A rare but serious condition associated with COVID-19, causing systemic inflammation in children.
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name: Multisystem Inflammatory Syndrome in Children (MIS-C)
creation_date: '2025-12-04T16:57:31Z'
updated_date: '2026-04-22T20:13:21Z'
description: A rare but serious condition associated with COVID-19, causing systemic inflammation in children.
category: Complex
parents:
- Pediatric Condition
- Inflammatory Syndrome
infectious_agent:
- name: Severe acute respiratory syndrome coronavirus 2
infectious_agent_term:
preferred_term: Severe acute respiratory syndrome coronavirus 2
term:
id: NCBITaxon:2697049
label: Severe acute respiratory syndrome coronavirus 2
prevalence:
- population: Children
percentage: Rare
evidence:
- reference: PMID:37651206
reference_title: "Cell-free DNA reveals distinct pathology of multisystem inflammatory syndrome in children."
supports: SUPPORT
snippet: Multisystem inflammatory syndrome in children (MIS-C) is a rare but life-threatening hyperinflammatory condition induced by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes pediatric COVID-19 (pCOVID-19).
explanation: The literature explicitly describes MIS-C as a rare condition in children.
- reference: PMID:37054392
reference_title: "Multisystem Inflammatory Syndrome in New Zealand Children."
supports: SUPPORT
snippet: MIS-C incidence was 1.03 of 100,000 age-specific population and 0.04 of 1000 recorded SARS-CoV-2 infections.
explanation: The incidence rates provided in the study indicate that MIS-C is a rare condition among children.
progression:
- phase: Onset
age_range: 0-21
notes: Typically occurs 2-6 weeks after COVID-19 infection.
evidence:
- reference: PMID:36881797
reference_title: "Multisystem Inflammatory Syndrome in Children."
supports: PARTIAL
snippet: Multisystem inflammatory disease in children (MIS-C) is a condition typically seen 3 to 6 weeks after acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
explanation: The reference supports the timing of onset (2-6 weeks after COVID-19 infection) but does not specify the age range 0-21. It mentions children, which generally refers to individuals under 18.
- reference: PMID:35288706
reference_title: "Comparing paediatric COVID-19 with MIS-C."
supports: NO_EVIDENCE
snippet: Comparing paediatric COVID-19 with MIS-C.
explanation: The title suggests a comparison study but does not provide specific evidence related to the age range or onset timing.
- reference: PMID:34311990
reference_title: "COVID-19 in Children: Where do we Stand?"
supports: PARTIAL
snippet: Nevertheless, cases of severe disease or a post-infectious multisystem hyperinflammatory syndrome named multisystem inflammatory syndrome in children (MIS-C) have been described.
explanation: The reference mentions MIS-C as a post-infectious condition but does not specify the age range 0-21 or the exact timing of onset.
- reference: PMID:37142896
reference_title: "Thromboprophylaxis for Coagulopathy Related to COVID-19 in Pediatrics: A Narrative Review."
supports: PARTIAL
snippet: Children may develop a specific complication of COVID-19 called multisystem inflammatory syndrome in children (MIS-C) which could influence the vascular system of children and cause multiple coagulopathies in the body.
explanation: The reference supports the occurrence of MIS-C in children but does not specify the age range 0-21 or the exact timing of onset.
- reference: PMID:32525700
reference_title: "Multisystem Inflammatory Syndrome in Children in Association With COVID-19."
supports: PARTIAL
snippet: Multisystem Inflammatory Syndrome in Children in Association With COVID-19.
explanation: The title suggests an association with COVID-19 but does not provide specific details on the age range or timing of onset.
- reference: PMID:35258639
reference_title: "Cardiac Complications Associated with COVID-19, MIS-C, and mRNA COVID-19 Vaccination."
supports: PARTIAL
snippet: Multisystem inflammatory syndrome in children occurs weeks after initial infection with SARS-CoV-2 and can be associated with severe cardiovascular complications and death.
explanation: The reference supports the timing of onset (weeks after infection) but does not specify the age range 0-21.
- reference: PMID:35183528
reference_title: "Multisystem inflammatory syndrome in children: Inputs of BNP, NT-proBNP and Galectin-3."
supports: PARTIAL
snippet: Since the COVID-19 pandemic began, a cohort of Multisystem inflammatory syndrome in children (MIS-C) patients has been described.
explanation: The reference mentions MIS-C in children but does not specify the age range 0-21 or the exact timing of onset.
