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

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__NOTOC__
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{{COVID-19}}
{{SI}}
'''For COVID-19 main page, click [[COVID-19|here]]'''


'''For COVID-19 frequently asked inpatient questions, click [[COVID-19 frequently asked inpatient questions|here]]'''
'''For COVID-19 frequently asked inpatient questions, click [[COVID-19 frequently asked inpatient questions|here]]'''
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{{CMG}}; {{AE}} {{HAR}}  
{{CMG}}; {{AE}} {{HAR}} {{Jose}} {{Sahar}} {{Aisha}}


{{SK}} '''Multisystem Inflammatory Syndrome in Children (MIS-C)'''
{{SK}} '''Multisystem Inflammatory Syndrome in Children (MIS-C)'''


==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.<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
[[COVID-19]]-associated multisystem inflammatory syndrome (also known as PIMS-TS - pediatric inflammatory multisystem syndrome temporally with [[SARS-CoV2]] infection or MIS-C - multisystem inflammatory syndrome in children) is an uncommon clinical entity caused by [[SARS-CoV2]] and seen mostly on children. It presents with: [[fever]] > 3 days and elevated markers of [[inflammation]] and 2 of the following 5 criteria: [[rash]] or [[conjunctivitis]]; [[hypotension]] or [[shock]]; [[myocardial]] dysfunction, [[pericarditis]], [[valvulitis]] or [[coronary]] abnormalities; evidence of [[COVID-19 Hematologic Complications|coagulopathy]] and/or acute [[gastrointestinal]] problems along with evidence of [[COVID-19]]. It seems to be a severe form of [[COVID-19]] in children presenting with symptoms that can be challenging to differentiate from other pediatric infectious diseases such as [[toxic shock syndrome]] and [[Kawasaki disease]]. The [[pathophysiology]] of this form of SARS-CoV2 infection remains unknown.
syndrome temporally associated with COVID-19|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
==Historical Perspective==
== Classification of Disease Severity of MIS-C ==


*'''Mild Disease'''
*<nowiki/> [[COVID-19]]-associated multisystem inflammatory syndrome was first reported as a new [[febrile]] pediatric entity, which began to appear in late April 2020 during the [[COVID-19]] pandemic in Wes<nowiki/>tern Europe.<ref name="pmid32441751">{{cite journal| author=Shulman ST| title=Pediatric Coronavirus Disease-2019-Associated Multisystem Inflammatory Syndrome. | journal=J Pediatric Infect Dis Soc | year= 2020 | volume= 9 | issue= 3 | pages= 285-286 | pmid=32441751 | doi=10.1093/jpids/piaa062 | pmc=7313948 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32441751  }} </ref>
*Children with MIS-C fall under this category who-<ref name="AL">{{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
*Cases of children with such symptoms were quickly identified in the New York City area, which was at that time the most heavily affected city in the U.S. by the [[COVID-19]] pandemic;<ref name="pmid32441751" />
Syndrome in Children (MIS-C) |first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* A repor<nowiki/><nowiki/>t of 8 cases from Evelina London Children's Hospital was published on 6 May 2020, showing very prominent markers of [[inflammation]] such as [[ferritin]], [[D-dimers]], [[triglycerides]], eleva<nowiki/>ted [[cardiac enzymes]], high [[NT-pro-BNP]] levels and [[troponin]], being empirically treated with [[IVIG]];<ref name="pmid32441751" />
**require minimal to no respiratory support.
* On May 22, an article from the Journal of [[Pediatric]] Infectious Diseases Society addressed some of the similarities and differences of this new entity with [[Kawasaki's disease]], noting th<nowiki/>at the demographics affected were significantly different, as it was not seen in Asia despite the pandemic also affecting such countries, but it was affecting mostly children of African ethnicity. The author also differentiated some of the laboratory findings, resembling the [[macrophage activation syndrome]] and not [[Kawasaki's disease]].<ref name="pmid32441751" />
**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-<ref name="AL" />
**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==
==Classification of Disease Severity of COVID-19-associated multisystem inflammatory syndrome ==


* 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.
* There is no established system for the [[classification]] of COVID-19-associated multisystem inflammatory syndrome.
* 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==
==Pathophysiology==
It should be differentiated from following diseases


* Bacterial sepsis
* The exact pathophysiological mechanism of [[COVID-19]]-associated multisystem inflammatory syndrome is unclear;
* Staphylococcal and streptococcal toxic shock syndrome
*It is thought that [[COVID-19]]-associated multisystem inflammatory syndrome is caused by either [[IgG]] [[antibody]]-mediated enhancement of the disease, an [[acute]] [[viral]] presentation, or due to [[cytokine storm]].<ref name="pmid32546853">{{cite journal| author=Rowley AH| title=Understanding SARS-CoV-2-related multisystem inflammatory syndrome in children. | journal=Nat Rev Immunol | year= 2020 | volume=  | issue=  | pages=  | pmid=32546853 | doi=10.1038/s41577-020-0367-5 | pmc=7296515 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32546853  }} </ref>
* Kawasaki disease.
*Since there is a lag time between [[COVID-19]]-associated multisystem inflammatory syndrome appearance and [[COVID-19]] infection ([[median]] time: 25 days)<ref name="pmid32598831">{{cite journal| author=Feldstein LR, Rose EB, Horwitz SM, Collins JP, Newhams MM, Son MBF | display-authors=etal| title=Multisystem Inflammatory Syndrome in U.S. Children and Adolescents. | journal=N Engl J Med | year= 2020 | volume=  | issue=  | pages=  | pmid=32598831 | doi=10.1056/NEJMoa2021680 | pmc=7346765 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32598831  }} </ref> it is suspected to be a post-infectious phenomenon related to [[IgG]] antibody-mediated enhancement of disease. There are two arguments that support this theory: the presence of [[IgG]] [[antibodies]] against SARS-CoV2 and the presence of the lag time between [[COVID-19]] symptoms and COVID-19-associated multisystem inflammatory syndrome.<ref name="pmid32546853" />
* More information about the differential diagnosis could be found [[COVID-19-associated dermatologic manifestations|her]]<nowiki/>e.
*There is, however, another theory that states that it is still an [[acute]] [[viral]] presentation of the [[disease]] due to the fact that children presenting with such symptoms undergone exploratory [[laparotomy]] which found [[mesenteric adenitis]], supporting GI infection. [[SARS-CoV2]] is also known to easily infect [[enterocytes]]. Another interesting point to consider is that the worsening of illness has not been observed in [[patients]] with [[COVID-19]] who are treated with convalescent plasma, which could have occurred if it was an antibody-mediated enhancement.<ref name="pmid32546853" />
*There is another hypothesis for the [[cytokine storm]] seen on children with COVID-19-associated multisystem inflammatory syndrome is originated from the known ability of [[coronaviruses]] to block type I and type III [[interferon]] responses, delaying the [[cytokine storm]] in [[patients]] that could not control the [[viral replication]] on earlier phases of the disease.<ref name="pmid32546853" />


