COVID-19: Multisystem inflammatory syndrome in children (MIS-C) management and outcome

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: Oct 2021. | This topic last updated: Oct 12, 2021.

INTRODUCTION A novel coronavirus was identified in late 2019 that rapidly reached pandemic proportions.

The World Health Organization (WHO) 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 and Italy documented a
severe shock-like illness in children with features of incomplete Kawasaki disease (KD) or toxic shock syndrome [2,3].
Subsequently, there have been reports of similarly affected children from most 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 continues to evolve. Guidance has been issued by the WHO and by the
United States Centers for Disease Control and Prevention (CDC) [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.

●Severity assessment – Moderate-to-severe manifestations of MIS-C may include any of the following [14]:
•Abnormal vital signs (tachycardia, tachypnea)
•Shock
•Respiratory distress, including an oxygen requirement
•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
 An underlying medical condition that may place the child at increased risk for complications (eg,
immunodeficiency, cardiac or pulmonary conditions) should be taken into consideration in regard to
supportive care and treatment.
●Inpatient management – Nearly all children with MIS-C are managed in the inpatient setting. In addition, we
generally hospitalize children with clinical findings that strongly suggest a diagnosis of MIS-C while they are
undergoing evaluation, 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 or equivocal cases, and other centers may not admit such patients but rather observe them closely in
the outpatient setting.
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 observation – It is reasonable to observe select patients with mild symptoms in whom the
diagnosis is suspected but not confirmed 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 observed 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 24 to 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 and their contacts 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 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. (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 intravenous immune globulin (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,
diffuse 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 has
not been well studied, but such therapies are rarely implemented, unless there are overlapping clinical features due
to COVID-19 [20]. Many patients are polymerase chain reaction (PCR) negative for SARS-CoV-2, and MIS-C likely
represents a postinfectious complication, not 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. 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, and some centers limit the maximum dose to 100 grams
given IVIG shortages as well as expense. 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 a reasonable option. (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 [2,8-11,15,17,21-25]. 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 intravenous immune globulin (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 two 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 [11,15,17,23-28].
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 and Prevention (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 [24]. 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 [25]. 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 [23]. All three studies used
propensity score analysis and/or weighting techniques 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 [23-25]:
•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 LV dysfunction (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'.)
Tumor necrosis factor inhibitors — Infliximab, a tumor necrosis factor (TNF) inhibitor, has been used as second-
line therapy in patients with MIS-C who have persistent inflammation or myocardial dysfunction [29,30] and also has
been used in conjunction with intravenous immune globulin (IVIG) for initial therapy. Further data are needed to
confirm efficacy before infliximab is used routinely for initial therapy.
In a single-center, retrospective cohort study of 72 children with MIS-C, 20 children received IVIG alone (2 g/kg) as
initial therapy, and 52 received IVIG plus infliximab (10 mg/kg) [31]. Compared with IVIG alone, the combined therapy
group had a higher percentage of patients with CA dilation and/or LV dysfunction on admission (71 versus 40
percent, respectively) and were more likely to have been admitted to the ICU (56 versus 10 percent, respectively).
After initial treatment, fewer patients who received IVIG and infliximab required additional therapy (31 versus 65
percent, respectively) or had new or worsening LV dysfunction (4 versus 20 percent, respectively). The patients on
combination therapy also had a greater decrease in CRP levels at 24 and 48 hours after treatment initiation.
Adjunctive therapies — The benefits and risks of adjunctive therapies (interleukin [IL] 1 inhibitors
[eg, anakinra, canakinumab], IL-6 inhibitors [eg, tocilizumab]) 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 [11,26]. 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 [32,33]. For
example, patients with severe LV dysfunction are at risk for apical LV thrombus, and those with CA aneurysms are
theoretically at risk for myocardial infarction, although this is rare even in patients with KD and giant aneurysms. 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 [32]. 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) [32]. 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 [34,35]. (See "Treatment and prognosis of
myocarditis in children", section on 'Activity'.)

OUTCOME The prognosis of MIS-C requires further characterization but overall looks positive as most

children have a full clinical recovery. Long-term follow-up studies are limited. The disease course in MIS-C can be
quite severe, with many children requiring intensive care interventions. The vast majority of children survive, but
deaths have been reported [9,17,26]. In a systematic review of 16 case series including a total of 655 patients with
MIS-C, there were 11 deaths (1.7 percent) [26]. In another case series of 2818 patients hospitalized for MIS-C from
February 2020 to March 2021, of whom 35 died, odds of death were higher in 16 to 20 year olds compared with 6 to
11 year olds (adjusted OR [aOR] 6.8, 95% CI 2.7-17.1) and in those with at least one comorbidity (aOR 2.8, 95% CI
1.4-5.9), most commonly neurologic disease or a noncardiac congenital abnormality [36]. Those with stroke, kidney
failure, or liver failure were 38-, 12-, and 11-fold more likely, respectively, to die than those without the same
complication. Of over 5000 cases reported to the US Centers for Disease Control and Prevention (CDC) by October
2021, <1 percent of patients had died [37].
Most patients with cardiac involvement had recovery of ventricular function, regression of coronary artery (CA)
aneurysms, and resolution of arrhythmias [20,26,38-40]. In some reports, up to 20 percent of affected patients still
had mildly depressed function at the time of hospital discharge, but, in a longer-term series, LV dysfunction and CA
abnormalities had resolved in all patients by six months [41]. Several studies have demonstrated abnormalities in
echocardiographic measures of diastolic dysfunction and abnormal strain patterns that persist up to six months
[28,40-43]. 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 [44]. However, these are also commonly reported findings during the
pandemic unrelated to identifiable infection. Additional findings included normalization of inflammatory markers by six
weeks and cardiac and kidney function by six months in nearly all patients. Gastrointestinal symptoms, dysphonia,
anosmia, and dysgeusia persisted in a small percentage of patients. Three patients were readmitted to the hospital
for either MIS-C relapse or infectious complications (including pneumonia, urosepsis, and skin and soft tissue
infection) during the follow-up period. Most patients 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 5 th 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 – 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. (See 'Outcome' above and 'Follow-
up' above.)