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May.27.2022

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

Synopsis

Key Points

  • MIS-C and MIS-A are 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-A; 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), and 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)
  • Patients with very mild manifestation of disease may be managed conservatively with close monitoring for progressive worsening of disease
  • 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 appears to be effective in preventing MIS-C in children aged 12 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 oxygen supplementation (including mechanical ventilation), and many require hemodynamic support
  • Begin treatment with high-dose IV immunoglobulin and methylprednisolone 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 unknown

Terminology

Clinical Clarification

  • MIS-C (multisystem inflammatory syndrome in children) r2
    • Clinical syndrome thought to represent a postinfectious, dysregulated inflammatory response to previous exposure or infection with SARS-CoV-2 in children and adolescents
    • 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 r3
    • Illness is characterized by persistent fever, laboratory markers of inflammation, and evidence of organ dysfunction r4r5
      • 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; therefore, it is not yet possible to make firm evidence-based recommendations r2r6
      • Estimated to affect less than 1% of children with COVID-19 infection; 7880 cases have been reported in United States as of March 28, 2022 r3r7
      • Studies are ongoing to determine best diagnostic and management strategies
    • Multisystem inflammatory syndrome in children is designation used by CDC and WHO r4r5
      • Condition is also referred to as:
        • PIMS-TS (pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 infection)
        • PMIS (pediatric multisystem inflammatory syndrome) temporally associated with COVID-19
  • MIS-A (multisystem inflammatory syndrome in adults) r8r9
    • Rare but serious hyperinflammatory clinical syndrome with multiorgan dysfunction that presents in adults about 4 weeks after onset of acute COVID-19
    • Cardiovascular system involvement is often prominent; myocarditis, cardiac dysfunction, arterial thrombosis, pulmonary embolism, and/or deep venous thrombosis appear to be most common cardiovascular manifestations

