment is based on Z-scores, with the same
classification schema used in KD
CASE IS A 6-MONTH-OLD INFANT BOY ADMITTED TO HOSPITAL DUE TO RESPIRATORY
DISTRESS THEN WORSENED BY A PERICARDIAL EFFUSION AND SOLITARY KIDNEY AND
RENAL FAILURE. DIAGNOSED AS MULTISYSTEM INFLAMMATORY SYNDROME IN
CHILDREN (MIS-C) DUE TO COVID-19 EXPOSURE.

 CARDIAC ULTRASOUND CASE SUBMITTED TO DAIC BY MOHAMED

SHAHWAN, EUROPEAN GAZA HOSPITAL.

DAIC: DIAGNOSTIC AND INTERVENTIONAL CARDIOLOGY -

DIFFERENTIAL DIAGNOSIS
 ‫النبي ‪-‬صلى هللا عليه وسلم‪ -‬قال‪:‬‬ ‫ّ‬ ‫روى أبو هريرة ‪-‬رضي هللا عنه‪ -‬أن‬
‫يض‪ ،‬حتَّى يَ ْخ ُر َج ال َّر ُج ُل ب َزكا ِة مالِ ِه فال يَ ِج ُد‬‫سا َعةُ حتَّى يَ ْكثُ َر الما ُل ويَفِ َ‬
‫ال“ تَقُو ُم ال َّ‬
‫وجا وَأ ْنها ًرا‬ ‫ب ُم ُر ً‬ ‫ض ال َع َر ِ‬
‫أر ُ‬‫أح ًدا يَ ْقبَلُها منه‪ ،‬وحتَّى تَ ُعو َد ْ‬ ‫” َ‬
‫وادي العتيق‪ ،‬الوادي المبارك لرسول هللا صلى هللا عليه وسلم‪،‬‬
‫ال تذكر الكتب المعاصرة اخر مرة جرى فيه الماء!! ‪،،‬‬
‫‪ .‬تشق األمطار نهرا داخله من غزارتها‬
MANAGEMENT&
OUTCOME
SETTING OF CARE

 Essentially all children who meet the case definition for MIS-C
are managed in the inpatient setting because they have
multisystem involvement and are moderately to severely ill,
even if their symptoms are relatively mild initially.

 Admission to a PICU is appropriate for children with

hemodynamic instability (shock, arrhythmia), significant
respiratory compromise, or other potentially life-threatening
complications. 

 Outpatient observation ?
MULTIDISCIPLINARY CARE
 MULTIDISCIPLINARY CARE: By definition, MIS-C is a
multisystem disease, and care for affected children requires
coordination of many different pediatric specialties. This may
include:
●Emergency medicine providers
●Rheumatologists
●Cardiologists
●Intensivists
●Hematologists
●Neurologists
●Infectious disease specialists
 INFECTION CONTROL
 identifying and isolating patients and their contacts with suspected
COVID-19,
 
 universal source control (covering the patient's nose and mouth with a
mask to contain respiratory secretions),

 use of appropriate personal protective equipment when caring for

patients with COVID-19, and environmental disinfection.

 Institutional infection control guidelines related to testing for COVID-

19 and managing test positive patients should be followed. 
(MIS-C) MANAGEMENT AND OUTCOME

 Management of shock and cardiac dysfunction 

 Empiric antibiotic therapy
 Immunomodulatory therapy
-intravenous immune globulin (IVIG)
-glucocorticoid therapy
-Biologic therapies
 Prevention of thrombotic complications 
MANAGEMENT OF SHOCK AND CARDIAC DYSFUNCTION
SHOULD BE RESUSCITATED ACCORDING TO STANDARD SSC
Copyrights apply
 EMPIRIC ANTIBIOTIC THERAPY
 Patients presenting with severe multisystem involvement and shock should also
receive prompt empiric broad-spectrum antibiotic therapy pending culture results
because MIS-C can present with signs and symptoms that mimic those of septic
shock and toxic shock syndrome. 
- 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- persistent erythema of the skin involving at least 90
percent of the body surface. 

