Authors: Mary Beth F Son, MD, Kevin Friedman, MD

Section Editors: David R Fulton, MD, Sheldon L Kaplan, MD, Robert Sundel, MD, Adrienne G
Randolph, MD, MSc
Deputy Editor: Elizabeth TePas, MD, MS

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jul 2021. | This topic last updated: Jul 20, 2021.

What's New

Sequelae after hospital discharge for children with MIS-C (June 2021)

The nature and frequency of long-term complications from COVID-19-rela…

Read more

What's New

Thrombotic complications in pediatric patients with COVID-19 and MIS-

C (May 2021)

Patients with COVID-19 can have coagulation abnormalities that create a …

Read more

What's New

Combined therapy with IVIG plus glucocorticoids in pediatric patients

with MIS-C (March 2021)

Optimal immune-modifying therapy for COVID-19-related multisystem infl…

Read more
:
 INTRODUCTION

A novel coronavirus was identified in late 2019 that rapidly reached pandemic
proportions. The World Health Organization designated the disease COVID-19,
which stands for coronavirus disease 2019 [1]. The virus that causes COVID-19 is
designated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

In children, COVID-19 is usually mild. However, in rare cases, children can be

severely affected, and clinical manifestations may differ from adults. In April of
2020, reports from the United Kingdom documented a presentation in children
similar to incomplete Kawasaki disease (KD) or toxic shock syndrome [2,3]. Since
then, there have been reports of similarly affected children in other parts of the
world [4-11]. 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, or
pediatric hyperinflammatory shock).

The management and prognosis of MIS-C will be discussed here. The

epidemiology, clinical features ( table 1), evaluation ( algorithm 1), and
diagnosis ( table 2) of MIS-C are discussed separately, as are other aspects of
COVID-19 in children and adults:

● (See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C)

clinical features, evaluation, and diagnosis".)
● (See "COVID-19: Clinical manifestations and diagnosis in children".)
● (See "COVID-19: Management in children".)
● (See "COVID-19: Epidemiology, virology, and prevention".)
● (See "COVID-19: Clinical features" and "COVID-19: Diagnosis".)
● (See "COVID-19: Infection control for persons with SARS-CoV-2 infection".)
● (See "COVID-19: Management in hospitalized adults".)
● (See "COVID-19: Hypercoagulability".)
● (See "COVID-19: Outpatient evaluation and management of acute illness in
adults".)
:
 Understanding of COVID-19 and MIS-C is evolving. Interim guidance has been
issued by the WHO and by the United States Centers for Disease Control and
Prevention [4,12,13]. Links to these and other related society guidelines are found
elsewhere. (See 'Society guideline links' below.)

SETTING OF CARE

The appropriate setting of care is determined by the severity of illness, risk of

complications, and adequacy of follow-up. Most children with MIS-C are managed
in the inpatient setting.

● Inpatient management – Children with moderate to severe manifestations of

MIS-C and those at risk for complications should be admitted to the hospital.
This includes any of the following [14]:

• Abnormal vital signs (tachycardia, tachypnea)

• Shock
• Respiratory distress
• Evidence of cardiac involvement (eg, elevated troponin or brain natriuretic
peptide, depressed ventricular function or coronary artery [CA]
abnormality on echocardiogram, abnormal electrocardiogram)
• Features of Kawasaki disease (KD) ( table 3)
• Neurologic changes (eg, depressed mental status, abnormal neurologic
examination, seizures)
• Severe abdominal pain or vomiting, especially if unable to tolerate oral
feeding
• Clinical or laboratory evidence of dehydration
• Laboratory evidence of acute kidney injury, acute hepatic injury, or
coagulopathy
• Underlying medical condition that may place the child at increased risk for
complications (eg, immunodeficiency, cardiac or pulmonary conditions)
• Inability to return for follow-up

In addition, we generally hospitalize children with clinical findings that

strongly suggest a diagnosis of MIS-C, even if their symptoms are relatively
:
 mild initially. This is because children with MIS-C often have worsening of their
clinical status as the illness progresses. Thus, hospital admission and
treatment with immune-modifying therapy is suggested for all patients who
meet diagnostic criteria for MIS-C, as discussed below (see 'Immune-
modifying therapies' below). However, practice varies regarding management
of mild cases, and other centers may not admit such patients.

The level of care (ward versus pediatric intensive care unit [PICU]) is
determined by the severity of illness. Admission to a PICU is appropriate for
children with hemodynamic instability (shock, arrhythmia), significant
respiratory compromise, or other potentially life-threatening complications. In
the available case series, approximately 60 to 80 percent of affected patients
required PICU care [9,11,15-17], but this may change as milder cases come to
attention.

● Outpatient management – It may be reasonable to manage select patients

with mild symptoms in the outpatient setting, provided that the child is well
appearing (ie, normal vital signs and reassuring physical examination) and
close clinical follow-up can be assured. Such patients are typically those who
have undergone evaluation for MIS-C because of nonspecific symptoms or
findings (eg, fever, rash), who lack worrisome findings, and in whom the
diagnosis of MIS-C is uncertain. By contrast, children with more convincing
findings who either meet diagnostic criteria for MIS-C ( table 2) or in whom
the diagnosis is strongly suspected should generally be hospitalized, even if
the manifestations are mild initially. As described above, such patients are at
risk for worsening of their clinical status as the illness progresses.