Classification

  • Classification based on case definition
    • Several national and international organizations have established case definitions for MIS-C that are broadly similar r5r10r11
      • MIS-C exists as a spectrum; it includes patients with milder manifestations that do not meet case definitions and who may or may not progress to meet all criteria r12
    • CDC case definition for MIS-Cr10 applies to individuals younger than 21 years with all of the following:
      • Fever 24 hours or longer (38.0° C or higher or report of subjective fever)
      • Laboratory evidence of inflammation, including but not limited to:
        • Elevated C-reactive protein, erythrocyte sedimentation rate, fibrinogen, procalcitonin, D-dimer, ferritin, lactic acid dehydrogenase, interleukin-6, or neutrophils
        • Reduced lymphocytes or albumin
      • Clinically severe illness requiring hospitalization
      • Multisystem involvement (2 or more organ systems: cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic, or neurological)
      • No alternative plausible diagnosis
      • Current or recent COVID-19 infection or exposure, as indicated by positive SARS-CoV-2 reverse transcription polymerase chain reaction, serologic, or antigen test result, or exposure to suspected or confirmed COVID-19 case within 4 weeks prior to onset of symptoms
    • WHOr11 and Royal College of Paediatrics and Child Healthr5 definitions are similar to CDC with the following differences:
      • WHO applies to ages 19 years and younger, requires 3 days of fever, and does not specify that hospitalization is required
      • Royal College of Paediatrics and Child Health allows single or multiorgan dysfunction and that SARS-CoV-2 polymerase chain reaction test results may be positive or negative
    • Some children fulfill full or partial criteria for Kawasaki syndrome, but MIS-C diagnosis is applied if they otherwise meet case definition r5r10
    • 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 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 r14
    • MIS-C and PIMS-TS criteria.CRP, C-reactive protein; LDH, lactate dehydrogenase; RCPCH, 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). Case Definition for MIS-C. CDC website. Last reviewed October 7, 2021. Accessed May 16, 2022. https://www.cdc.gov/mis-c/hcp/; WHO: Multisystem Inflammatory Syndrome in Children and Adolescents With COVID-19. Scientific Brief. WHO website. Published May 15, 2020. Accessed May 16, 2022. https://www.who.int/publications-detail/multisystem-inflammatory-syndrome-in-children-and-adolescents-with-covid-19; 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 May 16, 2022. 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 manifestationsFever 38° C or higher for 24 hours or longer or report of subjective fever lasting 24 or more hours AND evidence of clinically severe illness requiring hospitalization AND multisystem (involvement of 2 or more organs): cardiac, respiratory, renal, gastrointestinal, hematologic, dermatologic, neurologicFever 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
      Laboratory evidence of inflammationAND 1 or more of the following: elevated CRP, erythrocyte sedimentation rate, fibrinogen, procalcitonin, D-dimer, ferritin, LDH, interleukin-6, neutrophils, diminished albumin, lymphocytesAND elevated markers of inflammation including erythrocyte sedimentation rate, CRP, or procalcitoninAND evidence of inflammation (neutrophilia, elevated CRP, lymphopenia)
      SARS-CoV-2 testingAND positive for current or recent SARS-CoV-2 infection by reverse transcription polymerase chain reaction, serology, or antigen test; or exposure to a suspected or confirmed COVID-19 case within the 4 weeks before onset of symptomsAND evidence of COVID-19 (reverse transcription polymerase chain reaction, antigen test, or serology positive), or likely contact with patients with COVID-19AND positive or negative SARS-CoV-2 polymerase chain reaction testing
      Alternate diagnosis evaluationAND no alternate plausible diagnosisAND 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, infections associated with myocarditis such as enterovirus
  • Classification based on predominant presenting clinical phenotype
    • General understanding and classification of disease phenotypes and subphenotypes is evolving r15
    • Class 1: typical MIS-C (shock and myocarditis) r16
      • Children are more likely to present in shock with myocarditis and significant cardiac dysfunction; children tend to be older (median age is approximately 9 years) than those presenting with Kawasaki disease–like phenotype r17
      • Predominant manifestations involve cardiovascular (100%) and gastrointestinal (98%) systems r16
      • Inflammatory markers (eg, C-reactive protein, ferritin) tend to be exceedingly elevated compared with other subgroups r17
      • Almost all children (98%) exhibit positive SARS-CoV-2 serology, and positive polymerase chain reaction is present in up to 36% r16
      • ICU admission is required in up to 84% of patients with class 1 r16
    • Class 2: MIS-C overlapping with severe acute COVID-19 r16
      • Children tend to be older (median age about 10 years)r16 than children presenting with Kawasaki disease–like features r17
      • Significant underlying comorbidity is often present r17
      • Manifestations often include significant respiratory involvement (eg, cough, dyspnea, pneumonia, acute respiratory distress syndrome) more than other phenotypes r17
      • Children present with positive SARS-CoV-2 polymerase chain reaction (100%) and negative serology in most cases; serology is positive in about 16% of children with class 2 r16
      • ICU admission is required in up to 62% of children with class 2; relative mortality may be higher than that noted in children with other phenotypesr17r16
    • Class 3: Kawasaki disease–like phenotype r15r16
      • Higher frequency of rash (63%) and mucocutaneous lesions (45%) is present compared with other phenotypes r16
      • Children usually meet complete or incomplete Kawasaki disease criteria as defined by American Heart Association r18
      • Children are often younger than those in other phenotypes (median age 6 years)r16 and less likely to present with shock or myocardial dysfunction r17
      • Most children (up to 97%) have positive SARS-CoV-2 serology and about 36% are polymerase chain reaction positive r16
      • Illness course in children with class 3 tends to be milder than in children with other classes; approximately 44% of children with class 3 require ICU admission r16
  • Classification based on severity r15
    • Severe disease features may be indicated by any of the following:
      • Physiologic features r15
        • Signs of poor perfusion (eg, prolonged capillary refill, persistent tachycardia)
        • Shock (eg, persistent hypotension, fluid bolus of 40 mL/kg or more required)
        • Hypoxia (eg, oxygen saturation less than 92% in room air)
      • Hematologic and biochemical features r15
        • Noticeable increase in levels of markers of inflammation (eg, C-reactive protein above 150 mg/L, ferritin, lactate dehydrogenase)
        • Clinically significant increased or increasing cardiac biomarker levels (eg, troponin, NT-proBNP [N-terminal pro–brain natriuretic peptide])
        • Clinically significant increased or increasing markers of poor perfusion, shock, or acidosis (eg, lactate)
        • Clinically meaningful changes in coagulation profile (eg, increased or increasing D-dimer level, increased or decreased fibrinogen level)
        • Increased or increasing creatinine level
      • Cardiac features
        • Abnormal echocardiogram r15
        • Left ventricular failure r15
        • Abnormal coronary arteries on echocardiogram r15
        • According to expert opinion, the following additional findings suggest severe disease:
          • ECG abnormalities (eg, electrical conduction abnormalities)
          • Myocarditis and/or pericarditis with or without pericardial effusion

Diagnosis

Clinical Presentation

History

  • Background
    • Onset of symptoms typically occurs 2 to 6 weeks after exposure to SARS-CoV-2 r2
    • Most patients are asymptomatic or experience mild illness at time of inciting SARS-CoV-2 infection and therefore may not report prior infection r19
    • Disease manifestations present on a spectrum of severity, ranging from mild symptoms to multiorgan failure r20
    • Manifestations may not appear simultaneously but may evolve over several days r20
    • Mucocutaneous manifestations typically appear early in course of illness (mean duration after development of fever until appearance is about 2 and a half days) r21
  • Common presenting symptoms in children include:
    • Persistent fever, often lasting 4 days or more, is universal r22
    • Gastrointestinal symptoms are second most common complaints after fever r22r23
      • Abdominal pain may be severe, suggesting acute abdomen
      • Nonbloody diarrhea may be profuse
      • Vomiting
    • Kawasaki disease–like symptoms are common r24
      • Rash
      • Conjunctivitis
      • Oral mucosal changes and odynophagia
      • Nonspecific extremity pain and swelling r5
    • Neurologic symptoms
      • Headache r5
      • Altered mental status (confusion, somnolence) r5
      • Aseptic meningitis presentation (mild neck stiffness, photophobia) r19
      • Vision changes
      • Cranial nerve palsies
      • Seizures
    • Cardiovascular symptoms
      • Rapid breathing, dyspnea, fatigue, and chest pain may suggest presence of myocarditis
      • Syncope related to arrhythmia may be noted
  • Less common symptoms in children include:
    • Respiratory symptoms (eg, rhinorrhea, cough) may be present but are not common and are not predominant r5
    • Myalgia is sometimes reported r5
  • In adults, based on a review of 221 patients worldwide, common presenting symptoms include fever, shortness of breath (52%), and diarrhea (52%) r8
    • Other symptoms noted include abdominal pain (48%), vomiting (44%), chest pain (29%), rash (38%), cough (37%), and headache (42%) r8