== Epidemiology and Demographics ==
==Differentiating COVID-19-associated multisystem inflammatory syndrome Disease from other disease==
 
*For further information about the differential diagnosis, click [[COVID-19-associated multisystem inflammatory syndrome differential diagnosis|here]].
*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.
*To view the differential diagnosis of COVID-19, [[COVID-19 differential diagnosis|click here]].<br />
*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" />
*The mortality rate among 186 children with MIS-C was 2%.<ref name="FeldsteinRose2020" />


==Epidemiology and Demographics==
'''Age'''
'''Age'''


*Among the 186 children with MIS-C distribution of age group was<ref name="FeldsteinRose2020" />
*Children aged 5 years and older seem to have a worse [[prognosis]] than children less than 5 years old.<ref name="pmid32511676">{{cite journal| author=Cheung EW, Zachariah P, Gorelik M, Boneparth A, Kernie SG, Orange JS | display-authors=etal| title=Multisystem Inflammatory Syndrome Related to COVID-19 in Previously Healthy Children and Adolescents in New York City. | journal=JAMA | year= 2020 | volume=  | issue=  | pages=  | pmid=32511676 | doi=10.1001/jama.2020.10374 | pmc=7281352 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32511676  }} </ref>
**<1yr-7%
*A recent study published in the Journal of American Medical Associated reported that children with this disease had a [[median]] age of 9 years.<ref name="pmid32511692" />
**1-4yr-28%
**5-9yr-25%
**10-14yr-24%
**15-20yr-16%.


'''Gender'''
'''Gender'''


*Among the 186 children with MIS-C
* Most of the cases presented in males.<ref name="pmid32511692" /><ref name="pmid32386565">{{cite journal| author=Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P| title=Hyperinflammatory shock in children during COVID-19 pandemic. | journal=Lancet | year= 2020 | volume= 395 | issue= 10237 | pages= 1607-1608 | pmid=32386565 | doi=10.1016/S0140-6736(20)31094-1 | pmc=7204765 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32386565  }} </ref>


'''Comorbidities'''
'''Race'''


*Children with MIS-C had following underlying comorbidities.<ref name="FeldsteinRose2020" />
*It seems to affect predominantly blacks and Asian children.<ref name="pmid32511692" /><ref name="pmid32386565" />
**Clinically diagnosed Obesity-8%
**BMI-Based Obesity-29%
**Cardiovascular diasease-3%
**Respiratory disease-18%
**Autoimmune disease or immunocompromising condition-5%


'''Organ System Involved'''
'''Comorbidities'''


*71% of children had involvement of at least four organ systems.<ref name="FeldsteinRose2020" />
* Clinical evidence of the association with underlying diseases is still undetermined.<ref>{{Cite web|url=https://www.who.int/news-room/commentaries/detail/multisystem-inflammatory-syndrome-in-children-and-adolescents-with-covid-19|title=World Health Organization - Multisystem inflammatory syndrome in children and adolescents temporally related to COVID-19|last=|first=|date=07/13/2020|website=WHO|archive-url=|archive-date=|dead-url=|access-date=}}</ref>


The most common organ system involved in MIS-C children among a total of 186 children were.<ref name="FeldsteinRose2020" />
==Natural History, Complications, and Prognosis==
 
Complications of COVID-19-associated multisystem inflammatory syndrome include:<ref name="RiphagenGomez2020">{{cite journal|last1=Riphagen|first1=Shelley|last2=Gomez|first2=Xabier|last3=Gonzalez-Martinez|first3=Carmen|last4=Wilkinson|first4=Nick|last5=Theocharis|first5=Paraskevi|title=Hyperinflammatory shock in children during COVID-19 pandemic|journal=The Lancet|volume=395|issue=10237|year=2020|pages=1607–1608|issn=01406736|doi=10.1016/S0140-6736(20)31094-1}}</ref><ref name="DeBiasiSong2020">{{cite journal|last1=DeBiasi|first1=Roberta L.|last2=Song|first2=Xiaoyan|last3=Delaney|first3=Meghan|last4=Bell|first4=Michael|last5=Smith|first5=Karen|last6=Pershad|first6=Jay|last7=Ansusinha|first7=Emily|last8=Hahn|first8=Andrea|last9=Hamdy|first9=Rana|last10=Harik|first10=Nada|last11=Hanisch|first11=Benjamin|last12=Jantausch|first12=Barbara|last13=Koay|first13=Adeline|last14=Steinhorn|first14=Robin|last15=Newman|first15=Kurt|last16=Wessel|first16=David|title=Severe COVID-19 in Children and Young Adults in the Washington, DC Metropolitan Region|journal=The Journal of Pediatrics|year=2020|issn=00223476|doi=10.1016/j.jpeds.2020.05.007}}</ref><ref name="VerdoniMazza2020">{{cite journal|last1=Verdoni|first1=Lucio|last2=Mazza|first2=Angelo|last3=Gervasoni|first3=Annalisa|last4=Martelli|first4=Laura|last5=Ruggeri|first5=Maurizio|last6=Ciuffreda|first6=Matteo|last7=Bonanomi|first7=Ezio|last8=D'Antiga|first8=Lorenzo|title=An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study|journal=The Lancet|volume=395|issue=10239|year=2020|pages=1771–1778|issn=01406736|doi=10.1016/S0140-6736(20)31103-X}}</ref><ref name="BelhadjerMéot2020">{{cite journal|last1=Belhadjer|first1=Zahra|last2=Méot|first2=Mathilde|last3=Bajolle|first3=Fanny|last4=Khraiche|first4=Diala|last5=Legendre|first5=Antoine|last6=Abakka|first6=Samya|last7=Auriau|first7=Johanne|last8=Grimaud|first8=Marion|last9=Oualha|first9=Mehdi|last10=Beghetti|first10=Maurice|last11=Wacker|first11=Julie|last12=Ovaert|first12=Caroline|last13=Hascoet|first13=Sebastien|last14=Selegny|first14=Maëlle|last15=Malekzadeh-Milani|first15=Sophie|last16=Maltret|first16=Alice|last17=Bosser|first17=Gilles|last18=Giroux|first18=Nathan|last19=Bonnemains|first19=Laurent|last20=Bordet|first20=Jeanne|last21=Di Filippo|first21=Sylvie|last22=Mauran|first22=Pierre|last23=Falcon-Eicher|first23=Sylvie|last24=Thambo|first24=Jean-Benoît|last25=Lefort|first25=Bruno|last26=Moceri|first26=Pamela|last27=Houyel|first27=Lucile|last28=Renolleau|first28=Sylvain|last29=Bonnet|first29=Damien|title=Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic|journal=Circulation|year=2020|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.120.048360}}</ref><ref name="KlokKruip2020">{{cite journal|last1=Klok|first1=F.A.|last2=Kruip|first2=M.J.H.A.|last3=van der Meer|first3=N.J.M.|last4=Arbous|first4=M.S.|last5=Gommers|first5=D.|last6=Kant|first6=K.M.|last7=Kaptein|first7=F.H.J.|last8=van Paassen|first8=J.|last9=Stals|first9=M.A.M.|last10=Huisman|first10=M.V.|last11=Endeman|first11=H.|title=Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis|journal=Thrombosis Research|volume=191|year=2020|pages=148–150|issn=00493848|doi=10.1016/j.thromres.2020.04.041}}</ref><ref name="HennonPenque2020">{{cite journal|last1=Hennon|first1=Teresa R.|last2=Penque|first2=Michelle D.|last3=Abdul-Aziz|first3=Rabheh|last4=Alibrahim|first4=Omar S.|last5=McGreevy|first5=Megan B.|last6=Prout|first6=Andrew J.|last7=Schaefer|first7=Beverly A.|last8=Ambrusko|first8=Steven J.|last9=Pastore|first9=John V.|last10=Turkovich|first10=Stephen J.|last11=Gomez-Duarte|first11=Oscar G.|last12=Hicar|first12=Mark D.|title=COVID-19 associated Multisystem Inflammatory Syndrome in Children (MIS-C) guidelines; a Western New York approach|journal=Progress in Pediatric Cardiology|volume=57|year=2020|pages=101232|issn=10589813|doi=10.1016/j.ppedcard.2020.101232}}</ref>
*Gastrointestinal(92%)
*[[Ventricular dysfunction]]  
*Cardiovascular(80%)
*[[Coronary artery]] changes
*Hematologic(76%)
*Atrioventricular valve regurgitation
*Mucocutaneous(74%)
*Pericardial effusions
*Pulmonary(70%)
*[[Shock]]
*Historical perspective
*Venous thromboembolic events
 
