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Jan.18.2022

Multisystem Inflammatory Syndrome in Children (MIS-C)

Synopsis

Key Points

  • MIS-C is characterized by persistent fever, elevated laboratory markers of inflammation, and evidence of single or multiorgan dysfunction, including myocarditis; acute gastrointestinal symptoms (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 children with MIS-C; 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 lack evidence of alternate microbial or alternate cause for illness
  • 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, renal function with electrolyte panel, urinalysis, liver function testing, 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 laboratory evidence of evolving cytokine release syndrome, significant coagulopathy, and assessment for myocarditis (eg, troponin, NT-proBNP, ECG, echocardiogram), 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 a mainstay of management; a significant proportion of children require vasopressor support
  • First line treatment for patients fulfilling criteria for diagnosis of MIS-C is admission to hospital for high-dose immunoglobulin with or without methylprednisolone
  • Second line treatment usually involves adding methylprednisolone course (if not already administered first line) or intensified course of pulse IV methylprednisolone (if corticosteroids were already administered first line)
  • Third line treatment involves adding immunomodulatory medications
  • Thromboprophylaxis with low-dose aspirin is recommended for all patients diagnosed with MIS-C
  • Most patients have responded well to therapy and have favorable short-term prognosis
  • Cardiology follow-up with serial echocardiography is recommended after recovery from acute phase of MIS-C to monitor for latent development of and evolution of coronary artery aneurysms and monitor cardiac function

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 a 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-C 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) is a clinical syndrome thought to represent a postinfectious, dysregulated inflammatory response to a previous (nonacute) exposure or infection with SARS-CoV-2 in children and adolescents r1
    • 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
  • Illness is characterized by persistent fever, laboratory markers of inflammation, and evidence of single or multiorgan dysfunction r2r3r4
    • 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 (occurs in less than 1% of children with COVID-19 infection) and novel disease; therefore, it is not yet possible to make firm evidence-based recommendations r1r5
    • Rigorous data to guide most diagnostic and management strategies are lacking and optimal treatment is unknown
  • Multisystem inflammatory syndrome in children is the designation used by CDC and WHO r3r4
    • Condition is also referred to as PIMS-TS (pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 infection) and PMIS (pediatric multisystem inflammatory syndrome) temporally associated with COVID-19

Classification

  • Classification based on case definition
    • Several national and international organizations have established case definitions for MIS-C (multisystem inflammatory syndrome in children) that are broadly similar r4r6r7
      • 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 r8
    • WHO definition applies to children and adolescents aged 0 to 19 years who meet all of the following clinical criteria: r7
      • Fever for 3 days or longer
      • 2 or more of the following:
        • Rash or bilateral conjunctivitis (nonpurulent) or mucocutaneous inflammation of mouth, hands, or feet
        • Hypotension or shock
        • Features of myocardial dysfunction, pericarditis, valvulitis, or coronary artery abnormalities, including evidence found through imaging (echography) and laboratory studies (elevated levels of troponin, NT-proBNP [N-terminal–pro hormone brain natriuretic peptide])
        • Coagulopathy (eg, elevated prothrombin time/INR, partial thromboplastin time, D-dimer level)
        • Acute gastrointestinal symptoms (vomiting, diarrhea) or abdominal pain
      • Elevated levels of nonspecific indicators of inflammation (eg, erythrocyte sedimentation rate, C-reactive protein, procalcitonin)
      • No obvious alternate microbial cause of inflammation (bacterial sepsis, staphylococcal or streptococcal toxic shock syndrome)
      • Evidence of COVID-19 (positive reverse transcription polymerase chain reaction test result, detectable antigen, or antibody) or likely exposure to COVID-19
    • CDCr6 and Royal College of Paediatrics and Child Healthr4 have published case definitions that are slightly broader, emphasize temporal nature of association to COVID-19 (ie, causation not proven), and expand upon resemblance of syndrome to Kawasaki disease
      • Some children fulfill full or partial criteria for Kawasaki syndrome, but MIS-C diagnosis is applied if they otherwise meet the case definition r2r4
      • Royal College of Paediatrics and Child Health notes that polymerase chain reaction results for SARS-CoV-2 (earlier provisional name was 2019-nCoV) may be positive or negative r4
    • MIS-C and PIMS-TS criteria.RCPCH, Royal College of Paediatrics and Child Health.Data from Case SM et al: COVID-19 in pediatrics. Rheum Dis Clin North Am. 47(4):797-811, 2021; 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; CDC: Multisystem Inflammatory Syndrome (MIS): Information for Healthcare Providers About Multisystem Inflammatory Syndrome in Children (MIS-C). CDC website. Last reviewed May 20, 2021. Accessed November 19, 2021. https://www.cdc.gov/mis/mis-c/hcp/index.html; WHO: Multisystem Inflammatory Syndrome in Children and Adolescents Temporally Related to COVID-19. Scientific Brief. WHO website. Published May 15, 2020. Accessed December 15, 2021. https://www.who.int/news-room/commentaries/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. RCPCH website. Published May 1, 2020. Updated September 2020. Accessed December 15, 2021. 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 higher than 38° C 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, C-reactive protein, or procalcitoninAND evidence of inflammation (neutrophilia, elevated C-reactive protein, lymphopenia)
      SARS-CoV-2 testingAND positive for current or recent SARS-CoV-2 infection by real time 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 (RT-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
    • Kawasaki disease–like phenotype r9
      • Children who meet complete or incomplete Kawasaki disease criteria as defined by the American Heart Association r10
      • Children are often younger than those in other phenotypes and less likely to present with shock or myocardial dysfunction r11
      • Most children (about two-thirds) have positive SARS-CoV-2 serology with negative polymerase chain reaction; most of the remaining one-third are positive for SARS-CoV-2 serology with positive polymerase chain reaction r11
    • Nonspecific phenotype
      • Children presenting with shock or fever, not meeting criteria for Kawasaki disease, with other predominant manifestations that may include abdominal pain and gastrointestinal, respiratory, or neurologic symptomsr9
        • MIS-C overlapping with severe acute COVID-19 subgroup r11
          • Children tend to be older than children presenting with Kawasaki disease-like features. They often have significant comorbidities and have relative mortality higher than other phenotypes
          • Manifestations may include some degree of respiratory involvement (eg, cough, dyspnea, pneumonia, acute respiratory distress syndrome) more so than other phenotypes
          • Children tend to present with positive SARS-CoV-2 polymerase chain reaction and negative serology
        • MIS-C without Kawasaki disease features subgroup r11
          • Children are more likely to present in shock with cardiac dysfunction
          • Predominant manifestations involve gastrointestinal and cardiovascular systems
          • Inflammatory markers (eg, C-reactive protein, ferritin) tend to be exceedingly elevated compared with other subgroups
          • Almost all children exhibit positive SARS-CoV-2 serology with or without positive polymerase chain reaction
  • Classification based on severity r9
    • Severe disease features may be indicated by any of the following:
      • Physiologic features
        • 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
        • Noticeable increase in markers of inflammation (eg, C-reactive protein above 150 mg/L, ferritin, l-lactate dehydrogenase)
        • Clinically significant increased or increasing cardiac biomarker levels (eg, troponin, NT-proBNP)
        • 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
        • Left ventricular failure
        • Abnormal coronary arteries on echocardiogram

