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    Mar.27.2023

    Multisystem Inflammatory Syndrome (MIS-C and MIS-A)

    Synopsis

    Key Points

    • MIS is characterized by persistent fever, elevated laboratory markers of inflammation, and evidence of organ dysfunction, including myocarditis; acute gastrointestinal symptoms (eg, vomiting, diarrhea) or abdominal pain are common presenting manifestations
    • May include features suggestive of Kawasaki syndrome or toxic shock syndrome; some patients present with cardiogenic shock
    • Myocardial involvement is frequent in MIS; coronary artery dilation and aneurysm may develop
    • Diagnosis is based on case definition comprised of a constellation of clinical, laboratory, echocardiographic, and epidemiologic factors. Most patients have evidence of recent SARS-CoV-2 infection and no evidence of alternate microbial or alternate cause for illness
    • Limited information is available regarding MIS affecting adults (MIS-A) or neonates (MIS-N); management is primarily extrapolated from MIS-C
    • Tiered testing strategy is suggested for most patients with suspected MIS-C. Second tier testing is indicated if results of first tier testing are concerning for MIS-C development. Obtain complete testing panel (ie, first and second tier testing) in patients presenting with shock or critical illness
      • First tier testing includes:
        • CBC with differential
        • Complete metabolic panel
        • Erythrocyte sedimentation rate
        • C-reactive protein
        • Testing for COVID-19 (eg, SARS-CoV-2 polymerase chain reaction and antibodies)
        • Focused microbiologic evaluation for alternate infectious causes directed by clinical presentation
      • Second tier testing includes:
        • Evaluation for evidence of evolving cytokine release syndrome,
        • Significant coagulopathy, and
        • Myocarditis and blood draw to hold in laboratory for additional future serologic testing (before administration of IV immunoglobulin)
    • Supportive care is mainstay of management; significant proportion of patients require vasopressor support
    • First line treatment for patients fulfilling criteria for diagnosis of MIS-C is IV immunoglobulin and methylprednisolone
    • Second line treatment for refractory disease is intensified IV methylprednisolone, anakinra, or infliximab
    • Thromboprophylaxis with low-dose aspirin is recommended for all patients diagnosed with MIS-C; therapeutic anticoagulation is indicated for those with large coronary artery aneurysms, significant left ventricular dysfunction, or documented thrombosis
    • Most patients have responded well to therapy and have favorable short-term prognosis, but mortality is 1% to 2% in children and 7% in adults; minority of survivors have sequelae as late as 6 to 12 months post diagnosis
    • Cardiology follow-up with serial echocardiography is recommended after recovery from acute phase of MIS-C to monitor for latent development and evolution of coronary artery aneurysms and monitor cardiac function
    • COVID-19 vaccination is effective in preventing MIS-C in children aged 5 to 18 years, and is likely effective at preventing MIS overall by lowering risk of preceding COVID-19 infection r1

    Urgent Action

    • Patients with shock require immediate intervention beginning with fluid resuscitation; they may need respiratory support (potentially including mechanical ventilation), and many require hemodynamic support
    • Begin treatment with methylprednisolone and IV immunoglobulin after initial stabilization for any patient presenting with shock under consideration for MIS-C

    Pitfalls

    • Maintain high degree of suspicion for MIS-C because children with this illness can deteriorate rapidly if not expediently and appropriately managed; early recognition and management are important for optimal outcomes
    • 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
    • MIS is a rare and novel disease; therefore, it is not yet possible to make firm evidence-based recommendations. Rigorous data to guide most diagnostic and management strategies are lacking and optimal treatment is not yet known

    Terminology

    Clinical Clarification

    • MIS-C (multisystem inflammatory syndrome in children) r2
      • Clinical syndrome due to hyperinflammatory response to previous exposure or infection with SARS-CoV-2 in children and adolescents r3
      • Syndrome is noted to have a strong temporal association with high local prevalence of COVID-19, occurring in clusters following a regional COVID-19 outbreak r4
      • Illness is characterized by persistent fever, laboratory markers of inflammation, and evidence of organ dysfunction r5r6
        • 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)
      • MIS-C is a rare and novel disease with ongoing research r7
        • Estimated risk of MIS-C following SARS-CoV-2 exposure is 1 in 3000 to 4000 r3
          • 9370 cases have been reported in United States as of February 27, 2023, with thousands also reported around the world r4r8
            • Reporting in United States is voluntary and is very likely to underestimate true number of cases, as seen in studies utilizing hospital data r9r10
        • Studies are ongoing to determine best diagnostic and management strategies
      • Multisystem inflammatory syndrome in children is the designation used by CDC and WHO r2r11
        • Condition has also been referred to as pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 infection (PIMS or PIMS-TS) or pediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 infection (PMIS or PMIS-TS) r5r6r7
    • MIS-A (multisystem inflammatory syndrome in adults) r12r13r14
      • Rare but serious hyperinflammatory clinical syndrome with multiorgan dysfunction that presents in adults about 4 weeks after onset of acute COVID-19
      • Cardiovascular and gastrointestinal systems are most commonly involved, with mucocutaneous symptoms also affecting a majority of patients r15
    • MIS-N (multisystem inflammatory syndrome in neonates) r16r17
      • Rare cases have been reported of a hyperinflammatory syndrome in infants born to mothers with COVID-19 during pregnancy, with proposed name MIS-N
      • Transplacental transfer of antibodies, which occurs in first week of life, is hypothesized to cause illness
      • Significant cardiovascular and respiratory dysfunction and preterm birth are reported in a majority of these infants

    Classification

    • Classification based on case definition
      • Several national and international organizations have established case definitions for MIS-C that are similar r2r6r11
        • Initial case definitions were intentionally broad to capture possible cases of a new disease when all manifestations were not yet known
        • Subsequent CDC case definition better discriminates among MIS-C, acute severe COVID-19, Kawasaki disease, and toxic shock syndrome
      • CDC, in conjunction with CSTE (Council of State and Territorial Epidemiologists), revised the case definition for MIS-Cr2 as of January 1, 2023; cases are defined by clinical, laboratory, and epidemiologic criteria
        • Clinical criteria: illness in individuals younger than 21 years, without a more likely alternative diagnosis, with all of the following:
          • Subjective or documented fever (temperature of 38.0 °C or higher)
          • Clinically severe illness requiring hospitalization or resulting in death
          • Evidence of systemic inflammation indicated by C-reactive protein of 3.0 mg/dL or greater
          • New onset manifestations in at least 2 of the following categories:
            • Cardiac involvement indicated by left ventricular ejection fraction less than 55%; coronary artery dilatation, aneurysm, or ectasia; or troponin elevated above laboratory reference range or indicated as elevated in a clinical note
            • Mucocutaneous involvement indicated by rash, inflammation of oral mucosa (eg, mucosal erythema or swelling, drying, or fissuring of lips; strawberry tongue), conjunctivitis or conjunctival injection, or extremity findings (eg, erythema or edema of hands or feet)
            • Shock
            • Gastrointestinal involvement indicated by abdominal pain, vomiting, or diarrhea
            • Hematologic involvement indicated by platelet count less than 150,000 cells/μL or absolute lymphocyte count less than 1000 cells/μL
        • Laboratory criteria: 1 of the following:
          • Detection of SARS-CoV-2 RNA in a clinical specimen up to 60 days before or during hospitalization or in a postmortem specimen using a diagnostic molecular amplification test (eg, polymerase chain reaction)
          • Detection of SARS-CoV-2 specific antigen in a clinical specimen up to 60 days before or during hospitalization or in a postmortem specimen (includes home antigen testing)
          • Detection of SARS-CoV-2 specific antibodies in serum, plasma, or whole blood associated with current illness resulting in or during hospitalization
        • Epidemiologic criteria:
          • Close contact with a confirmed or probable COVID-19 case within 60 days prior to hospitalization
        • Cases meeting clinical and laboratory criteria are confirmed cases; cases meeting clinical and epidemiologic criteria are probable cases; cases in which only death certificate lists MIS as an underlying cause of death or a significant condition contributing to death are suspect cases
        • Children diagnosed with Kawasaki syndrome should no longer be reported as an MIS-C case r2r6
      • WHO and Royal College of Paediatrics and Child Health MIS-C definitions are similar to CDC with the following differences: r6r11
        • WHO definition applies to individuals aged 19 years and younger, requires 3 or more days of fever, and does not specify that hospitalization is required
        • Royal College of Paediatrics and Child Health definition allows single or multiorgan dysfunction and that SARS-CoV-2 polymerase chain reaction test results may be positive or negative (without addressing other testing or exposure)
      • CDC case definition for MIS-Ar13 applies to individuals aged 21 years or older with hospitalization for 24 hours or more or illness resulting in death and with the following clinical and laboratory criteria and no alternative diagnosis:
        • Clinical: fever and at least 3 of the following criteria before hospitalization or within the first 3 days of hospitalization, including at least 1 primary criterion:
          • Primary
            • Severe cardiac illness (eg, myocarditis, pericarditis, coronary artery aneurysm, new-onset ventricular dysfunction, new-onset second- or third-degree atrioventricular block, new-onset ventricular tachycardia)
            • Rash and nonpurulent conjunctivitis
          • Secondary
            • New-onset neurologic dysfunction (eg, seizures, encephalopathy, meningeal signs, peripheral neuropathy, Guillain-Barré syndrome)
            • Shock or hypotension not attributable to medical treatment
            • Abdominal pain, vomiting, or diarrhea
            • Thrombocytopenia with platelet count less than 150,000 cells/mm³
        • Laboratory:
          • At least 2 of the following markers are elevated: C-reactive protein, ferritin, interleukin-6, erythrocyte sedimentation rate, procalcitonin, and
          • Positive polymerase chain reaction, antigen, or serologic test result for COVID-19
      • Case definition for MIS-C and MIS-A that also includes exposure to COVID-19 vaccination was developed to monitor adverse effects from vaccination r18
        • MIS following vaccination that is unrelated to SARS-CoV-2 infection is exceedingly rare, and vaccination has been shown to be highly effective at preventing MIS-C r3r19r20
      • A definition for MIS-N has been proposed based on MIS-C case definition r21
        • Modifications account for SARS-CoV-2 infection during pregnancy rather than in the neonate and for absence of fever common in newborns; the definition also differentiates MIS-C in the newborn period from MIS-N
        • Criteria include:
          • Neonate younger than 28 days at time of presentation
          • Laboratory or epidemiologic evidence of any of the following:
            • SARS-CoV-2 infection in mother, such as positive SARS-CoV-2 test result during pregnancy (polymerase chain reaction, antigen, or serology)
            • COVID-19 symptoms or confirmed exposure during pregnancy
            • Positive serology in neonate (IgG but not IgM)
          • Clinical criteria: severe illness necessitating hospitalization and
            • 2 or more organ systems affected (eg, cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic, neurologic, temperature instability [fever or hypothermia]) or
            • Cardiac atrioventricular conduction abnormalities or coronary dilation or aneurysms (without involvement of second organ system)
          • Laboratory evidence of inflammation:
            • Elevated C-reactive protein, erythrocyte sedimentation rate, fibrinogen, procalcitonin, D-dimer, ferritin, lactate dehydrogenase, or interleukin-6
            • Elevated neutrophils or reduced lymphocytes
            • Low albumin
          • No alternative diagnosis, such as:
            • Birth asphyxia, indicated by cord pH of 7.0 or less and Apgar score of 3 or less at 5 minutes
            • Viral or bacterial sepsis with confirmed blood culture
            • Maternal lupus resulting in neonatal atrioventricular conduction abnormalities
      • MIS-C and PIMS-TS criteria.CRP, C-reactive protein; LDH, lactate dehydrogenase; NT-proBNP, N-terminal pro–brain type natriuretic peptide; PCR, polymerase chain reaction; RCPCH, UK Royal College of Paediatrics and Child Health.Data from CDC: Multisystem Inflammatory Syndrome (MIS): Information for Healthcare Providers About Multisystem Inflammatory Syndrome in Children (MIS-C). CDC website. Last reviewed January 3, 2023. Accessed March 14, 2023. https://www.cdc.gov/mis/mis-c/hcp_cstecdc/index.html; WHO: COVID-19 Clinical Management of COVID-19 Patients: Living Guideline version 6.0. Magic app website. Published January 12, 2023. Accessed March 14, 2023. https://app.magicapp.org/#/guideline/j1WBYn; and Royal College of Paediatrics and Child Health: Paediatric Multisystem Inflammatory Syndrome Temporally Associated With COVID-19 (PIMS) - Guidance for Clinicians. Royal College of Paediatrics and Child Health website. Published May 1, 2020. Accessed March 14, 2023. https://www.rcpch.ac.uk/resources/paediatric-multisystem-inflammatory-syndrome-temporally-associated-covid-19-pims-guidance.
        CriteriaCDCWHORCPCH
        PopulationAge younger than 21 yearsAge younger than 20 yearsChildren
        Clinical manifestationsSubjective or documented fever (38 °C or higher) and illness with clinical severity requiring hospitalization or resulting in death and new onset involvement in 2 or more of the following categories:

