Elsevier Logo

ThisisPatientEngagementcontent

WHAT HAPPENS WHEN YOUR PATIENT GOES HOME?

Learn more about our Patient Engagement products now! Turn your patients into active participants in their healthcare by giving them easy access to the same evidence-based information you trust – but delivered in an easy-to-understand format.

Oct.19.2020View related content

Multisystem inflammatory syndrome in children (MIS-C)

Synopsis

Key Points

  • MIS-C (multisystem inflammatory syndrome in children) is a recently described clinical syndrome in children and adolescents, first recognized in temporal association with a high local prevalence of COVID-19. Subsequently, most reported cases have had laboratory evidence of recent infection with SARS-CoV-2, the virus that causes COVID-19 r1r2r3
  • Characterized by persistent fever, laboratory markers of inflammation, and evidence of single or multiorgan dysfunction, including myocarditis. Abdominal pain (often severe) and diarrhea (which may be profuse) are common presenting symptoms r4
  • 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) r4r5r6
  • Some patients develop severe shock and require fluid resuscitation and hemodynamic support
  • There is no specific diagnostic test; diagnosis is based on a constellation of clinical, laboratory, echocardiographic, and epidemiologic factors. Most patients have laboratory evidence of SARS-CoV-2 (polymerase chain reaction, antigen, or antibody) r4r6
  • Patients with mild disease can be managed conservatively. Treat patients who have more severe disease, including those with myocarditis or who meet criteria for Kawasaki disease or toxic shock syndrome, with IV immunoglobulin. Corticosteroids and immune modulators also have been used r2r7r8r9r10
  • Most patients have responded promptly to therapy and have done well. Owing to resemblance to Kawasaki syndrome and observation of coronary artery aneurysms in some patients with MIS-C, serial follow-up echocardiographyr11r7 is recommended r2r7r8r9

Urgent Action

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

Pitfalls

  • Physical findings may not appear simultaneously but may evolve over several days
  • Coronary artery aneurysms may develop late in disease course or after apparent improvement r7

Terminology

Clinical Clarification

  • MIS-C (multisystem inflammatory syndrome in children) is a recently described clinical syndrome in children and adolescents, originally recognized in temporal association with a high local prevalence of COVID-19 (coronavirus disease 2019). Subsequently, most reported cases have been shown to have laboratory evidence of recent infection with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the virus that causes COVID-19 r1r2r3r12
  • Illness is characterized by persistent fever, laboratory markers of inflammation, and evidence of single or multiorgan dysfunction r4r5r13
    • May include features suggestive of Kawasaki syndrome (conjunctival and mucosal injection, rash, swelling of hands and feet, coronary artery dilation) or toxic shock syndrome (erythroderma, renal involvement, hypotension)
  • Multisystem inflammatory syndrome in children is the designation used by CDC and WHO. It is also known as PIMS-TS (paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 infection) in Europe and paediatric multisystem inflammatory syndrome temporally associated with COVID-19 in the United Kingdom r4r5
    • In October 2020, an analogous syndrome was reported in adults and is called MIS-A (multisystem inflammatory syndrome in adults) r14
  • Several comprehensive clinical reviews of published individual reports and series have been compiled and provide extensive clinical and demographic data on this emerging disease r12r15

Classification

  • Several national and international organizations have established case definitions that are broadly similar. WHO definition applies to children and adolescents aged 0 to 19 years who meet all of the following clinical criteria: r16
    • 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
  • CDCr1 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 diagnosis of MIS-C is applied if they otherwise meet the case definition r1r4
    • Royal College of Paediatrics and Child Health notes that polymerase chain reaction results for SARS-CoV-2 (earlier provisional name was 2019-nCoV) may be positive or negative r4
  • MIS-C is suspected to exist as a spectrum that includes patients with milder manifestations that do not meet case definitions and who may or may not progress to meet all criteria r3

Diagnosis

Clinical Presentation

History

  • Persistent fever, generally lasting 4 days or more, is reported in published cases r8
  • Gastrointestinal symptoms including nonbloody diarrhea (which may be profuse), vomiting, and abdominal pain are the most common complaints; the latter may be severe, suggesting acute abdomen r8r17
  • Nonspecific extremity pain and swelling have been reported r4
  • Other reported symptoms include odynophagia, vomiting, headache, myalgia, and rash r4
  • Respiratory symptoms may be present but are not common and are not predominant r4
  • Chest pain is uncommon but may be noted
  • Altered mental status (confusion, somnolence) and/or syncope may occur r4