Diagnosis

Clinical Presentation

History

  • Background
    • Onset of symptoms typically occurs 2 to 6 weeks after exposure to SARS-CoV-2 r1
    • Most patients are asymptomatic or experience mild illness at time of inciting SARS-CoV-2 infection r12
    • Disease manifestations present on a spectrum of severity, ranging from mild symptoms to multiorgan failure r13
    • Manifestations may not appear simultaneously but may evolve over several days r13
    • Mucocutaneous manifestations typically appear early in the course of illness (mean duration after development of fever until appearance is about 2 and a half days) r14
  • Common presenting symptoms include:
    • Persistent fever, often lasting 4 days or more, is universal r15
    • Gastrointestinal symptoms are the most common complaints after fever r15r16
      • Abdominal pain may be severe, suggesting acute abdomen
      • Nonbloody diarrhea may be profuse
      • Vomiting
    • Kawasaki-like symptoms are common r17
      • Rash
      • Conjunctivitis
      • Oral mucosal changes and odynophagia
      • Nonspecific extremity pain and swelling r4
    • Neurologic symptoms
      • Headache r4
      • Altered mental status (confusion, somnolence) r4
      • Aseptic meningitis presentation (mild neck stiffness, photophobia) r12
    • Cardiovascular symptoms
      • Rapid breathing, dyspnea, fatigue, and chest pain may suggest presence of myocarditis
      • Syncope related to arrhythmia may be noted
  • Less common symptoms include:
    • Respiratory symptoms (eg, rhinorrhea, cough) may be present but are not common and are not predominant r4
    • Myalgia is sometimes reported r4

Physical examination

  • Patients may appear severely ill with signs of shock
    • Approximately 50% to 60% of patients present with shock requiring some type of inotropic support r13r18
    • Hypotension plus 2 or more of the following criteria: r19
      • 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); alternatively, pulses may be bounding (so-called warm vasodilatory/distributive shock)
      • Tachypnea
      • Mottled or cool skin, petechiae, or purpura
      • Oliguria
      • Altered mental status
      • Hyperthermia or hypothermia
  • Common presenting signs include:
    • Abnormal vital signs
      • Fever is present by definitionr2r7r4 and may be quite high (40° C or higherr15)
      • 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-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 the 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
  • Pulmonary findings typically are not prominent

Causes and Risk Factors

Causes

  • MIS-C is thought to occur secondary to a postinfectious dysregulated inflammatory response to previous (nonacute) exposure or infection with SARS-CoV-2 r1r13
  • Temporal association exists with COVID-19 both in individual cases (positive RNA test or serology) and in the epidemiologic curve of both conditions r2
  • In areas heavily affected by the pandemic, incidence of MIS-C parallels that of COVID-19 after a 3- to 6-week interval, consistent with a postinflammatory mechanism related to COVID-19 r12

Risk factors and/or associations

Age
  • Case definitions include patients aged 0 to 19r7 (or younger than 21r6) years r3
Sex
  • Males (approximately 60% of cases) are affected more often than females (approximately 40% of cases) r17
Ethnicity/race
  • More common among patients of African, African-Caribbean, and Hispanic ancestry than other groups r2r18r20
Other risk factors/associations
  • About half of patients diagnosed are obese or overweight based on BMI r18

Diagnostic Procedures

Primary diagnostic tools

  • There is no confirmatory diagnostic test; 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) r4r6
    • 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 r4r6
    • Available guidance is in agreement that laboratory evidence of current infection (positive SARS CoV-2 antigen or polymerase chain reaction) or suspected recent infection (positive SARS CoV-2 antibodies) 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 r5
  • Suspect diagnosis when clinical presentation is concerning for diagnosis, particularly in the 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
    • Common presenting patterns include: r1r21
      • Persistent, unexplained high fever in a child with laboratory evidence of marked inflammation
      • Presentation with, or rapid development of, shock or shocklike state secondary to significant cardiac dysfunction, multiorgan dysfunction, or cytokine release syndrome (so-called 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 r5r21
      • 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 a Kawasaki diseaselike phenotype and older children are more likely to develop myocarditis and shock r21
  • A tiered diagnostic testing approach may be followed to assess children without life-threatening manifestations with suspicion for MIS-C based on clinical presentation; obtain full diagnostic evaluation for children with myocarditis or shock or shocklike state with an epidemiologic link to COVID-19 r1r21
    • 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 r9
          • Consistent findings include anemia, thrombocytopenia, neutrophilia, and lymphopenia; elevated creatinine, BUN, transaminases; proteinuria, hyponatremia, and hypoalbuminemia
        • Obtain inflammatory markers including erythrocyte sedimentation rate and C-reactive protein
          • Inflammatory markers are often markedly elevated
        • Obtain specific testing for COVID-19
          • SARS-CoV-2 antibodies are often positive, whereas polymerase chain reaction or antigen test results are more often negative r21
        • Perform focused microbiologic evaluation for alternate infectious causes as directed by clinical suspicion; evaluation may include studies including the following: r13r22r23
          • Blood, throat, urine, stool, and cerebrospinal fluid cultures as clinically indicated
          • Nasopharyngeal swabs for common respiratory viruses, 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 a 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
        • 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
        • Assess for myocarditis with troponin, NT-proBNP, ECG, chest radiograph, and emergent echocardiogram
      • Send serum to laboratory to hold for possible further serologic testing after administering IV immunoglobulin r5r17
        • Serum cannot be used for serologic testing after IV immunoglobulin has been administered
      • Consult current comprehensive lists of possible laboratory investigations r4r9
  • Obtain additional testing as directed by clinical presentation
    • May need abdominal ultrasonography to assess for possible appendicitis or intussusception r2r4
  • Diagnostic pathways are available from professional societies, institutions, and publications
    • American College of Rheumatology clinical guidance task force r21
    • Published algorithms r13r24
    • Children's Hospital of Philadelphia r25
    • Children's Minnesota r26
  • Serial monitoring of laboratory markers of inflammation and echocardiography is recommended r8

