Key Points

• MIS-C (multisystem inflammatory syndrome in children) is a recently described clinical syndrome in children and adolescents aged 0 to 19 years, first recognized in temporal association with a high local prevalence of COVID-19 ^r1r2r3
• Characterized by persistent fever, laboratory markers of inflammation, and evidence of single or multiorgan dysfunction, including myocarditis. Abdominal pain (often severe) and diarrhea (which may be profuse) are common presenting symptoms. By definition, no microbial cause is evident; most patients have epidemiologic links to or laboratory evidence of COVID-19 ^r4
• May include features suggestive of Kawasaki syndrome (conjunctival injection, mucosal membrane changes, rash, lymphadenopathy, swelling of hands and feet, coronary artery aneurysms), or toxic shock syndrome (fever, erythroderma, edema, renal involvement, hypotension) ^r4r5r6
• Some patients develop shock and require fluid resuscitation and hemodynamic support
• There is no specific diagnostic test; diagnosis is based on a constellation of clinical, laboratory, echocardiographic, and epidemiologic factors. Most patients have evidence of evidence of SARS-CoV-2 antibodies, even when polymerase chain reaction or antigen test results are negative ^r4r5
• Patients with mild disease can be managed conservatively. Treat patients who have more severe disease, including those with myocarditis or who meet criteria for Kawasaki disease or toxic shock syndrome, with IV immunoglobulin. Corticosteroids, immune modulators, and aspirin also have a therapeutic role ^r1r7r8r9r10
• Most patients have responded promptly to therapy and have done well. Because MIS-C resembles Kawasaki syndrome and because observation of coronary artery aneurysms is needed in some patients with MIS-C, serial follow-up echocardiography^r11r9 is recommended ^r1r7r8r9

Urgent Action

• Patients in shock require immediate intervention beginning with fluid resuscitation; they may need oxygen supplementation (including mechanical ventilation) and hemodynamic support as well
• If IV immunoglobulin is indicated, administer promptly. In Kawasaki disease, greatest efficacy in preventing coronary artery aneurysms occurs when IV immunoglobulin is given within 10 days of disease onset ^r11

Pitfalls

• Physical findings may not appear simultaneously but may evolve over several days
• Coronary artery aneurysms may develop late in disease course or after apparent improvement ^r9

Clinical Clarification

• MIS-C (multisystem inflammatory syndrome in children) is a clinical syndrome in children and adolescents, originally recognized in temporal association with a high local prevalence of COVID-19. Subsequently, most reported cases have been shown to have laboratory evidence of recent infection with SARS-CoV-2, the virus that causes COVID-19 ^r1r2r3
• Illness is characterized by persistent fever, laboratory markers of inflammation, and evidence of single or multiorgan dysfunction ^r2r4r6
  • May include features suggestive of Kawasaki syndrome (conjunctival and mucosal injection, rash, swelling of hands and feet, coronary artery dilation) or toxic shock syndrome (erythroderma, renal involvement, hypotension)
• Multisystem inflammatory syndrome in children is the designation used by CDC and WHO. It is also known as PIMS-TS (pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 infection) in Europe and pediatric multisystem inflammatory syndrome temporally associated with COVID-19 in the United Kingdom ^r4r6

Classification

• Several national and international organizations have established case definitions for MIS-C (multisystem inflammatory syndrome in children) that are broadly similar. WHO definition applies to children and adolescents aged 0 to 19 years who meet all of the following clinical criteria: ^r12
  • Fever for 3 days or longer
  • 2 or more of the following:
    • Rash or bilateral conjunctivitis (nonpurulent) or mucocutaneous inflammation of mouth, hands, or feet
    • Hypotension or shock
    • Features of myocardial dysfunction, pericarditis, valvulitis, or coronary artery abnormalities, including evidence found through imaging (echography) and laboratory studies (elevated levels of troponin, NT-proBNP [N-terminal–pro hormone brain natriuretic peptide])
    • Coagulopathy (eg, elevated prothrombin time/INR, partial thromboplastin time, D-dimer level)
    • Acute gastrointestinal symptoms (vomiting, diarrhea) or abdominal pain
  • Elevated levels of nonspecific indicators of inflammation (eg, erythrocyte sedimentation rate, C-reactive protein, procalcitonin)
  • No obvious alternate microbial cause of inflammation (bacterial sepsis, staphylococcal or streptococcal toxic shock syndrome)
  • Evidence of COVID-19 (positive reverse transcription polymerase chain reaction test result, detectable antigen, or antibody) or likely exposure to COVID-19
• CDC^r2 and Royal College of Paediatrics and Child Health^r4 have published case definitions that are slightly broader, emphasize temporal nature of association to COVID-19 (ie, causation not proven), and expand upon resemblance of syndrome to Kawasaki disease
  • Some children fulfill full or partial criteria for Kawasaki syndrome, but MIS-C diagnosis is applied if they otherwise meet the case definition ^r2r4
  • Royal College of Paediatrics and Child Health notes that polymerase chain reaction results for SARS-CoV-2 (earlier provisional name was 2019-nCoV) may be positive or negative ^r4
• MIS-C is suspected to exist as a spectrum that includes patients with milder manifestations that do not meet case definitions and who may or may not progress to meet all criteria ^r3