For children who are managed in the outpatient setting, it is critical to provide
instructions for when to seek care and to ensure appropriate follow-up (see
'Information for patients' below). Most children should have follow-up within
48 hours if persistently febrile. Follow-up should include clinical assessment
and repeat laboratory testing. (See "COVID-19: Multisystem inflammatory
syndrome in children (MIS-C) clinical features, evaluation, and diagnosis",
section on 'Laboratory testing'.)
:
 MULTIDISCIPLINARY CARE

By definition, MIS-C is a multisystem disease, and care for affected children

requires coordination of many different specialties. This may include:

● Pediatric infectious disease specialists

● Pediatric rheumatologists
● Pediatric cardiologists
● Pediatric intensivists
● Pediatric hematologists

INFECTION CONTROL

Limiting transmission of SARS-CoV-2 is an essential component of care in patients

with suspected or documented COVID-19 and COVID-19-related illnesses,
including MIS-C. This includes identifying and isolating patients with suspected
COVID-19, universal source control (eg, 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.

While specific infection control measures may vary from institution to institution,
the general approach is as follows:

● All patients with suspected MIS-C should undergo testing for SARS-CoV-2 at
the time of presentation. (See "COVID-19: Multisystem inflammatory
syndrome in children (MIS-C) clinical features, evaluation, and diagnosis",
section on 'Testing for SARS-CoV-2'.)

● Infection control precautions should be used pending the results of initial

testing. (See "COVID-19: Infection control for persons with SARS-CoV-2
infection", section on 'General approach'.)

● If SARS-CoV-2 polymerase chain reaction (PCR) is positive, infection control

precautions should be continued. (See "COVID-19: Infection control for
persons with SARS-CoV-2 infection", section on 'General approach'.)
:
 ● If the initial PCR is negative, a second PCR should be collected ≥24 hours from
the first. (See "COVID-19: Infection control for persons with SARS-CoV-2
infection", section on 'Discontinuation of precautions'.)

● Infection control measures can generally be discontinued if the patient has

defervesced and at least two consecutive PCRs obtained ≥24 hours apart are
negative (regardless of serology results). (See "COVID-19: Infection control for
persons with SARS-CoV-2 infection", section on 'Discontinuation of
precautions'.)

A detailed discussion of COVID-19-related infection control measures, including

advice regarding visitors and family members, is provided separately. (See "COVID-
19: Infection control for persons with SARS-CoV-2 infection".)

MANAGEMENT

Management of MIS-C has evolved over the course of the pandemic. Most children
with moderate to severe manifestations are treated initially with both intravenous
immune globulin (IVIG) and glucocorticoids ( algorithm 2). (See 'Intravenous
immune globulin' below and 'Glucocorticoids' below.)

Additional interventions depend upon the severity of illness, constellation of

findings, and response to initial therapy.

Our approach outlined below is generally consistent with published guidance from
the American College of Rheumatology, American Academy of Pediatrics, and
pediatric inflammatory multisystem syndrome temporally associated with SARS-
CoV-2 (PIMS-TS) National Consensus Management Study Group in the United
Kingdom [14,18,19]. (See 'Society guideline links' below.)

Treatment considerations based on presentation — Management of children

with MIS-C depends in part on the constellation of clinical findings.

Shock — Children presenting with shock should be resuscitated according to

standard protocols ( algorithm 3). 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 milrinone may be helpful. Management of shock in pediatric patients is
discussed in greater detail separately. (See "Initial management of shock in
children".)

Features of Kawasaki disease — Patients who meet criteria for incomplete or

complete Kawasaki disease (KD) ( table 3) should receive standard therapies for
KD, including 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. (See
'Intravenous immune globulin' below and 'Glucocorticoids' below.)

Treatment of KD is summarized in the algorithms ( algorithm 4A-B) and is

discussed in greater detail separately. (See "Kawasaki disease: Initial treatment
and prognosis" and "Incomplete (atypical) Kawasaki disease" and "Overview of
intravenous immune globulin (IVIG) therapy", section on
'Inflammatory/autoimmune disorders'.)

Cardiac dysfunction — During the acute inflammatory phase of illness,

children with cardiac involvement may present with hemodynamic compromise
and can develop arrhythmias during their course of illness. Serial
echocardiographic assessment of cardiac function and monitoring of brain
natriuretic peptide and troponin levels can help guide therapy. Management
focuses on supportive care to maintain hemodynamic stability and ensure
adequate systemic perfusion. We suggest IVIG and glucocorticoids for all patients
with cardiac involvement, as discussed below. (See 'Intravenous immune globulin'
below and 'Glucocorticoids' below.)

