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

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). Understanding of COVID-19 and MIS-C continues to evolve.

The management and prognosis of MIS-C are 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 prevention for persons with SARS-CoV-2 infection".)

●(See "COVID-19: Management in hospitalized adults".)

●(See "COVID-19: Hypercoagulability".)

●(See "COVID-19: Evaluation of adults with acute illness in the outpatient setting" and "COVID-19: Management of adults with acute illness in the outpatient setting".)

SETTING OF CARE — The appropriate setting of care is determined by the severity of illness, risk of complications, and adequacy of follow-up.

●Inpatient management – Essentially all children who meet the case definition for MIS-C (table 2) are managed in the inpatient setting because they have multisystem involvement and are moderately to severely ill. 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 (eg, no hemodynamic instability). This is because children with MIS-C often have worsening of their clinical status as the illness progresses. 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. An underlying medical condition that may place the child at increased risk for complications (eg, immunodeficiency, cardiac or pulmonary conditions) also should be taken into consideration when deciding need for supportive care and treatment.

The level of care (ward versus intensive care unit [ICU]) is determined by the severity of illness. Admission to an ICU 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 ICU care [9,11-14], 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 other than fever 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 unlikely. Vaccination status should also be considered as MIS-C is quite unlikely in a child vaccinated against SARS-CoV-2. 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 pediatric specialties. This may include:

●Emergency medicine providers

●Rheumatologists

●Cardiologists

●Intensivists

●Hematologists

●Neurologists

●Infectious disease specialists

●Hospitalists

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. Institutional infection control guidelines related to testing for COVID-19 and managing test positive patients should be followed. A detailed discussion of COVID-19-related infection control measures, including advice regarding visitors and family members, is provided separately. (See "COVID-19: Infection prevention for persons with SARS-CoV-2 infection" and "COVID-19: General approach to infection prevention in the health care setting" and "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis", section on 'Testing for SARS-CoV-2'.)

MANAGEMENT

Overview — Management of MIS-C has evolved over the course of the pandemic. Most children with MIS-C 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 (ACR), American Academy of Pediatrics (AAP), the US National Institutes of Health (NIH), the World Health Organization (WHO), and pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) National Consensus Management Study Group in the United Kingdom [15-19]. (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 "Shock in children in resource-abundant settings: Initial management".)

Patients presenting with severe multisystem involvement and shock should also receive prompt empiric broad-spectrum antibiotic therapy pending culture results because MIS-C can present with signs and symptoms that mimic those of septic shock and toxic shock syndrome [15,17]. 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 in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)", section on 'Empiric regimens' and "Staphylococcal toxic shock syndrome", section on 'Empiric therapy'.)

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-CoV-2 infections from patients with MIS-C who meet KD criteria. (See "Kawasaki disease: Initial treatment and prognosis", section on 'Identification of patients at high risk for IVIG resistance' and '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 (IV) 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".)

Positive SARS-CoV-2 polymerase chain reaction test — 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 acute COVID-19 [17,20]. 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 polymerase chain reaction (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".)

Immunomodulatory therapy

Our approach — Our approach to immunomodulatory therapy in patients with MIS-C is generally consistent with published guidelines (algorithm 2) [15-19]:

●Initial therapy – For most patients who meet diagnostic criteria for MIS-C (table 2), we suggest treatment with both intravenous immune globulin (IVIG) and glucocorticoids rather than either drug alone. IVIG alone may be reasonable in the patient with mild disease (no evidence of cardiovascular dysfunction), especially if the patient has a preexisting condition that may warrant avoidance of glucocorticoids (eg, diabetes mellitus, hypertension, obesity). However, if the patient has persistent fevers and rising C-reactive protein (CRP), D-dimer, and/or ferritin despite treatment with IVIG, we suggest adding glucocorticoid therapy. If IVIG is not available, treating patients with systemic glucocorticoids alone is acceptable. (See 'Intravenous immune globulin' below and 'Glucocorticoids' below.)

●Therapy for refractory disease – Patients are considered refractory to initial therapy if they do not show improvement within 24 hours of treatment (eg, resolution of fever, improving organ function, decreasing levels of inflammatory markers). For patients with MIS-C who do not respond to IVIG plus low-to-moderate dose glucocorticoids, we suggest pulse-dose glucocorticoids, infliximab (a tumor necrosis factor [TNF] inhibitor), or anakinra (an interleukin [IL] 1 inhibitor). (See 'Glucocorticoids' below and 'Biologic therapies' below.)

