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 definition^r5r10r11 and may be quite high (40° C or higher^r22)
    • 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

• 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

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

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.

      Manifestation	Classic prepandemic Kawasaki disease	MIS-C
      Age	Significantly more common in children younger than 5 years. Less than 20% of patients with Kawasaki disease are older than 5 years	Less than 25% of cases occur in children younger than 5 years; most common age group affected is 5 to 11 years
      Ethnicity	Most commonly noted in children of East Asian descent	Most commonly noted in children of African, African-Caribbean, and Hispanic descent
      Severity	Tend to be less sick than typical MIS-C patients	Tend 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 feature	Abdominal pain is often a prominent feature and may mimic acute abdomen; large majority have some gastrointestinal involvement
      Neurologic symptoms	Tend to be less prominent; exception may be irritability, as most children with classic Kawasaki disease are notably irritable	Tend to be more prominent with severe headache, altered sensorium, mental status depression, frank meningismus, cranial nerve palsies
      Cardiac dysfunction at presentation	Most 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-C	Significant 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 shock	Shock (Kawasaki disease shock syndrome) is rare (about 5%) at presentation and development during the course of acute phase of illness is uncommon	Shock 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 abnormalities	Thrombocytopenia is rare; patients often develop marked thrombocytosis beginning in the second week of illness	Thrombocytopenia is characteristic
      Anemia	About half of children develop mild normocytic anemia	Anemia is characteristic; peripheral smear may show findings associated with microangiopathic changes in RBCs
      WBC changes	Leukocytosis (WBC >15,000 cells/mm³) is present in about half of patients; neutrophilic predominance is typical for acute phase of disease	Lymphopenia is characteristic; neutrophilia may be present
      Inflammatory markers	CRP 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 biomarkers	Usually normal. Troponin and NT-proBNP may be modestly elevated in patients with ventricular wall stress and inflammation, as well as patients with coronary artery abnormalities	Elevation of troponin and NT-proBNP is typically more marked than in patients with Kawasaki disease
      Echocardiographic findings	Initial 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 illness	Initial 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 illness	Absence of bacterial or viral cause for manifestations is a key aspect of clinical diagnostic criteria	Laboratory 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 syndrome	Mild (+) risk	Moderate to severe (++) risk
      Pattern of coronary artery involvement	Aneurysms that are separated by normal vessel segments and inflammation usually spares the left main coronary artery orifice	Distinct pattern of uniformly ectatic vessel dilation with consistent involvement of left main coronary artery orifice
      Treatment response	Typically responds promptly to first dose of IV immunoglobulin administration	Left 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 protein

      Data from Case SM et al: COVID-19 in pediatrics. Rheum Dis Clin North Am. 47(4):797-811, 2021; Badal S et al: Prevalence, clinical characteristics, and outcomes of pediatric COVID-19: a systematic review and meta-analysis. J Clin Virol. 135:104715, 2021; Feldstein LR et al: Multisystem inflammatory syndrome in U.S. children and adolescents. N Engl J Med. 383(4):334-46, 2020; Godfred-Cato S et al: COVID-19-associated multisystem inflammatory syndrome in children - United States, March-July 2020. MMWR Morb Mortal Wkly Rep. 69(32):1074-80, 2020; Ahmed M et al: Multisystem inflammatory syndrome in children: a systematic review. EClinicalMedicine. 26:100527, 2020.

      Manifestation or finding	MIS-C	Pediatric COVID-19
      Age	Most common in 5 to 11 year age range	Severe disease is more common in younger age groups (aged <1 year) and older teenagers
      Presence of comorbidity	More common in otherwise healthy children and children with obesity	Presence of comorbidity (eg, medical complexity, severe immunocompromise, significant cardiopulmonary disease, obesity) is very common
      Asymptomatic	0%	13%
      Fever	100%	55%
      Gastrointestinal involvement	Common: reported in 87% (abdominal pain, diarrhea, vomiting)	Uncommon: reported in 6% (abdominal pain, diarrhea, vomiting)
      Mucocutaneous involvement	Common: 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 markers	Markedly increased CRP (median 152 mg/L) much more likely	Markedly increased CRP less likely (median 33 mg/L)
      CBC abnormalities	Thrombocytopenia 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 serology	Relatively higher antibody titers are expected compared with lower titers seen with acute COVID-19	Relatively 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

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 study^r63)

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

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

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 CDC^r7
• For fluid management and other nondrug treatment for shock, follow published guidelines (eg, Surviving Sepsis Campaign^r74r78)

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