Continuous telemetry monitoring is essential so that arrhythmias are promptly

detected and treated. Patients with severe LV dysfunction are treated with
intravenous diuretics and inotropic agents, such as milrinone, dopamine, and
dobutamine. In cases of fulminant disease, mechanical hemodynamic support
:
 may be necessary in the form of extracorporeal membrane oxygenation (ECMO) or
a ventricular assist device. Management is generally similar to that of acute
myocarditis, which is discussed in greater detail separately. (See "Treatment and
prognosis of myocarditis in children".)

Antimicrobial therapy

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, erythroderma). Antibiotics should be discontinued once bacterial
infection has been excluded if the child's clinical status has stabilized. Additional
details regarding choice of empiric regimen, options for penicillin-allergic children,
and duration of treatment are provided separately. (See "Septic shock in children:
Rapid recognition and initial resuscitation (first hour)", section on 'Empiric
regimens' and "Staphylococcal toxic shock syndrome", section on 'Empiric
therapy'.)

Antiviral therapy — The role of SARS-CoV-2 antiviral therapies (eg, remdesivir)

in the management of MIS-C is uncertain. Many patients are polymerase chain
reaction (PCR) negative for SARS-CoV-2, and MIS-C likely represents a
postinfectious complication rather than active infection. (See "COVID-19:
Multisystem inflammatory syndrome in children (MIS-C) clinical features,
evaluation, and diagnosis", section on 'Pathophysiology'.)

However, some children do have positive PCR testing and may have active
infection. Thus, antiviral therapy may have potential to impact the disease process
in some, but not all, patients. Use of antiviral agents is generally limited to children
with severe MIS-C manifestations who have evidence of active infection. We advise
consultation with an infectious disease specialist to guide decision making.

Details regarding choice of SARS-CoV-2 antiviral agent, dosing, side effects, and
:
 monitoring are provided separately. (See "COVID-19: Management in children",
section on 'SARS-CoV-2 antiviral therapy for select patients'.)

Immune-modifying therapies — Our approach to immune-modifying therapy in

patients with MIS-C is summarized in the algorithm ( algorithm 2) and discussed
in the following sections.

Intravenous immune globulin — We suggest intravenous immune globulin

(IVIG) for all patients who meet diagnostic criteria for MIS-C ( table 2).

The dosing for IVIG in this setting is 2 g/kg administered in a single infusion over 8
to 12 hours [14]. In obese patients, the dose should be based upon ideal body
weight. For patients with significant LV dysfunction, if there is concern that the
patient will not tolerate the volume load of the full dose in a single infusion, it can
be given in divided doses over two days. (See "Kawasaki disease: Initial treatment
and prognosis", section on 'Intravenous immune globulin'.)

If IVIG is not available, treatment with glucocorticoids alone is appropriate. (See

'Glucocorticoids' below.)

Patients should have blood drawn for serologic testing for SARS-CoV-2 and other
pathogens prior to administration of IVIG. In addition, immunoglobulins elevate
the erythrocyte sedimentation rate, so following this parameter is less useful after
delivering a 2 g/kg dose of IVIG. Other inflammatory markers (eg, C-reactive
protein [CRP], ferritin) are more reliable for serial monitoring after IVIG. (See
"COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical
features, evaluation, and diagnosis", section on 'Evaluation'.)

The evidence supporting the use of IVIG in MIS-C is limited to case series in which
approximately 70 to 95 percent of patients were treated with IVIG, with or without
additional medications [2,8-11,15,17,20-24]. The vast majority of patients in these
series improved and had recovery of cardiac function.

Indirect evidence supporting IVIG use comes from studies involving patients with
similar conditions, including KD, toxic shock syndrome, and myocarditis, which are
described in separate topic reviews:

● KD (see "Kawasaki disease: Initial treatment and prognosis", section on

:
 'Intravenous immune globulin')
● Toxic shock syndrome (see "Invasive group A streptococcal infection and toxic
shock syndrome: Treatment and prevention", section on 'Intravenous immune
globulin')
● Myocarditis (see "Treatment and prognosis of myocarditis in children", section
on 'Intravenous immune globulin')

Glucocorticoids — Practice regarding use of glucocorticoid therapy in MIS-C is

not standardized. Our general approach is as follows ( algorithm 2):

● Whom to treat – We suggest glucocorticoid therapy in addition to IVIG in

patients with any of the following:

• Moderate or severe manifestations (eg, shock requiring vasopressors, LV

systolic dysfunction, elevated troponin or brain natriuretic peptide,
arrythmia, CA aneurysm [Z-score ≥2.5], or other manifestations requiring
pediatric intensive care unit [PICU] care).

• Persistent fevers and rising inflammatory markers (eg, CRP, ferritin) or

evidence of intravascular coagulopathy (eg, rising D-dimer) despite
treatment with IVIG. These findings may suggest macrophage activation
syndrome (MAS) or cytokine release syndrome (CRS; also called cytokine
storm), which may not respond to IVIG therapy. (See "Clinical features and
diagnosis of hemophagocytic lymphohistiocytosis".)

If IVIG is not available, treating these patients with systemic glucocorticoids alone
is a reasonable option.

● Timing – For patients with moderate or severe manifestations, glucocorticoid

therapy is typically given concomitantly with IVIG. In patients who initially
have less severe manifestations, glucocorticoids may be given as a second-line
treatment if there is an inadequate response to IVIG (eg, persistent fevers,
rising inflammatory markers) [14].