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 r20r25
    • WHO defines shock in children as any hypotension (systolic blood pressure below 5th percentile or more than 2 standard deviations below normal for age) or 2 or more of the following: r26
      • 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
    • Pulses may be bounding (so-called warm vasodilatory or distributive shock)
  • Presenting signs in children include: r25r27
    • Abnormal vital signs
      • Fever is present by definitionr5r10r11 and may be quite high (40° C or higherr22)
      • Tachycardia and irregular rhythms have been reported
      • Tachypnea is often related to myocardial dysfunction in the setting of MIS-C
      • Hypotension secondary to cardiogenic or distributive (vasodilatory) shock
    • 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: r8
    • Hypotension and shock
    • Arrhythmia
    • Rash, mucocutaneous lesions, conjunctival injection
    • Periorbital edema

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 r2r20
  • 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 r3r27
    • 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 r19r27

Risk factors and/or associations

Age
  • Depending on case definition, MIS-C may include patients up to age 19 years or 21 years r4r10r11
  • Median age among children is reported to be 9 years r16
  • Highest proportion of MIS-C diagnoses is reported to involve children aged 5 to 11 years r3r16
  • Median age among adults with MIS-A is reported to be 21 years (in a series that included diagnoses in patients aged 18 years and older), with 75% of patients aged 34 years or younger r8
    • It is not yet clear whether MIS-A occurs primarily or exclusively in younger populations or whether this represents detection bias r8
      • A retrospective chart review found 11 cases (in which 73% of patients were younger than age 50 years) meeting MIS-A criteria in a hospital system with 5755 COVID-19 cases over the same time period; none of the MIS-A cases were diagnosed by treating clinicians r28
      • MIS in adults may be difficult to distinguish from biphasic acute hyperinflammatory COVID-19 r8
Sex
  • Males are affected more often than females in both children (approximately 60% male) and adults (approximately 70% male) r8r24
Ethnicity/race
  • More common among patients of African, African-Caribbean, Hispanic/Latino, and Asian/Pacific Islander ancestry than other groups r16r25r29
    • Non-Hispanic Black: 32% occurrence in children and 36% in adults r8r16
    • Hispanic/Latino: 27% occurrence in children and 30% in adults r8r16
  • Similar to other racial disparities found in COVID-19, this appears to be due to social determinants of health and inequities rather than biological differences r30r31
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 r8r25
  • Association with vaccination
    • Limited data suggest that up to 95% of hospitalized children with MIS-C are unvaccinated and that vaccination is very effective at preventing MIS-C r1
    • MIS-C following vaccination appears to be extremely rare r32
      • 1 per million children vaccinated developed MIS-C at some point following vaccination, most of whom also had evidence of prior COVID-19 infection, which may have been the trigger for MIS-C
      • Only 0.3 per million vaccinated children had a diagnosis of MIS-C following vaccination and no evidence of prior infection, compared to 200 cases MIS-C per million unvaccinated children with prior COVID-19 infection or exposure r32

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. Most patients have laboratory evidence of SARS-CoV-2 (positive polymerase chain reaction, antigen, or antibody test result) r5r10
    • A subset of patients may fully or partially meet criteria for Kawasaki disease; others may meet criteria for toxic shock syndrome
  • WHO, CDC, and Royal College of Paediatrics and Child Health have published case definitions that are broadly similar r5r10r11r13
    • Available guidance is in agreement that laboratory evidence of current infection (positive SARS-CoV-2 antigen or polymerase chain reaction test result) or suspected recent infection (positive SARS-CoV-2 antibody test result) is not necessary for meeting case definition for MIS-C
    • All available guidance strongly recommends exclusion of alternate sources of infection and noninfectious conditions that can present similar to MIS-C r6
  • 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 r27
    • Common presenting patterns include: r2r27
      • Persistent, unexplained high fever in patient with laboratory evidence of marked inflammation
      • Presentation with, or rapid development of, shock or shock-like 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 r6r27
      • 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)
        • Younger children tend to present with Kawasaki disease–like phenotype and older children and adults are more likely to develop myocarditis and shock r8r27
  • 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 shock-like state with epidemiologic link to COVID-19 r2r27
    • 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 r15
          • Consistent findings include anemia, thrombocytopenia, neutrophilia, and lymphopenia; elevated creatinine, BUN, 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 r27
        • Perform focused microbiologic evaluation for alternate infectious causes as directed by clinical suspicion; evaluation may include studies including the following: r20r33r34
          • 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: r15r27
          • 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):
          • Blood gas and lactate
          • Chest radiograph
          • Abdominal ultrasound
        • 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 r6r24
        • Serum cannot be used for serologic testing after IV immunoglobulin has been administered
  • Diagnostic pathways are available from professional societies, institutions, and publications
    • American College of Rheumatology clinical guidance task force r27
    • Published algorithms r20r35
    • Children's Hospital of Philadelphia r36
    • Children's Minnesota r37
  • MIS is a reportable illness in United States
    • Report all possible MIS-C cases to local, state, or territorial health department or contact CDC with questions r10
    • Report potential MIS-C and MIS-A cases following vaccination to VAERS (Vaccine Adverse Event Reporting System) r38

