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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.
[[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.
==Historical Perspective==
==Historical Perspective==


* Reports of a new febrile pediatric entity began to appear in late April 2020 during the COVID-19 pandemic in the Western Europe, characterized by systemic hyperinflammation, abdominal pain with gastrointestinal symptoms and multiorgan involvement affecting specially the myocardium causing cardiogenic shock which reminded the physicians of Kawasaki disease;<ref name=":0">Shulman, Stanford T. "Pediatric coronavirus disease-2019–associated multisystem inflammatory syndrome." ''Journal of the Pediatric Infectious Diseases Society'' (2020).</ref>
* Reports of a new febrile pediatric entity began to appear in late April 2020 during the [[COVID-19]] pandemic in the Western Europe, characterized by systemic hyperinflammation, [[Abdominal pain|abdominal pai]]<nowiki/>n with [[gastrointestinal]] symptoms and [[Multiorgan failure|multiorgan]] involvement affecting especially the [[myocardium]] causing [[cardiogenic shock]] which reminded the physicians of [[Kawasaki disease]];<ref name=":0">Shulman, Stanford T. "Pediatric coronavirus disease-2019–associated multisystem inflammatory syndrome." ''Journal of the Pediatric Infectious Diseases Society'' (2020).</ref>
* Cases of children with such symptoms were quickly identified in the New York City area, which was then the most heavily affected city in the U.S. by the COVID-19 pandemic;<ref name=":0" />
* Cases of children with such symptoms were quickly identified in the New York City area, which was then the most heavily affected city in the U.S. by the [[COVID-19]] pandemic;<ref name=":0" />
* 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;<ref name=":0" />
* 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]];<ref name=":0" />
* In 22 May, an article from the Journal of Pediatric Infectious Diseases Society addressed some of the similarities and differences of this new entity with Kawasaki's Syndrome, noting that the demographics affected was 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=":0" />
* In 22 May, 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 was 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=":0" />


==Classification of Disease Severity of MIS-C ==
==Classification of Disease Severity of COVID-19-associated multisystem inflammatory syndrome ==


*'''Mild Disease'''
* There is no established system for the classification of COVID-19-associated multisystem inflammatory syndrome.
*Children with MIS-C fall under this category who-
**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-
**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==
==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 exact pathophysiological mechanism of COVID-19-associated multisystem inflammatory syndrome is unclear.  
*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).
*Since there is a lag time between COVID-19-associated multisystem inflammatory syndrome appearance and [[COVID-19]] infection ([[median]] time: 25 days)<ref name=":2">Feldstein, Leora R., et al. "Multisystem inflammatory syndrome in US children and adolescents." ''New England Journal of Medicine'' (2020).</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=":3">Rowley, Anne H. "Understanding SARS-CoV-2-related multisystem inflammatory syndrome in children." ''Nature Reviews Immunology'' (2020): 1-2.</ref>
* It is also suspected that since MIS-C presents predominantly with gastrointestinal manifestations, it replicates predominantly in the gastrointestinal tract.
*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 seen in patients with [[COVID-19]] who are treated with convalescent plasma, which could have occurred if it was an antibody-mediated enhancement.<ref name=":3" />
*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=":3" />


==Differentiating Any Disease from other disease==
==Differentiating Any Disease from other disease==


* Children who met criteria for PIMS-TS presented features that overlapped with the ones seen on Kawasaki Disease and Toxic Shock Syndrome.<ref name=":1">Whittaker E, Bamford A, Kenny J, et al; PMIS-TS Study Group; EUCLIDS and PERFORM Consortia. Clinical and laboratory characteristics of 58 children with a pediatric multisystem inflammatory syndrome temporally associated with SARSCoV-2. JAMA. doi:10.1001/jama.2020.10369</ref>
* Children who met criteria for COVID-19-associated multisystem inflammatory syndrome presented features that overlapped with the ones seen on [[Kawasaki's disease]] and [[toxic shock syndrome]], such as [[conjunctival injection]], [[oropharyngeal]] findings (red and/or cracked lips, [[strawberry tongue]]), [[rash]], [[Swelling|swollen]] and/or [[erythematous]] hands and feet, and cervical [[lymphadenopathy]].<ref name=":1">Whittaker E, Bamford A, Kenny J, et al; PMIS-TS Study Group; EUCLIDS and PERFORM Consortia. Clinical and laboratory characteristics of 58 children with a pediatric multisystem inflammatory syndrome temporally associated with SARSCoV-2. JAMA. doi:10.1001/jama.2020.10369</ref>
* PCR tests for SARS-CoV-2 were positive in the minority of cases (26%), while the IgG antibody was positive in most patients (87%)<ref name=":1" /> and it remains as the preferred laboratory for differentiating such diseases;
*[[PCR]] tests for SARS-CoV-2 were positive in the minority of cases (26%), while the [[IgG]] [[antibody]] was positive in most patients (87%)<ref name=":1" /> and it remains as the preferred laboratory test for differentiating such diseases;
*The first cases of COVID-19-associated multisystem inflammatory syndrome presented with: unrelenting [[fever]] (38–40°C), [[conjunctivitis]], cutaneous [[rash]], [[peripheral edema]], extremity pain and remarkable [[gastrointestinal]] symptoms. Most didn't have any respiratory symptoms, and all progressed to warm vasoplegic [[Shock (circulatory)|shock]], refractory to volume resuscitation demanding [[vasopressors]] for [[hemodynamic]] support.<ref name=":4">Riphagen, Shelley, et al. "Hyperinflammatory shock in children during COVID-19 pandemic." ''The Lancet'' 395.10237 (2020): 1607-1608.</ref>
*[[Serum]] [[IL-6]] level was elevated in most patients. IL-2R, IL-18, and CXCL 9 levels were elevated in all patients of a cohort and mildly increased IFN-γ and [[IL-8]] levels in some.
*[[TNF-α]], IL-1b, [[IL-2]], [[IL-4]], [[IL-5]], and [[IL-13]] levels remained normal in one in a series of cases from New York City.<ref>Cheung, Eva W., et al. "Multisystem Inflammatory Syndrome Related to COVID-19 in Previously Healthy Children and Adolescents in New York City." ''JAMA'' (2020).</ref>