● Dosing – Glucocorticoid therapy is initially given intravenously with

methylprednisolone at a dose of 2 mg/kg/day in two divided doses [14]. Once
the patient has defervesced and is improved clinically, this can be transitioned
:
 to an equivalent oral dose of prednisolone or prednisone by the time of
discharge and then tapered off over three to four weeks. In life-threatening
circumstances or refractory cases, pulse doses of glucocorticoids have been
used (intravenous methylprednisolone 30 mg/kg/dose, with a maximum of 1
g), though there are few supporting data [14].

● Efficacy – The evidence supporting glucocorticoids for MIS-C is limited to case

series in which approximately 30 to 60 percent of patients were treated with
glucocorticoids at varying doses, and most patients recovered rapidly
[11,15,17,22-27].

The three largest observational studies varied in disease severity and inclusion
criteria, treatments compared, and outcomes measured, but all found clinical
benefit with IVIG plus glucocorticoids compared with IVIG alone. The US study
included 518 patients from March through October 2020 with confirmed MIS-
C based upon US Centers for Disease Control (CDC) criteria, of whom 89
received initial treatment with IVIG alone; 241 received IVIG plus
glucocorticoids; 107 received IVIG, glucocorticoids, and biologics; and 81
received other treatments, including 43 who received glucocorticoids only
[23]. The international study included 614 patients from June 2020 through
February 2021 with suspected MIS-C (80 percent met the World Health
Organization [WHO] criteria), of whom 246 received initial treatment with IVIG
alone, 208 received IVIG plus glucocorticoids, 99 received glucocorticoids
alone, 22 received other immunomodulatory therapy, and 39 received no
immunomodulatory treatment [24]. The French study included 111 children
who were diagnosed with MIS-C according to the WHO criteria, of whom 72
received initial treatment with IVIG alone, 34 received IVIG plus
methylprednisolone, and 5 received neither agent [22]. All three studies used
propensity score analysis to examine outcomes in patients treated with
combined therapy (IVIG plus glucocorticoids) compared with IVIG alone. The
international study also compared both of these with glucocorticoids alone.
The following findings were noted [22-24]:

• Reduced need for adjunctive therapy – In all studies, combination

therapy was associated with reduced need for adjunctive
immunomodulatory therapy (US study: risk ratio [RR] 0.49, 95% CI 0.36-
:
 0.65; international study: odds ratio [OR] 0.18, 95% CI 0.10-0.33; French
study: OR 0.19, 95% CI, 0.06-0.61).

• Possible improvement in persistent or recurrent fevers – In all three

studies, patients who received combination therapy were less likely to
have persistent or recurrent fevers; however, this finding was statistically
significant only in the French study (US study: RR 0.78, 95% CI 0.53-1.13;
international study: OR 0.60, 95% CI 0.31-1.17; French study: OR 0.25, 95%
CI 0.09-0.70).

• Possible reduced need for hemodynamic support – Both the US and

French studies found that combination therapy, as compared with IVIG
alone, was associated with reduced need for hemodynamic support at
one to two days after initial treatment (US study: RR 0.59, 95% CI 0.40-
0.85; French study: OR 0.21, 95% CI 0.06-0.76); however, the international
study did not detect a significant difference in this outcome (OR 1.43, 95%
CI 0.57-3.62).

• Possible improvement in ventricular function – In the US and French

studies, patients who received combination therapy were less likely to
have LV dysfunction (ie, LV ejection fraction [LVEF] <55 percent) at one to
two days after initial treatment, a finding that was statistically significant
only in the French study (US study: RR 0.46, 95% CI 0.19-1.15; French
study: OR 0.20, 95% CI 0.06-0.66). However, there was a significant
improvement in the primary outcome of cardiovascular dysfunction in the
US study, which was a composite of shock requiring vasopressor use and
LV dysfunction, in the combination therapy versus IVIG alone groups (RR
0.56, 95% CI 0.34-0.94). The international study did not detect a significant
difference in this outcome (OR 1.65, 95% CI 0.78-3.49). In addition, the
international study did not detect a difference in disease severity, per an
ordinal scale of clinical factors, among three treatment groups (IVIG
alone, glucocorticoids alone, and combination therapy).

• No apparent difference in mortality – In all studies, there were very few

deaths in each treatment group, and the low number of events precludes
drawing any conclusions as to whether different treatment approaches
:
 have any impact on mortality.

The inconsistent findings between the international study and the other two
studies may be accounted for, at least in part, by differences in patient
selection. Disease severity was considerably higher in the US and French
studies compared with the international study (eg, in the US and French
studies, 45 to 60 percent of patients required vasopressors versus 12 percent
in the international study; 40 to 47 percent had LV dysfunction versus 12
percent, respectively; and 8 to 20 percent required mechanical ventilation
versus 1.5 percent, respectively). In addition, all patients in the US and French
studies met CDC or WHO diagnostic criteria for MIS-C, whereas 20 percent of
patients in the international study did not meet WHO criteria. Lastly, the
outcomes differed among the studies. In the French study, the primary
outcome was fever persistence at 48 hours or recrudescence within seven
days following treatment. In the US study, the primary outcome was a
composite of LV dysfunction or shock requiring vasopressor use on or two
days after treatment. In the international study, the primary outcomes
included a composite of inotropic support or mechanical ventilation by two
days or later after treatment or death, as well as a reduction on an ordinal
scale of clinical severity. These differences across the studies may explain the
dissimilar findings.

