COVID-19-associated multisystem inflammatory syndrome: Difference between revisions

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==Overview==
==Overview==
Multisystem Inflammatory Syndrome in Children (MIS-C) is a condition that causes [[inflammation]] of some parts of the body like [[heart]], [[blood vessels]], [[Kidney|kidneys]], digestive system, [[brain]], [[skin]], or [[Eye|eyes]]. According to recent evidence, it is suggested that children with MIS-C had antibodies against [[COVID-19]] suggesting children had [[COVID-19]] infection in the past. This syndrome appears to be similar in presentation to [[Kawasaki disease]], hence also called Kawasaki -like a disease. It also shares features with s[[Streptococcal toxic shock syndrome|taphylococcal and streptococcal toxic shock syndromes]], [[Sepsis|bacterial sepsis]], and macrophage activation syndromes.
Multisystem Inflammatory Syndrome in Children (MIS-C) is a condition that causes [[inflammation]] of some parts of the body like [[heart]], [[blood vessels]], [[Kidney|kidneys]], digestive system, [[brain]], [[skin]], or [[Eye|eyes]]. According to recent evidence, it is suggested that children with MIS-C had antibodies against [[COVID-19]] suggesting children had [[COVID-19]] infection in the past. This syndrome appears to be similar in presentation to [[Kawasaki disease]], hence also called Kawasaki -like a disease. It also shares features with s[[Streptococcal toxic shock syndrome|taphylococcal and streptococcal toxic shock syndromes]], [[Sepsis|bacterial sepsis]], and macrophage activation syndromes.<ref>{{Cite web|url=https://www.rcpch.ac.uk/sites/default/files/2020-05/COVID-19-Paediatric-multisystem-%20inflammatory%20syndrome-20200501.pdf|title=Guidance: Paediatric multisystem inflammatory
syndrome temporally associated with COVID-19|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
==Historical Perspective==
==Historical Perspective==
== Classification of Disease Severity of MIS-C ==
== Classification of Disease Severity of MIS-C ==


*'''Mild Disease'''
*'''Mild Disease'''
*Children with MIS-C fall under this category who-
*Children with MIS-C fall under this category who-<ref>{{Cite web|url=https://www.chkd.org/uploadedFiles/Documents/COVID-19/CHKD%20MIS-C%20Guideline%20D2.pdf |title=Evaluation and Management of COVID-19 Multisystem Inflammatory
Syndrome in Children (MIS-C) |first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
**require minimal to no respiratory support.
**require minimal to no respiratory support.
**minimal to no organ injury
**minimal to no organ injury
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**Do not meet the criteria for ICU admission.
**Do not meet the criteria for ICU admission.
*'''Severe Disease'''
*'''Severe Disease'''
*Children with MIS-C fall under this category who-<ref name=":0" />
*Children with MIS-C fall under this category who-<ref>{{Cite web|url=https://www.chkd.org/uploadedFiles/Documents/COVID-19/CHKD%20MIS-C%20Guideline%20D2.pdf |title=Evaluation and Management of COVID-19 Multisystem Inflammatory
Syndrome in Children (MIS-C) |first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
**have significant oxygen requirements (HFNC, BiPAP, mechanical ventilation).
**have significant oxygen requirements (HFNC, BiPAP, mechanical ventilation).
**have a mild-severe organ injury and ventricular dysfunction.
**have a mild-severe organ injury and ventricular dysfunction.
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==Pathophysiology==
==Pathophysiology==