        Cardiac: left ventricular ejection fraction <55%; or coronary artery dilatation, aneurysm, or ectasia; or troponin elevated above normal

        Mucocutaneous: rash, or inflammation of the oral mucosa, or
        conjunctivitis or conjunctival injection, or erythema or edema of the hands or feet

        Shock

        Gastrointestinal: abdominal pain, or vomiting, or diarrhea

        Hematologic: platelet count <150,000 cells/μL or absolute lymphocyte count <1,000 cells/μL
        Fever for at least 3 days and 2 of the following:

        Rash or bilateral nonpurulent conjunctivitis or muco-cutaneous inflammation signs (oral, hands or feet)

        Hypotension or shock

        Features of myocardial dysfunction, pericarditis, valvulitis, or coronary abnormalities (including echocardiographic findings or elevated troponin/NT-proBNP)

        Evidence of coagulopathy (by prolonged prothrombin time, partial thromboplastin time, elevated D-dimers)

        Acute gastrointestinal problems (diarrhea, vomiting, or abdominal pain)
        Persistent fever higher than 38.5 °C and evidence of single or multisystem dysfunction: shock, cardiac, respiratory, renal, gastrointestinal, or neurologic disorder. May include children fulfilling full or partial criteria for Kawasaki disease
        Evidence of inflammationAnd evidence of systemic inflammation indicated by CRP ≥3.0 mg/dLAnd elevated markers of inflammation including erythrocyte sedimentation rate, CRP, or procalcitoninAnd evidence of inflammation (neutrophilia, elevated CRP, lymphopenia)
        SARS-CoV-2 testingDetection of SARS-CoV-2 RNA or antigen in a clinical specimen up to 60 days prior to or during hospitalization, or in a postmortem specimen using a diagnostic molecular amplification test (eg, PCR, rapid antigen test), or detection of SARS-CoV-2 specific antibodies in serum, plasma, or whole blood associated with current illnessAnd evidence of COVID-19 (reverse transcription PCR, antigen test or serology positive) or likely contact with patients with COVID-19And positive or negative SARS-CoV-2 PCR testing
        Alternate diagnosis evaluationAnd no more likely diagnosis (note: a case with a diagnosis of Kawasaki disease by clinical team should not be reported as an MIS-C case)And no other obvious microbial cause of inflammation, including bacterial sepsis, staphylococcal or streptococcal shock syndromesAnd exclusion of any other microbial cause, including bacterial sepsis, staphylococcal or
        streptococcal shock syndromes, or infections associated with myocarditis such as enterovirus
    • Classification based on predominant presenting clinical phenotype
      • Different clinical presentations, such as Kawasaki disease–like or similar to severe acute COVID-19, led experts to attempt classification within MIS-C r3r22r23
      • Newer case definition better discriminates among Kawasaki disease, acute severe COVID-19, and toxic shock syndrome r2r24
        • A case that meets criteria for Kawasaki disease will no longer be counted as MIS-C; similarly, an illness that results from acute severe COVID-19 is less likely to meet new MIS-C criteria r2

    Diagnosis

    Clinical Presentation

    History

    • Background
      • Onset of symptoms typically occurs 2 to 6 weeks after exposure to SARS-CoV-2 r25
      • Many patients are asymptomatic or experience mild illness at time of inciting SARS-CoV-2 infection and therefore may not report prior infection r26
      • Initial disease manifestations present on a spectrum of severity, ranging from mild symptoms to multiorgan failure r27
      • Manifestations may not appear simultaneously but may evolve over several days r27
      • Mucocutaneous manifestations typically appear early in course of illness (mean duration after development of fever until appearance is about 2 and a half days) r28
    • Common presenting symptoms in children include:
      • Persistent fever, often lasting 4 days or more, is universal r29
        • With increased awareness and faster diagnosis of MIS, the length of time fever is present has been removed from CDC case definition r2
      • Gastrointestinal symptoms are very common r3r29r30
        • Abdominal pain may be severe, suggesting acute abdomen
        • Nonbloody diarrhea may be profuse
        • Vomiting
      • Mucocutaneous symptoms are very common r3r31
        • Rash
        • Conjunctivitis
        • Oral mucosal changes (eg, mucosal erythema, dry or fissured lips, strawberry tongue) and odynophagia
        • Nonspecific extremity pain and swelling, typically hands and/or feet
      • Cardiovascular symptoms r30
        • Rapid breathing, dyspnea, fatigue, and chest pain may suggest presence of myocarditis
        • Syncope related to arrhythmia may be noted
      • Neurologic symptoms r3
        • Headache r6
        • Altered mental status (confusion, somnolence) r6
        • Aseptic meningitis presentation (mild neck stiffness, photophobia) r26
        • Vision changes
        • Cranial nerve palsies
        • Seizures
    • Less common symptoms in children include:
      • Respiratory symptoms (eg, rhinorrhea, cough) may be present but are not common and are not predominant r6
      • Myalgia is sometimes reported r6
    • In adults, based on a review of 221 patients worldwide, common presenting symptoms include fever, shortness of breath (52%), and diarrhea (52%) r14
      • Other symptoms noted include abdominal pain (48%), vomiting (44%), chest pain (29%), rash (38%), cough (37%), and headache (42%) r14
    • Neonates with MIS-N similarly develop symptoms in multiple organ systems, such as vomiting, diarrhea, rash, seizures; symptoms that differ from infants and children with MIS-C include: r17
      • May present with fever but much less likely than in MIS-C (18% versus 84% of infants younger than 6 months with MIS-C) r17
      • Hypothermia and temperature instability are also manifestations
      • Respiratory symptoms (eg, grunting, tachypnea, apnea) are more prevalent
      • Feeding intolerance is also a gastrointestinal symptom in neonates

    Physical examination

    • Patients may appear severely ill with signs of shock
      • Approximately 50% to 60% of children present with shock requiring some type of inotropic support r27r32
      • WHO defines shock in children as any hypotension (systolic blood pressure below 5th percentile or more than 2 standard deviations below reference range for age) or 2 or more of the following: r11
        • Tachycardia (heart rate higher than 160 beats per minute in infants or 150 beats per minute in older children) or bradycardia (heart rate lower than 90 beats per minute in infants or 70 beats per minute in older children)
        • Prolonged capillary refill (longer than 2 seconds) or weak pulse (cardiogenic shock)
        • Tachypnea
        • Mottled or cool skin, petechiae, or purpura
        • Oliguria
        • Altered mental status
        • Hyperthermia or hypothermia
        • Elevated lactate
      • Pulses may be bounding (so-called warm vasodilatory or distributive shock)
    • Presenting signs in children include: r3r32r33
      • Abnormal vital signs
        • Fever is present by definitionr2r6r11 and may be quite high (40 °C or higherr29)
        • Tachycardia and irregular rhythms have been reported
        • Tachypnea is often related to myocardial dysfunction in the setting of MIS-C
        • Hypotension secondary to cardiogenic, distributive (vasodilatory), or hypovolemic shock, or combination of these r7
      • Gastrointestinal signs
        • Abdominal tenderness and guarding may be noted
        • Findings mimicking appendicitis (eg, focal right lower quadrant tenderness worsened with movement) may be present
      • Kawasaki disease–like signs
        • Rash is common; may be polymorphic in nature
        • Conjunctival injection is often seen, but purulence and exudate are not typical
        • Oral mucosa may be dry and reddened (eg, fissured lips, strawberry tongue)
        • Cervical lymphadenopathy may be palpable in a minority
        • Erythema of palms and soles as well as firm edema or induration of dorsal surfaces may be present
      • Myocarditis
        • Tachycardia out of proportion to degree of fever or dehydration
        • Respiratory distress with increased work of breathing and pulmonary rales develop with pulmonary venous congestion
        • Hepatomegaly, new murmurs (eg, mitral valve insufficiency, tricuspid valve insufficiency), and S3 or S4 gallop may develop with ventricular dysfunction
        • Poor pulse quality and significantly delayed capillary refill develop with cardiovascular instability
      • Neurologic signs
        • Meningismus is present in some patients
        • Altered mental status
        • Cranial nerve palsies
        • Findings of ischemic or hemorrhagic stroke
      • Pulmonary findings typically are not prominent
    • Potential findings in adults are similar and commonly include: r14
      • Hypotension and shock
      • Arrhythmia
      • Rash, mucocutaneous lesions, conjunctival injection
      • Periorbital edema
    • Neonatal signs are also similar (eg, hypotension, rash, abdominal distension, tachycardia, bradycardia, drowsiness, lethargy); however, findings of respiratory distress are significantly more common in infants with MIS-N or MIS-C than in older children or adults with MIS-C or MIS-A
      • Respiratory distress was present in 67% of infants with MIS-N and 72% of infants younger than 6 months with MIS-C; half or more patients with either diagnosis required mechanical ventilation r17r21

    Causes and Risk Factors

    Causes

    • MIS is thought to occur secondary to a postinfectious, dysregulated inflammatory response to previous exposure or infection with SARS-CoV-2 r3r25r27
      • Over successive pandemic waves, the incidence of MIS has decreased, likely attributable to increased immunity from vaccination and exposure and to differences in variants r3r34r35r36
    • Temporal association exists with COVID-19 both in individual cases (positive RNA or serologic test result) and in epidemiologic curve of both conditions; MIS commonly appears 2 to 6 weeks after COVID-19 r4r33
      • In areas heavily affected by the pandemic, incidence of MIS-C parallels that of COVID-19 after a 2- to 6-week interval, consistent with a postinflammatory mechanism related to COVID-19 r26r33