Laboratory

  • CBC
    • WBC count is often elevated r17
    • Lymphopenia is common; neutrophilia may occur r5
    • Anemia or thrombocytopenia may be present
  • Electrolytes and renal panel
    • Hyponatremia may be noted r5r33
    • Increased creatinine and BUN levels may develop r33
  • Inflammatory markers
    • C-reactive protein, erythrocyte sedimentation rate, procalcitonin, and ferritin levels are typically elevated, often markedly r5r22r33r39
    • Initial ferritin levels above 500 mcg/L have been associated with more severe disease requiring ICU admission r40
    • 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 r5r22r33r39
    • 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 may be elevated, indicating myocardial inflammation, sometimes to very high levels r22r33r41
  • Others
    • Hypoalbuminemia is common r17
    • Cytokines (if available): characteristic findings include elevated interleukin-6, interleukin-10, soluble interleukin-2 receptor, and tumor necrosis factor r5r19r22r39
    • Mild cerebrospinal fluid pleocytosis has been reported in patients who underwent lumbar puncture for possible meningitis r33r34
    • Triglyceride levels may be above reference range r5
    • Aspartate transaminase and alanine transaminase may be slightly elevated r17
    • 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 r22r33r34r39r41
      • Positive antibody test response to SARS-CoV-2 is estimated to be present in over 80% of children with MIS-C r2
      • Positive polymerase chain reaction test result for SARS-CoV-2 infection occurs in an estimated 20% to 45% of children with MIS-C r2r24
      • 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 r42r43
      • Among adults, approximately 98% have laboratory evidence of current or past infection r8
    • Combined test results r19r23r29r39r41r44
      • 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
      • A 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 r8
    • SARS-CoV-2 serologic testing r45
      • Quantitative SARS-CoV-2 serology r46
        • 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 r27
      • Anti-nucleocapsid SARS-CoV-2 antibody r16r47
        • Positive results are consistent with evidence of resolving or previous infection with SARS-CoV-2 that could have occurred before or after vaccination
        • Vaccination does not result in antibody production against anti-nucleocapsid antigen because nucleocapsid is not a component of current vaccines; therefore, vaccination does not render a positive anti-nucleocapsid antibody result
      • Anti-spike SARS-CoV-2 antibody
        • Positive results are consistent with either previous infection or vaccination against SARS-CoV-2 r16r45

Imaging

  • Chest radiography
    • Baseline chest radiograph is prudent; many patients exhibit abnormalities at presentation or during disease course r4r5r17
    • Nonspecific patchy infiltrates are not unusual with MIS-C; evidence of pleural effusion and cardiomegaly may be visible r5r33r39
    • Precise occurrence of infiltrates on chest imaging at presentation is variably reported and yet to be fully defined. Data from a single large cohort study indicates that rates of infiltrates noted on chest imaging are similar in children with MIS-C (38%) and severe COVID-19 (36%) r48
    • Higher proportion of adults have pulmonary involvement; chest radiography may be needed to evaluate cough, shortness of breath, or chest pain r8
  • 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) r20r39r41
      • Left ventricular ejection fraction is diminished in at least 34% of children at admission r49
    • Findings (eg, dilation or aneurysms of coronary arteries) may develop during course of illness and even after hospital discharge r39r41r50
    • 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 r27
      • 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
    • May reveal hepatosplenomegaly, mesenteric adenitis, ileocolitis, ascites, gallbladder inflammation, or appendiceal inflammation r20

Functional testing

  • ECG
    • Abnormal ECG findings may be apparent in up to about 35% of children at admission and may include: r49
      • Prolonged PR interval and prolonged QTc interval
      • Repolarization changes (eg, abnormal ST- or T-wave segment) (most common) r41r49r50
      • 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 patients with arrhythmias, continuous telemetry during hospitalization is recommended and Holter monitoring after discharge should be considered r27