* The excat pathophysiological mechanism of MIS-C is unclear. Since there is a lag time between MIS-C appearance and COVID-19 infection it is suspected to be causing by antibody dependent enhancement.
* The excat pathophysiological mechanism of MIS-C is unclear. Since there is a lag time between MIS-C appearance and COVID-19 infection it is suspected to be causing by antibody dependent enhancement.<ref name="Rowley2020">{{cite journal|last1=Rowley|first1=Anne H.|title=Understanding SARS-CoV-2-related multisystem inflammatory syndrome in children|journal=Nature Reviews Immunology|year=2020|issn=1474-1733|doi=10.1038/s41577-020-0367-5}}</ref>
* Another hypothesis is that since coronavirus block type1 and type III interferons, it results in delayed cytokine response in children with initially high viral load or whose immune response is unable to control infections causing MIS-C. Therefore, IFN responses result in viral clearance when the viral load is low resulting in mild infection. However, when the viral load is high and /or immune system is not able to clear the virus, the cytokine storm result in multisystem inflammatory syndrome in children (MIS-C).
* Another hypothesis is that since coronavirus block type1 and type III interferons, it results in delayed cytokine response in children with initially high viral load or whose immune response is unable to control infections causing MIS-C. Therefore, IFN responses result in viral clearance when the viral load is low resulting in mild infection. However, when the viral load is high and /or immune system is not able to clear the virus, the cytokine storm result in multisystem inflammatory syndrome in children (MIS-C).
* It is also suspected that since MIS-C presents predominantly with gastrointestinal manifestations, it replicates predominantly in the gastrointestinal tract.
* It is also suspected that since MIS-C presents predominantly with gastrointestinal manifestations, it replicates predominantly in the gastrointestinal tract.
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== Epidemiology and Demographics ==
== Epidemiology and Demographics ==


*According to a recent study among the 186 children with MIS-C, the rate of hospitalization was 12%  between March 16 and April 15 and 88% between April 16 and May 20.
*According to a recent study among the 186 children with MIS-C, the rate of hospitalization was 12%  between March 16 and April 15 and 88% between April 16 and May 20.<ref name="FeldsteinRose2020">{{cite journal|last1=Feldstein|first1=Leora R.|last2=Rose|first2=Erica B.|last3=Horwitz|first3=Steven M.|last4=Collins|first4=Jennifer P.|last5=Newhams|first5=Margaret M.|last6=Son|first6=Mary Beth F.|last7=Newburger|first7=Jane W.|last8=Kleinman|first8=Lawrence C.|last9=Heidemann|first9=Sabrina M.|last10=Martin|first10=Amarilis A.|last11=Singh|first11=Aalok R.|last12=Li|first12=Simon|last13=Tarquinio|first13=Keiko M.|last14=Jaggi|first14=Preeti|last15=Oster|first15=Matthew E.|last16=Zackai|first16=Sheemon P.|last17=Gillen|first17=Jennifer|last18=Ratner|first18=Adam J.|last19=Walsh|first19=Rowan F.|last20=Fitzgerald|first20=Julie C.|last21=Keenaghan|first21=Michael A.|last22=Alharash|first22=Hussam|last23=Doymaz|first23=Sule|last24=Clouser|first24=Katharine N.|last25=Giuliano|first25=John S.|last26=Gupta|first26=Anjali|last27=Parker|first27=Robert M.|last28=Maddux|first28=Aline B.|last29=Havalad|first29=Vinod|last30=Ramsingh|first30=Stacy|last31=Bukulmez|first31=Hulya|last32=Bradford|first32=Tamara T.|last33=Smith|first33=Lincoln S.|last34=Tenforde|first34=Mark W.|last35=Carroll|first35=Christopher L.|last36=Riggs|first36=Becky J.|last37=Gertz|first37=Shira J.|last38=Daube|first38=Ariel|last39=Lansell|first39=Amanda|last40=Coronado Munoz|first40=Alvaro|last41=Hobbs|first41=Charlotte V.|last42=Marohn|first42=Kimberly L.|last43=Halasa|first43=Natasha B.|last44=Patel|first44=Manish M.|last45=Randolph|first45=Adrienne G.|title=Multisystem Inflammatory Syndrome in U.S. Children and Adolescents|journal=New England Journal of Medicine|year=2020|issn=0028-4793|doi=10.1056/NEJMoa2021680}}</ref>
*80% of the children were admitted to the intensive care unit and 20% of the children required mechanical ventilation.<ref name="FeldsteinRose2020" />
*80% of the children were admitted to the intensive care unit and 20% of the children required mechanical ventilation.<ref name="FeldsteinRose2020" />
*4% of the children required extracorporeal membrane oxygenation.<ref name="FeldsteinRose2020" />
*4% of the children required extracorporeal membrane oxygenation.<ref name="FeldsteinRose2020" />
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=====Preliminary [[World Health Organization|WHO]] case definition: Children and adolescents=====
=====Preliminary [[World Health Organization|WHO]] case definition: Children and adolescents=====