Laboratory

  • CBC
    • WBC count is often elevated r11
    • Lymphopenia is common; neutrophilia may occur r4
    • Anemia or thrombocytopenia may be present
  • Electrolytes and renal panel
    • Hyponatremia may be noted r4r22
    • Increased creatinine and BUN levels may develop r22
  • Inflammatory markers
    • C-reactive protein, erythrocyte sedimentation rate, procalcitonin, and ferritin levels are typically elevated, often markedly r4r15r22r27
    • 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 r4r15r22r27
    • 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 proBNP levels may be elevated, indicating myocardial inflammation, sometimes to very high levels r15r22r28
  • Others
    • Hypoalbuminemia is common r11
    • Cytokines (if available): characteristic findings include elevated interleukin-6, interleukin-10, soluble interleukin-2 receptor, and tumor necrosis factor r4r12r15r27
    • Mild cerebrospinal fluid pleocytosis has been reported in patients who underwent lumbar puncture for possible meningitis r22r23
    • Triglyceride levels may be above reference range r4
    • AST and ALT may be slightly elevated r11
    • Creatine kinase may be increased
  • SARS-CoV-2 testing
    • Polymerase chain reaction, antigen, or antibody test result has been positive in nearly all patients; however, negative test results do not exclude disease r2r15r22r23r27r28
      • Class-switched antibody response to SARS-CoV-2 antigens is estimated to be present in over 80% of children with MIS-C r1
      • Positive polymerase chain reaction for SARS-CoV-2 infection occurs in an estimated 20% to 45% of children with MIS-C r1r17
      • 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 to family member confirmed positive for SARS-CoV-2 r29r30
    • Combined test results r2r12r16r20r27r28r31
      • About 60% of children with MIS-C have positive SARS-CoV-2 antibodies by serology 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 serology 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
    • Quantitative SARS-CoV-2 serology r32
      • May aid in differentiating acute severe COVID-19 and MIS-C because higher titers are expected to occur in children with MIS-C

Imaging

  • Chest radiography
    • Although existing guidance does not specifically recommend chest imaging, a baseline chest radiograph is prudent and many patients exhibit abnormalities at presentation or during disease course r3r4r11
    • Nonspecific patchy infiltrates are not unusual with MIS-C; evidence of pleural effusion and cardiomegaly may be visible r4r22r27
    • 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%) r33
  • Echocardiogram
    • 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) r13r27r28
      • Left ventricular ejection fraction is diminished in at least 34% of children at admission r34
    • Findings (eg, dilation or aneurysms of coronary arteries) may develop during the course of illness and even after hospital discharge r27r28r35
  • Abdominal ultrasonography
    • May reveal hepatosplenomegaly, mesenteric adenitis, ileocolitis, ascites, gallbladder inflammation, or appendiceal inflammation r13

Functional testing

  • ECG
    • Abnormal ECG may be apparent in up to about 35% of children at admission r34
    • Findings may include: r28r34r35
      • Repolarization changes (abnormal ST- or T-wave segment) are most common
      • Prolonged PR interval and prolonged QTc interval
      • Heart block (first, second, or third degree)
      • Premature atrial and ventricular beats
      • Ventricular arrhythmias

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 r36
    • A 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: r10
        • 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 the Kawasaki disease clinical criteria with compatible laboratory and echocardiographic findings r36
    • Some 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 r2
      • Abdominal pain and gastrointestinal symptoms (eg, diarrhea, vomiting) are often predominant features in children with MIS-C r27
      • 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 r27
      • 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) r36
      • 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 r36
      • 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 the left main coronary artery orifice r36
    • May be extremely challenging to confirm Kawasaki disease in some cases. SARS-CoV-2 testing (including quantitative antibody titers) and exposure history may aid the most in differentiating 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). Coronary artery dilation and aneurysm may develop during the disease course in both conditions. NT-proBNP, N-terminal–pro hormone brain natriuretic peptide.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 December 15, 2021. 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 2. Arthritis Rheumatol. 73(4):e13-29, 2021; 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. ePub, 2021; 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 yearsMore than half of cases occur in children older than 5 years; most common age group affected is 7 to 9 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
        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 is much more common than it is in patients with classic (pre-COVID-19) 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 in pre-COVID-19 era
        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 markersC-reactive protein and erythrocyte sedimentation rate are typically modestly elevated; C-reactive protein is usually less than 100 mg/dL; mild elevations in other inflammatory markers may be present (eg, ferritin, D-dimer)C-reactive protein and erythrocyte sedimentation rate are typically markedly elevated; C-reactive protein 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
    • Like in MIS-C, patients present with fever and rash; hypotension, thrombocytopenia, central nervous system involvement (eg, confusion), and renal failure are common. A 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 non-streptococcal toxic shock syndrome: r4r37
        • 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 measles
      • Features of streptococcal toxic shock syndrome r38
        • Hypotension (systolic pressure less 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 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 ALT levels compared with those with toxic shock syndrome r12
  • Acute COVID-19 d3
    • Acute severe COVID-19 and MIS-C have overlapping clinical features, and presentations may be quit similar
    • Some differences in clinical presentation and organ system involvement may help to differentiate
      • Patients 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 r33
      • Severe COVID-19 illness often occurs in children with significant underlying medical comorbidity, whereas MIS-C tends to occur in otherwise previously healthy children
      • Exposure history may help differentiate. Exposure to SARS-CoV-2 occurs days before onset of illness in children with COVID-19 and weeks before onset of illness in children with MIS-C
      • 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 for SARS-CoV-2 infection
      • Quantitative SARS-CoV-2 antibody titers may hep to differentiate, as patients with MIS-C often present with a 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-CData 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; and Case SM et al: COVID-19 in pediatrics. Rheum Dis Clin North Am. 47(4):797-811, 2021.
        Manifestation or findingMIS-CPediatric COVID-19
        AgeMost common in 6- to 12-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 and usually insignificant with 14% (rhinorrhea in 13%, cough in 7%)Common and significant with cough (45%) and dyspnea (19%)
        Inflammatory markersMarkedly increased C-reactive protein (median 152 mg/L) much more likelyMarkedly increased C-reactive protein 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 r39
    • This is a dysfunctional immune response resulting in cytokine storm. It may develop as a complication or presenting feature of rheumatologic disorders—particularly systemic juvenile idiopathic arthritis and systemic lupus erythematosus—or it 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 r12
    • Differing clinical features may include: r12
      • 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 ferritin, high soluble interleukin-2 receptor, interleukin-18, and CXCL9 are typically much more profound in children with macrophage activation syndrome and less marked in children with MIS-C r12
    • Diagnosis of macrophage activation syndrome is based on clinical classification criteria and requires advanced immunologic testing as directed by a rheumatologist r40
  • 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
  • Rubeola 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