    Risk factors and/or associations

    Age
    • Depending on case definition, MIS-C may include patients up to age 19 years or 21 years r2r5r11
      • Median age among children is reported to be 9 years r4
      • Half of children diagnosed with MIS-C are between ages 5 and 13 years r4
      • Over course of pandemic, age of children diagnosed with MIS-C shifted younger in certain countries, corresponding with the sequential rollout and uptake of vaccination from older to younger age groups r35r36
    • MIS-A has now been reported in adults of all ages r37
      • MIS in adults may be difficult to distinguish from biphasic acute hyperinflammatory COVID-19 r14r37
    • 73% of neonates with MIS-N were born preterm; it is unknown if MIS-N may trigger preterm labor or if prematurity is a risk factor for MIS-N r17
    Sex
    • Males are affected more often than females in both children (approximately 60% male) and adults (approximately 70% male) r14r31
    Ethnicity/race
    • More common among patients of African, African-Caribbean, Hispanic/Latino, and Asian/Pacific Islander ancestry than other groups r14r22r32
      • Non-Hispanic Black: 30% of MIS-C cases in United States and 36% of MIS-A cases worldwide r4r14
      • Hispanic/Latino: 26% of MIS-C cases in United States and 30% of MIS-A cases worldwide r4r14
      • Similar to other racial disparities found in COVID-19, this disparity appears to be due to social determinants of health and inequities rather than biological differences r9r38
    • Very few MIS-C cases reported from China or Japan r3
    Other risk factors/associations
    • About half of children diagnosed are obese or overweight based on BMI; about 26% of adults diagnosed with MIS-A are obese r14r32
    • Association with vaccination
      • Data suggest the vast majority of children who develop MIS-C are unvaccinated and that vaccination is extremely effective at preventing MIS-C r3r20
      • MIS-C cases occurring after vaccination (and not associated with SARS-CoV-2 exposure) appear to be extremely rare r3r19

    Diagnostic Procedures

    Primary diagnostic tools

    • No confirmatory diagnostic test exists; diagnosis is based on case definition using constellation of clinical, laboratory, echocardiographic, and epidemiologic factors r2r6
      • Majority of patients have laboratory evidence of prior SARS-CoV-2 (positive antibody test result); some patients have positive SARS-CoV-2 polymerase chain reaction or antigen testing r3r15
    • WHO, CDC, and Royal College of Paediatrics and Child Health have published case definitions that are broadly similar r2r6r11r13
      • All available guidance strongly recommends exclusion of alternate sources of infection and noninfectious conditions that can present similarly
    • Suspect diagnosis when clinical presentation is concerning for diagnosis, particularly in 2- to 6-week timeframe following COVID-19 community outbreak
      • Clinical manifestations may not appear simultaneously but instead may evolve over several days; constellation of presenting manifestations varies from patient to patient, and disease severity also varies
      • Patients may have MIS‐C even in absence of preceding COVID‐19–like illness or clear history of exposure to SARS-CoV-2, especially in setting of high community prevalence r33
      • Common presenting patterns include: r25r33
        • Persistent, unexplained high fever in patient with laboratory evidence of marked inflammation
        • Presentation with, or rapid development of, shock or shocklike state secondary to significant cardiac dysfunction, multiorgan dysfunction, or cytokine release syndrome (ie, cytokine storm)
          • Patients require judicious fluid resuscitation and aggressive hemodynamic support. Children under investigation for MIS-C with life-threatening manifestations may require immunomodulatory treatment for MIS-C before full diagnostic evaluation can be completed r33
        • Fever with significant gastrointestinal distress mimicking acute abdomen or concerning neurologic manifestations (eg, meningismus, altered mental status, lethargy)
        • Features of Kawasaki disease (eg, conjunctival and mucosal injection, rash, swelling of hands and feet, coronary artery dilation) or toxic shock syndrome (eg, erythroderma, hypotension, renal and multiorgan involvement)
          • Note that if alternative diagnosis is ultimately considered more likely (eg, Kawasaki disease, toxic shock syndrome), then case should not be reported as MIS-C
          • Younger children tend to present with Kawasaki disease–like phenotype and older children and adults are more likely to develop myocarditis and shock r14r33
    • Tiered diagnostic testing approach may be followed to assess children with suspicion for MIS-C based on clinical presentation; obtain full diagnostic evaluation for children with myocarditis, shock, or shocklike state with epidemiologic link to COVID-19 r25r33
      • First tier testing
        • Includes initial screening laboratory tests, tests for inflammation, specific tests for SARS-CoV-2, and microbiologic evaluation for alternate infectious causes of presentation
          • Obtain general baseline tests including CBC with differential, electrolyte panel with renal function, urinalysis, and liver function r23
            • Consistent findings include:
              • Anemia, thrombocytopenia, neutrophilia, and lymphopenia
              • Elevated creatinine, BUN, and transaminases
              • Proteinuria, hyponatremia, and hypoalbuminemia
          • Obtain inflammatory marker levels including erythrocyte sedimentation rate and C-reactive protein
            • Inflammatory markers are often markedly elevated
          • Obtain specific testing for COVID-19
            • SARS-CoV-2 antibody test results are often positive, whereas polymerase chain reaction or antigen test results are more often negative r33
          • Perform focused microbiologic evaluation for alternate infectious causes as directed by clinical suspicion; evaluation may include studies such as: r27r39r40
            • Blood, throat, urine, stool, and cerebrospinal fluid cultures as clinically indicated
            • Nasopharyngeal swabs for common respiratory viruses, such as Epstein-Barr virus, enteroviruses, adenovirus, human herpesvirus 6, and rubeola (measles) virus
      • Second tier (full diagnostic) evaluation
        • Complete in patients with initial findings consistent with significant inflammatory response and concerning for MIS-C; order full diagnostic evaluation in children presenting in extremis
        • Often includes testing for laboratory evidence of evolving picture of cytokine release syndrome, evidence of significant coagulopathy, and assessment for myocarditis
          • Testing recommended by American College of Rheumatology includes: r23r33
            • B‐type natriuretic peptide
            • Troponin T
            • Procalcitonin
            • Ferritin
            • Prothrombin time
            • Partial thromboplastin time
            • D-dimer
            • Fibrinogen
            • Lactate dehydrogenase
            • Urinalysis
            • Cytokine panel
            • Triglycerides
            • SARS-CoV-2 serology (if not already sent)
            • Blood smear
            • ECG
            • Echocardiogram
          • In addition, UK National Health Service suggests the following tests as needed to rule out other diagnoses (eg, appendicitis, intussusception): r6
            • Blood gas and lactate
            • Chest radiograph
            • Abdominal ultrasonograph
          • Consistent laboratory findings often include elevated levels of ferritin, procalcitonin, cytokines (eg, interleukin-6), lactate dehydrogenase, fibrinogen, D-dimer, triglycerides, lactate, and creatine kinase as well as prolonged prothrombin time and partial thromboplastin time
        • Obtain serum specimen before administering IV immunoglobulin and submit to laboratory hold for possible future serologic testing r6r31
          • Serum cannot be used for serologic testing after IV immunoglobulin has been administered
    • Diagnostic algorithms have been published, although these do not yet conform to updated CDC case definition r3r27r33r41
    • MIS cases should be voluntarily reported in United States
      • Report cases to local, state, or territorial health department or contact CDC with questions r2r13
      • Report potential MIS-C and MIS-A cases following vaccination to VAERS (Vaccine Adverse Event Reporting System) r42

    Laboratory

    • CBC
      • WBC count is often elevated r15r43
      • Lymphopenia is common; neutrophilia may occur r6r15
      • Anemia or thrombocytopenia may be present
    • Electrolytes and renal panel
      • Hyponatremia may be noted r6r39
      • Increased creatinine and BUN levels may develop r15r39
    • Inflammatory markers
      • C-reactive protein, erythrocyte sedimentation rate, procalcitonin, and ferritin levels are typically elevated, often markedly r6r15r29r39r44
      • Initial ferritin levels above 500 mcg/L have been associated with more severe disease requiring ICU admission r45
      • Erythrocyte sedimentation rate may be falsely elevated after administering IV immunoglobulin; therefore, many experts recommend no longer measuring erythrocyte sedimentation rate after administering IV immunoglobulin
    • Coagulation studies r6r15r29r39r44
      • Prothrombin time/INR and partial thromboplastin time may be prolonged
      • D-dimer may be markedly elevated
      • Fibrinogen levels may be high
    • Cardiac markers
      • Troponin and NT-proBNP levels (N-terminal pro–brain type natriuretic peptide) may be elevated, indicating myocardial inflammation, sometimes to very high levels r15r29r39r46
    • Others
      • Hypoalbuminemia is common r43
      • Cytokines (if available): characteristic findings include elevated interleukin-6, interleukin-10, soluble interleukin-2 receptor, and tumor necrosis factor r6r26r29r44
      • Mild cerebrospinal fluid pleocytosis has been reported in patients who underwent lumbar puncture for possible meningitis r39r40
      • Triglyceride levels may be above reference range r6
      • Aspartate transaminase and alanine transaminase may be slightly elevated r43
      • Creatine kinase may be increased
    • SARS-CoV-2 testing
      • Polymerase chain reaction, antigen, or antibody test results have been positive in nearly all patients; however, negative test results do not exclude disease r29r39r40r44r46
        • Positive antibody test response to SARS-CoV-2 is estimated to be present in over 80% of children with MIS-C r25
        • Positive polymerase chain reaction test result for SARS-CoV-2 infection occurs in an estimated 20% to 45% of children with MIS-C r25r31
        • Up to an estimated 15% of children with suspected MIS-C have negative SARS-CoV-2 test results at presentation but have a significant exposure (eg, family member) confirmed positive for SARS-CoV-2 r47r48
        • Among adults, approximately 98% have laboratory evidence of current or past infection r14
      • Combined test results r22r26r30r44r46r49
        • About 60% of children with MIS-C have positive SARS-CoV-2 antibody serologic test results and negative polymerase chain reaction or antigen test results
        • Approximately 30% to 35% of children with MIS-C are positive for both SARS-CoV-2 antibodies by serologic and polymerase chain reaction or antigen testing
        • Minority of children are negative for both SARS-CoV-2 antibodies and polymerase chain reaction or antigen testing
        • About 25% of adults with MIS-A have positive polymerase chain reaction test results only, 40% have positive antibody test results only, and 32% have positive test results for both r14
      • SARS-CoV-2 serologic testing r50
        • Quantitative SARS-CoV-2 serology r51
          • May aid in differentiating acute severe COVID-19 and MIS because higher titers are expected to occur in patients with MIS
          • As pandemic progresses, positive serologic test results may not reflect recent infection, which complicates interpretation r33
        • Antinucleocapsid SARS-CoV-2 antibody r2r52
          • Positive results are consistent with evidence of resolving or previous infection with SARS-CoV-2
          • Nucleocapsid is not a component of current vaccines; therefore, vaccination does not render a positive antinucleocapsid antibody result
        • Antispike SARS-CoV-2 antibody
          • Positive results are consistent with either previous infection or vaccination against SARS-CoV-2 r2