*Cytokine storm syndrome
== Complications and Prognosis==
Factors associated with poor prognosis in COVID-19-associated multisystem inflammatory syndrome include:<ref name=":5">Pouletty, Marie, et al. "Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 mimicking Kawasaki disease (Kawa-COVID-19): a multicentre cohort." ''Annals of the Rheumatic Diseases'' (2020).</ref>
 
* Children younger than 1 month<ref name="urlClinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: prospective multicentre observational cohort study | The BMJ">{{cite web |url=https://www.bmj.com/content/370/bmj.m3249 |title=Clinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: prospective multicentre observational cohort study &#124; The BMJ |format= |work= |accessdate=}}</ref>
===Complications===
* Children older than 5 years old (age 10-14years)
 
* A [[ferritin]] level of higher than 1400 µg/L
*[[Myocardial infarction|Severe myocardial infarction]]
* Black ethnicity<ref name="urlClinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: prospective multicentre observational cohort study | The BMJ">{{cite web |url=https://www.bmj.com/content/370/bmj.m3249 |title=Clinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: prospective multicentre observational cohort study &#124; The BMJ |format= |work= |accessdate=}}</ref>
*[[Cardiac arrest in covid-19|Cardiac failure/arrest]]
*[[ARDS]]
*[[Hypervolemia]]
*[[Acute kidney injury|Acute Kidney Injury]]
*[[Peritonitis]]
*[[Thrombotic complications.]]


== Diagnosis ==
== Diagnosis ==
===Diagnostic Criteria===
===Diagnostic Criteria===
=====Preliminary [[World Health Organization|WHO]] case definition: Children and adolescents=====
The table below describes various diagnostic criteria for COVID-19-associated multisystem inflammatory syndrome:<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><ref name="urlMultisystem inflammatory syndrome in children and adolescents temporally related to COVID-19">{{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 |format= |work= |accessdate=}}</ref><ref name="urlGuidance - Paediatric multisystem inflammatory syndrome temporally associated with COVID-19 (PIMS) | RCPCH">{{cite web |url=https://www.rcpch.ac.uk/resources/guidance-paediatric-multisystem-inflammatory-syndrome-temporally-associated-covid-19-pims |title=Guidance - Paediatric multisystem inflammatory syndrome temporally associated with COVID-19 (PIMS) &#124; RCPCH |format= |work= |accessdate=}}</ref><br />
{| class="wikitable"
|+
! align="center" style="background: #4479BA; color: #FFFFFF |Features
! align="center" style="background: #4479BA; color: #FFFFFF |World Health Organization  


*0–19 years of age with [[fever]] >3 days
Criteria
! align="center" style="background: #4479BA; color: #FFFFFF |Royal College of Paediatrics and Child Health


AND
(United Kingdom)  Criteria
! align="center" style="background: #4479BA; color: #FFFFFF |Centers for Disease Control and Prevention


*Two of the following:
(United States)  Criteria
 
|-
#[[Rash]] or bilateral non-purulent [[conjunctivitis]] or mucocutaneous inflammation signs (oral, hands or feet)
!Age
#Hypotension or shock
|
#Features of myocardial dysfunction, [[pericarditis]], [[valvulitis]], or coronary abnormalities (including ECHO findings or elevated [[Troponin]]/[[NT-proBNP]])
*0-19 years old
#Evidence of [[coagulopathy]] (by PT, [[Partial thromboplastin time|PTT]], elevated [[D-dimer|D-Dimers]])
|
#Acute gastrointestinal problems ([[diarrhea]], [[vomiting]], or [[abdominal pain]])
*Not specified
 
|
AND
*Younger than 21 years old
 
|-
*Elevated markers of [[inflammation]] such as [[Erythrocyte sedimentation rate|ESR]], [[C-reactive protein]], or [[procalcitonin]]
! rowspan="6" |Clinical Features
 
|
AND
*[[Fever]] lasting more than 3 days
 
|
*No other obvious microbial cause of [[inflammation]], including bacterial [[sepsis]], [[staphylococcal]] or [[streptococcal]] shock syndromes
*Persistent [[fever]]
 
|
AND
*[[Fever]] (body temperature, >38.0°C) or report of subjective [[fever]] present at least 24 hours
 
|-
*Evidence of [[COVID-19|COVID]]-19 ([[Reverse transcription-polymerase chain reaction|RT-PCR]], antigen test or serology-positive), or likely contact with patients with [[COVID-19|COVID]]-19
|
 