There are no available data comparing different dosing regimens for

glucocorticoids in MIS-C. Indirect evidence supporting glucocorticoid therapy
comes from studies involving patients with similar conditions, including KD
and myocarditis, which are described in separate topic reviews. (See "Kawasaki
disease: Initial treatment and prognosis", section on 'Glucocorticoids' and
"Treatment and prognosis of myocarditis in children", section on
'Glucocorticoids'.)

Adjunctive therapies — The benefits and risks of adjunctive therapies

(interleukin [IL] 1 inhibitors [eg, anakinra, canakinumab], IL-6 inhibitors [eg,
tocilizumab], tumor necrosis factor [TNF] inhibitors [eg, infliximab]) are uncertain.
Consultation with pediatric infectious disease and rheumatology specialists is
advised. We make decisions about the use of adjunctive therapies on a case-by-
case basis, according to disease severity and markers of inflammation or active
:
 SARS-CoV-2 infection.

Anakinra, canakinumab, and tocilizumab are alternative options for treatment of

MAS or CRS in patients who cannot receive glucocorticoids and those who are
refractory to glucocorticoids. In the available case series, IL-1 and IL-6 inhibitors
were used in approximately 10 to 20 percent of patients [11,25]. Use of these
agents should be guided by consultation with a pediatric rheumatologist and
should occur in the context of a clinical trial whenever possible. (See "COVID-19:
Management in hospitalized adults", section on 'Others' and "COVID-19:
Management in hospitalized adults", section on 'IL-6 pathway inhibitors (eg,
tocilizumab)'.)

Antithrombotic therapy — Patients with MIS-C are at risk of experiencing

thrombotic complications [28,29]. For example, patients with severe LV
dysfunction are at risk for apical LV thrombus, and those with CA aneurysms are at
risk for myocardial infarction. In addition, patients may be at risk for venous
thromboembolism (VTE), including deep vein thrombosis and pulmonary embolus,
due to hypercoagulability associated with COVID-19. (See "COVID-19:
Hypercoagulability".)

There are few data to guide treatment, and practice varies considerably. Our
general approach is as follows ( algorithm 5):

● Aspirin for all patients – We treat all patients with low-dose aspirin (3 to 5
mg/kg daily). This is based largely on indirect evidence from patients with KD.
(See "Kawasaki disease: Initial treatment and prognosis", section on 'Aspirin'.)

● Patients with current or prior VTE – Patients with current or prior VTE should
receive therapeutic anticoagulation (typically with low-molecular-weight
heparin [LMWH]). Therapeutic dosing of LMWH is summarized in the table (
table 4). Treatment of VTE is discussed in greater detail. (See "Venous
thrombosis and thromboembolism in children: Treatment, prevention, and
outcome", section on 'Approach to treatment'.)

● Patients with severe LV dysfunction – We suggest therapeutic

anticoagulation for patients with severe LV dysfunction, provided that the
child is not at increased risk of bleeding (eg, no thrombocytopenia, bleeding
:
 diathesis, or active bleeding). This is based largely on our experience
managing children with severe myocarditis, which is discussed separately.
(See "Treatment and prognosis of myocarditis in children", section on
'Anticoagulation'.)

● Patients with large or giant CA aneurysms – Patients with large or giant CA

aneurysms should receive therapeutic anticoagulation in addition to aspirin,
as discussed in detail separately. (See "Cardiovascular sequelae of Kawasaki
disease: Management and prognosis", section on 'Prevention of coronary
thrombosis'.)

● Patients with other severe MIS-C manifestations requiring PICU care – For
patients who do not have any of the above listed indications for therapeutic
anticoagulation but who have severe MIS-C manifestations requiring PICU
care, we suggest administering prophylactic-dose anticoagulant therapy
(typically LMWH), provided that bleeding risk is not high. For patients in this
category who also have a markedly elevated D-dimer (ie, >10 times the upper
limit of normal), we typically use treatment doses of LMWH.
Recommendations for prophylactic and treatment dosing of LMWH are
provided in the table ( table 4). VTE prophylaxis in children is discussed in
greater detail separately. (See "Venous thrombosis and thromboembolism in
children: Treatment, prevention, and outcome", section on 'Venous
thromboembolism prophylaxis'.)