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 a hospital with pediatric ICU capabilities, when available r8

  • Rapid deterioration requiring vasopressor and/or inotrope support has been required in a significant number of patients (73% in 1 large studyr41)

Additional admission recommendations include patients who: r21

  • Are under investigation for MIS-C (ie, do not yet meet full MIS-C criteria) and are ill-appearing
  • Have abnormal vital signs
  • Have evidence of end organ dysfunction (eg, respiratory distress, neurologic changes, hepatic or renal dysfunction, abnormal ECG, or serum markers of cardiac injury)
  • Have marked elevation of inflammatory markers (eg, C-reactive protein 10 mg/L or higher)

Regardless of whether the patient meets MIS-C criteria or is still undergoing evaluation for MIS-C, consider admission in the following circumstances: r42

  • Abnormal vital signs (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 or serum markers of cardiac injury
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 a multidisciplinary treatment team of specialists is preferred when possible r9r21
    • 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
  • MIS-C is a reportable illness
    • Report suspected cases to local, state, and territorial health departmentsr6

Treatment Options

General treatment overview

  • Select patients with mild manifestations can be managed conservatively with close outpatient follow-up and observation for progression of disease r1r21
  • Supportive care is a key aspect of management in all patients r6
  • Optimal treatment is not definitively known; different subtypes of MIS-C may require slightly different treatment strategies based on evolution of symptoms and laboratory abnormalities r5
  • IV immunoglobulin is a current mainstay of first line treatment; corticosteroids may be added as a first line adjunct in patients with severe disease r5r21
    • IV immunoglobulin is indicated for hospitalized patients diagnosed with MIS-C or 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
    • Initial combined treatment with IV immunoglobulin and corticosteroids may be beneficial; however, preliminary data from observational studies are somewhat inconsistent
      • Data from 1 study of 181 French children suggest that initial treatment with both IV immunoglobulin and corticosteroids results in several favorable outcome measures including: r43
        • 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: r44
        • 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: r45
        • 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
  • Corticosteroids and immune modulators are often added for severe or refractory disease r5
  • Infection control
    • Follow local infection control precautions appropriate for patients being investigated for COVID-19. Antiviral therapy generally is not indicated, given that MIS-C appears to represent a postinfectious inflammatory response to COVID-19 r4r5

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, cardiogenicr47 versus distributive/vasodilatoryr48) r46d7
    • 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 r49r50r51
  • 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 r21
  • 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 r4r5r6r48d5
    • Maintain awareness that patients with MIS-C may have superimposed bacterial infections r12

American College of Rheumatology guidelines recommend the following approach:

  • Patients in whom MIS-C is suspected and who have life-threatening manifestations may require immunomodulatory treatment for MIS-C before full diagnostic evaluation can be completed r21
  • Some patients with mild symptoms may require only close monitoring without immunomodulatory treatment r21
  • Primary immunomodulatory therapy is IV immunoglobulin; glucocorticoids are used adjunctively depending on severity of illness or clinical response to IV immunoglobulin r21
    • IV immunoglobulin
      • High dose IV immunoglobulin (typically 2 g/kg, based on ideal body weight) is recommended for MIS-C patients who are hospitalized or who fulfill Kawasaki disease criteria
      • Assess cardiac function and fluid status before prescribing or administering IV immunoglobulin treatment. Patients with severely impaired myocardium require close monitoring and may need diuretics to avoid volume overload; another recommended strategy is to administer in divided doses (1 g/kg daily over 2 days)
      • A second dose of IV immunoglobulin is not recommended owing to potential volume overload and hemolytic anemia seen with large doses of IV immunoglobulin
    • Glucocorticoids and biologics (eg, anakinra)
      • Low- to moderate-dose glucocorticoids (eg, methylprednisolone 1-2 mg/kg/day)
        • Use with IV immunoglobulin as adjunctive therapy to treat children with shock, organ-threatening disease, and moderate to severe symptoms
        • May benefit patients with milder forms of MIS-C whose fever and other symptoms do not resolve after a single dose of IV immunoglobulin
      • High-dose glucocorticoid pulse therapy (eg, methylprednisolone 10-30 mg/kg/day)
        • Consider for patients who do not respond to IV immunoglobulin or low- to moderate-dose glucocorticoids, especially in severe illness requiring high-dose or multiple inotropes or vasopressors
      • Anakinra (greater than 4 mg/kg/day IV or subcutaneous)
        • Treatment option for MIS-C:
          • When MIS-C does not respond adequately to IV immunoglobulin and glucocorticoids
          • When presentation suggests associated macrophage activation syndrome
          • When patient has contraindications to long-term use of glucocorticoids
      • Perform serial laboratory testing and cardiac assessment to check for response to therapy and to guide tapering of therapy
      • Tapering of immunomodulating agents may require 2 to 3 weeks or more
  • Antiplatelet and anticoagulation therapy in MIS-C r21
    • Low-dose aspirin (3-5 mg/kg/day; Max: 81 mg/day) is recommended for patients with MIS-C who do not have contraindications for aspirin therapy
      • Low-dose aspirin alone is recommended for patients with coronary artery aneurysms and a maximum z-score of 2.5 to 10
      • Avoid in patients with active bleeding, significant bleeding risk, or platelet count less than or equal to 80,000/µL
      • Continue until platelet count has returned to normal and echocardiogram 4 or more weeks after diagnosis confirms that coronary arteries are normal
    • Therapeutic anticoagulation indications
      • Patients with a z-score 10 or higher: use a combination of low-dose aspirin and therapeutic anticoagulation with enoxaparin (factor Xa level 0.5-1) or warfarin
      • Patients with documented intracardiac thrombosis or an ejection fraction less than 35%: provide therapeutic anticoagulation with enoxaparin until at least 2 weeks after discharge from the hospital
    • Recommended duration of enoxaparin varies depending on the indication:
      • Coronary artery aneurysm with z-score higher than 10: treat indefinitely
      • Documented thrombosis: treat for 3 or more months pending thrombus resolution
      • Ongoing moderate to severe left ventricular dysfunction: duration of treatment not specified but included as an indication for "longer outpatient therapeutic dosing"
    • For MIS-C patients who do not meet these criteria, individualize antiplatelet and anticoagulation management tailored to patient risk for thrombosis