    Imaging

    • Chest radiography
      • Baseline chest radiograph is prudent; many patients exhibit abnormalities at presentation or during disease course r5r6r43
      • Nonspecific patchy infiltrates are not unusual with MIS-C; evidence of pleural effusion and cardiomegaly may be visible r6r39r44
      • Occurrence of infiltrate findings on chest imaging at presentation is highly variable, with respiratory involvement reported in as few as 18% and as many as 78% of children with MIS-C in different cohorts r3r53
        • Updated case definition, which eliminates pulmonary system involvement in diagnosis of MIS-C, may decrease misclassification with acute, severe COVID-19, which has greater pulmonary involvement r2r24
      • Up to one-third of adults with MIS-A may have pulmonary involvement; chest radiography may be needed to evaluate cough, shortness of breath, or chest pain r14r15
    • Echocardiography
      • May reveal general features of myocarditis (left ventricular systolic dysfunction) or additional changes characteristic of pancarditis (coronary artery dilation, hyperechoic coronary arteries, valvulitis, pericarditis, pericardial effusion) r27r44r46
        • Left ventricular ejection fraction is diminished in at least 34% of children at admission and in a majority of adults with MIS-A r15r54
      • Findings (eg, dilation or aneurysms of coronary arteries) may develop during course of illness and even after hospital discharge r44r46r55
        • Coronary artery aneurysms have been reported in adults extremely infrequently r15r56
      • Recommended for all children at diagnosis and during follow-up (at minimum 7-14 days and 4-6 weeks after presentation) owing to high risk of cardiac involvement r33
        • Echocardiography should be evaluated for ventricular and valvular function, pericardial effusion, and coronary artery dimensions with z scores
        • Patients with coronary artery aneurysms or ventricular dysfunction need more frequent echocardiograms for evaluation; also consider follow-up echocardiogram 1 year after illness
    • Abdominal ultrasonography or CT
      • May reveal hepatosplenomegaly, mesenteric adenitis, ileocolitis, ascites, gallbladder inflammation, or appendiceal inflammation r15r27

    Functional testing

    • ECG
      • Abnormal ECG findings may be apparent in up to about 35% of children at admission and may include: r54
        • Prolonged PR interval and prolonged QTc interval
        • Repolarization changes (eg, abnormal ST- or T-wave segment) (most common) r46r54r55
        • Heart block (first, second, or third degree)
        • Premature atrial and ventricular beats
        • Ventricular arrhythmias
      • ECG is recommended at baseline and every 48 hours while hospitalized for children; for patients with arrhythmias, continuous telemetry during hospitalization is recommended and Holter monitoring after discharge should be considered r33
      • Given prevalence of cardiac involvement in MIS-A, ECG is recommended for all adults with MIS-A r37