*More than 2 of the followings:
=====CDC Case Definition for MIS-C=====
| rowspan="5" |
 
*Evidence of single or multi-organ involvement
*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);
|
 
*Severe disease course leading to hospitalization
AND
|-
 
|1. [[Rash]] or non-purulent [[Conjunctivitis|conjunctival injection]] or mucocutaneous involvement
No alternative plausible diagnoses;
| rowspan="4" |
 
*Multisystem organ involvement (at least two systems)
AND
|-
 
|2. Low blood pressure/[[Shock]]
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 ===
|3. Findings consistent with [[myocarditis]], [[pericarditis]], [[valvulitis]] or [[coronary]] involvement
|-
|4. Acute [[gastrointestinal]] symptoms
|-
! rowspan="2" |Laboratory Findings
|5. Laboratory evidence of [[coagulopathy]]
| rowspan="2" |
*Laboratory evidence of [[inflammation]]
| rowspan="2" |
*Laboratory evidence of [[inflammation]]
|-
|
*Laboratory evidence of [[inflammation]]
|-
!Diagnosis of SARS-CoV-2
|
*Laboratory-confirmed [[SARS-CoV-2]] infection
*A history of COVID-19 exposure
|
*Positive/Negative [[SARS-Cov-2]] test
|
*Laboratory-confirmed [[SARS-CoV-2]] infection
*A history of COVID-19 exposure within the 4 weeks prior to the onset of [[symptoms]] 
|-
!Others
|
*Absence of other possible cause
|
*Exclusion of other possible cause
|
*Absence of other diagnoses
|}


=== History and Symptoms ===
COVID-19 associated multisystem inflammatory syndrome is associated with the following symptoms:<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><ref name="HennonPenque2020">{{cite journal|last1=Hennon|first1=Teresa R.|last2=Penque|first2=Michelle D.|last3=Abdul-Aziz|first3=Rabheh|last4=Alibrahim|first4=Omar S.|last5=McGreevy|first5=Megan B.|last6=Prout|first6=Andrew J.|last7=Schaefer|first7=Beverly A.|last8=Ambrusko|first8=Steven J.|last9=Pastore|first9=John V.|last10=Turkovich|first10=Stephen J.|last11=Gomez-Duarte|first11=Oscar G.|last12=Hicar|first12=Mark D.|title=COVID-19 associated Multisystem Inflammatory Syndrome in Children (MIS-C) guidelines; a Western New York approach|journal=Progress in Pediatric Cardiology|volume=57|year=2020|pages=101232|issn=10589813|doi=10.1016/j.ppedcard.2020.101232}}</ref>
*[[Fever]] lasting 24 hours or longer.
*[[Fever]] lasting 24 hours or longer.
*[[Vomiting]]
*[[Vomiting]]
*[[Diarrhea]]
*[[Diarrhea]]
*[[Abdominal pain]]
*[[Abdominal pain]]
*[[Shortness of breath|Difficulty Breathing]]
*[[Chest pain]]
*[[Headache]]
*[[Sore throat]]
*[[Confusion|New onset confusion]]
===Physical Examination===
COVID-19 associated multisystem inflammatory syndrome is associated with the following physical examination findings:<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>
*[[Skin rash]]
*[[Skin rash]]
*[[Conjuctivitis]]
*[[Conjuctivitis]]
*[[Erythrocyte sedimentation rate|High ESR]]
*Redness or swelling of the lips and tongue
*Redness or swelling of the lips and tongue
*[[Lethargy]]
*[[Redness]] or swelling of the hands or feet
*[[Redness]] or swelling of the hands or feet
*[[Confusion]]
*[[Headache]]
*[[Sore throat]]
*[[Syncope]]
*[[Lymphadenopathy]]
*[[Lymphadenopathy]]
'''Emergency Warning Signs'''
*[[Shortness of breath|Difficulty Breathing]]
*[[Chest pain]]
*[[Confusion|New onset confusion]]
*[[Lethargy]]
*[[Lethargy]]
*[[Cyanosis]]
*[[Cyanosis]]
*[[Abdominal pain]]
===Laboratory Findings===
 
COVID-19 associated multisystem inflammatory syndrome is associated with the following laboratory findings:<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><ref name="CheungZachariah2020">{{cite journal|last1=Cheung|first1=Eva W.|last2=Zachariah|first2=Philip|last3=Gorelik|first3=Mark|last4=Boneparth|first4=Alexis|last5=Kernie|first5=Steven G.|last6=Orange|first6=Jordan S.|last7=Milner|first7=Joshua D.|title=Multisystem Inflammatory Syndrome Related to COVID-19 in Previously Healthy Children and Adolescents in New York City|journal=JAMA|year=2020|issn=0098-7484|doi=10.1001/jama.2020.10374}}</ref>
=== Physical Examination ===
'''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.


*[[Erythrocyte sedimentation rate|High ESR]]
*[[Lymphopenia]]
* [[Neutrophilia]]
*[[Anemia]]
*[[Thrombocytopenia]]
Less common laboratory findings include:
* [[Fibrinogen|Abnormal fibrinogen]]
* [[Hypoalbuminaemia]]
* Elevated [[Creatine kinase|creatiine kinase]] (CK)
* Elevated [[Lactate dehydrogenase|LDH]]
* Elevated [[Triglyceride|triglycerides]]
==== Inflammatory biomarkers ====
==== 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.
Elevation of [[inflammatory]] markers including [[erythrocyte sedimentation rate]], [[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 ====
==== Cardiac biomarkers ====
Elevation of cardic enzymes including  [[Cardiac troponin|cardiac troponins]] ([[Cardiac troponin I (cTnI) and T (cTnT)|cardiac troponin I(cTnI) and cardiac troponin T (cTnT)]]) and [[Brain natriuretic peptide]] ([[BNP]])) has been observed in MIS-C patients.
Elevation of [[cardic enzymes]] including  [[Cardiac troponin|cardiac troponins]] ([[Cardiac troponin I (cTnI) and T (cTnT)|cardiac troponin I(cTnI) and cardiac troponin T (cTnT)]]) and [[Brain natriuretic peptide]] ([[BNP]])) has been observed in MIS-C patients.
 
* To view the complete physical examination in COVID-19, [[COVID-19 physical examination|click here]].
=== Radiological Findings ===
* To view the [[laboratory]] findings on COVID-19, [[COVID-19 laboratory findings|click here]].
 
