Multisystem inflammatory syndrome in children

7 Interesting Facts of Multisystem inflammatory syndrome in children

  1. 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 
  2. 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 
  3. 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) 
  4. Some patients develop severe shock and require fluid resuscitation and hemodynamic support
  5. 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) 
  6. 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 
  7. 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 echocardiography is recommended 


  • 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 (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 

Illness is characterized by persistent fever, laboratory markers of inflammation, and evidence of single or multiorgan dysfunction 

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 

In October 2020, an analogous syndrome was reported in adults and is called MIS-A (multisystem inflammatory syndrome in adults) 

Several comprehensive clinical reviews of published individual reports and series have been compiled and provide extensive clinical and demographic data on this emerging disease 


  • 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: 
    • 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
  • CDC and Royal College of Paediatrics and Child Health 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 
    • 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 
  • 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 

Clinical Presentation


  • Persistent fever, generally lasting 4 days or more, is reported in published cases 
  • 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 
  • Nonspecific extremity pain and swelling have been reported 
  • Other reported symptoms include odynophagia, vomiting, headache, myalgia, and rash 
  • Respiratory symptoms may be present but are not common and are not predominant 
  • Chest pain is uncommon but may be noted
  • Altered mental status (confusion, somnolence) and/or syncope may occur 

Physical examination

  • Patients may appear severely ill with signs of shock
    • Hypotension plus 2 or more of the following criteria: 
      • 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 definition and may be quite high (40 °C or higher)
  • 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


  • 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:
    • 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 
    • 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 

Risk factors and/or associations

  • Case definitions include patients aged 0 to 19 (or 21) years; published cases have ranged from age 4 months to 17 years 
  • Among published cases that report sex, boys are affected more often than girls 
  • 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 

Diagnostic Procedures

Primary diagnostic tools

  • There is no specific diagnostic test; diagnosis is based on a constellation of clinical, laboratory, and epidemiologic factors 
    • 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: 
    • 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 
  • 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 
  • Abdominal ultrasonography is indicated for patients presenting with severe abdominal pain 
  • Serial monitoring of laboratory markers of inflammation and echocardiography is recommended 


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


  • Chest radiography
    • May reveal unilateral or bilateral infiltrates 
  • 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) 
    • Findings (eg, dilation or aneurysms of coronary arteries) may develop during disease course 
  • Abdominal ultrasonography
    • May reveal hepatosplenomegaly, lymphadenopathy, bowel wall edema, or ascites 

Functional testing

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

Differential Diagnosis

Most common

  • Kawasaki disease
  • Scarlet fever
  • Toxic shock syndrome
  • Septic shock 
  • Rubeola

Treatment Goals

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

Admission criteria

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

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

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) 

  • 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, versus ) cardiogenic vasodilatory/distributive
  • 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 guidelines encourage treatment as early as the diagnosis is established and preferably within 10 days of illness onset 

  • 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 
  • 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 

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

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 complete 

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

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

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

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 

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 

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.


  • During acute disease, frequently monitor laboratory studies until values stabilize and improve 
  • Serial ECGs (at least every 48 hours) and echocardiograms are appropriate during the acute phase, and follow-up echocardiograms should be obtained 2 and 6 weeks after discharge 
    • 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  


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


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


  • 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) 


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. Reference


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