*0–19 years of age with [[fever]] >3 days
*0–19 years of age with [[fever]] >3 days<ref>{{Cite web|url=https://www.who.int/news-room/commentaries/detail/multisystem-inflammatory-syndrome-in-children-and-adolescents-with-covid-19|title=Multisystem inflammatory syndrome in children and adolescents temporally related to COVID-19|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>


AND
AND
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=====CDC Case Definition for MIS-C=====
=====CDC Case Definition for MIS-C=====


*An individual aged <21 years presenting with fever, laboratory evidence of inflammation**, and evidence of clinically severe illness requiring hospitalization, with multisystem (>2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurological);
*An individual aged <21 years presenting with fever, laboratory evidence of inflammation**, and evidence of clinically severe illness requiring hospitalization, with multisystem (>2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurological);<ref>{{Cite web|url=https://www.cdc.gov/mis-c/hcp/|title=Case Definition for MIS-C|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>


AND
AND
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=== Signs and Symptoms ===
=== Signs and Symptoms ===


*[[Fever]] lasting 24 hours or longer.
*[[Fever]] lasting 24 hours or longer.<ref>{{Cite web|url=https://www.rcpch.ac.uk/sites/default/files/2020-05/COVID-19-Paediatric-multisystem-%20inflammatory%20syndrome-20200501.pdf|title=Guidance: Paediatric multisystem inflammatory
syndrome temporally associated with COVID-19|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
*[[Vomiting]]
*[[Vomiting]]
*[[Diarrhea]]
*[[Diarrhea]]
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'''Emergency Warning Signs'''
'''Emergency Warning Signs'''


*[[Shortness of breath|Difficulty Breathing]]
*[[Shortness of breath|Difficulty Breathing]]<ref>{{Cite web|url=https://www.rcpch.ac.uk/sites/default/files/2020-05/COVID-19-Paediatric-multisystem-%20inflammatory%20syndrome-20200501.pdf|title=Guidance: Paediatric multisystem inflammatory
syndrome temporally associated with COVID-19|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
*[[Chest pain]]
*[[Chest pain]]
*[[Confusion|New onset confusion]]
*[[Confusion|New onset confusion]]
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'''Blood Investigations'''
'''Blood Investigations'''


*[[Lymphopenia]], [[Neutrophilia]], [[Anemia]], [[Thrombocytopenia]] have been seen in MIS-C pateints. [[Fibrinogen|Abnormal fibrinogen]], [[Hypoalbuminaemia]], elevated [[Creatine kinase|creatiine kinase]] (CK), [[Lactate dehydrogenase|LDH]], [[Triglyceride|triglycerides]] have been observed in MIS-C patients.
*[[Lymphopenia]], [[Neutrophilia]], [[Anemia]], [[Thrombocytopenia]] have been seen in MIS-C pateints. [[Fibrinogen|Abnormal fibrinogen]], [[Hypoalbuminaemia]], elevated [[Creatine kinase|creatiine kinase]] (CK), [[Lactate dehydrogenase|LDH]], [[Triglyceride|triglycerides]] have been observed in MIS-C patients.<ref>{{Cite web|url=https://www.rcpch.ac.uk/sites/default/files/2020-05/COVID-19-Paediatric-multisystem-%20inflammatory%20syndrome-20200501.pdf|title=Guidance: Paediatric multisystem inflammatory
syndrome temporally associated with COVID-19|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>


==== Inflammatory biomarkers ====
==== Inflammatory biomarkers ====
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=== Radiological Findings ===
=== Radiological Findings ===