Physical examination

  • Patients may appear severely ill with signs of shock
    • Hypotension plus 2 or more of the following criteria: r18
      • 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 warm vasodilation and bounding pulses
      • Tachypnea
      • Mottled skin, petechiae, or purpura
      • Oliguria
      • Altered mental status
  • Fever is present by definitionr16r4r1 and may be quite high (40 °C or higherr8)
  • Conjunctival injection is often seen, but purulence and exudate are not typically present
  • Oral mucosa may be dry and reddened (eg, fissured lips, strawberry tongue)
  • Meningismus is present in some patients
  • Cervical lymphadenopathy may be palpable
  • Pulmonary findings have not been prominent in published cases
  • Tachycardia and irregular rhythms have been reported
  • Abdominal tenderness and guarding may be noted
  • Erythema of palms and soles, as well as firm edema or induration of the dorsal surfaces, may be present
  • Rash is commonly noted, but reported cases have lacked detailed descriptions
  • Physical findings may not appear simultaneously but may evolve over several days

Causes and Risk Factors

Causes

  • Cause and mechanism are uncertain; there is a temporal association with COVID-19 both in individual cases (positive RNA test or serology) and in the epidemiologic curve of both conditions: r1r4
    • Following onset of the pandemic wave in Bergamo, Italy, monthly incidence of Kawasaki disease (or Kawasaki-like disease) increased 30-fold over preceding 5 years r2
    • In areas heavily affected by the pandemic, incidence of this condition parallels that of COVID-19 after a 4- to 5-week interval, suggesting a postinflammatory mechanism related to COVID-19 r17r19r20

Risk factors and/or associations

Age
  • Case definitions include patients aged 0 to 19r16 (or 21r21) years; published cases have ranged from age 4 months to 17 years r5
Sex
  • Among published cases that report sex, boys are affected more often than girls r12r15
Ethnicity/race
  • Among published cases in which race and ethnicity are reported, the number of patients of African, African-Caribbean, and Hispanic ancestry is disproportionately high based on local demographics r1r12r15r22

Diagnostic Procedures

Primary diagnostic tools

  • There is no specific diagnostic test; diagnosis is based on a constellation of clinical, laboratory, and epidemiologic factors r4r6
    • A subset of patients may fully or partially meet criteria for Kawasaki disease; others may meet criteria for toxic shock syndrome
  • Suspect the diagnosis when history and physical examination reveal characteristic features, knowing that they may evolve over several days
  • Obtain laboratory studies that are typically indicated in the evaluation of severe febrile illness as well as those studies that have been shown to fit the pattern of laboratory abnormalities peculiar to this condition: r3r4r5r6r23
    • General tests: CBC, chemistry panel (including kidney and liver function, serum amylase, serum lactate, creatine kinase), inflammatory markers (erythrocyte sedimentation rate, C-reactive protein, or procalcitonin), cytokine panel (if available), coagulation studies (prothrombin time/INR, partial thromboplastin time, D-dimer), ferritin, troponin, NT-proBNP, and urinalysis
    • Specific tests: SARS-CoV-2 RNA or antigen test and serology; microbiologic evaluation for alternate infectious causes (blood, throat, urine, stool, and cerebrospinal fluid cultures as clinically indicated; viral nucleic acid amplification test panel for Epstein-Barr virus, enteroviruses, and common respiratory viruses)
      • Results of tests for SARS-CoV-2 antibodies are often positive, even when polymerase chain reaction or antigen test results are negative
  • Obtain ECG and echocardiogram r4r6
  • Assess oxygenation by pulse oximetry or arterial blood gas. Although existing guidance does not specifically recommend chest imaging, a baseline chest radiograph is prudent and many published cases report abnormalities at presentation or during disease course r4r5
  • Abdominal ultrasonography is indicated for patients presenting with severe abdominal pain r4
  • Serial monitoring of laboratory markers of inflammation and echocardiography is recommended r3