American Academy of Pediatrics guidance recommends the following approach:

  • IV immunoglobulin r5
    • Usual treatment at dose of 2 g/kg (Max: 100 g)
    • Duration of IV immunoglobulin therapy infusion may require modification, depending on cardiac function and fluid status
  • Glucocorticoids and biologics (eg, anakinra) r5
    • Recommended for use in patients who do not improve clinically after IV immunoglobulin and in those whose laboratory values do not improve
    • Dosing of methylprednisolone ranges from 2 to 30 mg/kg/day, depending on severity of illness r5
      • Consult with a pediatric cardiologist before prescribing corticosteroids if there is laboratory or imaging evidence of myocardial injury or findings concerning for coronary artery aneurysms r5
    • Dosing of anakinra is recommended at 2 to 10 mg/kg/day, subcutaneously or IV, divided every 6 to 12 hours r5
    • Taper corticosteroids or biologics over about 3 weeks; they can be completed after discharge r5
  • Low-dose aspirin
    • Give all patients low-dose aspirin for thromboprophylaxis unless contraindications exist (eg, less than 100,000 platelets or active bleeding) r5

PIMS-TS National Consensus Management Study Group has published consensus statements regarding management in children with Kawasaki disease–like phenotype and nonspecific presentations r9

  • First line therapy
    • IV immunoglobulin at a dose of 2 g/kg (based on ideal body weight) administered in a single or divided dose, depending on clinical picture and cardiac function
    • May consider a second dose for children who do not adequately respond to the first dose
  • Second line therapy
    • IV methylprednisolone (10-30 mg/kg) for children who remain unwell 24 hours after infusion of immunoglobulin, particularly those with persistent fever
    • Administer omeprazole to all children treated with high-dose steroids
    • It is not necessary to exclude serious bacterial infection before administering high dose corticosteroids in the setting of possible MIS-C; exclusion of occult infection that may be unmasked by biologics before starting immunomodulatory agents is ideal but likely not feasible given time constraints of management decisions
  • Third line therapy
    • Biologic therapy is recommended 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) r51
      • Tocilizumab (monoclonal antibody that functions as interleukin-6 inhibitor) r51
      • Infliximab (TNF-α blocker) r51
  • For children with Kawasaki disease-like phenotype, the study group additionally recommends
    • Concomitant (early) IV methylprednisolone (10-30 mg/kg) with IV immunoglobulin administration for children with high-risk features (ie, those younger than 12 months, those with coronary artery changes)
  • Antiplatelet and thrombosis prophylaxes considerations
    • Administer low-dose aspirin for a minimum of 6 weeks to all patients with PIMS-TS
    • Compression stockings are recommended for all children older than 12 years

Consensus-based recommendations for anticoagulant thromboprophylaxis in hospitalized children with COVID-19–related illness are additionally available; recommendations include: r52

  • In children with D-dimer levels exceeding 5-fold normal limits and in children with superimposed clinical risk factors for hospital-associated venous thromboembolism, use subcutaneous low-dose low molecular weight heparin twice daily in absence of contraindications; also use mechanical compression devices
  • In unstable children or with concomitant severe renal impairment, use unfractionated heparin by continuous IV infusion

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 r4
  • 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 r9r13
    • Remdesivir is the first choice antiviral therapy for SARS CoV-2
    • Initiate remdesevir in consultation with an infectious disease specialist in the setting of MIS-C r35

Management pathways

  • Management algorithms and strategies developed by professional societies, tertiary care pediatric hospitals, international collaboration groups, and individual contributor publications are available r13r24
    • American College of Rheumatology clinical guidance task force r42
    • Children's Hospital of Philadelphiar25 and Children's Minnesotar26
    • International collaboration suggested COVID-19 pediatric ICU guidelines r51
  • Treat patients who meet criteria for Kawasaki disease in standard fashion based on regional guidelines (eg, supportive care, high-dose IV immunoglobulin, aspirin) r4r10d1
  • 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) r9r37r38d2

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 grams/kg (based on ideal body weight; Max: 100 grams) IV. May be given as a single infusion or as divided doses, depending on patient's clinical status and cardiac function. A second dose may be considered for patients who do not adequately respond to the first dose.
  • Methylprednisolone
    • Methylprednisolone Sodium Succinate Solution for injection; Infants, Children, and Adolescents: 2 to 30 mg/kg/day IV for 3 days. Administer at the same time as intravenous immunoglobulin (IVIG) for high-risk children with Kawasaki disease-like phenotype (children younger than 12 months and those with coronary artery changes). Administer as second-line therapy in patients who remain unwell 24 hours after infusion of IVIG, especially if they have ongoing pyrexia.
      • Maximum dose: 1000 mg/dose r1
  • Anakinra
    • Anakinra (E. coli) Solution for injection; Children and Adolescents: Available data are limited, and efficacy has not been established. 2 to 10 mg/kg/day via subcutaneous injection or IV divided every 6 to 12 hours has been recommended with a 3-week at-home taper.
  • Aspirin
    • Aspirin Oral tablet; Infants, Children, and Adolescents: Available data are limited, and efficacy has not been established. Doses varying from 3 to 5 mg/kg/day PO (low dose) to 30 to 100 mg/kg/day PO (moderate to high dose) have been reported and are being used in combination with IVIG with or without methylprednisolone.
      • Maximum dose for low dose aspirin (3 to 5 mg/kg/day): 81 mg/day r21
      • Maximum dose for moderate to high dose aspirin (30 to 100 mg/kg/day): 325 mg/day