* Following Radiological Findings are observed in MIS-C patients.
* Following Radiological Findings are observed in MIS-C patients.<ref>{{Cite web|url=https://www.rcpch.ac.uk/sites/default/files/2020-05/COVID-19-Paediatric-multisystem-%20inflammatory%20syndrome-20200501.pdf|title=Guidance: Paediatric multisystem inflammatory
syndrome temporally associated with COVID-19|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>


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'''Blood Culture, Viral PCR'''
'''Blood Culture, Viral PCR'''


* Absence of other potential causative organisms. IgG levels and IgM levels of [[SARS-CoV-2]] are detected.
* Absence of other potential causative organisms. IgG levels and IgM levels of [[SARS-CoV-2]] are detected.<ref>{{Cite web|url=https://www.rcpch.ac.uk/sites/default/files/2020-05/COVID-19-Paediatric-multisystem-%20inflammatory%20syndrome-20200501.pdf|title=Guidance: Paediatric multisystem inflammatory
syndrome temporally associated with COVID-19|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>


== Treatment ==
== Treatment ==
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*Mild to Moderate cases of MIS-C are managed supportively.
*Mild to Moderate cases of MIS-C are managed supportively.
*Supplemental [[oxygen]] is required in children with low oxygen saturation.
*Supplemental [[oxygen]] is required in children with low oxygen saturation.
*[[Fluid replacement|Fluid resuscitation]] in 10 ml/kg aliquots with reevaluation after each bolus. Maintain euvolemia. Avoid hypervolemia.
*[[Fluid replacement|Fluid resuscitation]] in 10 ml/kg aliquots with reevaluation after each bolus. Maintain euvolemia. Avoid hypervolemia.<ref>{{Cite web|url=https://www.chkd.org/uploadedFiles/Documents/COVID-19/CHKD%20MIS-C%20Guideline%20D2.pdf |title=Evaluation and Management of COVID-19 Multisystem Inflammatory
*Anti-inflammatory treatments with [[Intravenous immunoglobulin|Intravenous immunoglobulin(IVIG]]) with or without [[Corticosteroid|corticosteroids]] have shown a good response rate.
Syndrome in Children (MIS-C) |first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
*Anti-inflammatory treatments with [[Intravenous immunoglobulin|Intravenous immunoglobulin(IVIG]]) with or without [[Corticosteroid|corticosteroids]] have shown a good response rate.<ref>{{Cite web|url=https://www.chkd.org/uploadedFiles/Documents/COVID-19/CHKD%20MIS-C%20Guideline%20D2.pdf |title=Evaluation and Management of COVID-19 Multisystem Inflammatory
Syndrome in Children (MIS-C) |first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
*[[Aspirin]] has been used primarily for its antiplatelet effect. It is recommended in all patients with [[MIS-C]].
*[[Aspirin]] has been used primarily for its antiplatelet effect. It is recommended in all patients with [[MIS-C]].
*[[Anakinra]] is considered if fevers last more than 24 hours post [[Steroid|steroids]]/[[Intravenous immunoglobulin|IVIG]] or in the moderate or severe presentation.
*[[Anakinra]] is considered if fevers last more than 24 hours post [[Steroid|steroids]]/[[Intravenous immunoglobulin|IVIG]] or in the moderate or severe presentation.<ref>{{Cite web|url=https://www.chkd.org/uploadedFiles/Documents/COVID-19/CHKD%20MIS-C%20Guideline%20D2.pdf |title=Evaluation and Management of COVID-19 Multisystem Inflammatory
*[[Tocilizumab]] is also considered if fevers last more than 24 hours post steroids/IVIG or in the moderate or severe presentation.
Syndrome in Children (MIS-C) |first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
*Empiric antibiotics like [[vancomycin]], [[ceftriaxone]], and [[clindamycin]] are given for community-acquired shock presentation until cultures are negative for 48 hours.
*[[Tocilizumab]] is also considered if fevers last more than 24 hours post steroids/IVIG or in the moderate or severe presentation.<ref>{{Cite web|url=https://www.chkd.org/uploadedFiles/Documents/COVID-19/CHKD%20MIS-C%20Guideline%20D2.pdf |title=Evaluation and Management of COVID-19 Multisystem Inflammatory
Syndrome in Children (MIS-C) |first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
*Empiric antibiotics like [[vancomycin]], [[ceftriaxone]], and [[clindamycin]] are given for community-acquired shock presentation until cultures are negative for 48 hours.<ref>{{Cite web|url=https://www.chkd.org/uploadedFiles/Documents/COVID-19/CHKD%20MIS-C%20Guideline%20D2.pdf |title=Evaluation and Management of COVID-19 Multisystem Inflammatory
Syndrome in Children (MIS-C) |first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>