Laboratory

  • CBC
    • Neutrophilia and lymphopenia are typical; anemia and/or thrombocytopenia may be present r4
  • Chemistry
    • Hypoalbuminemia is common; hyponatremia and/or elevated levels of creatinine, BUN, transaminases, and creatine kinase may be seen r4r9
  • Inflammatory markers
    • C-reactive protein, erythrocyte sedimentation rate, and procalcitonin levels are typically elevated, often markedly r2r4r8r9
  • Coagulation studies
    • Prothrombin time/INR, partial thromboplastin time, and D-dimer levels may be elevated, the latter often quite markedly; fibrinogen levels may be highr2r2r4r8r9
  • Cardiac markers
    • Troponin and proBNP levels may be elevated, sometimes to very high points r8r9r24
  • Others
    • High levels of ferritin are characteristic; IL-6 level (if available) may be elevated r2r4r8r9
    • Mild cerebrospinal fluid pleocytosis has been reported in patients who underwent lumbar puncture for possible meningitis r9r25
    • Triglyceride levels may be above reference range r4
  • 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 r1r2r8r9r24r25

Imaging

  • Chest radiography
    • May reveal unilateral or bilateral infiltrates r2r9
  • Echocardiogram
    • May reveal general features of myocarditis (left ventricular systolic dysfunction) and/or additional changes characteristic of Kawasaki disease (coronary artery dilation, valvulitis, pericardial effusion) r2r24
    • Findings (eg, dilation or aneurysms of coronary arteries) may develop during disease course r2r24
  • Abdominal ultrasonography
    • May reveal hepatosplenomegaly, lymphadenopathy, bowel wall edema, or ascites r1r4

Functional testing

  • ECG
    • Heart block (first, second, or third degree), increased QT interval, ventricular arrhythmias, and ST segment elevation have been reported r24r25

Differential Diagnosis

Most common

  • Kawasaki disease d1
    • A subset of patients who meet diagnostic criteria for MIS-C also meet the criteria for Kawasaki disease, partial Kawasaki disease, or Kawasaki disease shock syndrome. Patients in this subset commonly have features that are atypical in Kawasaki disease
      • Kawasaki diagnosis is established by fever lasting 5 or more days and at least 4 of the following criteria: r11
        • Polymorphous rash (excluding bullous or vesicular eruptions)
        • Conjunctival injection
        • Oropharyngeal mucous membrane changes
        • Extremity changes
        • Lymphadenopathy
      • Features common to MIS-C but not typical for classic Kawasaki disease: r1r2
        • Abdominal pain is often a predominant feature and severity exceeds that seen in classic Kawasaki disease
        • Thrombocytopenia, anemia, and lymphopenia
        • Elevated levels of ferritin, troponin, proBNP, and D-dimer
  • Scarlet fever d2
    • 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
  • Toxic shock syndrome d3
    • Severe systemic disease caused by certain toxin-producing strains of Staphylococcus aureus or group A streptococcus
    • Like 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 nonstreptococcal toxic shock syndrome: r4r26
        • 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 and/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 r27
        • 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
  • Septic shock d4
    • 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
    • Rash, lip changes, ocular changes, and edema of hands and feet are not typical
    • Diagnosis is based on recovery of pathogen by culture or other means
  • Rubeola d5
    • 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)

Disposition

Admission criteria

Admission is recommended for children who meet MIS-C criteria, preferably to a hospital with a pediatric ICU r3

  • Rapid deterioration has been observed, and vasopressor and/or inotrope support has been required in a significant number of patients (73% in 1 large studyr19)
  • It is recognized that there is a population of pediatric patients who have fever and evidence of an inflammatory response but are less severely ill and do not meet the MIS-C case definition; these children may not require admission but need to be closely monitored for progression.
  • Regardless of whether the patient meets MIS-C criteria or is still undergoing evaluation for it, consider admission in the following circumstances: r22
    • 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 borderline/unstable vital signs that suggest impending shock
  • Patient who needs mechanical ventilation

Recommendations for specialist referral

  • Management by a multidisciplinary team is recommended, including specialists in intensive care, immunology, cardiology, rheumatology, and infectious disease r19r22

Treatment Options

Excellent supportive care is essential in all cases; antiinflammatory and immunomodulatory therapies have been used in severely ill patients (particularly those who fulfill criteria for Kawasaki disease) r4r5r6r7r22r23

  • Specific guidance for treatment of shock and hypoxemia in MIS-C is lacking but includes oxygen administration (including mechanical ventilation, if necessary), cautious fluid resuscitation (preferably guided by assessment of likely responsiveness), and vasopressor support, using appropriate protocols for shock (ie, cardiogenicr28 versus vasodilatory/distributiver29) d6
  • Extracorporeal membrane oxygenation has been used in some patients