{| class="wikitable"
{| class="wikitable"
|+Summary of laboratory parameters of a PIMS-TS cohort compared with the historic cohorts of Kawasaki Disease, Kawasaki Disease Shock Syndrome and Toxic Shock Syndrome<ref name=":1" />
|+Summary of laboratory parameters of a COVID-19-associated multisystem inflammatory syndrome cohort compared with the historic cohorts of Kawasaki Disease, Kawasaki Disease Shock Syndrome and Toxic Shock Syndrome<ref name=":1" />
!Parameters
!Parameters
!Pediatric Inflammatoy Multisystem Syndrome Temporally associated with SARS-CoV-2 Infection (PIMS-TS)
!COVID-19-associated multisystem inflammatory syndrome (PIMS-TS)
!Kawasaki Disease (KD)
!Kawasaki Disease (KD)
!Kawasaki Disease Shock (KDS)
!Kawasaki Disease Shock (KDS)
Line 120: Line 113:
| -
| -
|}
|}
<br />
 
* Most patients presented with the following findings: elevated [[erythrocyte sedimentation rate]] or [[C-reactive protein (CRP)|C-reactive protein]] level, elevated [[ferritin]] level, [[lymphocytopenia]], [[hypoalbuminemia]], [[neutrophilia]], elevated [[alanine aminotransferase]] level, [[anemia]], [[thrombocytopenia]] prolonged [[INR]], elevated [[d-dimer]] level, or elevated [[fibrinogen]] level.<ref name=":2" />
 
==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.
*Poor prognostic factors include age over 5 years and [[ferritin]] larger than 1400 µg/L.<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>
*80% of the children were admitted to the intensive care unit and 20% of the children required mechanical ventilation.
*4% of the children required extracorporeal membrane oxygenation.
*The mortality rate among 186 children with MIS-C was 2%.


'''Age'''
'''Age'''


*Among the 186 children with MIS-C distribution of age group was
*Children aged age over 5 years seem to have a worse [[prognosis]] than younger ones.<ref name=":5" />
**<1yr-7%
*The [[median]] age found out in a study published by JAMA was 9 years.<ref name=":1" />
** 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, estimated in two thirds, seem to happen in boys.<ref name=":4" /><ref name=":1" />
 
'''Comorbidities'''


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


'''Organ System Involved'''
*It seems to affect predominantly blacks and asians.<ref name=":1" /><ref name=":4" />


*71% of children had involvement of at least four organ systems.
'''Comorbidities'''
 
The most common organ system involved in MIS-C children among a total of 186 children were.


*Gastrointestinal(92%)
* Clinical evidence of association with underlying diseases is still scarce since it is a rare presentation of [[COVID-19]] in children and teenagers.<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>
*Cardiovascular(80%)
*Hematologic(76%)
* Mucocutaneous(74%)
*Pulmonary(70%)
* Historical perspective


<br />
== References ==
== References ==
{{Reflist|32em}}
{{Reflist|32em}}

Revision as of 21:16, 13 July 2020

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

  • Reports of a new febrile pediatric entity began to appear in late April 2020 during the COVID-19 pandemic in the Western Europe, characterized by systemic hyperinflammation, abdominal pain with gastrointestinal symptoms and multiorgan involvement affecting especially the myocardium causing cardiogenic shock which reminded the physicians of Kawasaki disease;[1]
  • Cases of children with such symptoms were quickly identified in the New York City area, which was then 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]
  • In 22 May, 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 was 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.
  • Since there is a lag time between COVID-19-associated multisystem inflammatory syndrome appearance and COVID-19 infection (median time: 25 days)[2] 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.[3]
  • 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 seen in patients with COVID-19 who are treated with convalescent plasma, which could have occurred if it was an antibody-mediated enhancement.[3]
  • 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.[3]