Intravenous immune globulin

●Dosing – The dosing for intravenous immune globulin (IVIG) in this setting is 2 g/kg administered in a single infusion over 8 to 12 hours [21]. In patients with obesity, the dose should be based upon ideal body weight. In addition, many 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. A second dose of IVIG is generally avoided because of the risk of volume overload and hemolytic anemia. (See "Kawasaki disease: Initial treatment and prognosis", section on 'Intravenous immune globulin'.)

●Laboratory studies pre- and post-IVIG – 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, 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'.)

●Efficacy – 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 [2,8-12,14,22-26]. 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')

Additional factors related to IVIG treatment, including premedications, adverse effects, monitoring, and administration of vaccines after receiving IVIG, are reviewed in greater detail separately. (See "Overview of intravenous immune globulin (IVIG) therapy" and "Intravenous immune globulin: Adverse effects".)

Glucocorticoids

●Timing – For patients with moderate or severe manifestations, glucocorticoid therapy is typically given first, followed by IVIG. In patients who initially have less severe manifestations and are treated with IVIG alone, glucocorticoids may be given as a second-line treatment if there is an inadequate response to IVIG (eg, persistent fevers, rising inflammatory markers) [21].

●Dosing – Glucocorticoid therapy is initially given IV with methylprednisolone at a dose of 1 to 2 mg/kg/day in two divided doses (maximum daily dose 60 to 80 mg) [21]. 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 (maximum dose 60 mg) and then tapered off over two to three weeks [27].

In life-threatening circumstances or refractory cases, pulse doses of glucocorticoids have been used (IV methylprednisolone 10 to 30 mg/kg/day for one to three days, maximum daily dose 1 g), though there are few supporting data [21].

●Efficacy – The evidence supporting glucocorticoids for MIS-C is limited to case series in which approximately 30 to 80 percent of patients were treated with glucocorticoids at varying doses, either alone or with IVIG, and most patients recovered rapidly [11,12,14,24-26,28-31].

The four largest observational studies varied in disease severity and inclusion criteria, treatments compared, and outcomes measured. The first three found greater clinical benefit with IVIG plus glucocorticoids compared with IVIG alone. The single-center US study found similar benefit with IVIG plus glucocorticoids or glucocorticoids alone, although patients who received glucocorticoids alone had milder disease at presentation. All four studies used propensity score analysis and/or weighting techniques to examine outcomes in patients.

•The multicenter 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 [25].

•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 [26].

•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 [24].

•The single-center US study included 215 patients from March 2020 through February 2021 with MIS-C based upon CDC criteria, of whom 31 received initial treatment with IVIG alone, 115 received IVIG plus glucocorticoids, and 69 received glucocorticoids alone [31].

The following findings were noted [24-26,31]:

•Reduced need for adjunctive therapy – In the first three studies, combination therapy was associated with reduced need for adjunctive immunomodulatory therapy compared with IVIG alone (multicenter 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). In the single-center US study, need for adjunctive immunomodulatory therapy did not differ significantly between combination therapy and glucocorticoid-only groups (OR 0.95, 95% CI 1.07-3.60).

•Possible improvement in persistent or recurrent fevers – In the first three studies, patients who received combination therapy were less likely to have persistent or recurrent fevers compared with IVIG alone; however, this finding was statistically significant only in the French study (multicenter 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). The rate of persistent or recurrent fever was similar in the groups receiving combination therapy or glucocorticoids alone in the single-center US study (OR 0.98, 95% CI 0.47-2.02).

•Possible reduced need for hemodynamic support – Both the multicenter 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). In the single-center US study, the number of days vasoactive medication was required was similar in the groups receiving combination therapy or glucocorticoids alone (OR 0.32, 95% CI -0.59-1.24).

•Possible improvement in ventricular function – In the multicenter 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 (multicenter 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 multicenter 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). In the single-center US study, the time to normal LVEF in days was similar in the groups receiving combination therapy or glucocorticoids alone (OR 2.46, 95% CI -0.86-5.78), and nearly all patients in both groups had normal LVEF at discharge.