Differential Diagnosis

Most common

  • 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 r51
    • Subset of patients who meet diagnostic criteria for MIS-C also meet criteria for Kawasaki disease, incomplete Kawasaki disease, or Kawasaki disease shock syndrome
      • Kawasaki diagnosis is established by fever lasting 5 or more days and at least 4 of the following 5 clinical criteria: r18
        • 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 r51
    • 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 r27
      • Abdominal pain and gastrointestinal symptoms (eg, diarrhea, vomiting) are often predominant features in children with MIS-C r39
      • 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 r39
      • Differing laboratory markers in MIS-C compared with Kawasaki disease may include presence of thrombocytopenia, lymphopenia, profoundly elevated inflammatory markers (eg, erythrocyte sedimentation rate, C-reactive protein, ferritin), marked elevation of cardiac biomarkers (eg, troponin, NT-proBNP), and development of consumptive coagulopathy (markedly elevated D-dimer, fibrinogen, prolonged prothrombin time/partial thromboplastin time) r51
      • 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 r51
      • Coronary artery changes appear to be different between conditions. Children with MIS-C have evidence of 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 r51
    • 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.Up to about one-quarter of patients with MIS-C fulfill Kawasaki disease criteria (most commonly incomplete presentation). CRP, C-reactive protein.Data from Berard RA et al; Acute Care Committee: Practice Point: Paediatric Inflammatory Multisystem Syndrome Temporally Associated with COVID-19. Canadian Paediatric Society website. Published July 6, 2020. Updated May 3, 2021. Accessed April 25, 2022. 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.
        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 yearsLess than 25% of cases occur in children younger than 5 years; most common age group affected is 5 to 11 years
        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 the 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 the 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 the 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. Subset of patients with MIS-C fulfills clinical criteria for toxic shock syndrome
    • 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: r5r52
        • 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 r53
        • 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. Children with MIS-C tend to be older with more marked anemia, higher C-reactive protein levels, and higher alanine aminotransferase levels compared with those with toxic shock syndrome r19
  • Acute COVID-19 d3
    • Acute severe COVID-19 and MIS-C/MIS-A have overlapping clinical features, and presentations may be quite similar
    • 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 r48
      • Adults with severe COVID-19 tend to be older than those with MIS-A
      • 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
      • 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-C
      • 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 proteinData 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 is 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 r54
    • Dysfunctional immune response resulting in cytokine storm. May develop as complication or presenting feature of rheumatologic disorders—particularly systemic juvenile idiopathic arthritis and systemic lupus erythematosus—or may occur in previously healthy children when triggered by inciting infection
    • 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 r19
    • Differing clinical features may include: r19
      • 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 r19r55
      • 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) r55
      • 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) r55
    • Diagnosis of macrophage activation syndrome is based on clinical classification criteria and requires advanced immunologic testing as directed by rheumatologist r56
  • 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. Diagnosis is usually clinical in most immunocompetent children; however, infection may be confirmed with polymerase chain reaction testing r57
    • 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. Nucleic acid amplification tests are primary means to detect enterovirus in clinical specimens (eg, cerebrospinal fluid, serum, respiratory secretions) r58
  • Rubeola (measles) d6
    • Like MIS-C, characterized by high fever that persists for several days, conjunctival involvement, and diffuse rash
    • Unlike MIS-C, rash typically progresses from head to toe
    • 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-C 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-C r59
      • 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 r59
    • Empiric treatment with doxycycline is started with presumptive clinical diagnosis r59
    • Serologic testing (eg, indirect immunofluorescence assay for IgG reactive against many types of tickborne rickettsial pathogens) is typical method for confirming tickborne rickettsial disease r60
  • Serum sickness–like reactions r61
    • 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-C
    • May be difficult to distinguish on clinical grounds alone; presence of significant cardiac manifestations and neurologic manifestations suggest MIS-C rather than serum sickness–like reaction
    • Laboratory markers of inflammation typically are not as markedly elevated as in children with MIS-C
    • Serum sickness and serum sickness–like reactions are strictly clinical diagnoses
  • Myocarditis r62d8
    • Inflammation of myocardium secondary to other non–MIS-C and COVID-19–related causes presents identically to myocarditis that is characteristic of MIS-C
    • 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 children with myocarditis related to MIS-C typically are markedly elevated compared with those in children 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

Admission is recommended for children who meet MIS-C criteria, preferably to hospital with pediatric ICU capabilities when available r12

  • Rapid deterioration requiring vasopressor and/or inotrope support has been required in a significant number of patients (73% in 1 large studyr63)

Regardless of whether patient meets MIS-C criteria or is still undergoing evaluation for MIS-C, consider admission in the following circumstances: r27