    Differential Diagnosis

    Most common

    • Charts and diagnostic scores have been published to help discriminate MIS-C from other hyperinflammatory conditions r3r24
    • Kawasaki disease d1
      • Medium-sized vessel vasculitis most commonly affecting children younger than 5 years. Coronary arteries may be affected, resulting in coronary artery aneurysms r57
      • Subset of patients who meet diagnostic criteria for MIS-C also meet criteria for Kawasaki disease, incomplete Kawasaki disease, or Kawasaki disease shock syndrome; these children should not be reported as MIS-C cases if Kawasaki disease is diagnosed by clinical team r2
        • Kawasaki diagnosis is established by fever lasting 5 or more days and at least 4 of the following 5 clinical criteria: r58
          • Polymorphous rash (excluding bullous or vesicular eruptions)
          • Conjunctival injection
          • Oropharyngeal mucous membrane changes
          • Extremity changes
          • Lymphadenopathy
        • Incomplete Kawasaki disease presents similarly; diagnosis is based on fulfilling fewer (2 or 3) of Kawasaki disease clinical criteria with compatible laboratory and echocardiographic findings r57
      • Differentiating features include:
        • Demographic trends are different. Most children affected by Kawasaki disease are younger than those with MIS-C. MIS-C disproportionately affects patients of African, African-Caribbean, and Hispanic descent, whereas Kawasaki disease disproportionately affects patients of East Asian descent r33
        • Gastrointestinal symptoms and neurologic symptoms are more common, and rash and conjunctival injection are less common, in children with MIS-C than those with Kawasaki disease r24r44
        • Overall disease severity exceeds that seen in classic Kawasaki disease; development of shock is common in children with MIS-C and rare in children with Kawasaki disease r44
          • In children with shock due to MIS-C, abdominal pain was more common, coronary artery abnormalities were less common, lymphocyte counts were lower, and duration of fever was shorter, compared to children with Kawasaki disease shock syndrome r24
        • Cardiovascular involvement is more common in MIS-C than Kawasaki disease, with the exception of coronary artery changes, which are more common in Kawasaki disease (29%) than MIS-C (15%) r24
          • When coronary artery changes are present, children with MIS-C tend to have uniformly ectatic vessel dilation with consistent involvement of left main coronary artery orifice, whereas Kawasaki pattern includes aneurysms that are separated by normal vessel segments and usually spares left main coronary artery orifice r57
        • Differing laboratory markers in MIS-C compared with Kawasaki disease may include lower nadir of platelet counts and lymphocyte counts and higher elevation of C-reactive protein, fibrinogen, and ferritin r24r57
        • Overall clinical course is often more severe in MIS-C than in Kawasaki disease. Children with MIS-C require heightened supportive care and are more often resistant to single dose IV immunoglobulin than children with Kawasaki disease r57
      • May be extremely challenging to confirm Kawasaki disease in some cases. SARS-CoV-2 testing (including quantitative antibody titers) and exposure history may aid differentiation the most in presence of continued clinical uncertainty
        • Comparison of MIS-C and classic (pre-COVID-19) Kawasaki disease characteristics.CRP, C-reactive protein; NT-proBNP, N-terminal pro–brain type natriuretic peptide.Data from Berard RA et al: Canadian Paediatric Society Practice Point. Paediatric Inflammatory Multisystem Syndrome Temporally Associated With COVID-19 (Spring 2021 Update). Canadian Paediatric Society website. Published July 6, 2020. Updated May 16, 2021. Accessed March 14, 2023. https://cps.ca/en/documents/position/pims; Carter MJ et al: Paediatric inflammatory multisystem syndrome temporally-associated with SARS-CoV-2 infection: an overview. Intensive Care Med. 47(1):90-3, 2021; Henderson LA et al: American College of Rheumatology Clinical Guidance for Multisystem Inflammatory Syndrome in Children Associated With SARS-CoV-2 and Hyperinflammation in Pediatric COVID-19: Version 3. Arthritis Rheumatol. ePub, 2022; Kaushik A et al: A systematic review of multisystem inflammatory syndrome in children associated with SARS-CoV-2 infection. Pediatr Infect Dis J. 39(11):e340-e46, 2020; McCrindle BW et al: Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association. Circulation. 135(17):e927-99, 2017; Waseem M et al: Multisystem inflammatory syndrome in children. J Emerg Med. 62(1):28-37, 2022; and Kiss A et al: Management of COVID-19-associated multisystem inflammatory syndrome in children: a comprehensive literature review. Prog Pediatr Cardiol. 101381, 2021; CDC: Emergency Preparedness and Response: Clinician Outreach and Communication Activity: COCA Calls/Webinars: Updates on Multisystem Inflammatory Syndrome in Children (MIS-C): Epidemiology, Case Definition, and COVID-19 Vaccination. CDC website. Published December 8, 2022. Accessed March 14, 2023. https://emergency.cdc.gov/coca/calls/2022/callinfo_120822.asp.
          ManifestationClassic prepandemic Kawasaki diseaseMIS-C
          AgeSignificantly more common in children younger than 5 years. Less than 20% of patients with Kawasaki disease are older than 5 yearsHalf of children are between 5 and 13 years, although cases are shifting to younger age groups
          EthnicityMost commonly noted in children of East Asian descentMost commonly noted in children of African, African-Caribbean, and Hispanic descent
          SeverityTend to be less sick than typical MIS-C patientsTend to be relatively sicker than the typical patient with Kawasaki disease
          Gastrointestinal manifestations (vomiting, diarrhea, abdominal pain)Mild gastrointestinal and abdominal pain may occur but are not usually a prominent featureAbdominal pain is often a prominent feature and may mimic acute abdomen; large majority have some gastrointestinal involvement
          Neurologic symptomsTend to be less prominent; exception may be irritability, as most children with classic Kawasaki disease are notably irritableTend to be more prominent with severe headache, altered sensorium, mental status depression, frank meningismus, cranial nerve palsies
          Cardiac dysfunction at presentationMost do not present with significant cardiac dysfunction. Myocarditis tends to develop gradually with peak involvement around day 7 of illness followed by tapering off by day 14. Myocarditis and cardiac dysfunction tends to be less severe than in patients with MIS-CSignificant proportion present with cardiac dysfunction. Severe dysfunction (eg, arrhythmias, ventricular dysfunction) and development of cardiogenic shock are much more common than in patients with classic Kawasaki disease
          Shock at presentation or development of shockShock (Kawasaki disease shock syndrome) is rare (about 5%) at presentation and development during the course of acute phase of illness is uncommonShock and shocklike state are much more common (about 26%) presenting features among children with Kawasaki–like features, and requirement for vasoactive support at some point during course of illness is considerably more prevalent than in patients with Kawasaki disease
          Platelet abnormalitiesThrombocytopenia is rare; patients often develop marked thrombocytosis beginning in second week of illnessThrombocytopenia is characteristic
          AnemiaAbout half of children develop mild normocytic anemiaAnemia is characteristic; peripheral smear may show findings associated with microangiopathic changes in RBCs
          WBC changesLeukocytosis (WBC >15,000 cells/mm³) is present in about half of patients; neutrophilic predominance is typical for acute phase of diseaseLymphopenia is characteristic; neutrophilia may be present
          Inflammatory markersCRP and erythrocyte sedimentation rate are typically modestly elevated; CRP is usually less than 100 mg/dL; mild elevations in other inflammatory markers may be present (eg, ferritin, D-dimer)CRP and erythrocyte sedimentation rate are typically markedly elevated; CRP is frequently elevated above 100 mg/dL; other markers of hyperinflammatory response are often pronounced (eg, elevated ferritin, D-dimer, fibrinogen)
          Cardiac biomarkersUsually normal. Troponin and NT-proBNP may be modestly elevated in patients with ventricular wall stress and inflammation, as well as patients with coronary artery abnormalitiesElevation of troponin and NT-proBNP is typically more marked than in patients with Kawasaki disease
          Echocardiographic findingsInitial echocardiogram findings in the first week of illness are usually normal. Some findings that may evolve during the course of illness may be similar (eg, myocarditis, valvulitis, pericardial effusion) but are usually less severe than noted in patients with MIS-C. Coronary artery lesions are present in a minority of patients on initial evaluation; aneurysms usually start to develop around week 3 of illnessInitial echocardiographic findings of myocarditis with significant left ventricular dysfunction may be prominent abnormal presenting features. Up to one-third of patients with severe presentations exhibit coronary artery dilation in acute phase. Other prominent findings may include valvulitis and pericardial effusion
          Evidence of infectious disease or alternate cause for illnessAbsence of bacterial or viral cause for manifestations is a key aspect of clinical diagnostic criteriaLaboratory findings suggestive of recent infection with COVID-19 are positive in many cases, either by serologic or positive polymerase chain reaction/antigen testing. Other patients have recent link to COVID-19 by known contact or exposure to outbreak in community. Otherwise, no other infection or obvious microbial cause or association is found, and other noninfectious alternative diagnoses (eg, rheumatologic, oncologic) have been excluded
          Development of coagulopathy and macrophage activation syndromeMild (+) riskModerate to severe (++) risk
          Pattern of coronary artery involvementAneurysms that are separated by normal vessel segments and inflammation usually spares left main coronary artery orificeDistinct pattern of uniformly ectatic vessel dilation with consistent involvement of left main coronary artery orifice
          Treatment responseTypically responds promptly to first dose of IV immunoglobulin administrationLeft ventricular dysfunction often responds rapidly (over a couple of days) and well to treatment; however, when compared to classic prepandemic Kawasaki disease, MIS-C often requires more overall therapy over a longer course
    • Toxic shock syndrome d2
      • Severe systemic disease caused by certain toxin-producing strains of Staphylococcus aureus or group A streptococcus
      • As in MIS-C, patients present with fever and rash; hypotension, thrombocytopenia, central nervous system involvement (eg, confusion), and renal failure are common
      • History of retained foreign body (eg, tampon, nasal packing material) may be elicited
      • Edema is generally diffuse and not limited to hands and feet; articular signs are generally absent
      • Case definitions include hypotension and multisystem involvement
        • Features of nonstreptococcal toxic shock syndrome: r6r59
          • Fever (39 °C or higher)
          • Generalized erythroderma followed by desquamation
          • Hypotension (systolic pressure lower than 90 mm Hg in adults and older adolescents or less than fifth percentile for age in children younger than 16 years)
          • Multiorgan involvement characterized by 3 or more of the following:
            • Gastrointestinal symptoms (vomiting or diarrhea, usually at onset of illness)
            • Muscle involvement (severe myalgias or creatine phosphokinase level twice reference range or higher)
            • Mucus membrane changes (hyperemia of conjunctivae, oropharynx, or vagina)
            • Renal impairment (BUN or creatinine level twice upper reference limit or higher or urinary sediment with pyuria in absence of urinary tract infection)
            • Hepatic impairment (transaminase or bilirubin level twice reference range or higher)
            • Coagulopathy (platelet count 100,000/mm³ or less)
            • Central nervous system manifestations (confusion, altered level of consciousness)
          • Cultures are negative (other than Staphylococcus aureus, which may or may not be found)
          • No serologic evidence of recent Rocky Mountain spotted fever, leptospirosis, or rubeola
        • Features of streptococcal toxic shock syndrome r60
          • Hypotension (systolic pressure 90 mm Hg or lower in adults and older adolescents or less than fifth percentile for age in children younger than 16 years)
          • Multiorgan involvement characterized by 2 or more of the following:
            • Renal impairment (creatinine level 2 mg/dL or higher for adults or twice upper reference limit or higher for age)
            • Coagulopathy (platelet count 100,000/mm³ or less or presence of disseminated intravascular coagulation)
            • Hepatic impairment (transaminase or bilirubin level twice reference range or higher)
            • Acute respiratory distress syndrome
            • Generalized erythematous rash; may desquamate
            • 1 or more sites of soft tissue necrosis
          • Isolation of group A streptococcus
      • Conditions may be difficult to clinically differentiate. Differentiating features include:
        • Children with MIS-C are more likely to have conjunctival injection, neck pain, lymphadenopathy, and pleural effusion than those with toxic shock syndrome r3r24
        • Children with MIS-C may have more marked anemia, higher C-reactive protein levels, and higher alanine aminotransferase levels and are more likely to have presence of lymphopenia and hypertriglyceridemia, compared with those with toxic shock syndrome r3r26
        • Subset of patients with MIS-C fulfills clinical criteria for toxic shock syndrome; children should not be reported as MIS-C cases if toxic shock syndrome is diagnosed by clinical team r2
    • Acute COVID-19 d3
      • Acute severe COVID-19 and MIS-C/MIS-A have overlapping clinical features, and presentations may be quite similar r15r24r36
      • Some differences in clinical presentation and organ system involvement may help to differentiate
        • Children with severe COVID-19 tend to fall in bimodal age distribution (ie, very young or adolescent age), whereas MIS-C is most common in 6- to 12-year age range r53
        • Adults with severe COVID-19 tend to be older than those with MIS-A, although MIS-A may be underreported r10r15r37
        • Severe COVID-19 illness often occurs in children and adults with significant underlying medical comorbidity, whereas MIS-C or MIS-A occurs more frequently in previously healthy individuals r7r15
        • Exposure history may help differentiate. Exposure to SARS-CoV-2 occurs days before onset of illness in COVID-19 and weeks before onset of illness in MIS
        • Gastrointestinal, mucocutaneous, and cardiovascular involvement and shock is more prevalent in children with MIS-C than in those with COVID-19
        • Respiratory symptoms and pulmonary involvement are much more common and profound in patients with COVID-19 than in those with MIS
        • Inflammatory markers are elevated in patients with severe COVID-19 but markedly elevated in children with MIS-C
        • Most, if not all, patients with acute COVID-19 have positive polymerase chain reaction or antigen test result for SARS-CoV-2 infection
        • Quantitative SARS-CoV-2 antibody titers may help to differentiate, as patients with MIS-C often present with more robust antibody response than patients with acute COVID-19
      • Differentiation may be extremely challenging in some cases
        • Manifestations in pediatric COVID-19 and MIS-C.CRP, C-reactive protein.Data from Case SM et al: COVID-19 in pediatrics. Rheum Dis Clin North Am. 47(4):797-811, 2021; Badal S et al: Prevalence, clinical characteristics, and outcomes of pediatric COVID-19: a systematic review and meta-analysis. J Clin Virol. 135:104715, 2021; Feldstein LR et al: Multisystem inflammatory syndrome in U.S. children and adolescents. N Engl J Med. 383(4):334-46, 2020; Godfred-Cato S et al: COVID-19-associated multisystem inflammatory syndrome in children - United States, March-July 2020. MMWR Morb Mortal Wkly Rep. 69(32):1074-80, 2020; Ahmed M et al: Multisystem inflammatory syndrome in children: a systematic review. EClinicalMedicine. 26:100527, 2020.
          Manifestation or findingMIS-CPediatric COVID-19
          AgeMost common in 5 to 11 year age rangeSevere disease is more common in younger age groups (aged <1 year) and older teenagers
          Presence of comorbidityMore common in otherwise healthy children and children with obesityPresence of comorbidity (eg, medical complexity, severe immunocompromise, significant cardiopulmonary disease, obesity) is very common
          Asymptomatic0%13%
          Fever100%55%
          Gastrointestinal involvement Common: reported in 87% (abdominal pain, diarrhea, vomiting)Uncommon: reported in 6% (abdominal pain, diarrhea, vomiting)
          Mucocutaneous involvementCommon: reported in 73% (rash 53%, conjunctivitis 48%, mucocutaneous lesions 35%)Rare: only present in severe cases (10.2% in severe cases only)
          Cardiovascular involvement Common: reported in 71% (hypotension in 50%, cardiac dysfunction in 40%, shock in 35%)Rare: only present in severe cases (2.9% in severe cases only)
          Neurologic involvement 22% (headache, altered mental status, aseptic meningitis)Common: headache is very common (67%)
          Respiratory involvement Uncommon (around 14%) and usually insignificant (eg, rhinorrhea in 13%, cough in 7%)Common and significant with cough (45%) and dyspnea (19%)
          Inflammatory markersMarkedly increased CRP (median 152 mg/L) much more likelyMarkedly increased CRP less likely (median 33 mg/L)
          CBC abnormalitiesThrombocytopenia and lymphopenia are common. Higher median neutrophil to lymphocyte ration (median 6.4)WBC count is normal in about three-quarters of patients. Thrombocytopenia and lymphopenia less likely. Lower median neutrophil to lymphocyte ratio (median 2.7)
          Quantitative SARS-CoV-2 serologyRelatively higher antibody titers are expected compared with lower titers seen with acute COVID-19Relatively lower antibody titers are expected compared with higher titers seen with MIS-C
    • Macrophage activation syndrome/hemophagocytic lymphohistiocytosis r61r62
      • Dysfunctional immune response resulting in cytokine storm r62
        • May develop as complication or presenting feature of rheumatologic disorders, particularly systemic juvenile idiopathic arthritis and systemic lupus erythematosus, known as macrophage activation syndrome or rheumatologic hemophagocytic lymphohistiocytosis
        • May occur in susceptible individuals when triggered by inciting infection, malignancy, certain immunocompromising disorders, or immune-activating treatments
      • Presents similarly, with fever and rapid-onset multiorgan failure requiring aggressive supportive care. Other manifestations in common with both conditions include cytopenias, hyperferritinemia, coagulopathy, and high soluble interleukin-2 receptor r26
      • Differing clinical features may include: r26
        • Significant generalized lymphadenopathy and hepatosplenomegaly are commonly present in macrophage activation syndrome
        • Neurologic manifestations tend to be more prominent in macrophage activation syndrome
        • Cardiac and gastrointestinal manifestations tend to be less pronounced in macrophage activation syndrome
        • Increases in cytokines such as high soluble interleukin-2 receptor, interleukin-12, interleukin-18, and CXCL9 are typically much more profound in children with macrophage activation syndrome and less marked in children with MIS-C r26r63
        • Elevation of ferritin levels is generally much more significant in macrophage activation syndrome (median 10,442 ng/mL) than in MIS-C (median 440 ng/mL) r63
        • Elevation of fibrinogen levels tends to be less pronounced in macrophage activation syndrome (median 238 g/L) than in MIS-C (median 482 g/L in MIS-C) r63
      • Diagnosis of macrophage activation syndrome is based on clinical classification criteria and requires advanced immunologic testing as directed by rheumatologist r64
    • Scarlet fever d4
      • Severe systemic disease caused by certain strains of group A streptococcus
      • Rash, fever, and lymphadenopathy are present as in MIS-C
      • Lip, ocular, and extremity changes are not present
      • Positive rapid streptococcal test or culture result is diagnostic
    • Septic shock d5
      • Life-threatening systemic syndrome caused by microbial infection and dysregulated physiologic response
      • Presentation varies depending on source of infection but includes fever, tachypnea, tachycardia, hypotension, and signs of tissue hypoperfusion
      • Not typical: rash, lip changes, ocular changes, and edema of hands and feet
      • Diagnosis is based on recovery of pathogen by culture or other means
    • Viral infections
      • Numerous viral infections, including enterovirus and adenovirus, may present similarly with nonspecific symptoms such as fever, rash, conjunctivitis, gastrointestinal manifestations, and myocarditis
      • Adenoviral infections manifest in a variety of clinical syndromes including upper respiratory tract infection, conjunctivitis, pharyngitis, gastroenteritis, hemorrhagic cystitis, meningoencephalitis, and myocarditis r65
        • Diagnosis is usually clinical in most immunocompetent children; however, infection may be confirmed with polymerase chain reaction testing
      • Enteroviral infections manifest in a variety of clinical syndromes including central nervous system infection (especially acute viral meningitis), fever and rash, acute respiratory disease, acute hemorrhagic conjunctivitis, gastrointestinal illness, myositis, and myopericarditis r66
        • Nucleic acid amplification tests are primary means to detect enterovirus in clinical specimens (eg, cerebrospinal fluid, serum, respiratory secretions)
    • Measles (rubeola) d6
      • Like MIS, characterized by high fever that persists for several days, conjunctival involvement, and diffuse rash
        • Unlike MIS, rash typically progresses from head to toe
      • Respiratory system involvement is common and prominent in measles (eg, cough, coryza, pharyngitis, pleuritic chest pain) but not in MIS; gastrointestinal and neurologic involvement are more common in MIS
      • Koplik spots, gray-white punctate spots on buccal mucosa near parotid duct, are pathognomic for measles, if present
      • Diagnosis is confirmed by detection of rubeola IgM in serum
    • Rocky Mountain spotted fever d7
      • Tickborne rickettsial disease endemic to American continents; vast majority of infections occur from April to September in United States
      • Presents in manner similar to MIS with nonspecific manifestations (eg, fever, rash, conjunctival injection, headache, abdominal pain) and occasionally with neurologic findings (eg, altered mental status, neurologic deficits)
      • Characteristic rash of Rocky Mountain spotted fever may help distinguish it from MIS r67
        • Maculopapular rash typically appears about 2 days after onset of fever; starts on ankles, wrists, and forearms; spreads centripetally; and sometimes evolves over several days to include petechiae
      • Typical laboratory findings include thrombocytopenia, mild hyponatremia, and mild elevation of hepatic transaminase levels r67
      • Empiric treatment with doxycycline is started with presumptive clinical diagnosis r67
      • Serologic testing (eg, indirect immunofluorescence assay for IgG reactive against many types of tickborne rickettsial pathogens) is typical method for confirming tickborne rickettsial disease r68
    • Serum sickness–like reactions r69
      • Serum sickness is a type III delayed immune complex–mediated hypersensitivity reaction that characteristically develops about 1 to 2 weeks after exposure to a high-molecular-weight protein (eg, equine-derived antisera, antitoxins, murine and chimeric monoclonal antibodies)
      • Serum sickness–like reactions are less well defined than serum sickness. Serum sickness–like antigen-antibody complex hypersensitivity reactions are associated with a wide variety of offending antigens such as drugs (eg, antibiotics), vaccines, allergy extracts, hormones, and enzymes
      • Both types of hypersensitivity reaction commonly present with combination of fever, arthralgia, and pruritic rash that spares mucosa; other manifestations may include headache, diarrhea, and myalgias
      • Presence of significant arthralgia involving metacarpophalangeal joints, knees, wrists, ankles, and shoulders suggests serum sickness–like reaction because arthralgia is not typical of MIS
      • Presence of significant cardiac manifestations and neurologic manifestations suggest MIS rather than serum sickness–like reaction
      • Laboratory markers of inflammation typically are not as markedly elevated as in patients with MIS
      • Serum sickness and serum sickness–like reactions are strictly clinical diagnoses
    • Myocarditis r70d8
      • Inflammation of myocardium secondary to other non–MIS and COVID-19–related causes presents identically to myocarditis that is characteristic of MIS
      • Wide range of underlying causes of myocarditis includes toxins, inflammatory diseases and infections (eg, viral, bacterial, fungal, parasitic), hypersensitivity reactions, and systemic disorders (eg, celiac disease, connective tissue disease, sarcoidosis, thyrotoxicosis, Wegener granulomatosis, hypereosinophilia)
      • Laboratory markers of inflammation in patients with myocarditis related to MIS typically are markedly elevated compared with most other underlying causes of myocarditis
      • Myocarditis is diagnosed using noninvasive testing modalities including ECG, echocardiogram, and occasionally cardiac MRI. Endomyocardial biopsy is gold standard but not often required for confirmation in clinical setting
      • Determining underlying noninfectious and infectious causes of myocarditis usually is a multitiered process directed by clinical suspicion for most likely underlying etiology