● Patients with less severe MIS-C – For hospitalized patients without

indications for therapeutic anticoagulation who have less severe MIS-C (ie,
patients managed in the general pediatric ward), the decision to administer an
anticoagulant in addition to low-dose aspirin for VTE prophylaxis is
individualized, weighing the risk of thrombosis and risk of bleeding. The
diagnosis of COVID-19-related MIS-C itself should be considered a major risk
factor for VTE. Other important risk factors include the presence of a central
venous catheter, underlying malignancy, prolonged immobility, obesity, oral
contraceptive use, and family history of thrombophilia ( table 5). VTE
prophylaxis is appropriate for most adolescents hospitalized with MIS-C,
provided that bleeding risk is not high. In younger children, the decision is
made on a case-by-case basis. When VTE prophylaxis is used, LMWH is
:
 generally the preferred agent. Prophylactic dosing of LMWH is summarized in
the table ( table 4). Nonpharmacologic strategies for VTE prophylaxis (eg,
intermittent pneumatic compression devices [size permitting] and early
mobilization) are encouraged, but MIS-C-related coagulopathy may merit a
higher level of intervention. The approach to VTE prophylaxis in hospitalized
children is discussed in greater detail separately. (See "Venous thrombosis and
thromboembolism in children: Treatment, prevention, and outcome", section
on 'Venous thromboembolism prophylaxis'.)

Our suggested approach is supported by limited observational data [28]. In a

retrospective study that included 138 children hospitalized for MIS-C, nine patients
(6.5 percent) had documented thrombotic events, including upper-extremity deep
vein thrombosis (n = 4), lower-extremity deep vein thrombosis (n = 3), intracardiac
thrombus (n = 1), and acute ischemic stroke (n = 1) [28]. All of these episodes
occurred in adolescents ≥12 years old who had central venous catheters in place.
Most of the affected patients (67 percent) were critically ill. Markedly elevated D-
dimer (ie, >5 times the upper limit of normal) was an independent predictor of
thrombosis. There was wide practice variation regarding the use and dosing of
anticoagulant therapy in the study; overall, 58 percent of patients received
thromboprophylaxis during their hospitalization. Thus, the incidence of
thrombosis in this study may underestimate the true baseline risk of thrombosis in
patients with MIS-C. Nevertheless, the rate of thrombosis in this study is
considerably higher than in the general pediatric inpatient population (which is <1
percent). (See "Venous thrombosis and thromboembolism in children: Risk factors,
clinical manifestations, and diagnosis", section on 'Epidemiology'.)

FOLLOW-UP

The risk of long-term cardiovascular complications and approach to monitoring is

extrapolated from follow-up studies of children with Kawasaki disease (KD) and
viral myocarditis since there are few data on post-discharge follow-up of patients
with MIS-C.

At our center, follow-up echocardiography is performed at the following intervals:

:
 ● In patients who initially have normal function and normal coronary artery (CA)
dimensions, follow-up echocardiogram is performed one to two weeks post-
diagnosis to recheck CA size.

● 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 [30,31]. (See "Treatment and prognosis of myocarditis
in children", section on 'Activity'.)

OUTCOME

The prognosis of MIS-C is uncertain, given that it is a relatively new clinical entity
and long-term follow-up studies are lacking. The disease course in MIS-C can be
quite severe, with many children requiring intensive care interventions. Most
children survive, but deaths have been reported [9,17,25]. In a systematic review
of 16 case series including a total of 655 patients with MIS-C, there were 11 deaths
(1.7 percent) [25].

Most patients with cardiac involvement had recovery of ventricular function,

regression of coronary artery (CA) aneurysms, and resolution of arrhythmias,
though, in some reports, up to 20 percent of affected patients still had mildly
depressed function at the time of hospital discharge [25,32-35]. Several studies
:
 have demonstrated abnormalities in echocardiographic measures of diastolic
dysfunction and abnormal strain patterns that persist beyond three to four weeks
[27,34,36,37]. These studies and other reports of echocardiographic findings in
children with MIS-C are discussed in greater detail separately. (See "COVID-19:
Multisystem inflammatory syndrome in children (MIS-C) clinical features,
evaluation, and diagnosis", section on 'Echocardiography'.)

In a study of 46 children hospitalized for MIS-C from April to September of 2020

who were evaluated in a multidisciplinary follow-up clinic after discharge, common
sequelae included muscular weakness, reduced exercise capacity, anxiety, and
emotional difficulties [38]. Additional findings included:

● Systemic inflammation – Inflammatory markers (eg, C-reactive protein [CRP],

fibrinogen) normalized in nearly all children by six weeks and remained
normal at six months.

● Cardiac involvement – Systolic function and cardiac markers (troponin and

NT-proBNP) were normal in all patients by six months. Two patients had CA
aneurysms, one of which was large (Z-score of 9.18) and the other was small
(Z-score <3), which either improved or remained stable at six months.

● Exercise capacity – At six months, nearly half of patients were found to have
reduced exercise capacity (ie, six-minute walk test <3rd percentile for age).

● Quality of life (QoL) – At six months, 21 percent of patients reported reduced

QoL due to physical impairments (mild in 13 percent, severe in 8 percent); 35
percent reported emotional difficulties (mild in 14 percent, severe in 22
percent); 16 percent reported social difficulties (mild in 11 percent, severe in 5
percent); and 13 percent reported school difficulties (mild in 5 percent, severe
in 8 percent). Parental reports of QoL suggested a greater degree of
impairment. All but one child had resumed full-time education by six months.