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 r4
    • Frequent monitoring of laboratory markers of inflammation (eg, erythrocyte sedimentation rate, C-reactive protein) is important until values stabilize and improve r4
    • Monitor abnormal cardiac biomarkers (eg, brain natriuretic peptide, troponin T) until values normalize r21
    • Perform serial ECGs (at least every 48 hours) and echocardiograms as appropriate based on clinical status r21r35r42
    • Monitor with telemetry patients who have evidence of conduction abnormalities r21
    • If cultures remain negative at 48 hours, consider discontinuing empiric antibiotics (if started) r24
  • Discharge criteria from hospital includes:
    • Stable cardiac function, absence of fever for 24 hours, and otherwise well appearance with reassuring physical examination r9
    • 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 r24
  • Follow-up cardiac assessments
    • Standardized follow-up regimen has not yet been firmly established; some experts have suggested a preliminary regimen for outpatient follow-up r35
    • Outpatient Holter monitoring may be required for children with evidence of significant conduction abnormalities on telemetry during hospitalization r21
    • Cardiology follow-up is recommended starting 1 to 2 weeks after discharge r5
      • Restrict strenuous physical activity until cleared by cardiologist; many experts suggest following return to sports guidelines after myocarditis r53r54
    • Follow-up echocardiograms
      • Obtain follow-up echocardiograms 2 and 6 weeks after discharge in patients with initially normal findings r9r22r31
        • Recommendations are based on those established for Kawasaki disease and on concern that MIS-C patients (like patients with classic Kawasaki disease) may develop coronary artery aneurysms late in the disease course or after apparent improvement r10
      • 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 the acute phase of illness r21
    • Consider cardiac MRI 2 to 6 months after acute illness for patients with significant transient or persistent left ventricular dysfunction r42
    • Children with persistent left ventricular dysfunction and coronary artery aneurysms require vigilant and frequent cardiology and echocardiography follow-up r21
  • 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 r24
    • Caregiver must clearly understand specific reasons to return and recognize the low threshold to return for reassessment given that sometimes, rapid clinical deterioration may develop with progression of disease
  • Follow-up vaccine recommendations for children recovered from MIS-C r55
    • Data are lacking regarding safety and efficacy after MIS-C; weigh theoretical risk of dysregulated immune response after vaccination with risk of COVID-19 infection
    • CDC guidance notes that benefits of vaccination most likely outweigh risks, particularly when the following criteria are met:
      • High to substantial SARS-CoV-2 transmission in community
      • 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

Complications and Prognosis

Complications

  • Morbidity
    • Coronary artery aneurysms
      • Estimated to develop in up to 24% of patients; however, most reported are mild (z score 2-2.5) r17
      • Development of large and giant coronary artery aneurysms are rare r15r31
      • Coronary artery aneurysms may develop after acute inflammatory phase of illness r35
    • Cardiac dysfunction
      • Ventricular dysfunction is estimated to occur in most children (specific estimates vary widely depending on definition and study inclusion criteria) r35
        • One-quarter to one-half of children develop evidence of myocarditis r29r56d8
      • Most children with cardiac dysfunction require ionotropic support (about 53%r36-58%), approximately 26% require mechanical ventilation, and about 5% require extracorporeal membrane oxygenation r17
    • Systemic thrombosis
      • MIS-C is characterized by a hypercoagulable state. Other factors that place children at increased risk for thrombotic complications include possible endothelial injury, immobilization, ventricular dysfunction, and coronary artery aneurysm development r17
      • Other risk factors for thrombosis include age older than 12 years, comorbid malignancy, and presence of central venous catheter r57
      • Thrombosis is uncommon (estimated at 3.5%-6.5% of hospitalized children) but may occur despite appropriate thromboprophylaxis measures r30r57
    • Respiratory failure
      • Mechanical ventilation is required in up to 30% of hospitalized patients with shock or respiratory manifestations r17
    • Acute kidney injury
      • Estimated to develop in about 12% of hospitalized patients r30
    • 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 patients r58
    • Serositis
      • Small pleural effusions, pericardial effusions, and ascites develop in a minority of patients r13
  • Mortality
    • Mortality rate is estimated at approximately 1.3% to 2% of affected children r17r30r36

Prognosis

  • Recovery in the 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; however, long-term prognosis and outcome data are lacking r15r22r27r31
    • Median duration of hospitalization is about 6 days for patients with MIS-C r56
    • Over three-quarters of children affected who need hospitalization require ICU level of care and over 50% of hospitalized children require some degree of ionotropic support r36
  • Myocardial dysfunction
    • Major source of short-term morbidity and mortality in patients with MIS-C is myocardial dysfunction r21
    • Data suggest that short-term recovery of ventricular function is typical; however, long-term complications of myocardial inflammation are largely unknown r34r35
    • Limited data suggest that decreased left ventricular systolic function resolves in over 90% of patients by 30 days follow-up r33
  • Coronary artery aneurysms
    • Clinical significance and evolution of coronary artery dilation noted during acute phase of illness has yet to be determined r1
    • May develop late in disease course or after apparent improvement r22r31
    • Limited data suggests that most coronary artery aneurysms resolve by 30 days follow-up r33
  • Abnormal ECG findings
    • Most abnormal ECG findings (about 72% of patients) appear to normalize during hospitalization r34