For patients who meet Kawasaki disease criteria, consider treating with IV immunoglobulin and aspirin; Kawasaki disease guidelinesr11 encourage treatment as early as the diagnosis is established and preferably within 10 days of illness onset r4r26d1

  • Most patients respond promptly to a single dose of IV immunoglobulin, but as in Kawasaki disease, resistance occurs in some patients. A second dose of IV immunoglobulin, with or without methylprednisolone, is often effective r17
  • Patients with aneurysms and z scores of 10 or higher, documented thrombosis, or ejection fraction less than 35% are given therapeutic anticoagulation in addition to aspirin r22

For patients who meet criteria for toxic shock, consider using IV immunoglobulin r4d3

IV immunoglobulin has also been used successfully in children who do not meet criteria for Kawasaki disease or toxic shock but who do have severe manifestations of MIS-C, including myocarditis, shock, persistent fever, and elevated inflammatory markers or other clinical indicators of severe illness. Consider such therapy for critically ill patients even before the evaluation is completer22r7r9r30r31d7

Glucocorticoids are commonly used in conjunction with IV immunoglobulin or as follow-up to it if response is less than desired r22

Other treatments that have been associated with apparently successful outcomes include infliximab, anakinra, and tocilizumab, but data are scant and noncomparative r2r7r8r9r10

  • American College of Rheumatology suggests considering using anakinra for patients who do not respond to IV immunoglobulin and glucocorticoids r22

For patients in whom sepsis caused by other pathogens has not been ruled out, begin empiric antibiotics, which can be de-escalated if indicated based on results of microbiologic studies r6d4

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

Drug therapy

  • IV immunoglobulin
    • Immune Globulin (Human) Solution for injection; Infants, Children, and Adolescents: Available data are limited, and efficacy has not been established. 1,000 to 2,000 mg/kg IV as a single dose in combination with aspirin and/or methylprednisolone has been reported and is being used in some institutional protocols. Depending on the severity of illness, additional doses have been administered.
  • 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.
  • Methylprednisolone
    • Methylprednisolone Sodium Succinate Solution for injection; Infants, Children, and Adolescents: Available data are limited, and efficacy has not been established. 2 to 30 mg/kg/day IV has been reported, depending on the severity of illness, and is being used in combination with IVIG with or without aspirin. A 3-week at-home taper has been recommended.

Monitoring

  • During acute disease, frequently monitor laboratory studies until values stabilize and improve r4r22
  • Serial ECGs (at least every 48 hoursr22) and echocardiograms are appropriate during the acute phase, and follow-up echocardiograms should be obtained 2 and 6 weeks after discharge r7r9r11
    • Based on recommendations for Kawasaki disease management and on preliminary observations that MIS-C patients may (like patients with classic Kawasaki disease) develop coronary artery aneurysms late in the disease course or after apparent improvement
  • Consider cardiac MRI 2 to 6 months after acute illness for patients with significant transient or persistent left ventricular dysfunction  r22

Complications and Prognosis

Complications

  • Development of coronary aneurysms has been documented, and such patients are at risk for thrombosis r7r9

Prognosis

  • Published reports indicate recovery in nearly all patients, with resolution of shock and organ function. However, several deathsr5 have been reported, and long-term prognosis of survivors is unknown