  • 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 r27

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 r15r27
    • Consultants often include pediatric intensive care specialists, rheumatologist or immunologist, infectious disease 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 r27
    • 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 r10
  • Optimal treatment is not definitively known, and recommended treatment guidelines are regularly changing r6
    • Slightly different management strategies are recommended by various expert consensus groups and professional organizations r15r26r27r64
    • Different subtypes of MIS-C may require slightly different treatment approaches based on evolution of symptoms and laboratory abnormalities
    • Management of MIS-A is largely based on extrapolation from MIS-C, as little data are available and no guidelines exist r64
  • Selection of patients for treatment:
    • Select patients with mild manifestations can be managed without immunomodulatory treatment with close outpatient follow-up and observation for progression of disease r2r27
    • Immunomodulatory treatment is recommended for hospitalized patients r27r64
    • 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 r27
  • Treatment summarized below reflects NIH COVID-19 treatment guidelines and American College of Rheumatology clinical guidance, which are the most recent and comprehensive r27r64
    • American Academy of Pediatrics guidance is similar but less detailed r6
  • First line immunomodulatory treatment
    • IV immunoglobulin with corticosteroids is mainstay of first line immunomodulatory treatment r27r64
      • IV immunoglobulin plus IV methylprednisolone is recommended r27r64
        • 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
        • Use of IV immunoglobulin monotherapy is discouraged unless a contraindication to glucocorticoids exists r64
      • As yet, no randomized controlled trials directly compare IV immunoglobulin alone, steroids alone, and combination therapy, but current evidence suggests combination therapy should be first line treatment r27r64r65
        • Data from a study of 181 French children suggest that initial treatment with both IV immunoglobulin and corticosteroids results in several favorable outcome measures including: r66
          • 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
        • Data from a second 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: r67
          • 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 third study of 614 children from 32 countries suggest that combination therapy is associated with the following outcome: r68
          • Lower risk of need for second line immunomodulatory therapy
          • Otherwise, no significant differences in outcome measures were noted (eg, fever resolution, disease severity, need for hemodynamic support, left ventricular dysfunction)
        • Inconsistencies noted in available studies may be, at least in part, explained by differing inclusion criteria (eg, disease severity, fulfillment of standardized WHO or CDC diagnostic criteria) and outcome measures
        • WHO guidelines suggest use of corticosteroids alone and of corticosteroids with IV immunoglobulin in the subset of patients meeting criteria for both Kawasaki disease and MIS-C due to inconsistent evidence of effectiveness of IV immunoglobulin r26
  • Refractory disease immunomodulatory treatment r6r64
    • Refractory disease is defined as lack of improvement within 24 hours of initial immunomodulatory therapy as indicated by persistent fever, worsening organ dysfunction, and increasing inflammatory marker levels
    • High-dose corticosteroids and immune modulators are recommended as options; no evidence is available yet to select which one of the following options is best: r27r64
      • 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 r64
    • Second dose of IV immunoglobulin is not recommended due to risk of volume overload and hemolytic anemia
  • Antiplatelet and anticoagulation treatment r27r64
    • 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 r27r64
      • Enoxaparin with target of anti-factor Xa level of 0.5 to 1.0 is recommended initial therapy for 2 weeks r27r64
        • For alternative medications, consult Table 7 in American Heart Association guideline for Kawasaki diseaser18r27r64
      • 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 diseaser18
      • In unstable children or with concomitant severe renal impairment, use unfractionated heparin by continuous IV infusion r69
    • 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) r27
    • For patients without large coronary artery aneurysms or left ventricular dysfunction, consider prophylactic versus therapeutic anticoagulation on individual basis r27r64
      • Independent risk factors for thrombosis include: r70
        • 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 r5r6
  • Gastric prophylaxis
    • Gut protection (eg, omeprazole) is recommended for children treated with corticosteroids and aspirin r15r27r64
  • PIMS-TS National Consensus Management Study Group also has consensus statements regarding management in children with Kawasaki disease–like phenotype and nonspecific presentations; however, evidence from the above trials was not incorporated into these recommendations r15
    • Similar to NIH recommendations, IV immunoglobulin administered in single or divided dose, depending on clinical picture and cardiac function, is considered first line therapy
    • In contrast, steroids are considered for co-administration with IV immunoglobulin to high-risk patients (eg, children younger than age 12 months, those with coronary artery changes) and as second line therapy
    • Also differing from NIH and American College of Rheumatology guidance, both of which caution clinicians on risk of volume overload, second dose of IV immunoglobulin may be considered for patients who did not fully or partially respond to first dose
    • Biologic therapy is considered third line therapy for children who do not respond to IV immunoglobulin and methylprednisolone in consultation with multidisciplinary team. Various biologics that may be recommended include:
      • Anakinra (interleukin-1 receptor antagonist) r71
      • Tocilizumab (monoclonal antibody that functions as interleukin-6 inhibitor) r71
      • Infliximab (TNF-α blocker) r71
    • This guidance also recommends low-dose aspirin for minimum of 6 weeks for all patients with PIMS-TS, compression stockings for all children older than 12 years, and management of thrombosis or coronary artery abnormalities based on local protocols and consultation with specialists

Initial stabilization and urgent management priorities

  • Provide airway, breathing, and circulatory support as indicated clinically; specific guidance for treatment of shock and hypoxia secondary to MIS-C in children is limited
    • Address hypoxia with oxygen, secure airway, and provide mechanical ventilation, when necessary
    • Treat shock with judicious fluid resuscitation, paying close attention to responsiveness, and vasopressor support using appropriate shock protocols (eg, cardiogenicr73 versus distributive/vasodilatoryr74) r72d9
    • Epinephrine and norepinephrine may be preferred initial vasoactive medications in children with shock related to COVID-19 illness; vasopressin may be required in children requiring high doses of catecholamines r71r75r76
  • 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 r27
  • 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 r5r6r10r74d5
    • Maintain awareness that patients with MIS-C may have superimposed bacterial infections r19