Screening and Prevention

Prevention

  • The only known preventive measures involve avoiding infection with SARS-CoV-2
    • Vaccination is recommended for children aged 5 years and older without contraindications to vaccine r59d3
    • Encourage diligent distancing, widespread use of facial covering, and careful hand and environmental hygiene d9
  • 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
Berard RA et al: Canadian Paediatric Society Practice Point. Paediatric Inflammatory Multisystem Syndrome Temporally Associated With COVID-19 (Spring 2021 Update). Canadian Paediatric Society website. Posted July 6, 2020. Updated May 3, 2021. Accessed December 13, 2021. https://cps.ca/en/documents/position/pimshttps://cps.ca/en/documents/position/pimsCDC Center for Preparedness and Response: Multisystem Inflammatory Syndrome in Children (MIS-C) Associated With Coronavirus Disease 2019 (COVID-19). Clinician Outreach and Communication Activity (COCA) Webinar. CDC website. Published May 19, 2020. Accessed December 13, 2021. https://emergency.cdc.gov/coca/ppt/2020/COCA_Call_Slides_05_19_2020.pdfhttps://emergency.cdc.gov/coca/ppt/2020/COCA_Call_Slides_05_19_2020.pdfEuropean Centre for Disease Prevention and Control: Rapid Risk Assessment: Paediatric Inflammatory Multisystem Syndrome and SARS-CoV-2 Infection in Children. European Center for Disease Prevention and Control website. Published May 15, 2020. Accessed November 22, 2021. https://www.ecdc.europa.eu/en/search?s=rapid+risk+assessment%3A+paediatric+inflammatory+syndrome+and+sarshttps://www.ecdc.europa.eu/en/search?s=rapid+risk+assessment%3A+paediatric+inflammatory+syndrome+and+sarsRoyal 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 December 13, 2021. https://www.rcpch.ac.uk/resources/paediatric-multisystem-inflammatory-syndrome-temporally-associated-covid-19-pims-guidancehttps://www.rcpch.ac.uk/resources/paediatric-multisystem-inflammatory-syndrome-temporally-associated-covid-19-pims-guidanceAmerican Academy of Pediatrics: Multisystem Inflammatory Syndrome in Children (MIS-C) Interim Guidance. AAP website. Updated November 15, 2021. Accessed December 13, 2021. https://services.aap.org/en/pages/2019-novel-coronavirus-covid-19-infections/clinical-guidance/multisystem-inflammatory-syndrome-in-children-mis-c-interim-guidance/https://services.aap.org/en/pages/2019-novel-coronavirus-covid-19-infections/clinical-guidance/multisystem-inflammatory-syndrome-in-children-mis-c-interim-guidance/CDC: Multisystem Inflammatory Syndrome (MIS-C): Information for Healthcare Providers About Multisystem Inflammatory Syndrome in Children (MIS-C). Case Definition for MIS-C. CDC website. Last reviewed May 20, 2021. Accessed December 13, 2021. https://www.cdc.gov/mis-c/hcp/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 December 13, 2021. https://www.who.int/publications-detail/multisystem-inflammatory-syndrome-in-children-and-adolescents-with-covid-19https://www.who.int/publications-detail/multisystem-inflammatory-syndrome-in-children-and-adolescents-with-covid-19Pediatric Intensive-Care-COVID-19 International Collaborative: Statement to the Media Following the 2 May Pediatric Intensive Care-COVID-19 International Collaborative Conference Call. Kawasaki Disease Foundation website. Published May 2020. Accessed December 13, 2021. https://kdfoundation.org/statement-to-the-media-following-the-2-may-pediatric-intensive-care-covid-19-international-collaborative-conference-call/https://kdfoundation.org/statement-to-the-media-following-the-2-may-pediatric-intensive-care-covid-19-international-collaborative-conference-call/Harwood R et al: A national consensus management pathway for paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS): results of a national Delphi process. Lancet Child Adolesc Health. 5(2):133-41, 202132956615McCrindle 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, 201728356445Matic KM: SARS-CoV-2 and multisystem inflammatory syndrome in children (MIS-C). Curr Probl Pediatr Adolesc Health Care. 51(4):101000, 202134120861Case SM et al: COVID-19 in pediatrics. Rheum Dis Clin North Am. 47(4):797-811, 202134635305Waseem M et al: Multisystem inflammatory syndrome in children. J Emerg Med. ePub, 202134538678Young TK et al: Mucocutaneous manifestations of multisystem inflammatory syndrome in children during the COVID-19 pandemic. JAMA Dermatol. 157(2):207-12, 202133295957Riphagen S et al: Hyperinflammatory shock in children during COVID-19 pandemic. Lancet. 395(10237):1607-8, 202032386565Feldstein LR et al: Multisystem inflammatory syndrome in U.S. children and adolescents. N Engl J Med. 383(4):334-46, 202032598831Carter MJ et al: Paediatric inflammatory multisystem syndrome temporally-associated with SARS-CoV-2 infection: an overview. Intensive Care Med. 47(1):90-3, 202133057783Ahmed M et al: Multisystem inflammatory syndrome in children: a systematic review. EClinicalMedicine. 26:100527, 202032923992WHO: COVID-19 Clinical Management. Living Guidance. WHO website. Published January 25, 2021. Accessed November 22, 2021. https://www.who.int/publications/i/item/WHO-2019-nCoV-clinical-2021-1https://www.who.int/publications/i/item/WHO-2019-nCoV-clinical-2021-1Godfred-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, 202032790663Henderson 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 2. Arthritis Rheumatol. 73(4):e13-29, 202133277976Chiotos K et al: Multisystem inflammatory syndrome in children during the COVID-19 pandemic: a case series. J Pediatric Infect Dis Soc. 13;9(3):393-8, 202032463092Toubiana J et al: Kawasaki-like multisystem inflammatory syndrome in children during the COVID-19 pandemic in Paris, France: prospective observational study. BMJ. 369:m2094, 202032493739Hennon TR et al: COVID-19 associated multisystem inflammatory syndrome in children (MIS-C) guidelines; a Western New York approach. Prog Pediatr Cardiol. 101232, 202032837142Children's Hospital of Philadelphia: Emergency Department, ICU and Inpatient Clinical Pathway for Evaluation of Possible Multisystem Inflammatory Syndrome (MIS-C). CHOP website. Revised July 2021. Accessed December 13, 2021. https://www.chop.edu/clinical-pathway/multisystem-inflammatory-syndrome-mis-c-clinical-pathwayhttps://www.chop.edu/clinical-pathway/multisystem-inflammatory-syndrome-mis-c-clinical-pathwayChildren's Minnesota: Clinical Guideline: MIS-C: Clinic-Diagnosed/Dispo Recs for Suspected Multisystem Inflammatory Syndrome in Children (Age <21 Years). Revised June 2021. Accessed December 13, 2021. https://www.childrensmn.org/Departments/infectioncontrol/pdf/mis-c-clinical-guideline.pdfhttps://www.childrensmn.org/Departments/infectioncontrol/pdf/mis-c-clinical-guideline.pdfVerdoni L et al: An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study. Lancet. 