● Repeat hospitalizations – During the follow-up period, three patients were

readmitted to the hospital for either MIS-C relapse or infectious complications
(including pneumonia, urosepsis, and skin and soft tissue infection).

● Speech, smell, and taste – At six weeks, 15 percent of patient reported

:
 dysphonia, anosmia, dysgeusia, and/or dysphagia. At six months, dysphonia
persisted in 9 percent, and anosmia/dysgeusia persisted 4 percent.

● Gastrointestinal symptoms – Persistent gastrointestinal symptoms

(abdominal pain, nausea, vomiting, diarrhea) were noted in 13 percent of
patients at six months.

● Neurologic abnormalities – Abnormalities on neurologic examination were

noted in 39 percent of patients at six months. Proximal and lower limb
weakness were the most common findings. Other findings, which were
generally subtle and only noticeable on detailed neurologic examination,
included abnormal reflexes, dysmetria, abnormal eye movements, difficulty in
tandem walking, and sensory abnormalities.

● Kidney function – Creatinine normalized during follow-up in all patients. At

six weeks, 9 percent of patients had persistent proteinuria, which resolved in
all but one patient by six months. Ten percent of children had elevated blood
pressure at six-month follow-up, with only one child requiring
antihypertensive therapy.

● Thrombosis – Two patients had thrombi during the acute illness, both of
whom completed a course of anticoagulation without complication, and both
had resolution of the thrombi on repeat imaging at six weeks.

● Seropositivity – Most patients (90 percent) remained seropositive for SARS-

CoV-2 antibodies at six months.

VACCINATION FOR COVID-19

COVID-19 vaccination of people with a history of MIS-C is discussed separately.

(See "COVID-19: Vaccines to prevent SARS-CoV-2 infection", section on 'History of
SARS-CoV-2 infection'.)

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries

:
 and regions around the world are provided separately. (See "Society guideline
links: Kawasaki disease" and "Society guideline links: COVID-19 – Index of guideline
topics".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and
"Beyond the Basics." The Basics patient education pieces are written in plain
language, at the 5th to 6th grade reading level, and they answer the four or five key
questions a patient might have about a given condition. These articles are best for
patients who want a general overview and who prefer short, easy-to-read
materials. Beyond the Basics patient education pieces are longer, more
sophisticated, and more detailed. These articles are written at the 10th to 12th
grade reading level and are best for patients who want in-depth information and
are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We
encourage you to print or email these topics to your patients. (You can also locate
patient education articles on a variety of subjects by searching on "patient
education" and the keyword[s] of interest.)

● Basics topics:

• (See "Patient education: COVID-19 and children (The Basics)".)

• (See "Patient education: COVID-19 overview (The Basics)" and "Patient
education: COVID-19 vaccines (The Basics)".)
• (See "Patient education: Kawasaki disease (The Basics)".)

SUMMARY AND RECOMMENDATIONS

● Overview – Multisystem inflammatory syndrome in children (MIS-C) is an

uncommon complication of COVID-19 that has a presentation similar to
Kawasaki disease (KD) or toxic shock syndrome ( table 2). (See 'Introduction'
above and "COVID-19: Multisystem inflammatory syndrome in children (MIS-C)
clinical features, evaluation, and diagnosis".)
:
 ● Setting of care – The appropriate setting of care is determined by the severity
of illness, risk of complications, and adequacy of follow-up. Most children with
MIS-C are managed in the inpatient setting. (See 'Setting of care' above.)

● Multidisciplinary care – Care for patients with MIS-C requires coordination of

many different specialties. Infectious disease, rheumatology, and cardiology
specialists should be consulted early. (See 'Multidisciplinary care' above.)

● Management of shock and cardiac dysfunction – Children presenting with

shock should be resuscitated according to standard protocols ( algorithm 3).
Management focuses on supportive care to maintain hemodynamic stability
and ensure adequate systemic perfusion. Continuous cardiac monitoring is
essential so that arrhythmias are promptly detected and treated. (See "Initial
management of shock in children" and 'Cardiac dysfunction' above.)

● Empiric antibiotic therapy – Because MIS-C can present with signs and
symptoms that mimic those of septic shock and toxic shock syndrome,
patients presenting with severe multisystem involvement and shock should
generally receive prompt empiric broad-spectrum antibiotic therapy pending
culture results. (See 'Antibiotic therapy' above and "Septic shock in children:
Rapid recognition and initial resuscitation (first hour)", section on 'Empiric
antibiotic therapy'.)

● Limited role of antiviral therapy – Because MIS-C likely represents a

postinfectious complication rather than active infection, the role of antiviral
therapies (eg, remdesivir) in the management of MIS-C is limited. (See
'Antiviral therapy' above.)