===X-ray===
* Following Radiological Findings are observed in MIS-C patients.
[[X-ray]] of patients with COVID-19 associated multiorgan system inflammatory syndrome may be normal. When abnormal, findings may include the followings:<ref name="HameedElbaaly2020">{{cite journal|last1=Hameed|first1=Shema|last2=Elbaaly|first2=Heba|last3=Reid|first3=Catriona E. L.|last4=Santos|first4=Rui M. F.|last5=Shivamurthy|first5=Vinay|last6=Wong|first6=James|last7=Jogeesvaran|first7=K. Haran|title=Spectrum of Imaging Findings on Chest Radiographs, US, CT, and MRI                    Images in Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with                    COVID-19|journal=Radiology|year=2020|pages=202543|issn=0033-8419|doi=10.1148/radiol.2020202543}}</ref>
 
*Peribronchial cuffing
{| border="1" cellpadding="2"
*Perihilar interstitial thickening
! width="225" |Test
*Perihilar opacification
! width="225" |Findings
*Perihilar [[consolidation]]
|-
*Low volume [[pleural effusion]] affecting both lungs
|Chest Xray||patchy symmetrical infiltrates, [[pleural effusion]]
*Left lower lobe [[atelectasis]]
|-
===Echocardiography or Ultrasound===
|Echocardiogram and EKG||[[myocarditis]], valvulitis, [[pericardial effusion]], coronary artery dilatation
Abdominal ultrasound imaging of patients with COVID-19 associated multiorgan system inflammatory syndrome may include the following findings:<ref name="HameedElbaaly2020">{{cite journal|last1=Hameed|first1=Shema|last2=Elbaaly|first2=Heba|last3=Reid|first3=Catriona E. L.|last4=Santos|first4=Rui M. F.|last5=Shivamurthy|first5=Vinay|last6=Wong|first6=James|last7=Jogeesvaran|first7=K. Haran|title=Spectrum of Imaging Findings on Chest Radiographs, US, CT, and MRI                    Images in Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with                    COVID-19|journal=Radiology|year=2020|pages=202543|issn=0033-8419|doi=10.1148/radiol.2020202543}}</ref>
|-
*Free-fluid
|Abdominal USG||[[colitis]], [[ileitis]], [[lymphadenopathy]], [[ascites]], [[hepatosplenomegaly]]
*Localised inflammatory change within the right iliac fossa
|}
*A combination of echogenic expanded mesenteric fat and enlarged lymph nodes
'''Blood Culture, Viral PCR'''
*Bowel wall thickening of parts of [[ileum]] and [[cecum]]
*[[Gall bladder]] wall thickening and edema
To view the [[echocardiographic]] findings on COVID-19, [[COVID-19 echocardiography and ultrasound|click here]].<br />


* Absence of other potential causative organisms. IgG levels and IgM levels of [[SARS-CoV-2]] are detected.
===CT scan===
Chest CT scan of patients with COVID-19-associated multisystem inflammatory syndrome includes the following patterns:<ref name="HameedElbaaly2020">{{cite journal|last1=Hameed|first1=Shema|last2=Elbaaly|first2=Heba|last3=Reid|first3=Catriona E. L.|last4=Santos|first4=Rui M. F.|last5=Shivamurthy|first5=Vinay|last6=Wong|first6=James|last7=Jogeesvaran|first7=K. Haran|title=Spectrum of Imaging Findings on Chest Radiographs, US, CT, and MRI                    Images in Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with                    COVID-19|journal=Radiology|year=2020|pages=202543|issn=0033-8419|doi=10.1148/radiol.2020202543}}</ref>
*Consolidation and collapse of the lung bases
*[[Pleural effusions]]
*Diffuse bilateral ground-glass opacities with dense, patchy consolidation
Abdominal CT scan may show the following abnormalities:
*[[Intestinal]] wall thickening particularly in the [[terminal ileum]] and [[cecum]]
To view the [[CT scan]] findings on COVID-19, [[COVID-19 CT scan|click here]].
===MRI===
* To view the [[MRI]] findings on COVID-19, [[COVID-19 MRI|click here]].<br />
===Other Imaging Findings===
* To view other imaging findings on COVID-19, [[COVID-19 other imaging findings|click here]].<br />
===Other Diagnostic Studies===
* To view other [[diagnostic]] studies for COVID-19, [[COVID-19 other diagnostic studies|click here]].<br />


== Treatment ==
== Treatment ==
=== Medical Therapy ===
=== Medical Therapy ===
 
Treatment of patients with COVID-19-associated multisystem inflammatory syndrome includes:<ref name="HennonPenque2020">{{cite journal|last1=Hennon|first1=Teresa R.|last2=Penque|first2=Michelle D.|last3=Abdul-Aziz|first3=Rabheh|last4=Alibrahim|first4=Omar S.|last5=McGreevy|first5=Megan B.|last6=Prout|first6=Andrew J.|last7=Schaefer|first7=Beverly A.|last8=Ambrusko|first8=Steven J.|last9=Pastore|first9=John V.|last10=Turkovich|first10=Stephen J.|last11=Gomez-Duarte|first11=Oscar G.|last12=Hicar|first12=Mark D.|title=COVID-19 associated Multisystem Inflammatory Syndrome in Children (MIS-C) guidelines; a Western New York approach|journal=Progress in Pediatric Cardiology|volume=57|year=2020|pages=101232|issn=10589813|doi=10.1016/j.ppedcard.2020.101232}}</ref>
*All the children with MIS-C are treated as suspected [[COVID-19|COVID-19.]]
* [[Antibiotics]]: broad-spectrum antibiotics are recommended initially.
*Mild to Moderate cases of MIS-C are managed supportively.
** If the symptoms are mild, [[ceftriaxone]] may be sufficient.
*Supplemental [[oxygen]] is required in children with low oxygen saturation.
** If the [[gastrointestinal]] symptoms are predominant, then metronidazole is recommended.
*[[Fluid replacement|Fluid resuscitation]] in 10 ml/kg aliquots with reevaluation after each bolus. Maintain euvolemia. Avoid hypervolemia.
** In case of severe [[symptoms]] including [[shock]] the following antibiotics have been recommended:
*Anti-inflammatory treatments with [[Intravenous immunoglobulin|Intravenous immunoglobulin(IVIG]]) with or without [[Corticosteroid|corticosteroids]] have shown a good response rate.
***[[Vancomycin]], [[clindamycin]], and [[cefepime]]
*[[Aspirin]] has been used primarily for its antiplatelet effect. It is recommended in all patients with [[MIS-C]].
***[[Vancomycin]], [[meropenem]], and [[gentamicin]]
*[[Anakinra]] is considered if fevers last more than 24 hours post [[Steroid|steroids]]/[[Intravenous immunoglobulin|IVIG]] or in the moderate or severe presentation.
* [[Remdesivir]] is indicated in children with  PCR positive COVID-19 and/or with a presentation consistent with typical COVID-19.
*[[Tocilizumab]] is also considered if fevers last more than 24 hours post steroids/IVIG or in the moderate or severe presentation.
** It should be administered 5 mg/kg loading dose IV once (max dose 200 mg) on day 1, then 2.5 mg/kg (100 mg max dose) IV daily for nine days.
*Empiric antibiotics like [[vancomycin]], [[ceftriaxone]], and [[clindamycin]] are given for community-acquired shock presentation until cultures are negative for 48 hours.
*Cardiac and respiratory support is recommended for patients presenting with [[shock]].
 