    Treatment

    Goals

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

    Disposition

    Admission criteria

    By definition, patients with MIS-C or MIS-A require hospitalization r2r13

    • Up to 80% of children with MIS-C require intensive care; therefore, admission to hospital with pediatric ICU capabilities is advised whenever possible r7r71
      • Certain features may indicate severe disease, including: r23
        • Persistent hypotension or tachycardia
        • Worsening laboratory markers such as increasing troponin, NT-proBNP, lactate, ferritin, or D-dimer
        • Significant cardiac abnormalities such as coronary artery aneurysms or left ventricular failure
    • Where level of care was known, a majority of patients with MIS-A required intensive care r15

    Consider admission for patients under investigation for MIS in the following circumstances: r33

    • Abnormal vital signs (eg, tachypnea, tachycardia, hypotension)
    • Respiratory distress to any degree
    • Neurologic deficits or altered mental status to any degree
    • Hepatic or renal dysfunction (even if mild)
    • Marked elevation of inflammatory markers
    • Abnormal ECG results or serum markers of cardiac injury (eg, troponin, B‐type natriuretic peptide)

    Outpatient evaluation may be appropriate for well-appearing children with normal vital signs provided close clinical follow-up is assured r33

    Criteria for ICU admission
    • Shock (either cardiogenic or vasodilatory/distributive) or clinical status suggesting impending shock
    • Mechanical ventilation requirement

    Recommendations for specialist referral

    • Management in consultation with multidisciplinary treatment team of specialists is preferred when possible r23r33
      • Consultants often include pediatric intensive care specialists, rheumatologist or immunologist, infectious diseases specialist, cardiologist, and hematologist
      • May include pediatric neurologist, nephrologist, hepatologist, and gastroenterologist, depending on disease manifestations
    • All children with MIS-C require consultation and follow up with cardiologist r33
      • Timing of referral depends on individual patient clinical presentation
        • Early involvement of cardiologist for diagnostic and treatment recommendations is necessary for children with evidence of myocardial dysfunction or coronary artery aneurysms at presentation
        • All children require follow-up and ongoing evaluation to monitor for development of coronary artery aneurysms during convalescent phase of illness

    Treatment Options

    General treatment overview

    • Supportive care is key aspect of management in all patients r2
    • Optimal treatment is not definitively known and treatment guidelines are being updated r7
      • Slightly different management strategies are recommended by various expert consensus groups and professional organizations, including: r7r11r23r33
        • NIH COVID-19 treatment guidelines r7
        • WHO clinical management of COVID-19 r11
        • American College of Rheumatology clinical guidance r33
        • American Academy of Pediatrics interim guidance r72
      • Management of MIS-A and of MIS-N is largely based on extrapolation from MIS-C, as little data are available and no guidelines exist r7
    • Selection of patients for treatment:
      • Select patients with mild manifestations may be managed without immunomodulatory treatment with close observation for progression of disease r25r33
      • Immunomodulatory treatment is recommended for hospitalized patients r7r33
      • Patients presenting with severe disease who are under investigation for MIS-C, including those with myocarditis or who otherwise meet criteria for Kawasaki disease or toxic shock syndrome, may require immunomodulatory treatment even before diagnostic evaluation is complete r33
    • Most guidelines recommend that all patients who require treatment have both immunomodulatory therapy and thromboprophylaxis
    • First line immunomodulatory treatment
      • IV immunoglobulin with corticosteroids is a recommended option for first line immunomodulatory treatment r7r33
        • IV immunoglobulin plus IV methylprednisolone is recommended r7r33
          • Equivalent dose of alternative steroid may be used if methylprednisolone is unavailable
          • In patients with significant cardiac dysfunction in whom volume overload is a concern, IV immunoglobulin may be given in a divided dose over 2 days
          • Immunomodulatory treatment should be tapered over 2 to 3 weeks or longer as guided by laboratory and cardiac evaluations
      • Corticosteroids alone may also be considered for first line immunomodulatory treatment r3r11r73r74r75r76
        • IV methylprednisolone is most widely used
        • Corticosteroids are more widely available and less expensive than IV immunoglobulin; corticosteroid monotherapy may be particularly useful for resource-limited settings
      • IV immunoglobulin monotherapy is not recommended, unless corticosteroids are contraindicated r7r11
        • Data from observational studies of IV immunoglobulin alone compared to IV immunoglobulin plus corticosteroids suggest that combination therapy is beneficial over IV immunoglobulin alone; these studies did not include information on corticosteroids alone r77r78
      • Available evidence for MIS-C treatment is limited to a single open-label randomized controlled trial (not yet incorporated into guidelines) and observational data
        • An open-label, multicenter, randomized controlled trial of 75 patients in Switzerland compared IV methylprednisolone to IV immunoglobulins r74
          • Fewer patients in the methylprednisolone group needed respiratory support compared to the IV immunoglobulin group, potentially due to fluid overload associated with IV immunoglobulins
          • Hospital length of stay, need for inotropes, ICU care, cardiac events after baseline, major bleeding, and thrombotic events did not differ between the 2 groups
        • A retrospective study of 356 patients hospitalized with MIS-C in United States compared patients who received IV immunoglobulin alone, IV immunoglobulin plus steroids, corticosteroids alone, or neither treatment r79
          • Results show a statistically significant decrease in ICU length of stay for patients receiving IV immunoglobulin plus steroids compared to patients receiving neither
          • No significant differences were detected in any of the groups for hospital length of stay, inotrope use, need for mechanical ventilation, or normalization of inflammatory mediators
        • A retrospective cohort study of 368 children in India demonstrated no significant difference in a composite of inotropic support, mechanical ventilation, or death in patients treated with IV immunoglobulin alone, IV immunoglobulin plus steroids, or steroids alone r76
        • Evidence from a retrospective cohort study of 215 patients in United States indicated that initial therapy with corticosteroids alone was associated with similar rates of treatment failure and shorter hospital length of stay compared with IV immunoglobulin plus corticosteroids r73
          • Longer duration of corticosteroid use and longer hospital length of stay seen in the IV immunoglobulin plus corticosteroids group may have been related to sequelae of severe disease; notably, cardiovascular outcomes were not worse in the group who did not receive IV immunoglobulin
        • Data from BATS (Best Available Treatment Study) of 614 children from 32 countries indicates no difference in recovery from MIS-C after primary treatment with IV immunoglobulin alone, IV immunoglobulin plus glucocorticoids, or glucocorticoids alone r75
          • Lower risk of need for second line immunomodulatory therapy was detected in patients who initially received IV immunoglobulin plus corticosteroids compared to those who received IV immunoglobulin alone or corticosteroids alone
            • Finding may be attributable to failure of initial treatment, severity of illness, or increased clinical desire to escalate therapy when only 1 treatment was given
          • Incidence of coronary artery aneurysm was not increased in patients who did not receive any IV immunoglobulin compared to patients who did receive IV immunoglobulin, although number of coronary artery aneurysm in total was too low for definitive conclusions
          • When analysis was restricted to patients who met WHO criteria for MIS-C, modest evidence of benefit with glucocorticoids alone over IV immunoglobulin alone was found
          • Otherwise, no significant differences in outcome measures were noted (eg, fever resolution, disease severity, need for hemodynamic support, left ventricular dysfunction)
        • Data from a study of 518 children from United States suggest that initial treatment with both IV immunoglobulin and corticosteroids (compared with IV immunoglobulin alone) results in the following measured outcomes: r78
          • Lower risk of need for hemodynamic support and lower overall risk for cardiovascular dysfunction (combined left ventricular dysfunction plus presence of shock requiring vasopressor use) on or after day 2 of treatment and lower requirement for second line immunomodulatory therapy
          • No significant differences were noted in time to fever resolution or isolated acute left ventricular dysfunction
        • Data from a study of 181 French children suggest that initial treatment with both IV immunoglobulin and corticosteroids compared to IV immunoglobulin alone results in several favorable outcome measures including: r77
          • Earlier resolution of fever, less need for second line immunomodulatory therapy or hemodynamic support, shorter ICU stay, and less acute left ventricular dysfunction after initial therapy than IV immunoglobulin alone in children with MIS-C
        • Inconsistencies noted in available studies may be explained, at least in part, by differing inclusion criteria (eg, disease severity, fulfillment of standardized WHO or CDC diagnostic criteria) and outcome measures as well as use of combination therapy in sicker patients;
        • Larger randomized controlled trials are needed with longer follow-up to better guide treatment
    • Intensification immunomodulatory treatment r7
      • Because children usually respond rapidly to treatment, refractory disease is defined as lack of improvement within 24 hours of initial immunomodulatory therapy as indicated by: r7
        • Persistent fever
        • Worsening organ dysfunction
        • Increasing inflammatory marker levels
      • High-dose corticosteroids and immune modulators are recommended as options based on use for Kawasaki disease and other inflammatory disorders; no evidence is available yet to select which of the following options is best: r7r33
        • Methylprednisolone at high dose
        • Anakinra, a recombinant interleukin-1 receptor antagonist, at high dose
        • Infliximab, a monoclonal TNF-α blocker
          • Infliximab should not be used if features of macrophage activation syndrome are present
      • Dual therapy with higher dose glucocorticoid and anakinra or infliximab may be used in select patients with severe illness; do not use anakinra and infliximab in combination r7
      • Second dose of IV immunoglobulin is not recommended due to risk of volume overload and hemolytic anemia
      • Research is underway to determine best treatments and sequence of treatments r80
    • Antiplatelet and anticoagulation treatment r7r33
      • Low-dose aspirin is indicated for all patients without contraindications (eg, significant risk of bleeding, platelet count of 80,000/mcL or lower)
        • Aspirin is continued until normalization of platelet count and confirmation of normal coronary arteries at 4 weeks or longer after diagnosis
      • Children with large coronary artery aneurysms (z score 10 or higher) or with moderate to severe left ventricular dysfunction should receive therapeutic anticoagulation unless contraindicated r7r33
        • Enoxaparin with target of anti-factor Xa level of 0.5 to 1.0 is recommended initial therapy for 2 weeks r7r33
          • For alternative medications, consult Table 7 in American Heart Association guideline for Kawasaki diseaser58r7r33
        • Following enoxaparin treatment, warfarin or a direct‐acting oral anticoagulant may be continued until criteria are met for discontinuation in consultation with cardiologist and as outlined in American Heart Association guideline for Kawasaki diseaser58
        • In unstable children or with concomitant severe renal impairment, use unfractionated heparin by continuous IV infusion r81
      • In patients with documented thrombosis, start therapeutic anticoagulation in addition to low-dose aspirin and continue for 3 months or until resolution of thrombosis (eg, if resolved by recommended re-imaging 4-6 weeks after diagnosis) r33
      • For patients without large coronary artery aneurysms or left ventricular dysfunction, consider prophylactic versus therapeutic anticoagulation on individual basis r7r33
        • Independent risk factors for thrombosis include: r82
          • Central venous catheterization
          • Age older than 12 years
          • Malignancy
          • ICU admission
          • D‐dimer levels elevated more than 5 times upper reference limit
    • Infection control
      • Follow local infection control precautions appropriate for patients being investigated for COVID-19 r6r72
    • Gastric prophylaxis
      • Gut protection (eg, omeprazole) is recommended for children treated with corticosteroids and aspirin r7r23r33