Screening and Prevention

Prevention

  • The only known preventive measures involve efforts to avoid infection with SARS-CoV-2 (ie, diligent distancing, widespread use of facial covering, careful hand and environmental hygiene) d8
CDC 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 October 16, 2020. 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.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, 202032410760Pediatric Intensive-Care-COVID-19 International Collaborative: Statement to the Media Following the 2 May Pediatric Intensive Care-COVID-19 International Collaborative Conference Call. World Federation of Pediatric Intensive and Critical Care Societies. Published May 2020. Accessed October 16, 2020. http://www.wfpiccs.org/wp-content/uploads/2020/05/Media-statement-Final.pdfhttp://www.wfpiccs.org/wp-content/uploads/2020/05/Media-statement-Final.pdfRoyal College of Paediatrics and Child Health: Guidance - Paediatric Multisystem Inflammatory Syndrome Temporally Associated With COVID-19 (PIMS). Royal College of Paediatrics and Child Health website. Published May 1, 2020. Accessed October 16, 2020. https://www.rcpch.ac.uk/resources/guidance-paediatric-multisystem-inflammatory-syndrome-temporally-associated-covid-19-pimshttps://www.rcpch.ac.uk/resources/guidance-paediatric-multisystem-inflammatory-syndrome-temporally-associated-covid-19-pimsEuropean 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 October 19, 2020. 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+sarsCDC: Multisystem Inflammatory Syndrome (MIS-C): Information for Healthcare Providers About Multisystem Inflammatory Syndrome in Children (MIS-C). Case Definition for MIS-C. Reviewed August 28, 2020. Accessed October 16, 2020. https://www.cdc.gov/mis-c/hcp/https://www.cdc.gov/mis-c/hcp/Whittaker 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, 202032511692Riphagen S et al: Hyperinflammatory shock in children during COVID-19 pandemic. Lancet. 395(10237):1607-8, 202032386565Chiotos 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, 202032463092Cabrero-Hernández M et al: Severe SARS-CoV-2 Infection in children with suspected acute abdomen: a case series from a tertiary hospital in Spain. Pediatr Infect Dis J. 39(8):e195-8, 202032467457McCrindle 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, 201728356445Godfred-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, 202032790663CDC: Emergency Preparedness and Response: Multisystem Inflammatory Syndrome in Children (MIS-C) Associated With Coronavirus Disease 2019 (COVID-19). CDC website. Published May 14, 2020. Accessed October 16, 2020. https://emergency.cdc.gov/han/2020/han00432.asphttps://emergency.cdc.gov/han/2020/han00432.aspMorris SB et al: Case series of multisystem inflammatory syndrome in adults associated with SARS-CoV-2 infection - United Kingdom and United States, March-August 2020. MMWR Morb Mortal Wkly Rep. 69(40):1450-6, 202033031361Ahmed M et al: Multisystem inflammatory syndrome in children: a systematic review. EClinicalMedicine. ePub, September 4, 2020https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(20)30271-6/fulltextWHO: Multisystem Inflammatory Syndrome in Children and Adolescents With COVID-19. Scientific Brief. WHO website. Published May 15, 2020. Accessed October 16, 2020. 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-19Feldstein LR et al: Multisystem inflammatory syndrome in U.S. children and adolescents. N Engl J Med. 383(4):334-46, 202032598831WHO: Clinical Management of COVID-19: Interim Guidance. WHO: May 27, 2020https://www.who.int/publications/i/item/clinical-management-of-severe-acute-respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspectedBelot 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, 202032524957Dufort EM et al: Multisystem inflammatory syndrome in children in New York State. N Engl J Med. 383(4):347-58, 202032598830CDC: Coronavirus Disease 2019 (COVID-19). Information for Pediatric Healthcare Providers. CDC website. Updated August 19, 2020. Accessed October 18, 2020. https://www.cdc.gov/coronavirus/2019-ncov/hcp/pediatric-hcp.htmlhttps://www.cdc.gov/coronavirus/2019-ncov/hcp/pediatric-hcp.htmlAmerican 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. Draft Approved June 17, 2020. Accessed October 16, 2020. 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=2020-07-02-140939-180American Academy of Pediatrics: Multisystem Inflammatory Syndrome in Children (MIS-C) Interim Guidance. AAP website. Updated September 1, 2020. Accessed October 18, 2020. 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/Belhadjer Z et al: Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic. Circulation. ePub, 202032418446Toubiana J et al: Kawasaki-like multisystem inflammatory syndrome in children during the COVID-19 pandemic in Paris, France: prospective observational study. BMJ. 369:m2094, 202032493739CDC: National Notifiable Diseases Surveillance System (NNDSS): Toxic Shock Syndrome (Other Than Streptococcal) (TSS): 2011 Case Definition. CDC website. Published 2011. Accessed October 19, 2020. 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 October 19, 2020. 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/Brissaud 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, 202032032273Grimaud M et al: Acute myocarditis and multisystem inflammatory emerging disease following SARS-CoV-2 infection in critically ill children. Ann Intensive Care. 10(1):69, 202032488505Deza Leon MP et al: COVID-19 associated pediatric multi-system inflammatory syndrome. J Pediatric Infect Dis Soc. 9(3):407-8, 202032441749