* [[IVIG]] and aspirin for Kawasaki-like disease
{| border="1" cellpadding="2"
** [[IVIG]] 2 g/kg for all patients with
! width="225" |Presentation
** [[Aspirin]] 20–25 mg/kg/dose every 6 h (80–100 mg/kg/day) for all patients with
! width="225" |Treatment
[[Patients]] with KD-like illness in high-risk categories should receive IVIG with other agents.The high-risk category includes:
|-
*Infants
|Mild Disease||
*Those with KD shock syndrome
*Symptomatic Treatment
*Those with [[CRP]] > 130 g/dL
|-
*Those with admission echo Z score > 2.5 or [[aneurysms]]
|Severe Disease||
*Asian race
*Symptomatic Treatment
The following treatment regimen is recommended for patients with KD-like illness in high-risk categories:
*[[Intravenous immunoglobulin|IVIG(IV)]]
* [[IVIG]] 2 g/kg as a single infusion with three-day pulse methylprednisolone. If fails, then:
*[[Corticosteroid|Corticosteroids]](IV/PO)
* The second dose of [[IVIG]] or [[infliximab]] (a Tumor necrosis factor (TNF)-alpha inhibitor)
*Consider adding [[Anakinra]] or [[Tocilizumab]] if [[fever]] persist for more than 24 hours post [[Steroid|steroids]] and I[[Intravenous immunoglobulin|VIG]] use.
* Venous thromboembolism prophylaxis may be indicated as well.
|}
* Few studies have reported that [[interleukin-1]] inhibitors may be effective in the treatment of severe cases.<ref name="ShahMunoz2020">{{cite journal|last1=Shah|first1=Satish K.|last2=Munoz|first2=Alvaro Coronado|title=Multisystem Inflammatory Syndrome in Children in COVID-19 Pandemic|journal=The Indian Journal of Pediatrics|year=2020|issn=0019-5456|doi=10.1007/s12098-020-03440-7}}</ref>
 
* [[Tocilizumab]] ([[interleukin-6]] inhibitor) is another agent that has been used in some cases.  
== Prevention of MIS-C ==
=== Prevention ===
 
*MIS-C can be prevented by reducing the risk of a child's exposure to [[COVID-19|COVID]]-19 infection.
*MIS-C can be prevented by reducing the risk of child exposure to [[COVID-19|COVID]]-19 infection.


== References ==
== References ==
<references />
{{Reflist|2}}
[[Category:Up-To-Date]]

Latest revision as of 22:03, 31 August 2020

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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] José Eduardo Riceto Loyola Junior, M.D.[3] Sahar Memar Montazerin, M.D.[4] Aisha Adigun, B.Sc., M.D.[5]

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

Overview

COVID-19-associated multisystem inflammatory syndrome (also known as PIMS-TS - pediatric inflammatory multisystem syndrome temporally with SARS-CoV2 infection or MIS-C - multisystem inflammatory syndrome in children) is an uncommon clinical entity caused by SARS-CoV2 and seen mostly on children. It presents with: fever > 3 days and elevated markers of inflammation and 2 of the following 5 criteria: rash or conjunctivitis; hypotension or shock; myocardial dysfunction, pericarditis, valvulitis or coronary abnormalities; evidence of coagulopathy and/or acute gastrointestinal problems along with evidence of COVID-19. It seems to be a severe form of COVID-19 in children presenting with symptoms that can be challenging to differentiate from other pediatric infectious diseases such as toxic shock syndrome and Kawasaki disease. The pathophysiology of this form of SARS-CoV2 infection remains unknown.

Historical Perspective

  • COVID-19-associated multisystem inflammatory syndrome was first reported as a new febrile pediatric entity, which began to appear in late April 2020 during the COVID-19 pandemic in Western Europe.[1]
  • Cases of children with such symptoms were quickly identified in the New York City area, which was at that time the most heavily affected city in the U.S. by the COVID-19 pandemic;[1]
  • A report of 8 cases from Evelina London Children's Hospital was published on 6 May 2020, showing very prominent markers of inflammation such as ferritin, D-dimers, triglycerides, elevated cardiac enzymes, high NT-pro-BNP levels and troponin, being empirically treated with IVIG;[1]
  • On May 22, an article from the Journal of Pediatric Infectious Diseases Society addressed some of the similarities and differences of this new entity with Kawasaki's disease, noting that the demographics affected were significantly different, as it was not seen in Asia despite the pandemic also affecting such countries, but it was affecting mostly children of African ethnicity. The author also differentiated some of the laboratory findings, resembling the macrophage activation syndrome and not Kawasaki's disease.[1]

Classification of Disease Severity of COVID-19-associated multisystem inflammatory syndrome

  • There is no established system for the classification of COVID-19-associated multisystem inflammatory syndrome.

Pathophysiology

  • The exact pathophysiological mechanism of COVID-19-associated multisystem inflammatory syndrome is unclear;
  • It is thought that COVID-19-associated multisystem inflammatory syndrome is caused by either IgG antibody-mediated enhancement of the disease, an acute viral presentation, or due to cytokine storm.[2]
  • Since there is a lag time between COVID-19-associated multisystem inflammatory syndrome appearance and COVID-19 infection (median time: 25 days)[3] it is suspected to be a post-infectious phenomenon related to IgG antibody-mediated enhancement of disease. There are two arguments that support this theory: the presence of IgG antibodies against SARS-CoV2 and the presence of the lag time between COVID-19 symptoms and COVID-19-associated multisystem inflammatory syndrome.[2]
  • There is, however, another theory that states that it is still an acute viral presentation of the disease due to the fact that children presenting with such symptoms undergone exploratory laparotomy which found mesenteric adenitis, supporting GI infection. SARS-CoV2 is also known to easily infect enterocytes. Another interesting point to consider is that the worsening of illness has not been observed in patients with COVID-19 who are treated with convalescent plasma, which could have occurred if it was an antibody-mediated enhancement.[2]
  • There is another hypothesis for the cytokine storm seen on children with COVID-19-associated multisystem inflammatory syndrome is originated from the known ability of coronaviruses to block type I and type III interferon responses, delaying the cytokine storm in patients that could not control the viral replication on earlier phases of the disease.[2]

Differentiating COVID-19-associated multisystem inflammatory syndrome Disease from other disease

  • For further information about the differential diagnosis, click here.
  • To view the differential diagnosis of COVID-19, click here.