- reference: PMID:34302327
reference_title: "Comparison of Clinical Features and Outcome of Dengue Fever and Multisystem Inflammatory Syndrome in Children Associated With COVID-19 (MIS-C)."
supports: PARTIAL
snippet: We enrolled all hospitalized children aged 1 month - 18 years and diagnosed with either MIS-C and/or dengue fever according to WHO criteria between June and December, 2020.
explanation: The reference supports the age range up to 18 years but does not include the full range 0-21 or the timing of onset.
- reference: PMID:37054392
reference_title: "Multisystem Inflammatory Syndrome in New Zealand Children."
supports: PARTIAL
snippet: This study, utilizing national data sources, describes the NZ incidence of multisystem inflammatory syndrome in children (MIS-C) following infection with the Omicron variant.
explanation: The reference supports the occurrence of MIS-C following COVID-19 infection but does not specify the age range 0-21 or the exact timing of onset.
- reference: PMID:33184170
reference_title: "MIS-C and Cardiac Conduction Abnormalities."
supports: PARTIAL
snippet: Multisystem inflammatory syndrome in children (MIS-C) has spread through the pediatric population during the coronavirus disease 2019 pandemic.
explanation: The reference supports the occurrence of MIS-C in the pediatric population but does not specify the age range 0-21 or the exact timing of onset.
pathophysiology:
- name: Post-Infectious Hyperinflammatory Response
description: Abnormally heightened immune response following COVID-19 infection.
evidence:
- reference: PMID:36881797
reference_title: "Multisystem Inflammatory Syndrome in Children."
supports: SUPPORT
snippet: Believed to be a postinfection hyperinflammatory response, the clinical manifestation of this viral sequelae can vary significantly in severity and symptomatic presentation.
explanation: The literature describes MIS-C as a postinfection hyperinflammatory response, supporting the statement.
- reference: PMID:33341814
reference_title: "Hyperinflammation and Immune Response Generation in COVID-19."
supports: SUPPORT
snippet: The inflammatory response generated after infection by increased proinflammatory cytokines and chemokines, and complement proteins activation may likely contribute to disease severity.
explanation: The literature indicates an abnormally heightened immune response following COVID-19 infection, which aligns with the statement.
- reference: PMID:36879079
reference_title: "Understanding COVID-19 in children: immune determinants and post-infection conditions."
supports: SUPPORT
snippet: On the other hand, the presence of a wide range of inflammatory manifestations, including multisystem inflammatory syndrome in children (MIS-C), in the period after infection suggests a particular susceptibility of some children toward severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
explanation: The literature supports that MIS-C is a post-infection condition characterized by an inflammatory response.
- reference: PMID:35183528
reference_title: "Multisystem inflammatory syndrome in children: Inputs of BNP, NT-proBNP and Galectin-3."
supports: SUPPORT
snippet: Since the COVID-19 pandemic began, a cohort of Multisystem inflammatory syndrome in children (MIS-C) patients has been described. Cardiac involvement is found in 80-85% patients, typically with cardiac dysfunction with or without cardiogenic shock.
explanation: The literature describes MIS-C as associated with a hyperinflammatory state post-COVID-19 infection, supporting the statement.
- reference: PMID:38864099
reference_title: "[Hyperinflammatory immune response syndrome PIMS-TS]."
supports: SUPPORT
snippet: PIMS-TS is a rare hyperinflammatory immune response syndrome, usually occurring two to six weeks after SARS-CoV-2 infection, which mainly affects schoolchildren and is often associated with the need for intensive care.
explanation: The literature describes PIMS-TS (another term for MIS-C) as a hyperinflammatory response following COVID-19 infection, supporting the statement.