•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 French and multicenter US studies may be accounted for, at least in part, by differences in patient selection as well as severity of illness [32]. Disease severity was considerably higher in the US and French studies compared with the international study (eg, in the multicenter 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 French and multicenter US 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 multicenter 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'.)

Biologic therapies — TNF inhibitors (infliximab), IL-1 inhibitors (anakinra, canakinumab), and IL-6 inhibitors (tocilizumab) are alternative options for treatment of MIS-C in conjunction with IVIG in patients who cannot receive glucocorticoids or as second-line therapy in patients who are refractory to initial therapy with IVIG and low- to moderate-dose glucocorticoids. Of these drugs, anakinra (5 to 10 mg/kg IV or subcutaneous daily for approximately three days, maximum dose 400 mg/day) and infliximab (5 to 10 mg/kg IV for one dose) are the most commonly used. The evidence supporting these drugs for MIS-C is limited to case series and to indirect evidence from studies of patients with similar hyperinflammatory conditions such as macrophage activation syndrome (MAS) and KD. Of note, infliximab should not be used in patients with signs of MAS. 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. Use of these agents should be guided by consultation with pediatric rheumatology and infectious disease specialists and should occur in the context of a clinical trial whenever possible. (See "Refractory Kawasaki disease", section on 'Treatment approach' and "Systemic juvenile idiopathic arthritis: Course, prognosis, and complications", section on 'Macrophage activation syndrome'.)

IL-1, IL-6, and TNF inhibitors have been used as second-line therapy in approximately 10 to 20 percent of patients with MIS-C who have persistent inflammation or myocardial dysfunction, with favorable outcomes in nearly all patients [11,28,33-36].

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) [37]. 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 intensive care unit (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.

Antithrombotic therapy — Patients with MIS-C are at risk of experiencing thrombotic complications [38,39]. For example, patients with severe LV dysfunction (LVEF <35 percent) 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 most patients – We treat most patients with low-dose aspirin (3 to 5 mg/kg daily, maximum 81 mg per day, typical duration of treatment four to six weeks or to normalization of inflammatory markers [CRP, platelet count] and normalization of LV function and aneurysms if present). This is based largely on indirect evidence from patients with KD. Exceptions include those with contraindications such as platelets <100,000 or active bleeding. (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 (VTE) in children: Treatment, prevention, and outcome", section on 'Approach to VTE treatment'.)

●Patients with severe LV dysfunction – We suggest therapeutic anticoagulation for patients with severe LV dysfunction (ejection fraction <35 percent), 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. Exceptions include those with contraindications such as platelets <100,000 or active bleeding. Cardiology and hematology should be consulted to determine need for further intervention. (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 'Antithrombotic therapy'.)

●Patients with other severe MIS-C manifestations requiring pediatric intensive care unit (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 immobilization, central lines, and PICU care, we suggest administering prophylactic-dose anticoagulant therapy (typically LMWH), provided that bleeding risk is not high. 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 (VTE) in children: Treatment, prevention, and outcome", section on 'Approach to VTE 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 is an independent risk factor for VTE, occurring mainly in postpubertal children with MIS-C. 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 (VTE) in children: Treatment, prevention, and outcome", section on 'Approach to VTE prophylaxis'.)

Our suggested approach is supported by limited observational data. 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) [38]. 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, more than five 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 (VTE) in children: Risk factors, clinical manifestations, and diagnosis", section on 'Incidence'.)

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 postdischarge 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 (MRI) 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 [40,41]. Similar to other forms of myocarditis, when significant myocardial involvement is present in the acute phase (left ventricular [LV] systolic dysfunction, elevated troponin, or MRI evidence of myocardial edema/inflammation), follow-up cardiac MRI and exercise stress testing at approximately six months may help inform timing of return to full physical activity. Additionally, patients with myocardial involvement and arrhythmia should have follow-up ambulatory rhythm monitoring over the subacute and convalescent phases of illness. (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. However, 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 [9,14,28]. In a systematic review of 16 case series including a total of 655 patients with MIS-C, there were 11 deaths (1.7 percent) [28]. 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 odds ratio [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 [42]. 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 7400 cases reported to the US Centers for Disease Control and Prevention (CDC) by March 1, 2022, <1 percent (n = 63) of patients had died [43].