Clinical Presentation

Causes and Risk Factors

Diagnostic Procedures

Differential Diagnosis

Goals

• Reverse shock
• Reverse organ dysfunction and prevent further injury and complications (eg, coronary artery aneurysms, acute kidney injury)

Disposition

Treatment Options

Excellent supportive care is essential in all cases; antiinflammatory and immunomodulatory therapies have been used in severely ill patients (particularly those who fulfill criteria for Kawasaki disease) ^{r4r5r6r9r19r25}

• Specific guidance for treatment of shock and hypoxemia in MIS-C is lacking but includes oxygen administration (including mechanical ventilation, if necessary), cautious fluid resuscitation (preferably guided by assessment of likely responsiveness), and vasopressor support, using appropriate protocols for shock (ie, cardiogenic^r26 versus vasodilatory/distributive^r27) ^d6
• Extracorporeal membrane oxygenation has been used in some patients

American College of Rheumatology guidelines recommend the following approach:

• Patients in whom MIS-C is suspected and who have life-threatening manifestations may require immunomodulatory treatment for MIS-C before the full diagnostic evaluation can be completed. Some patients with mild symptoms may require only close monitoring without immunomodulatory treatment ^r20
• Primary immunomodulatory therapy is IV immunoglobulin; glucocorticoids are used adjunctively depending on severity of illness or clinical response to IV immunoglobulin ^r20
  • High dose IV immunoglobulin (typically 2 g/kg, based on ideal body weight) is recommended for MIS-C patients who are hospitalized or who fulfill Kawasaki disease criteria
  • Assess cardiac function and fluid status before prescribing or administering IV immunoglobulin treatment. Patients with severely impaired myocardium require close monitoring and may need diuretics to avoid volume overload; another recommended strategy is to administer in divided doses (1 g/kg daily over 2 days)
  • Administer low to moderate dose glucocorticoids (eg, methylprednisolone 1-2 mg/kg/day) with IV immunoglobulin as adjunctive therapy to treat patients in shock or who have organ-threatening disease
  • In patients who do not respond to IV immunoglobulin and low to moderate dose glucocorticoids, high dose glucocorticoid pulse therapy (eg, methylprednisolone 10-30 mg/kg/day) may be considered, especially in severe illness requiring high dose or multiple inotropes or vasopressors
  • A second dose of IV immunoglobulin is not recommended owing to potential volume overload and hemolytic anemia seen with large doses of IV immunoglobulin
  • Low to moderate dose corticosteroids (eg, methylprednisolone 1-2 mg/kg/day) also may benefit patients with milder forms of MIS-C whose fever and other symptoms do not resolve after a single dose of IV immunoglobulin
  • Anakinra (greater than 4 mg/kg/day IV or subcutaneous) is an option to treat MIS-C that does not respond adequately to IV immunoglobulin and glucocorticoids, when the clinical presentation suggests associated macrophage activation syndrome, or when there are contraindications to long-term use of glucocorticoids
  • Perform serial laboratory testing and cardiac assessment to assess for response to therapy and to guide tapering of therapy. Tapering of immunomodulating agents may require 2 to 3 weeks or more
• Antiplatelet and anticoagulation therapy in MIS-C: ^r20
  • Low-dose aspirin (3-5 mg/kg/day; Max: 81 mg/day) is recommended and should be continued until platelet count has returned to normal and echocardiogram 4 or more weeks after diagnosis confirms that coronary arteries are normal. Avoid aspirin therapy in patients with active bleeding, significant bleeding risk, and/or platelet count less than or equal to 80,000/µL
  • Treat patients who have coronary artery aneurysms and a maximal z-score of 2.5 to 10 with low-dose aspirin. In patients with a z-score 10 or higher use a combination of low-dose aspirin and therapeutic anticoagulation with enoxaparin (factor Xa level 0.5-1) or warfarin
  • In patients with documented thrombosis or an ejection fraction less than 35%, provide therapeutic anticoagulation with enoxaparin until at least 2 weeks after discharge from the hospital
  • Recommended duration of enoxaparin varies depending on the indication:
    • Coronary artery aneurysm with z-score higher than 10: treat indefinitely
    • Documented thrombosis: treat for 3 or more months pending thrombus resolution
    • Ongoing moderate to severe left ventricular dysfunction: duration of treatment not specified but included as an indication for "longer outpatient therapeutic dosing"
  • For MIS-C patients who do not meet these criteria, tailor antiplatelet and anticoagulation management to the patient's risk for thrombosis