    Treatment of MIS-A is based on extrapolation from other conditions including MIS-C r15r37r56

    • Supportive care (eg, fluid resuscitation, respiratory support, inotropes, extracorporeal membrane oxygenation) is required for MIS-A patients
    • Majority of patients receive corticosteroids, IV immunoglobulin, and aspirin
    • Other immunomodulatory medications have been tried (eg, anakinra, tocilizumab, rituximab, cyclophosphamide) based on theories of pathogenesis, but data to guide treatment choices are needed

    Treatment of MIS-N is similarly extrapolated from MIS-C therapy r16r17

    • Majority of neonates require respiratory support and many require inotropic support
    • Most neonates are given corticosteroids, IV immunoglobulin, or both; use of other immunomodulatory agents has not been reported
    • Other therapies utilized include antibiotics, aspirin, heparin, and diuretics r16

    Initial stabilization and urgent management priorities d9

    • Data specific to MIS for optimal treatment of critical illness are limited; follow guidelines for other critical conditions, such as pediatric acute respiratory distress syndromer84, pediatric sepsisr85, and critically ill adults with COVID-19r86r7r83
      • Provide airway, breathing, and circulatory support as indicated clinically r83
        • Address hypoxia with oxygen, secure airway, and provide mechanical ventilation, when necessary
        • Treat shock with judicious fluid resuscitation, paying close attention to responsiveness using clinical parameters, echocardiography, and/or lactate levels and other laboratory markers of response r7
        • Vasopressor support may be required for children with shock who have not responded to fluid resuscitation or with significant cardiac dysfunction r7r87
          • Epinephrine or norepinephrine are preferred initial vasoactive medications in children with shock related to COVID-19 illness
          • Evidence for use of dobutamine, milrinone, and vasopressin in MIS-C is lacking; follow other clinical indications for use r7r85r87
    • Early initiation of IV immunoglobulin and methylprednisolone for patients presenting in shock under consideration for MIS-C is critical given that early treatment may be associated with rapid clinical improvement and improved overall outcome r33
    • Until bacterial infection has been ruled out, begin broad spectrum empiric antibiotics for patients who are ill-appearing and for those with any concerns for sepsis or serious bacterial infection r2r6r72r85d5
      • Maintain awareness that patients with MIS-C may have superimposed bacterial infections r26

    Antiviral therapy considerations

    • Because MIS-C appears to be a postinfectious inflammatory response, antiviral therapy generally has not been initiated or recommended r6r7
      • If there is diagnostic uncertainty between acute COVID-19 and MIS, consult guidelines for treatment of COVID-19r7r11 and guidelines for hyperinflammation in children with COVID-19r33 to consider all therapeutic options d10
    • Use of infection control precautions appropriate for COVID-19 is recommended by some authorities until acute infection is ruled out r23r27r72

    Management pathways

    • Management algorithms developed by professional societies, pediatric hospitals, and other experts are available r3r33r41
    • Treat patients who meet criteria for Kawasaki disease in standard fashion based on regional guidelines (eg, supportive care, high-dose IV immunoglobulin, aspirin) r6r58r88d1
    • Treat patients who meet criteria for toxic shock syndrome in standard fashion based on regional guidelines (eg, supportive care, cephalosporin or vancomycin plus clindamycin, IV immunoglobulin) r23r59d2

    Extracorporeal membrane oxygenation is required in some patients with severe disease refractory to other medical management

    Drug therapy

    • IV immunoglobulin
      • Obtain blood to hold for serologic studies, when indicated, before administering IV immunoglobulin because erythrocyte sedimentation rate may be falsely elevated after IV immunoglobulin administration.
      • Immune Globulin (Human) Solution for injection; Infants, Children, and Adolescents: 2 g/kg (based on ideal body weight; Max: 100 g/dose) IV as a single dose with low-to-moderate methylprednisolone or equivalent glucocorticoid. The dose may be divided in patients with cardiac dysfunction or fluid overload (1 g/kg IV every 24 hours for 2 doses).
    • Methylprednisolone
      • Methylprednisolone Sodium Succinate Solution for injection; Infants, Children, and Adolescents: 1 to 2 mg/kg/day IV in 1 to 2 divided doses administered at the same time as IVIG. Increase to 10 to 30 mg/kg/day (Max: 1,000 mg/day) IV for 1 to 3 days in patients with refractory MIS-C who do not improve within 24 hours of initial immunomodulatory therapy. Taper over 3 weeks to avoid rebound inflammation.
      • Initiate steroid taper once clinical improvement is achieved (eg, afebrile, resolution of acute end organ dysfunction, trending down of inflammatory markers); taper over several weeks to avoid rebound inflammation as guided by clinical status. r7
    • Anakinra
      • Anakinra (E. coli) Solution for injection; Infants, Children, and Adolescents: 5 to 10 mg/kg/day IV (preferred) or subcutaneous in 1 to 4 divided doses in patients with refractory MIS-C who do not improve within 24 hours of initial immunomodulatory therapy. Tapering over 2 to 3 weeks, or even longer, may be necessary to avoid rebound inflammation.
    • Infliximab
      • Infliximab (Murine) Solution for injection; Infants, Children, and Adolescents: 5 to 10 mg/kg/day IV as a single dose in patients with refractory MIS-C who do not improve within 24 hours of initial immunomodulatory therapy. Do not use in patients with features of macrophage activation syndrome (MAS).
    • Aspirin
      • Aspirin Chewable tablet; Infants, Children, and Adolescents: 3 to 5 mg/kg/dose (Max: 81 mg) PO once daily for all patients without risk factors for bleeding. Continuation is recommended until platelet count is normalized and normal coronary arteries are confirmed at least 4 weeks after diagnosis.
    • Enoxaparin
      • Prophylaxis
        • Enoxaparin Sodium (Porcine) Solution for injection; Infants, Children, and Adolescents 2 months to 17 years†: 0.5 mg/kg subcutaneously every 12 hours; adjust dose to maintain an anti-factor Xa concentration of 0.1 to 0.3 International Units/mL.
      • Treatment
        • Enoxaparin Sodium (Porcine) Solution for injection; Infants, Children, and Adolescents 2 months to 17 years: 1 mg/kg/dose subcutaneous every 12 hours. Adjust dose to maintain anti-factor Xa concentration of 0.5 to 1 units/mL.

    Nondrug and supportive care

    • For fluid management and other nondrug treatment for shock, follow published guidelines (eg, Surviving Sepsis Campaignr85r86) d9
    • MIS-C resources for parents are available from CDCr89

    Special populations

    • MIS after COVID-19 vaccination r90
      • MIS following vaccination that is unrelated to SARS-CoV-2 infection is exceedingly rare, and vaccination has been shown to be highly effective at preventing MIS-C r3r19r20
      • In the rare instance a patient develops MIS or similar clinical illness after receiving COVID-19 vaccine: r90
        • Patient requires careful assessment for laboratory evidence of current or prior SARS-CoV-2 infection
          • Positive antinucleocapsid antibody test result (in serum before administration of IV immunoglobulin) may help identify those with history of SARS-CoV-2 infection r90
        • Consider managing patient in consultation with specialist (eg, infectious diseases specialist, rheumatologist)
        • Consider consulting with CISA (Clinical Immunization Safety Assessment) COVIDvax Project r91
        • Report using VAERS r42