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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Harmeet Kharoud M.D.[2]

Synonyms and keywords: Multisystem Inflammatory Syndrome in Children (MIS-C)

Overview

Multisystem Inflammatory Syndrome in Children (MIS-C) is a condition that causes inflammation of some parts of the body like heart, blood vessels, kidneys, digestive system, brain, skin, or eyes. According to recent evidence, it is suggested that children with MIS-C had antibodies against COVID-19 suggesting children had COVID-19 infection in the past. This syndrome appears to be similar in presentation to Kawasaki disease, hence also called Kawasaki -like a disease. It also shares features with staphylococcal and streptococcal toxic shock syndromes, bacterial sepsis, and macrophage activation syndromes.[1]

Historical Perspective

Classification of Disease Severity of MIS-C

  • Mild Disease
  • Children with MIS-C fall under this category who-[2]
    • require minimal to no respiratory support.
    • minimal to no organ injury
    • normotensive
    • Do not meet the criteria for ICU admission.
  • Severe Disease
  • Children with MIS-C fall under this category who-[3]
    • have significant oxygen requirements (HFNC, BiPAP, mechanical ventilation).
    • have a mild-severe organ injury and ventricular dysfunction.
    • have a vasoactive requirement.
    • meet the criteria for ICU admissions

Pathophysiology

  • The excat pathophysiological mechanism of MIS-C is unclear. Since there is a lag time between MIS-C appearance and COVID-19 infection it is suspected to be causing by antibody dependent enhancement.[4]
  • Another hypothesis is that since coronavirus block type1 and type III interferons, it results in delayed cytokine response in children with initially high viral load or whose immune response is unable to control infections causing MIS-C. Therefore, IFN responses result in viral clearance when the viral load is low resulting in mild infection. However, when the viral load is high and /or immune system is not able to clear the virus, the cytokine storm result in multisystem inflammatory syndrome in children (MIS-C).
  • It is also suspected that since MIS-C presents predominantly with gastrointestinal manifestations, it replicates predominantly in the gastrointestinal tract.

Differentiating Any Disease from other disease

Epidemiology and Demographics

  • According to a recent study among the 186 children with MIS-C, the rate of hospitalization was 12% between March 16 and April 15 and 88% between April 16 and May 20.[5]
  • 80% of the children were admitted to the intensive care unit and 20% of the children required mechanical ventilation.[5]
  • 4% of the children required extracorporeal membrane oxygenation.[5]
  • The mortality rate among 186 children with MIS-C was 2%.[5]

Age

  • Among the 186 children with MIS-C distribution of age group was[5]
    • <1yr-7%
    • 1-4yr-28%
    • 5-9yr-25%
    • 10-14yr-24%
    • 15-20yr-16%.