Epidemiology and Demographics

Age

  • Children aged 5 years and older seem to have a worse prognosis than children less than 5 years old.[4]
  • A recent study published in the Journal of American Medical Associated reported that children with this disease had a median age of 9 years.[5]

Gender

  • Most of the cases presented in males.[5][6]

Race

  • It seems to affect predominantly blacks and Asian children.[5][6]

Comorbidities

  • Clinical evidence of the association with underlying diseases is still undetermined.[7]

Natural History, Complications, and Prognosis

Complications of COVID-19-associated multisystem inflammatory syndrome include:[8][9][10][11][12][13]

Factors associated with poor prognosis in COVID-19-associated multisystem inflammatory syndrome include:[14]

  • Children younger than 1 month[15]
  • Children older than 5 years old (age 10-14years)
  • A ferritin level of higher than 1400 µg/L
  • Black ethnicity[15]

Diagnosis

Diagnostic Criteria

The table below describes various diagnostic criteria for COVID-19-associated multisystem inflammatory syndrome:[16][17][18]

Features World Health Organization  

Criteria

Royal College of Paediatrics and Child Health

(United Kingdom)  Criteria

Centers for Disease Control and Prevention

(United States)  Criteria

Age
  • 0-19 years old
  • Not specified
  • Younger than 21 years old
Clinical Features
  • Fever lasting more than 3 days
  • Fever (body temperature, >38.0°C) or report of subjective fever present at least 24 hours
  • More than 2 of the followings:
  • Evidence of single or multi-organ involvement
  • Severe disease course leading to hospitalization
1. Rash or non-purulent conjunctival injection or mucocutaneous involvement
  • Multisystem organ involvement (at least two systems)
2. Low blood pressure/Shock
3. Findings consistent with myocarditis, pericarditis, valvulitis or coronary involvement
4. Acute gastrointestinal symptoms
Laboratory Findings 5. Laboratory evidence of coagulopathy
Diagnosis of SARS-CoV-2
  • Laboratory-confirmed SARS-CoV-2 infection
  • A history of COVID-19 exposure
  • Laboratory-confirmed SARS-CoV-2 infection
  • A history of COVID-19 exposure within the 4 weeks prior to the onset of symptoms 
Others
  • Absence of other possible cause
  • Exclusion of other possible cause
  • Absence of other diagnoses

History and Symptoms

COVID-19 associated multisystem inflammatory syndrome is associated with the following symptoms:[16][13]

Physical Examination

COVID-19 associated multisystem inflammatory syndrome is associated with the following physical examination findings:[16]

Laboratory Findings

COVID-19 associated multisystem inflammatory syndrome is associated with the following laboratory findings:[16][19]

Less common laboratory findings include:

Inflammatory biomarkers

Elevation of inflammatory markers including erythrocyte sedimentation rate, 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.

X-ray

X-ray of patients with COVID-19 associated multiorgan system inflammatory syndrome may be normal. When abnormal, findings may include the followings:[20]

Echocardiography or Ultrasound

Abdominal ultrasound imaging of patients with COVID-19 associated multiorgan system inflammatory syndrome may include the following findings:[20]

  • Free-fluid
  • Localised inflammatory change within the right iliac fossa
  • A combination of echogenic expanded mesenteric fat and enlarged lymph nodes
  • Bowel wall thickening of parts of ileum and cecum
  • Gall bladder wall thickening and edema

To view the echocardiographic findings on COVID-19, click here.

CT scan

Chest CT scan of patients with COVID-19-associated multisystem inflammatory syndrome includes the following patterns:[20]

  • Consolidation and collapse of the lung bases
  • Pleural effusions
  • Diffuse bilateral ground-glass opacities with dense, patchy consolidation

Abdominal CT scan may show the following abnormalities:

To view the CT scan findings on COVID-19, click here.

MRI

Other Imaging Findings

  • To view other imaging findings on COVID-19, click here.

Other Diagnostic Studies

Treatment

Medical Therapy

Treatment of patients with COVID-19-associated multisystem inflammatory syndrome includes:[13]

  • Antibiotics: broad-spectrum antibiotics are recommended initially.
  • Remdesivir is indicated in children with PCR positive COVID-19 and/or with a presentation consistent with typical COVID-19.
    • It should be administered 5 mg/kg loading dose IV once (max dose 200 mg) on day 1, then 2.5 mg/kg (100 mg max dose) IV daily for nine days.
  • Cardiac and respiratory support is recommended for patients presenting with shock.
  • IVIG and aspirin for Kawasaki-like disease
    • IVIG 2 g/kg for all patients with
    • Aspirin 20–25 mg/kg/dose every 6 h (80–100 mg/kg/day) for all patients with

Patients with KD-like illness in high-risk categories should receive IVIG with other agents.The high-risk category includes:

  • Infants
  • Those with KD shock syndrome
  • Those with CRP > 130 g/dL
  • Those with admission echo Z score > 2.5 or aneurysms
  • Asian race

The following treatment regimen is recommended for patients with KD-like illness in high-risk categories:

  • IVIG 2 g/kg as a single infusion with three-day pulse methylprednisolone. If fails, then:
  • The second dose of IVIG or infliximab (a Tumor necrosis factor (TNF)-alpha inhibitor)
  • Venous thromboembolism prophylaxis may be indicated as well.
  • Few studies have reported that interleukin-1 inhibitors may be effective in the treatment of severe cases.[21]
  • Tocilizumab (interleukin-6 inhibitor) is another agent that has been used in some cases.