Differentiating Any Disease from other disease

Summary of laboratory parameters of a COVID-19-associated multisystem inflammatory syndrome cohort compared with the historic cohorts of Kawasaki Disease, Kawasaki Disease Shock Syndrome and Toxic Shock Syndrome[4]
Parameters COVID-19-associated multisystem inflammatory syndrome (PIMS-TS) Kawasaki Disease (KD) Kawasaki Disease Shock (KDS) Toxic Shock Syndrome (TSS)
Age (median, IQR) 9 (5.7-14) 2.7 (1.4-4.7) 3.8 (0.2-18) 7.38 (2.4-15.4)
Total white cell count (*10^9/L) 17 (12-22) 13.4 (10.5-17.3) 12.1 (7.9-15.5) 15.6 (7.5-20)
Neutrophil count (*10^9/L) 13 (10-19) 7.2 (5.1-9.9) 5.5 (3.2-10.3) 16.4 (12-22)
Lymphocyte count (*10^9/L) 0.8 (0.5-1.5) 2.8 (1.5-4.4) 1.6 (1-2.5) 0.63 (0.41, 1.13)
Hemoglobin (g/L) 92 (83-103) 111.0 (105-119) 107 (98-115) 114 (98-130)
Platelet number (10^9/L) 151 (104-210) 365.0 (288-462) 235 (138-352) 155 (92- 255)
C-reactive protein (mg/L) 229 (156-338) 67.0(40-150) 193 (83-237) 201 (122, 317)
ALT (IU/L) 42 (26-95) 42.0 (24-112) 73 (34-107) 30.00 (22.10, 49.25)
Albumin (g/L) 24 (21-27) 38.0 (35-41) 30 (27-35) 27.00 (21.00, 31.00)
Ferritin (ug/L) 610 (359-1280) 200 (143-243) 301 (228-337) -
NT-Pro-BNP (pg/ml) 788 (174-10548) 41 (12-102) 396 (57-1520) -
Troponin (ng/L) 45 (8-294) 10.0 (10-20) 10 (10-30) -
D-dimer (ng/ml) 3578 (2085- 8235) 1650 (970-2660) 2580 (1460- 2990) -

Epidemiology and Demographics

  • Poor prognostic factors include age over 5 years and ferritin larger than 1400 µg/L.[7]

Age

  • Children aged age over 5 years seem to have a worse prognosis than younger ones.[7]
  • The median age found out in a study published by JAMA was 9 years.[4]

Gender

  • Most of the cases, estimated in two thirds, seem to happen in boys.[5][4]

Race

  • It seems to affect predominantly blacks and asians.[4][5]

Comorbidities

  • Clinical evidence of association with underlying diseases is still scarce since it is a rare presentation of COVID-19 in children and teenagers.[8]

References

  1. ↑ 1.0 1.1 1.2 1.3 Shulman, Stanford T. "Pediatric coronavirus disease-2019–associated multisystem inflammatory syndrome." Journal of the Pediatric Infectious Diseases Society (2020).
  2. ↑ 2.0 2.1 Feldstein, Leora R., et al. "Multisystem inflammatory syndrome in US children and adolescents." New England Journal of Medicine (2020).
  3. ↑ 3.0 3.1 3.2 Rowley, Anne H. "Understanding SARS-CoV-2-related multisystem inflammatory syndrome in children." Nature Reviews Immunology (2020): 1-2.
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 Whittaker E, Bamford A, Kenny J, et al; PMIS-TS Study Group; EUCLIDS and PERFORM Consortia. Clinical and laboratory characteristics of 58 children with a pediatric multisystem inflammatory syndrome temporally associated with SARSCoV-2. JAMA. doi:10.1001/jama.2020.10369
  5. ↑ 5.0 5.1 5.2 Riphagen, Shelley, et al. "Hyperinflammatory shock in children during COVID-19 pandemic." The Lancet 395.10237 (2020): 1607-1608.
  6. ↑ Cheung, Eva W., et al. "Multisystem Inflammatory Syndrome Related to COVID-19 in Previously Healthy Children and Adolescents in New York City." JAMA (2020).
  7. ↑ 7.0 7.1 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).
  8. ↑ "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)

External links

Classification
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External resources

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Case courtesy of Dr Ian Bickle, Radiopaedia.org, rID: 76157




 
 
 
 
 
 
 
Syncope classification
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vasovagal
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Micturation
 
 
 
 
 
 
 
 
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Case courtesy of Dr Vinay V Belaval, Radiopaedia.org, rID: 66974


Disease Type Sign Symptom



Syncope is classified into three categories:



Disease Name Age of Onset Gender Preponderance Signs/Symptoms Imaging Feature(s) Macroscopic Feature(s) Microscopic Feature(s) Laboratory Findings(s) Other Feature(s) ECG view
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