Gender

  • Among the 186 children with MIS-C

Comorbidities

  • Children with MIS-C had following underlying comorbidities.[5]
    • Clinically diagnosed Obesity-8%
    • BMI-Based Obesity-29%
    • Cardiovascular diasease-3%
    • Respiratory disease-18%
    • Autoimmune disease or immunocompromising condition-5%

Organ System Involved

  • 71% of children had involvement of at least four organ systems.[5]

The most common organ system involved in MIS-C children among a total of 186 children were.[5]

  • Gastrointestinal(92%)
  • Cardiovascular(80%)
  • Hematologic(76%)
  • Mucocutaneous(74%)
  • Pulmonary(70%)
  • Historical perspective

Risk Factors

Complications and Prognosis

Complications

Diagnosis

Diagnostic Criteria

Preliminary WHO case definition: Children and adolescents
  • 0–19 years of age with fever >3 days[6]

AND

  • Two of the following:
  1. Rash or bilateral non-purulent conjunctivitis or mucocutaneous inflammation signs (oral, hands or feet)
  2. Hypotension or shock
  3. Features of myocardial dysfunction, pericarditis, valvulitis, or coronary abnormalities (including ECHO findings or elevated Troponin/NT-proBNP)
  4. Evidence of coagulopathy (by PT, PTT, elevated D-Dimers)
  5. Acute gastrointestinal problems (diarrhea, vomiting, or abdominal pain)

AND

AND

AND

  • Evidence of COVID-19 (RT-PCR, antigen test or serology-positive), or likely contact with patients with COVID-19
CDC Case Definition for MIS-C
  • An individual aged <21 years presenting with fever, laboratory evidence of inflammation**, and evidence of clinically severe illness requiring hospitalization, with multisystem (>2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurological);[7]

AND

No alternative plausible diagnoses;

AND

Positive for current or recent SARS-CoV-2 infection by RT-PCR, serology, or antigen test; or exposure to a suspected or confirmed COVID-19 case within the 4 weeks prior to the onset of symptoms.

Signs and Symptoms

Emergency Warning Signs

Physical Examination

Laboratory Findings

Blood Investigations

Inflammatory biomarkers

Elevation of inflammatory markers including ESR, C reactive protein and procalcitonin are usually seen in MIS-C. Increased level of Interleukin-6 (IL-6), Interleukin-10(IL-10) d-dimer, serum ferritin, prothrombin time have also been seen in MIS-C.

Cardiac biomarkers

Elevation of cardic enzymes including cardiac troponins (cardiac troponin I(cTnI) and cardiac troponin T (cTnT)) and Brain natriuretic peptide (BNP)) has been observed in MIS-C patients.

Radiological Findings

  • Following Radiological Findings are observed in MIS-C patients.[11]
Test Findings
Chest Xray patchy symmetrical infiltrates, pleural effusion
Echocardiogram and EKG myocarditis, valvulitis, pericardial effusion, coronary artery dilatation
Abdominal USG colitis, ileitis, lymphadenopathy, ascites, hepatosplenomegaly

Blood Culture, Viral PCR

  • Absence of other potential causative organisms. IgG levels and IgM levels of SARS-CoV-2 are detected.[12]

Treatment

Medical Therapy

  • All the children with MIS-C are treated as suspected COVID-19.
  • Mild to Moderate cases of MIS-C are managed supportively.
  • Supplemental oxygen is required in children with low oxygen saturation.
  • Fluid resuscitation in 10 ml/kg aliquots with reevaluation after each bolus. Maintain euvolemia. Avoid hypervolemia.[13]
  • Anti-inflammatory treatments with Intravenous immunoglobulin(IVIG) with or without corticosteroids have shown a good response rate.[14]
  • Aspirin has been used primarily for its antiplatelet effect. It is recommended in all patients with MIS-C.
  • Anakinra is considered if fevers last more than 24 hours post steroids/IVIG or in the moderate or severe presentation.[15]
  • Tocilizumab is also considered if fevers last more than 24 hours post steroids/IVIG or in the moderate or severe presentation.[16]
  • Empiric antibiotics like vancomycin, ceftriaxone, and clindamycin are given for community-acquired shock presentation until cultures are negative for 48 hours.[17]
Presentation Treatment
Mild Disease
  • Symptomatic Treatment
Severe Disease

Prevention of MIS-C

  • MIS-C can be prevented by reducing the risk of child exposure to COVID-19 infection.