● Immune-modifying therapies – Our approach to immune-modifying therapy

in MIS-C is as follows ( algorithm 2) (see 'Immune-modifying therapies'
above):

• Children with moderate to severe manifestations – For children with

moderate or severe manifestations (eg, shock requiring vasopressors, left
ventricular [LV] systolic dysfunction, elevated troponin or brain natriuretic
peptide, arrythmia, coronary artery [CA] aneurysm [Z-score ≥2.5], or other
manifestations requiring pediatric intensive care unit [PICU] care), we
:
 suggest initial therapy with combined intravenous immune globulin (IVIG)
plus a glucocorticoid rather than IVIG alone (Grade 2C). If IVIG is not
available, treatment with glucocorticoids alone is acceptable.
Observational studies suggest that initial combination therapy may
hasten cardiac recovery and reduce the need for hemodynamic support
and/or adjunctive immune-modifying therapy. The dosing for IVIG in this
setting is 2 g/kg administered in a single infusion over 8 to 12 hours.
Glucocorticoid therapy consists of intravenous methylprednisolone at a
dose of 2 mg/kg/day in two divided doses. Once the patient has
defervesced and is improved clinically, this can be transitioned to an
equivalent oral dose of prednisolone or prednisone by the time of
discharge and then tapered off over two to four weeks. (See 'Intravenous
immune globulin' above and 'Glucocorticoids' above.)

• Children with less severe manifestations – For children with less severe
manifestations, we suggest treatment with IVIG alone initially (Grade 2C).
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 (Grade 2C). (See 'Intravenous immune
globulin' above and 'Glucocorticoids' above.)

• Role of other agents – The role of other adjunctive therapies (interleukin

[IL] 1 inhibitors [eg, anakinra, canakinumab], IL-6 inhibitors [eg,
tocilizumab], tumor necrosis factor [TNF] inhibitors [eg, infliximab]) is
uncertain. Consultation with pediatric infectious disease and
rheumatology specialists is advised. (See 'Adjunctive therapies' above.)

● Prevention of thrombotic complications – Patients with MIS-C are at

increased risk of thrombosis. The optimal approach to thromboprophylaxis in
this setting is uncertain, and practice varies considerably. Our general
approach is as follows ( algorithm 5) (see 'Antithrombotic therapy' above):

• All patients with MIS-C – For all patients, we suggest low-dose aspirin (3
to 5 mg/kg daily) (Grade 2C). This is based largely on indirect evidence
from patients with KD. (See "Kawasaki disease: Initial treatment and
prognosis", section on 'Aspirin'.)
:
 • Patients with current or prior venous thromboembolism (VTE) –
Patients with current or prior VTE should receive therapeutic
anticoagulation (typically with low-molecular-weight heparin [LMWH]).
Therapeutic dosing of LMWH is summarized in the table ( table 4).
Treatment of VTE is discussed in greater detail separately. (See "Venous
thrombosis and thromboembolism in children: Treatment, prevention,
and outcome", section on 'Approach to treatment'.)

• Patients with severe LV dysfunction – We suggest therapeutic

anticoagulation for patients with severe LV dysfunction, provided that the
child is not at increased risk of bleeding (eg, no thrombocytopenia,
bleeding diathesis, or active bleeding) (Grade 2C). This is based largely on
our experience in managing children with severe myocarditis, which is
discussed separately. (See "Treatment and prognosis of myocarditis in
children", section on 'Anticoagulation'.)

• Patients with large or giant CA aneurysms – Patients with large or giant

CA aneurysms should receive therapeutic anticoagulation in addition to
aspirin, as discussed in detail separately. (See "Cardiovascular sequelae of
Kawasaki disease: Management and prognosis", section on 'Prevention of
coronary thrombosis'.)

• Patients with other severe MIS-C manifestations requiring PICU care

– For patients who do not have any of the above listed indications for
therapeutic anticoagulation but who have severe MIS-C manifestations
requiring PICU care, we suggest administering an anticoagulant at
prophylactic dosing, provided that bleeding risk is not high (Grade 2C).
For patients in this category who also have a markedly elevated D-dimer
(ie, >10 times to upper limit of normal), we suggest therapeutic
anticoagulation (Grade 2C). We typically use LMWH in both settings.
Prophylactic and treatment dosing of LMWH is summarized in the table (
table 4). VTE prophylaxis in children is discussed in greater detail
separately. (See "Venous thrombosis and thromboembolism in children:
Treatment, prevention, and outcome", section on 'Venous
thromboembolism prophylaxis'.)
:
 • Patients with less severe MIS-C – For hospitalized patients without
indications for therapeutic anticoagulation who have less severe MIS-C (ie,
patients managed on the general pediatric ward), the decision to
administer an anticoagulant in addition to low-dose aspirin for VTE
prophylaxis is individualized, weighing the individual risks and benefits.
The diagnosis of COVID-19-related MIS-C itself should be considered a
major risk factor for VTE. The approach to VTE prophylaxis in hospitalized
children is discussed in greater detail separately. (See "Venous thrombosis
and thromboembolism in children: Treatment, prevention, and outcome",
section on 'Venous thromboembolism prophylaxis'.)

● Prognosis and follow-up – The prognosis of MIS-C is uncertain as long-term

follow-up data are limited. 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. Other sequelae following discharge include
muscular weakness, reduced exercise capacity, anxiety, and emotional
difficulties. (See 'Outcome' above and 'Follow-up' above.)

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