395(10239):1771-8, 202032410760Belhadjer Z et al: Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic. Circulation. 142(5):429-36, 202032418446Kaushik 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, 202032925547Aronoff SC et al: The natural history of severe acute respiratory syndrome coronavirus 2-related multisystem inflammatory syndrome in children: a systematic review. J Pediatric Infect Dis Soc. 9(6):746-51, 202032924059Whittaker E et al: Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2. JAMA. 324(3):259-69, 202032511692Rostad CA et al: Quantitative SARS-CoV-2 serology in children with multisystem inflammatory syndrome (MIS-C). Pediatrics. 146(6), 202032879033Feldstein LR et al: Characteristics and outcomes of US children and adolescents with multisystem inflammatory syndrome in children (MIS-C) compared with severe acute COVID-19. JAMA. 325(11):1074-87, 202133625505Valverde I et al: Acute cardiovascular manifestations in 286 children with multisystem inflammatory syndrome associated with COVID-19 infection in Europe. Circulation. 143(1):21-32, 202133166189Sperotto F et al: Cardiac manifestations in SARS-CoV-2-associated multisystem inflammatory syndrome in children: a comprehensive review and proposed clinical approach. Eur J Pediatr. 180(2):307-22, 202132803422Kiss A et al: Management of COVID-19-associated multisystem inflammatory syndrome in children: a comprehensive literature review. Prog Pediatr Cardiol. 101381, 202133850412CDC: National Notifiable Diseases Surveillance System (NNDSS): Toxic Shock Syndrome (Other Than Streptococcal) (TSS): 2011 Case Definition. CDC website. Published 2011. Accessed December 13, 2021. https://wwwn.cdc.gov/nndss/conditions/toxic-shock-syndrome-other-than-streptococcal/case-definition/2011/https://wwwn.cdc.gov/nndss/conditions/toxic-shock-syndrome-other-than-streptococcal/case-definition/2011/CDC: National Notifiable Diseases Surveillance System (NNDSS): Streptococcal Toxic Shock Syndrome (STSS) (Streptococcus pyogenes): 2010 Case Definition. CDC website. Published 2010. Accessed December 13, 2021. https://wwwn.cdc.gov/nndss/conditions/streptococcal-toxic-shock-syndrome/case-definition/2010/https://wwwn.cdc.gov/nndss/conditions/streptococcal-toxic-shock-syndrome/case-definition/2010/Ravelli A et al: Macrophage activation syndrome. Hematol Oncol Clin North Am. 29(5):927-41, 201526461152Crayne C et al: Pediatric macrophage activation syndrome, recognizing the tip of the Iceberg. Eur J Rheumatol. 7(Suppl 1):1-8, 201931804174Belot A et al: SARS-CoV-2-related paediatric inflammatory multisystem syndrome, an epidemiological study, France, 1 March to 17 May 2020. Euro Surveill. 25(22):2001010, 202032524957American College of Rheumatology: Clinical Guidance for Pediatric Patients With Multisystem Inflammatory Syndrome in Children (MIS-C) Associated With SARS-CoV-2 and Hyperinflammation in COVID-19. ACR website. Approved June 17, 2020. Revised October 19, 2021. Accessed December 13, 2021. https://www.rheumatology.org/Portals/0/Files/ACR-COVID-19-Clinical-Guidance-Summary-MIS-C-Hyperinflammation.pdf?ver=2020-07-02-140939-180https://www.rheumatology.org/Portals/0/Files/ACR-COVID-19-Clinical-Guidance-Summary-MIS-C-Hyperinflammation.pdf?ver=2020-07-02-140939-180Ouldali N et al: Association of intravenous immunoglobulins plus methylprednisolone vs immunoglobulins alone with course of fever in multisystem inflammatory syndrome in children. JAMA. 325(9):855-64, 202133523115Son MBF et al: Multisystem inflammatory syndrome in children -- initial therapy and outcomes. N Engl J Med. 385(1):23-34, 202134133855McArdle AJ et al: Treatment of multisystem inflammatory syndrome in children. N Engl J Med. 385(1):11-22, 202134133854Edelson DP et al: Interim guidance for basic and advanced life support in adults, children, and neonates with suspected or confirmed COVID-19: from the Emergency Cardiovascular Care Committee and Get With The Guidelines-Resuscitation Adult and Pediatric Task Forces of the American Heart Association. Circulation. 141(25):e933-e43, 202032270695Brissaud O et al: Experts' recommendations for the management of cardiogenic shock in children. Ann Intensive Care. 6(1):14, 201626879087Weiss SL et al: Surviving Sepsis Campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children. Pediatr Crit Care Med. 21(2):e52-e106, 202032032273Topjian AA et al: Part 4: Pediatric basic and advanced life support 2020 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Pediatrics. 147(Suppl 1), 202133087552Annane D et al: A global perspective on vasoactive agents in shock. Intensive Care Med. 44(6):833-46, 201829868972Kache S et al: COVID-19 PICU guidelines: for high- and limited-resource settings. Pediatr Res. 88(5):705-16, 202032634818Goldenberg NA et al: Consensus-based clinical recommendations and research priorities for anticoagulant thromboprophylaxis in children hospitalized for COVID-19-related illness. J Thromb Haemost. 18(11):3099-105, 202033174388Canter CE et al: Diagnosis and treatment of myocarditis in children in the current era. Circulation. 129(1):115-28, 201424396015Caforio AL et al: Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 34(33):2636-48, 2648a-48d, 201323824828CDC: Interim Clinical Considerations for Use of COVID-19 Vaccines Currently Approved or Authorized in the United States. CDC website. Updated January 6, 2022. Accessed January 10, 2022. https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vaccines-us.htmlhttps://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vaccines-us.htmlDufort EM et al: Multisystem inflammatory syndrome in children in New York State. N Engl J Med. 383(4):347-58, 202032598830Whitworth H et al: Rate of thrombosis in children and adolescents hospitalized with COVID-19 or MIS-C. Blood. 138(2):190-8, 202133895804LaRovere KL et al: Neurologic involvement in children and adolescents hospitalized in the United States for COVID-19 or multisystem inflammatory syndrome. JAMA Neurol. 78(5):536-47, 202133666649CDC. COVID-19 Vaccines for Children and Teens. CDC website. Updated November 4, 2021. Accessed November 22, 2021. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/recommendations/children-teens.html?s_cid=11370:cdc%20covid%20vaccine%20children:sem.ga:p:RG:GM:gen:PTN:FY21https://www.cdc.gov/coronavirus/2019-ncov/vaccines/recommendations/children-teens.html?s_cid=11370:cdc%20covid%20vaccine%20children:sem.ga:p:RG:GM:gen:PTN:FY21
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