Prevention

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

References

  1. 1.0 1.1 1.2 1.3 Shulman ST (2020). "Pediatric Coronavirus Disease-2019-Associated Multisystem Inflammatory Syndrome". J Pediatric Infect Dis Soc. 9 (3): 285–286. doi:10.1093/jpids/piaa062. PMC 7313948 Check |pmc= value (help). PMID 32441751 Check |pmid= value (help).
  2. 2.0 2.1 2.2 2.3 Rowley AH (2020). "Understanding SARS-CoV-2-related multisystem inflammatory syndrome in children". Nat Rev Immunol. doi:10.1038/s41577-020-0367-5. PMC 7296515 Check |pmc= value (help). PMID 32546853 Check |pmid= value (help).
  3. Feldstein LR, Rose EB, Horwitz SM, Collins JP, Newhams MM, Son MBF; et al. (2020). "Multisystem Inflammatory Syndrome in U.S. Children and Adolescents". N Engl J Med. doi:10.1056/NEJMoa2021680. PMC 7346765 Check |pmc= value (help). PMID 32598831 Check |pmid= value (help).
  4. Cheung EW, Zachariah P, Gorelik M, Boneparth A, Kernie SG, Orange JS; et al. (2020). "Multisystem Inflammatory Syndrome Related to COVID-19 in Previously Healthy Children and Adolescents in New York City". JAMA. doi:10.1001/jama.2020.10374. PMC 7281352 Check |pmc= value (help). PMID 32511676 Check |pmid= value (help).
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  6. 6.0 6.1 Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P (2020). "Hyperinflammatory shock in children during COVID-19 pandemic". Lancet. 395 (10237): 1607–1608. doi:10.1016/S0140-6736(20)31094-1. PMC 7204765 Check |pmc= value (help). PMID 32386565 Check |pmid= value (help).
  7. "World Health Organization - Multisystem inflammatory syndrome in children and adolescents temporally related to COVID-19". WHO. 07/13/2020. Check date values in: |date= (help)
  8. Riphagen, Shelley; Gomez, Xabier; Gonzalez-Martinez, Carmen; Wilkinson, Nick; Theocharis, Paraskevi (2020). "Hyperinflammatory shock in children during COVID-19 pandemic". The Lancet. 395 (10237): 1607–1608. doi:10.1016/S0140-6736(20)31094-1. ISSN 0140-6736.
  9. DeBiasi, Roberta L.; Song, Xiaoyan; Delaney, Meghan; Bell, Michael; Smith, Karen; Pershad, Jay; Ansusinha, Emily; Hahn, Andrea; Hamdy, Rana; Harik, Nada; Hanisch, Benjamin; Jantausch, Barbara; Koay, Adeline; Steinhorn, Robin; Newman, Kurt; Wessel, David (2020). "Severe COVID-19 in Children and Young Adults in the Washington, DC Metropolitan Region". The Journal of Pediatrics. doi:10.1016/j.jpeds.2020.05.007. ISSN 0022-3476.
  10. Verdoni, Lucio; Mazza, Angelo; Gervasoni, Annalisa; Martelli, Laura; Ruggeri, Maurizio; Ciuffreda, Matteo; Bonanomi, Ezio; D'Antiga, Lorenzo (2020). "An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study". The Lancet. 395 (10239): 1771–1778. doi:10.1016/S0140-6736(20)31103-X. ISSN 0140-6736.
  11. Belhadjer, Zahra; Méot, Mathilde; Bajolle, Fanny; Khraiche, Diala; Legendre, Antoine; Abakka, Samya; Auriau, Johanne; Grimaud, Marion; Oualha, Mehdi; Beghetti, Maurice; Wacker, Julie; Ovaert, Caroline; Hascoet, Sebastien; Selegny, Maëlle; Malekzadeh-Milani, Sophie; Maltret, Alice; Bosser, Gilles; Giroux, Nathan; Bonnemains, Laurent; Bordet, Jeanne; Di Filippo, Sylvie; Mauran, Pierre; Falcon-Eicher, Sylvie; Thambo, Jean-Benoît; Lefort, Bruno; Moceri, Pamela; Houyel, Lucile; Renolleau, Sylvain; Bonnet, Damien (2020). "Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic". Circulation. doi:10.1161/CIRCULATIONAHA.120.048360. ISSN 0009-7322.
  12. Klok, F.A.; Kruip, M.J.H.A.; van der Meer, N.J.M.; Arbous, M.S.; Gommers, D.; Kant, K.M.; Kaptein, F.H.J.; van Paassen, J.; Stals, M.A.M.; Huisman, M.V.; Endeman, H. (2020). "Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis". Thrombosis Research. 191: 148–150. doi:10.1016/j.thromres.2020.04.041. ISSN 0049-3848.
  13. 13.0 13.1 13.2 Hennon, Teresa R.; Penque, Michelle D.; Abdul-Aziz, Rabheh; Alibrahim, Omar S.; McGreevy, Megan B.; Prout, Andrew J.; Schaefer, Beverly A.; Ambrusko, Steven J.; Pastore, John V.; Turkovich, Stephen J.; Gomez-Duarte, Oscar G.; Hicar, Mark D. (2020). "COVID-19 associated Multisystem Inflammatory Syndrome in Children (MIS-C) guidelines; a Western New York approach". Progress in Pediatric Cardiology. 57: 101232. doi:10.1016/j.ppedcard.2020.101232. ISSN 1058-9813.
  14. Pouletty, Marie, et al. "Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 mimicking Kawasaki disease (Kawa-COVID-19): a multicentre cohort." Annals of the Rheumatic Diseases (2020).
  15. 15.0 15.1 "Clinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: prospective multicentre observational cohort study | The BMJ".
  16. 16.0 16.1 16.2 16.3 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.
  17. "Guidance - Paediatric multisystem inflammatory syndrome temporally associated with COVID-19 (PIMS) | RCPCH".
  18. Cheung, Eva W.; Zachariah, Philip; Gorelik, Mark; Boneparth, Alexis; Kernie, Steven G.; Orange, Jordan S.; Milner, Joshua D. (2020). "Multisystem Inflammatory Syndrome Related to COVID-19 in Previously Healthy Children and Adolescents in New York City". JAMA. doi:10.1001/jama.2020.10374. ISSN 0098-7484.
  19. 20.0 20.1 20.2 Hameed, Shema; Elbaaly, Heba; Reid, Catriona E. L.; Santos, Rui M. F.; Shivamurthy, Vinay; Wong, James; Jogeesvaran, K. Haran (2020). "Spectrum of Imaging Findings on Chest Radiographs, US, CT, and MRI Images in Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with COVID-19". Radiology: 202543. doi:10.1148/radiol.2020202543. ISSN 0033-8419.
  20. Shah, Satish K.; Munoz, Alvaro Coronado (2020). "Multisystem Inflammatory Syndrome in Children in COVID-19 Pandemic". The Indian Journal of Pediatrics. doi:10.1007/s12098-020-03440-7. ISSN 0019-5456.