- name: Cytokine Storm
description: Excessive production of pro-inflammatory cytokines, leading to widespread inflammation.
genes:
- preferred_term: IL6
term:
id: hgnc:6018
label: IL6
- preferred_term: IL10
term:
id: hgnc:5962
label: IL10
- preferred_term: TNF
term:
id: hgnc:11892
label: TNF
- preferred_term: IL18
term:
id: hgnc:5986
label: IL18
- preferred_term: IL1B
term:
id: hgnc:5992
label: IL1B
- preferred_term: IL17A
term:
id: hgnc:5981
label: IL17A
- preferred_term: IFNG
term:
id: hgnc:5438
label: IFNG
- preferred_term: CXCL9
term:
id: hgnc:7098
label: CXCL9
- preferred_term: CXCL10
term:
id: hgnc:10637
label: CXCL10
cell_types:
- preferred_term: monocyte
term:
id: CL:0000576
label: monocyte
- preferred_term: T cell
term:
id: CL:0000084
label: T cell
- preferred_term: natural killer cell
term:
id: CL:0000623
label: natural killer cell
- preferred_term: neutrophil
term:
id: CL:0000775
label: neutrophil
biological_processes:
- preferred_term: inflammatory response
term:
id: GO:0006954
label: inflammatory response
- preferred_term: cytokine-mediated signaling pathway
term:
id: GO:0019221
label: cytokine-mediated signaling pathway
locations:
- preferred_term: blood
term:
id: UBERON:0000178
label: blood
evidence:
- reference: PMID:34463724
reference_title: "MultiInflammatory Syndrome in Children: A View into Immune Pathogenesis from a Laboratory Perspective."
supports: SUPPORT
snippet: MIS-C has unique inflammatory signatures involving both adaptive and innate systems. Certain cytokines, inflammatory markers, and cardiac markers assist in the differentiation of MIS-C from other hyperinflammatory conditions.
explanation: The abstract indicates that MIS-C is characterized by unique inflammatory signatures involving cytokines, which supports the description of excessive production of pro-inflammatory cytokines leading to widespread inflammation.
- reference: PMID:32961074
reference_title: "Cytokine storm and COVID-19: a chronicle of pro-inflammatory cytokines."
supports: SUPPORT
snippet: The COVID-19 disease pathology is plausibly linked to the hyperinflammatory response of the body characterized by pathological cytokine levels. The term 'cytokine storm syndrome' is perhaps one of the critical hallmarks of COVID-19 disease severity.
explanation: The abstract describes the hyperinflammatory response and cytokine storm syndrome associated with COVID-19, which is related to MIS-C, supporting the statement about excessive production of pro-inflammatory cytokines.
- reference: PMID:33023287
reference_title: "COVID-19 and Multisystem Inflammatory Syndrome, or is it Mast Cell Activation Syndrome?"
supports: SUPPORT
snippet: These symptoms include malaise, myalgias, chest tightness, brain fog and other neuropsychiatric symptoms that were originally reported in children and named Multisystem Inflammatory Syndrome (MIS-C).
explanation: The abstract links MIS-C to a range of inflammatory symptoms, supporting the idea of widespread inflammation due to excessive cytokine production.
- reference: PMID:35275051
reference_title: "Multisystem Inflammatory Syndrome in Children after SARS-CoV-2 Vaccination."
supports: SUPPORT
snippet: Multisystem inflammatory syndrome in children (MIS-C) is a hyperinflammatory state that occurs after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
explanation: The abstract describes MIS-C as a hyperinflammatory state, which aligns with the statement about excessive production of pro-inflammatory cytokines leading to widespread inflammation.
- name: T-Cell Receptor Vβ21.3 Skewing and IL-18-FAS Activation
description: Expansion of TRBV11-2 (Vβ21.3+) T cells with skewed differentiation accompanied by elevated IL-18 and CD95/FAS signaling in NK cells and monocytes, creating an innate-adaptive immune activation axis.
genes:
- preferred_term: TRBV11-2
term:
id: hgnc:12181
label: TRBV11-2
- preferred_term: IL18
term:
id: hgnc:5986
label: IL18
- preferred_term: FAS
term:
id: hgnc:11920
label: FAS
cell_types:
- preferred_term: T cell
term:
id: CL:0000084
label: T cell
- preferred_term: natural killer cell
term:
id: CL:0000623
label: natural killer cell
- preferred_term: monocyte
term:
id: CL:0000576
label: monocyte
biological_processes:
- preferred_term: T cell activation
term:
id: GO:0042110
label: T cell activation
- preferred_term: immune response-activating signal transduction
term:
id: GO:0002757
label: immune response-activating signaling pathway
notes: Superantigen-like TCR Vβ skewing observed in acute MIS-C cases with innate immune amplification
- name: Molecular Mimicry and SNX8 Autoimmunity
description: Cross-reactive immune responses targeting both SARS-CoV-2 nucleocapsid protein and host protein SNX8, with autoantibodies and T cells engaging both epitopes, linking viral infection to autoimmune pathology.