Antiviral therapy considerations

  • Because MIS-C appears to be a postinfectious inflammatory response, antiviral therapy generally has not been initiated; nevertheless, use of infection control precautions appropriate for COVID-19 is recommended by some authorities r5
  • Some children who are SARS-CoV-2 positive on reverse transcription polymerase chain reaction or antigen testing can be considered for antiviral therapy, particularly those with severe illness r15r20
    • Remdesivir is first choice antiviral therapy for SARS-CoV-2
    • Initiate remdesivir in consultation with infectious disease specialist in setting of MIS-C r50
    • NIH panel recommends against use of remdesivir in those diagnosed with MIS-C r64
  • If there is diagnostic uncertainty between acute COVID-19 and MIS, consult guidelines for treatment of COVID-19r64r26 and guidelines for hyperinflammation in children with COVID-19r27 to consider all therapeutic options d10

Management pathways

  • Management algorithms and strategies developed by professional societies, tertiary care pediatric hospitals, international collaboration groups, and individual contributor publications are available r20r35
    • American College of Rheumatology clinical guidance task force r27
    • Children's Hospital of Philadelphiar36 and Children's Minnesotar37
    • International collaboration suggested COVID-19 pediatric ICU guidelines r71
  • Treat patients who meet criteria for Kawasaki disease in standard fashion based on regional guidelines (eg, supportive care, high-dose IV immunoglobulin, aspirin) r5r18r77d1
  • 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) r15r52d2

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) IV as a single dose. 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. r64
  • 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).
  • Tocilizumab
    • Tocilizumab Solution for injection; Children and Adolescents 2 years and older weighing less than 30 kg: 12 mg/kg IV infusion once. If symptoms worsen or do not improve, 1 additional dose may be administered at least 8 hours after the first. The EUA requires concurrent use with a systemic corticosteroid. According to the NIH COVID-19 treatment guidelines, data are insufficient to recommend for or against use in hospitalized children with COVID-19 or multisystem inflammatory syndrome.
    • Tocilizumab Solution for injection; Children and Adolescents 2 years and older weighing 30 kg or more: 8 mg/kg (max: 800 mg) IV infusion once. If symptoms worsen or do not improve, 1 additional dose may be administered at least 8 hours after the first. The EUA requires concurrent use with a systemic corticosteroid. According to the NIH COVID-19 treatment guidelines, data are insufficient to recommend for or against use in hospitalized children with COVID-19 or multisystem inflammatory syndrome.
  • 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

  • MIS-C resources for parents are available from CDCr7
  • For fluid management and other nondrug treatment for shock, follow published guidelines (eg, Surviving Sepsis Campaignr74r78)

Special populations

  • MIS after COVID-19 vaccination r79
    • Extremely rare (overall reporting rate of 1 MIS-C case per million vaccinated) r16
      • Available data show that most patients diagnosed with MIS-C after COVID-19 vaccination exhibit laboratory evidence of past or recent SARS-CoV-2 infection (71%) r16r32
      • Only 0.3 cases of MIS-C reported per million vaccinated children with no evidence of prior infection, compared to 200 cases of MIS-C per million unvaccinated children with prior COVID-19 infection or exposure r32
      • Only scattered case reports are available of adults with MIS-A following vaccination
      • Potential contribution of COVID-19 vaccination, if any, to development of MIS is unknown r16
    • Evaluate and manage patient in consultation with specialist (eg, infectious disease specialist, rheumatologist) in rare instance patient develops MIS-C, MIS-A, or similar clinical illness after receiving COVID-19 vaccine
    • Patient requires careful assessment for laboratory evidence of current and prior SARS-CoV-2 infection
      • Positive anti-nucleocapsid antibody test result (in serum before administration of IV immunoglobulin) may help identify those with history of SARS-CoV-2 infection r16
    • Consider consulting with CISA (Clinical Immunization Safety Assessment) COVIDvax Project r80
    • Report using VAERS r38

Monitoring

  • 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 r5
    • Frequent monitoring of laboratory markers of inflammation (eg, erythrocyte sedimentation rate, C-reactive protein) is important until values stabilize and improve r5
    • Monitor abnormal cardiac biomarkers (eg, NT-proBNP, troponin T) until values normalize r27
    • Perform serial ECGs (at least every 48 hours) and echocardiograms as appropriate based on clinical status r27r50
    • Monitor with telemetry patients who have evidence of conduction abnormalities r27
    • If cultures remain negative at 48 hours, consider discontinuing empiric antibiotics (if started) r35
    • Monitor clinically for development of infection following immunomodulatory treatment r64
  • Discharge criteria from hospital includes:
    • Stable cardiac function, absence of fever for 24 hours, and otherwise well appearance with reassuring physical examination r15
    • 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 r35
  • Follow-up cardiac assessments
    • Standardized follow-up regimen has not yet been firmly established; some experts have suggested preliminary regimen for outpatient follow-up r27r50
    • Outpatient Holter monitoring may be required for children with evidence of significant conduction abnormalities on telemetry during hospitalization r27
    • Cardiology follow-up is recommended starting 1 to 2 weeks after discharge r6
      • Restrict strenuous physical activity until cleared by cardiologist; many experts suggest following return to sports guidelines after myocarditis r31r81r82
    • Follow-up echocardiograms
      • Obtain 1 to 2 weeks and 4 to 6 weeks after discharge in patients with initially normal findings r15r27r33r44
        • 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 r18
      • 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 r27
    • Consider cardiac MRI 2 to 6 months after acute illness for patients with significant transient or persistent left ventricular dysfunction r27
    • Children with persistent left ventricular dysfunction and coronary artery aneurysms require vigilant and frequent cardiology and echocardiography follow-up r27
  • 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 r35
    • 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 disease specialist, rheumatologist, cardiologist), and clinical team to assist decision-making about use of COVID-19 vaccines in these patients r79
      • Data are limited regarding safety and efficacy after MIS; weigh theoretical risk of dysregulated immune response after vaccination with risk of COVID-19 infection r79
        • It is unknown if some patients with history of MIS may be at risk for MIS–like illness after COVID-19 vaccination
      • 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: r79
        • High SARS-CoV-2 level in community, or patient is otherwise at increased risk for SARS-CoV-2 exposure and transmission
        • Clinical recovery (including return to normal myocardial function)
        • 90 days or more have elapsed since MIS-C diagnosis
        • MIS-C occurred before patient received any dose of COVID-19 vaccine
      • Additional doses of COVID-19 vaccine also may be considered for patients with history of MIS that developed 90 days or more after vaccination; if MIS was diagnosed within 90 days of a vaccine dose, defer additional doses until more evidence is available r79
      • Consultation with CISA COVIDvax Project is available for complex situations r80
    • 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 r83