Most patients with cardiac involvement had recovery of ventricular function, regression of coronary artery (CA) aneurysms, and resolution of arrhythmias [20,28,44-46]. 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, left ventricular (LV) dysfunction and CA abnormalities had resolved in all patients by six months [47]. Several studies have demonstrated abnormalities in echocardiographic measures of diastolic dysfunction and abnormal strain patterns that persist up to six months [30,46-49]. 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 [50]. 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 — MIS-C associated with vaccination for COVID-19 is vanishingly rare. In fact, there is increasing data that COVID-19 vaccination protects against the development of MIS-C and adds to the preponderance of data in favor of COVID-19 vaccination for all approved age groups [51-53]. COVID-19 vaccination for disease prevention and of people with a history of MIS-C is discussed separately; in brief, COVID-19 vaccination is recommended three months following an episode of MIS-C. (See "COVID-19: Vaccines", section on 'Children' and "COVID-19: Vaccines", 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 6^th 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 10^th to 12^th 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 but potentially life-threatening complication of coronavirus disease 2019 (COVID-19). The presentation is characterized by prominent cardiovascular, gastrointestinal, and mucocutaneous symptoms (table 2), with some features similar to Kawasaki disease (KD), septic shock, or toxic shock syndrome. (See 'Introduction' above and "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis".)

●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 "Shock in children in resource-abundant settings: Initial management" and 'Cardiac dysfunction' above.)

●Empiric antibiotic therapy – Patients presenting with severe multisystem involvement and shock should generally receive prompt empiric broad-spectrum antibiotic therapy pending culture results. (See 'Shock' above and "Septic shock in children in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)", section on 'Empiric antibiotic therapy'.)

●Immunomodulatory therapy

•Initial therapy – For most patients who meet diagnostic criteria for MIS-C, we suggest treatment with both intravenous immune globulin (IVIG) and glucocorticoids rather than either drug alone (Grade 2C). IVIG alone may be reasonable in the patient with mild disease (no evidence of cardiovascular dysfunction), especially if the patient has a preexisting condition that might warrant avoidance of glucocorticoids (eg, diabetes mellitus, hypertension, obesity). 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). If IVIG is not available, treating patients with systemic glucocorticoids alone is acceptable. (See 'Our approach' above and 'Intravenous immune globulin' above and 'Glucocorticoids' above.)

•Therapy for refractory disease – Patients are considered refractory to initial therapy if they do not show improvement within 24 hours of treatment (eg, resolution of fever, improving organ function, decreasing levels of inflammatory markers). For patients with MIS-C who do not respond to IVIG plus low-to-moderate dose glucocorticoids, we suggest pulse-dose glucocorticoid therapy, infliximab (a tumor necrosis factor [TNF] inhibitor), or anakinra (an interleukin [IL] 1 inhibitor) (Grade 2C). A second dose of IVIG is generally avoided because of the risk of volume overload and hemolytic anemia. Consultation with pediatric infectious disease and rheumatology specialists is advised. (See 'Our approach' above and 'Biologic 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):

•Most patients with MIS-C – For most 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. Exceptions include those with contraindications such as platelets <100,000 or active bleeding. (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 (VTE) in children: Treatment, prevention, and outcome", section on 'Approach to VTE treatment'.)

•Patients with severe left ventricular (LV) dysfunction – We suggest therapeutic anticoagulation for patients with severe LV dysfunction (ejection fraction <35 percent), 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 coronary artery (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 'Antithrombotic therapy'.)

•Patients with other severe MIS-C manifestations requiring pediatric intensive care unit (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 immobilization, central lines, and PICU care, we suggest administering an anticoagulant at prophylactic dosing, provided that bleeding risk is not high (Grade 2C). 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 (VTE) in children: Treatment, prevention, and outcome", section on 'Approach to VTE 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 risks and benefits. The diagnosis of COVID-19-related MIS-C itself is an independent risk factor for VTE, occurring mainly in postpubertal children with MIS-C. The approach to VTE prophylaxis in hospitalized children is discussed in greater detail separately. (See "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome", section on 'Approach to VTE 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.)