- Antibiotics should be discontinued once bacterial infection has been excluded if the
child's clinical status has stabilized.
 IMMUNOMODULATORY THERAPY
 Initial therapy – For most patients we suggest treatment with both
intravenous immune globulin (IVIG) and glucocorticoids rather than
either drug alone
 However, if the patient has persistent fevers and rising C-reactive protein
(CRP), D-dimer, and/or ferritin despite treatment with IVIG, we suggest
adding glucocorticoid therapy .
 if they do not show improvement within 24 hours of treatment (eg,
resolution of fever, improving organ function, decreasing levels of
inflammatory markers), Patients are considered refractory 
 we suggest pulse-dose glucocorticoid therapy WITH
 infliximab or anakinra ,IL-1 inhibitor .
 A second dose of IVIG is generally avoided because of the risk of volume
overload and hemolytic anemia. Consultation with pediatric infectious
disease and rheumatology specialists is advised.
 PREVENTION OF THROMBOTIC COMPLICATIONS 

 Most patients with MIS-C – For most patients, we suggest low-dose aspirin (3 to 5

mg/kg daily)
 Patients with current or prior venous thromboembolism (VTE) –should receive
therapeutic anticoagulation (typically with low-molecular-weight heparin [LMWH]).
 Patients with severe left ventricular (LV) dysfunction – (ejection fraction <35 percent),
We suggest therapeutic anticoagulation ,provided that the child is not at increased risk
of ,This is based largely on our experience in managing children with severe myocarditis.
 Patients with large or giant coronary artery (CA) aneurysms – Patients with large or
giant CA aneurysms should receive therapeutic anticoagulation in addition to aspirin.
 For patients who do not have any of the above listed indications for therapeutic
anticoagulation but who have severe MIS-C manifestations requiring
immobilization, central lines, and PICU care, we suggest administering an
anticoagulant at prophylactic dosing.
  For hospitalized patients on the general pediatric ward the decision to administer an
anticoagulant in addition to low-dose aspirin for VTE prophylaxis is individualized,
weighing the risks and benefits.
PREVENTION OF THROMBOTIC COMPLICATIONS 
PROGNOSIS AND FOLLOW-UP
 FOLLOW-UP
 Follow-up echocardiography is performed at the following intervals:
-In patients who have CA dilation/aneurysm on initial echocardiogram,
echocardiography is repeated every two to three days until CA size is stable and then
every one to two weeks for the next four to six weeks.
-For patients with systolic dysfunction and normal CAs on initial echocardiogram, the
echocardiogram is repeated as clinically indicated, including repeat imaging of the CAs
with each study.
-For patients who had evidence of CA involvement or systolic dysfunction in the acute
phase, cardiac magnetic resonance imaging can be considered at approximately two
to six months after the acute illness to assess ventricular function and evaluate for
edema, diffuse fibrosis, and scar by myocardial delayed enhancement.

 Usual practice is to limit physical activity for a period of time (typically three to
six months) until cardiac function fully recovers, as is the practice for children
recovering from myocarditis
 PROGNOSIS
 Long-term follow-up data are limited, but the prognosis of MIS-C
looks positive as most children have a full clinical recovery.

 The overall mortality rate is approximately 1 to 2 percent.

 Most children with cardiac involvement have recovery of function

by hospital discharge.

 Children with cardiac dysfunction should have follow-up with

cardiology after discharge. 
VACCINATION FOR COVID-19
 VACCINATION FOR COVID-19
 Vaccination for COVID-19 is rarely associated with development of MIS-
C and may protect against it 
 Vaccine trials in this age group have not identified a potential signal,
although rare case reports of MIS in adults following vaccination
highlight the importance of monitoring for this possible adverse effect .
 Nevertheless, some evidence suggests that vaccination may protect
against MIS-C . In a study of 102 patients aged 12 to 18 years
hospitalized with MIS-C, 95 percent were unvaccinated; of the 5 patients
with MIS-C who had previously received primary series of fizzer vaccine
none required invasive respiratory or cardiovascular support
 In a study of 186 individuals ≥5 years old with a history of MIS ≥90 days
prior to vaccine receipt, the side effect profile of mRNA vaccination was
similar to that in the general population; no cases of myocarditis or
recurrent MIS were observed 
SPECIALIZED UNIT TO TREAT MULTISYSTEM INFLAMMATORY
SYNDROME IN CHILDREN (MIS-C)
REFEERENCE:
 Centers for Disease Control and Prevention(CDC)

 world health organization (WHO)

 Surviving Sepsis Campaign (SSC)

 Egyptian Union of Pediatricians( E.U.P )

 UP TO DATE