Complications and Prognosis

Complications

  • Morbidity
    • Coronary artery aneurysms
      • Estimated to develop in up to 24% of children (primarily mild) and 8% of adults r8r24
      • Development of large and giant coronary artery aneurysms are rare r22r44
      • Coronary artery aneurysms may develop after acute inflammatory phase of illness r50
    • Cardiac dysfunction
      • Ventricular dysfunction is estimated to occur in most children and adults (specific estimates vary widely depending on definition and study inclusion criteria) r8r50
        • 25% to 50% of children and 30% of adults develop evidence of myocarditis r8r42r84d8
      • Most children with cardiac dysfunction require inotropic support (about 53%-58%), approximately 26% require mechanical ventilation, and about 5% require extracorporeal membrane oxygenation r24r51
    • Systemic thrombosis
      • MIS is characterized by a hypercoagulable state r24
        • 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 r8
      • 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 r27r70
      • Thrombosis is uncommon (estimated at 3.5%-6.5% of hospitalized children) but may occur despite appropriate thromboprophylaxis measures r43r70
    • 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 r8r24
      • Mechanical ventilation is needed in approximately 25% of MIS-A patients overall r8
    • Acute kidney injury
      • Estimated to develop in about 12% of hospitalized children r43
      • 8% of MIS-A patients required dialysis r8
    • 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 r85
    • Serositis
      • Small pleural effusions, pericardial effusions, and ascites develop in a minority of MIS-C patients r20
  • Mortality
    • Mortality rate is estimated at 1.3% to 2% of affected children r24r43r51
    • Mortality is higher in adults with MIS-A, estimated at 7% r8

Prognosis

  • Recovery in vast majority of patients is expected with aggressive supportive management and appropriate treatment
    • Most patients respond promptly to therapy with a favorable short-term outcome r22r33r39r44
    • Median duration of hospitalization is about 7 days for patients with MIS-C and 8 days for those with MIS-A r8r48r86
    • 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 r51
      • 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 r40
    • Similarly, among adults, 57% required ICU care and 51% required vasoactive medications to treat shock r8
    • Death is 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) r31
  • Myocardial dysfunction
    • Major source of short-term morbidity and mortality in patients with MIS-C is myocardial dysfunction r27
    • Data suggest that short-term recovery of ventricular function is typical, but minority of patients have longer term effects r49r50r86
    • Limited data suggest that decreased left ventricular systolic function resolves in over 90% of patients by 30 days follow-up but as many as 4% of patients continued to have diastolic dysfunction as late as 6 months after discharge r48r86
  • Coronary artery aneurysms
    • Clinical significance and evolution of coronary artery dilation noted during acute phase of illness has yet to be determined r2
    • Laboratory findings (eg, C-reactive protein, neutrophil counts, lymphocyte counts, albumen, 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
    • May develop late in disease course or after apparent improvement r33r44r86
    • Limited data suggest that most coronary artery aneurysms resolve by 30 days follow-up; however, a minority of patients may have longer-term effects r48r86
  • Abnormal ECG findings
    • Most abnormal ECG findings (about 72% of patients) appear to normalize during hospitalization r49
  • 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 r86
      • 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 r86
    • Risk of dysregulated immune response after reinfection with SARS-CoV-2 is unknown among patients with history of MIS-C r79
  • 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 r86
  • Quality of life
    • Majority of pediatric patients and their parents reported no impairments in physical, emotional, social, school, or psychosocial domains using PedsQL scale at 6 months follow-up r87
    • 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 r87

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 r79d3
      • COVID-19 vaccination (eg, 2 doses of Pfizer-BioNTech mRNA vaccine) appears to be effective in preventing MIS-C in children aged 12 to 18 years r1
        • Data suggest that vaccine effectiveness for MIS-C prevention approaches 91% r1
      • 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 r1
    • Encourage diligent distancing, widespread use of facial covering, and careful hand and environmental hygiene 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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