    Monitoring

    • Information on monitoring and follow-up is based on recommendations for children with MIS-C as there are no guidelines specific for MIS-A or MIS-N
    • Monitoring during acute disease
      • Monitor clinical assessments, with frequency guided by severity of disease. Also provide close cardiorespiratory monitoring with pulse oximetry, continuous respiratory and cardiac monitoring, and frequent blood pressure measurements r6
      • Frequent monitoring of laboratory markers of inflammation (eg, C-reactive protein) is important until values stabilize and improve r6
      • Monitor abnormal cardiac biomarkers (eg, NT-proBNP, troponin T) until values normalize r33
      • Perform serial ECGs (at least every 48 hours) and echocardiograms as appropriate based on clinical status r33r55
      • Monitor with telemetry patients who have evidence of conduction abnormalities r33
      • If cultures remain negative at 48 hours, consider discontinuing empiric antibiotics (if started) r92
      • Monitor clinically for development of infection following immunomodulatory treatment r7
      • In light of prevalent cardiovascular disease in adults, use of cardiac MRI and echocardiography to monitor progression or recovery of cardiovascular effects of MIS-A has been reported r37r56
    • Discharge criteria from hospital includes:
      • Stable cardiac function, absence of fever for 24 hours, and otherwise well appearance with reassuring physical examination r23
      • Some experts suggest considering downward trend of inflammatory markers and cardiac biomarkers, normalizing ECG, and stable or improving echocardiogram when deciding whether or not to discharge patients r92
    • Follow-up cardiac assessments
      • Standardized follow-up regimen has not yet been firmly established; some experts have suggested preliminary regimen for outpatient follow-up r33r55
      • Outpatient Holter monitoring may be required for children with evidence of significant conduction abnormalities on telemetry during hospitalization r33
      • Cardiology follow-up is recommended starting 1 to 2 weeks after discharge r72
        • Restrict strenuous physical activity until cleared by cardiologist; many experts suggest following return to sports guidelines after myocarditis r38r93r94
      • Follow-up echocardiograms
        • Obtain 1 to 2 weeks and 4 to 6 weeks after discharge in patients with initially normal findings r23r33r39r49
          • Recommendations are based on those established for Kawasaki disease and on concern that MIS-C patients (similar to patients with classic Kawasaki disease) may develop coronary artery aneurysms late in disease course or after apparent improvement r58
        • Individualize follow-up based on cardiology recommendations for children with abnormal findings on initial study
      • Some authorities recommend repeat echocardiogram about 1 year after discharge for children with cardiac involvement during acute phase of illness r33
      • Consider cardiac MRI 2 to 6 months after acute illness for patients with significant transient or persistent left ventricular dysfunction r33
      • Children with persistent left ventricular dysfunction and coronary artery aneurysms require vigilant and frequent cardiology and echocardiography follow-up r33
    • Follow-up for children who are suspected to have MIS-C but who do not require hospitalization
      • Patients initially well-appearing with mild manifestations and reassuring laboratory values require close and reliable follow-up within 24 to 72 hours after initial evaluation r92
      • Caregiver must clearly understand specific reasons to return and recognize low threshold to return for reassessment given that sometimes rapid clinical deterioration may develop with progression of disease
    • Follow-up vaccine recommendations for individuals recovered from MIS-C or MIS-A
      • Strongly encourage discussion among patient, guardians, medical specialists (eg, infectious diseases specialist, rheumatologist, cardiologist), and clinical team to assist decision-making about use of COVID-19 vaccines in these patients r90
        • Current data suggest that vaccination following MIS is safe; weigh theoretical risk of dysregulated immune response after vaccination with risk of COVID-19 infection r36r90r95r96
        • CDC guidance notes that benefits of vaccination (ie, reduced risk of severe disease including potential recurrence of MIS after reinfection) likely outweigh theoretical risk of MIS–like illness or risk of myocarditis after COVID-19 vaccination, particularly when the following criteria are met: r90
          • Clinical recovery (including return to normal myocardial function)
          • 90 days or more have elapsed since MIS-C or MIS-A diagnosis
        • Additional scheduled doses of COVID-19 vaccine should be considered for patients with history of MIS that developed 90 days or more after vaccination when they meet the above criteria r90
        • If MIS was diagnosed within 90 days of a vaccine dose, consider deferral of additional doses until more evidence is available, unless MIS is thought to be a complication of recent SARS-CoV-2 infection
        • Consultation with CISA COVIDvax Project is available for complex situations r91
      • Recommended interval between receipt of IV immunoglobulin (at dose of 2 g/kg) and administration of measles-mumps-rubella, varicella, or measles-mumps-rubella-varicella vaccine is 11 months owing to passively administered antibodies contained in IV immunoglobulin r97

    Complications and Prognosis

    Complications

    • Morbidity
      • Coronary artery aneurysms
        • Estimated to develop in up to 24% of children (primarily mild) and 8% of adults r14r31
        • Development of large and giant coronary artery aneurysms are rare r29r49
        • Coronary artery aneurysms may develop after acute inflammatory phase of illness r55
      • Cardiac dysfunction
        • Ventricular dysfunction is estimated to occur in most children and adults (specific estimates vary widely depending on definition and study inclusion criteria) r14r55
          • 25% to 50% of children and 30% of adults develop evidence of myocarditis r14r48r98d8
        • Most children with cardiac dysfunction require inotropic support (about 53%-58%), approximately 26% require mechanical ventilation, and about 5% require extracorporeal membrane oxygenation r31r57
      • Systemic thrombosis
        • MIS is characterized by a hypercoagulable state r31
          • Other factors that place children at increased risk for thrombotic complications include possible endothelial injury, immobilization, ventricular dysfunction, and coronary artery aneurysm development
          • An estimated 5% of adults with MIS-A had thrombosis but a majority had received anticoagulation r14
        • Risk factors for thrombosis in children may include age older than 12 years, comorbid malignancy, presence of central venous catheter, admission to ICU, and marked elevation of D-dimer levels r33r82
        • Thrombosis is uncommon in MIS-C (estimated at 3.5%-6.5% of hospitalized children) but may occur despite appropriate thromboprophylaxis measures r47r82
      • Respiratory failure
        • Mechanical ventilation is required in up to 30% of hospitalized children with shock or respiratory manifestations and about 9% of MIS-C patients overall r14r31
        • Mechanical ventilation is needed in approximately 25% of MIS-A patients overall r14
        • Mechanical ventilation is required in a majority of neonates with MIS-N r16r17
      • Acute kidney injury
        • Estimated to develop in 12% to 20% of hospitalized children; associated with higher risk of death r47r99
        • 8% of MIS-A patients required dialysis r14
      • Neurologic condition
        • Life-threatening neurologic conditions (eg, severe encephalopathy, cerebral edema, stroke, central nervous system demyelination, Guillain-Barré) may occur in up to 3% of children r100
      • Serositis
        • Small pleural effusions, pericardial effusions, and ascites develop in a minority of MIS-C patients r27
    • Mortality
      • Data from United States provides a mortality estimate for MIS-C of 0.8% (eg, 76 reported deaths from 9370 cases reported to CDC; 34 inpatient deaths out of 4107 MIS-C hospitalizations in 1 series); mortality from case series around the world were 0% to 11% of affected children r3r4r9r57
      • Mortality is higher in adults with MIS-A, estimated at 7% r14
      • Mortality in MIS-N is estimated to be 8% r16

    Prognosis

    • Recovery in majority of patients is expected with aggressive supportive management and appropriate treatment
      • Most patients respond promptly to therapy with a favorable short-term outcome r29r39r44r49
      • Median duration of hospitalization is about: r14r16r53r101
        • 7 days for patients with MIS-C
        • 8 days for those with MIS-A
        • 13 days for patients with MIS-N
      • Over three-quarters of children affected who need hospitalization require ICU level of care and over 50% of hospitalized children require some degree of inotropic support r57
        • Compared with children aged 0 to 5 years, children aged 6 to 17 years who were diagnosed with MIS-C had higher risk for requiring ICU admission r45
      • Similarly, among adults, 57% required ICU care and 51% required vasoactive medications to treat shock r14
      • Among neonates, approximately one-third required inotropic support; where reported, all patients with MIS-N were cared for in intensive care units r16r17
      • Death is relatively rare among children with MIS-C but occurs most frequently in previously healthy children with no comorbidities (in contrast to death from COVID-19 in children, about 75% of whom have a medical comorbidity) r38
    • Cardiac sequelae
      • Major source of short-term morbidity and mortality in patients with MIS-C is myocardial dysfunction r33
        • Data suggest that short-term recovery of ventricular function is typical, but minority of patients have longer term effects r54r55r101r102r103
          • Left ventricular systolic dysfunction, common during hospitalization, resolves in over 90% of patients by 30 days follow-up but mild dysfunction may persist in approximately 2% of children at 6 months follow-up r53r101r102
          • Diastolic dysfunction continues to affect 4% to 6% of patients as late as 6 months after discharge r101r103
      • Coronary artery aneurysms
        • Clinical significance and evolution of coronary artery dilation noted during acute phase of illness has yet to be determined r25
        • Laboratory findings (eg, B-type natriuretic peptide, troponin) do not appear to differ meaningfully between children who develop coronary artery dilation or aneurysms and those who do not r103
        • May develop late in disease course or after apparent improvement r39r49r101
        • Data suggest that most coronary artery aneurysms resolve by 30 days follow-up; however, a minority of patients may have longer-term effects r53r101
          • A systematic review including 547 patients indicated about 5% had persistent coronary artery abnormalities at 6 months r102r103
          • Another study following 80 patients 1 year after ICU care for MIS-C revealed a patient (1.9% of the population) with persistent giant coronary aneurysm at 12 months
      • Mitral regurgitation may still be present in 7.5% at 6-month follow-up r102
      • Abnormal ECG findings
        • Most abnormal ECG findings (about 72% of patients) appear to normalize during hospitalization r54
        • Prolonged PR interval was persistent in 2.5% at 1-year follow-up r103
    • Immunological effects
      • While a majority of patients had normalization of inflammatory markers within 1 to 4 weeks of discharge, a substantial minority had some abnormalities as late as 1 year post MIS-C r101
        • 2% of patients had abnormal cell counts (lymphocytes, neutrophils, and/or platelet counts), 25% had abnormal D-dimer levels, and 17% had abnormal ferritin levels 1 year after admission r101
      • Risk of dysregulated immune response after reinfection with SARS-CoV-2 is unknown among patients with history of MIS-C r90
    • Gastrointestinal findings
      • 6-month follow-up of MIS-C patients in United Kingdom indicated that although 98% of patients had gastrointestinal symptoms in acute phase, only 13% had symptoms at 6 months r101
    • Quality of life
      • Majority of pediatric patients and their parents reported no impairments in physical, emotional, social, school, or psychosocial domains using PedsQL scale (Pediatric Quality of Life Inventory) at 6 months follow-up r104
      • However, in same study, significant impairment in exercise tolerance was present in 13% of MIS-C patients and emotional lability in 15% after 6 months r104

    Screening and Prevention

    Prevention

    • Only known preventive measures involve avoiding infection with SARS-CoV-2
      • Vaccination is recommended for all individuals aged 5 years and older without contraindications to vaccine r90d3
        • COVID-19 vaccination (2 doses of Pfizer-BioNTech mRNA vaccine is most studied) appears to be extremely effective in preventing MIS-C in children r1r3r20r105
          • Data suggest that vaccine effectiveness for MIS-C prevention is 90% to 91% in persons aged 12 to 18 years and about 84% in those aged 5 to 18 years r1r20
          • A systematic review of over 13.5 million children aged 5 to 11 years showed substantial benefit of vaccination in preventing MIS-C: odds ratio 0.05 for 2 doses mRNA vaccine compared to no doses r105
        • Limited data suggest that vaccine may diminish severity of MIS-C among people aged 12 to 18 years who were previously vaccinated against SARS-CoV-2 r20
      • Public health measures to decrease infection (eg, improving ventilation, testing with rapid isolation, staying home when sick, high-quality mask usage) will also decrease risk of MIS d10
    • Measures to prevent secondary spread of SARS-CoV-2 include:
      • Proper use of quarantine (after potential exposure) and self-isolation (when infected) measures as needed
      • Strict health care facility infection and control measures
      • Improved indoor ventilation
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