American Academy of Pediatrics guidance recommends the following approach:

• Usual treatment is IV immunoglobulin, 2 g/kg (Max: 100 g); duration of IV immunoglobulin therapy infusion may require modification, depending on cardiac function and fluid status ^r19
• Glucocorticoids (ranging from 2-30 mg/kg/day of methylprednisolone, depending on severity of illness) and biologics (eg, anakinra, 2-10 mg/kg/day, subcutaneously or IV, divided every 6-12 hours) have been used in patients who do not improve clinically after IV immunoglobulin and in those whose laboratory values do not improve ^r19
• If there is laboratory or imaging evidence of myocardial injury or findings concerning for coronary artery aneurysms, consult with a pediatric cardiologist before prescribing corticosteroids ^r19
• Patients treated with corticosteroids or biologics often require a 3-week taper of medication, which can be completed after discharge ^r19
• Unless contraindications exist (eg, less than 100,000 platelets or active bleeding), give all patients low-dose aspirin for thromboprophylaxis ^r19

Pediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS) National Consensus Management Study Group has published consensus statements regarding management in children with Kawasaki disease–like phenotype and nonspecific presentations

• For children with nonspecific presentations, the study group recommends the following approach: ^r28
  • First line therapy is IV immunoglobulin at a dose of 2 g/kg (based on ideal body weight); may administer in a single or divided dose, depending on clinical picture and cardiac function. Can consider a second dose for children who have not responded adequately to the first dose
  • Second line therapy is IV methylprednisolone (10-30 mg/kg) for children who remain unwell 24 hours after infusion of immunoglobulin, particularly those with persistent fever
  • Third line therapy, for children who do not respond to IV immunoglobulin and methylprednisolone, is a biologic therapy: tocilizumab, anakinra, or infliximab
  • All children older than 12 years should wear compression stockings
  • Administer low-dose aspirin for a minimum of 6 weeks to all patients with PIMS-TS

For patients who meet Kawasaki disease criteria, Kawasaki disease guidelines^r11 encourage treatment as early as the diagnosis is established and preferably within 10 days of illness onset ^r4r23d1

For patients in whom sepsis caused by other pathogens has not been ruled out, begin empiric antibiotics, which can be de-escalated if indicated based on results of microbiologic studies ^r5d4

For children who meet the criteria for toxic shock syndrome, give clindamycin in addition to broad-spectrum antibiotics ^r28d3

Because MIS-C appears to be a postinfectious inflammatory response, antiviral therapy generally has not been initiated; nevertheless, use of infection control precautions appropriate for COVID-19 is recommended by some authorities ^r4

• Children who are SARS-CoV-2 positive on reverse transcription polymerase chain reaction or antigen testing might be considered for antiviral therapy; remdesivir is the first choice antiviral therapy for SARS-CoV-2 ^r28

Monitoring

• During acute disease, frequently monitor laboratory studies until values stabilize and improve ^r4r25
• Serial ECGs (at least every 48 hours^r25) and echocardiograms are appropriate during the acute phase; obtain follow-up echocardiograms 2 and 6 weeks after discharge. Some authorities recommend that children with cardiac involvement during the acute phase have repeat echocardiogram a year after discharge^r20r8r9r11
  • Based on recommendations for Kawasaki disease management and on preliminary observations that MIS-C patients may (like patients with classic Kawasaki disease) develop coronary artery aneurysms late in the disease course or after apparent improvement
  • Coronary artery aneurysms occur in about 20% of patients with MIS-C, even when criteria for Kawasaki disease are not met ^r20
• Consider cardiac MRI 2 to 6 months after acute illness for patients with significant transient or persistent left ventricular dysfunction ^r25

Complications

• Development of coronary aneurysms has been documented, and these patients are at risk for thrombosis ^r8r9

Prognosis

• Published reports indicate recovery in nearly all patients, with resolution of shock and organ function. However, several deaths^r6 have been reported, and long-term prognosis of survivors is unknown

Prevention

• The only known preventive measures involve efforts to avoid infection with SARS-CoV-2 (ie, diligent distancing, widespread use of facial covering, careful hand and environmental hygiene) ^d7