References

  1. "Guidance: Paediatric multisystem inflammatory syndrome temporally associated with COVID-19" (PDF). line feed character in |title= at position 46 (help)
  2. "Evaluation and Management of COVID-19 Multisystem Inflammatory Syndrome in Children (MIS-C)" (PDF). line feed character in |title= at position 63 (help)
  3. "Evaluation and Management of COVID-19 Multisystem Inflammatory Syndrome in Children (MIS-C)" (PDF). line feed character in |title= at position 63 (help)
  4. Rowley, Anne H. (2020). "Understanding SARS-CoV-2-related multisystem inflammatory syndrome in children". Nature Reviews Immunology. doi:10.1038/s41577-020-0367-5. ISSN 1474-1733.
  5. 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 Feldstein, Leora R.; Rose, Erica B.; Horwitz, Steven M.; Collins, Jennifer P.; Newhams, Margaret M.; Son, Mary Beth F.; Newburger, Jane W.; Kleinman, Lawrence C.; Heidemann, Sabrina M.; Martin, Amarilis A.; Singh, Aalok R.; Li, Simon; Tarquinio, Keiko M.; Jaggi, Preeti; Oster, Matthew E.; Zackai, Sheemon P.; Gillen, Jennifer; Ratner, Adam J.; Walsh, Rowan F.; Fitzgerald, Julie C.; Keenaghan, Michael A.; Alharash, Hussam; Doymaz, Sule; Clouser, Katharine N.; Giuliano, John S.; Gupta, Anjali; Parker, Robert M.; Maddux, Aline B.; Havalad, Vinod; Ramsingh, Stacy; Bukulmez, Hulya; Bradford, Tamara T.; Smith, Lincoln S.; Tenforde, Mark W.; Carroll, Christopher L.; Riggs, Becky J.; Gertz, Shira J.; Daube, Ariel; Lansell, Amanda; Coronado Munoz, Alvaro; Hobbs, Charlotte V.; Marohn, Kimberly L.; Halasa, Natasha B.; Patel, Manish M.; Randolph, Adrienne G. (2020). "Multisystem Inflammatory Syndrome in U.S. Children and Adolescents". New England Journal of Medicine. doi:10.1056/NEJMoa2021680. ISSN 0028-4793.
  6. "Multisystem inflammatory syndrome in children and adolescents temporally related to COVID-19".
  7. "Case Definition for MIS-C".
  8. "Guidance: Paediatric multisystem inflammatory syndrome temporally associated with COVID-19" (PDF). line feed character in |title= at position 46 (help)
  9. "Guidance: Paediatric multisystem inflammatory syndrome temporally associated with COVID-19" (PDF). line feed character in |title= at position 46 (help)
  10. "Guidance: Paediatric multisystem inflammatory syndrome temporally associated with COVID-19" (PDF). line feed character in |title= at position 46 (help)
  11. "Guidance: Paediatric multisystem inflammatory syndrome temporally associated with COVID-19" (PDF). line feed character in |title= at position 46 (help)
  12. "Guidance: Paediatric multisystem inflammatory syndrome temporally associated with COVID-19" (PDF). line feed character in |title= at position 46 (help)
  13. "Evaluation and Management of COVID-19 Multisystem Inflammatory Syndrome in Children (MIS-C)" (PDF). line feed character in |title= at position 63 (help)
  14. "Evaluation and Management of COVID-19 Multisystem Inflammatory Syndrome in Children (MIS-C)" (PDF). line feed character in |title= at position 63 (help)
  15. "Evaluation and Management of COVID-19 Multisystem Inflammatory Syndrome in Children (MIS-C)" (PDF). line feed character in |title= at position 63 (help)
  16. "Evaluation and Management of COVID-19 Multisystem Inflammatory Syndrome in Children (MIS-C)" (PDF). line feed character in |title= at position 63 (help)
  17. "Evaluation and Management of COVID-19 Multisystem Inflammatory Syndrome in Children (MIS-C)" (PDF). line feed character in |title= at position 63 (help)