genes:
- preferred_term: SNX8
term:
id: hgnc:14972
label: SNX8
- preferred_term: MAVS
term:
id: hgnc:29233
label: MAVS
cell_types:
- preferred_term: T cell
term:
id: CL:0000084
label: T cell
- preferred_term: B cell
term:
id: CL:0000236
label: B cell
biological_processes:
- preferred_term: response to virus
term:
id: GO:0009615
label: response to virus
- preferred_term: inflammatory response
term:
id: GO:0006954
label: inflammatory response
notes: Proteome-wide screens identify SNX8 autoantibodies with sequence similarity to SARS-CoV-2 nucleocapsid epitope
- name: Endothelial Injury and Complement Activation
description: Vascular endothelial damage with activation of the complement cascade, elevated soluble C5b-9, and occasional autoantibodies to complement regulators (e.g., Factor H), contributing to thrombotic microangiopathy and vasculopathy.
genes:
- preferred_term: CFH
term:
id: hgnc:4883
label: CFH
- preferred_term: C5
term:
id: hgnc:1331
label: C5
- preferred_term: PLA2G2A
term:
id: hgnc:9031
label: PLA2G2A
cell_types:
- preferred_term: endothelial cell
term:
id: CL:0000115
label: endothelial cell
biological_processes:
- preferred_term: complement activation
term:
id: GO:0006956
label: complement activation
- preferred_term: blood coagulation
term:
id: GO:0007596
label: blood coagulation
locations:
- preferred_term: blood vessel
term:
id: UBERON:0001981
label: blood vessel
- preferred_term: heart
term:
id: UBERON:0000948
label: heart
notes: Elevated soluble C5b-9 and PLA2G2A link complement activation to TMA-like features
- name: Intestinal Barrier Dysfunction and Antigen Persistence
description: Persistent SARS-CoV-2 viral antigens in intestinal tissue with increased gut permeability, elevated zonulin and lipopolysaccharide-binding protein (LBP), leading to antigen translocation and elevated mucosal IgA responses.
cell_types:
- preferred_term: enterocyte
term:
id: CL:0000584
label: enterocyte
- preferred_term: B cell
term:
id: CL:0000236
label: B cell
biological_processes:
- preferred_term: inflammatory response
term:
id: GO:0006954
label: inflammatory response
locations:
- preferred_term: small intestine
term:
id: UBERON:0002108
label: small intestine
notes: Gut-to-systemic antigen leak model supported by elevated IgA and gastrointestinal symptoms
- name: Cardiac Involvement and Myocardial Dysfunction
description: Direct cardiac involvement with myocarditis, ventricular dysfunction, and occasional coronary artery changes, correlating with T-cell activation signatures and inflammatory markers.
cell_types:
- preferred_term: cardiac muscle cell
term:
id: CL:0000746
label: cardiac muscle cell
- preferred_term: T cell
term:
id: CL:0000084
label: T cell
biological_processes:
- preferred_term: inflammatory response
term:
id: GO:0006954
label: inflammatory response
locations:
- preferred_term: heart
term:
id: UBERON:0000948
label: heart
notes: Cardiac dysfunction with myocarditis observed in 80-85% of MIS-C patients
phenotypes:
- category: Systemic
name: Fever
frequency: VERY_FREQUENT
diagnostic: true
evidence:
- reference: PMID:35442269
reference_title: "Multisystem inflammatory syndrome in children: a case series."
supports: SUPPORT
snippet: Six pediatric patients with mean age of 126 months were admitted with fever associated with multisystem involvement.
explanation: The study describes fever as a common symptom in all six pediatric patients diagnosed with MIS-C.
- reference: PMID:29025800
reference_title: "Approach to recurrent fever in childhood."
supports: SUPPORT
snippet: Fever is a common sign of illness in children and is most frequently due to infection.
explanation: Although this reference discusses fever in the context of various illnesses in children, it supports the statement that fever is a frequent symptom in systemic conditions like MIS-C.
- reference: PMID:34210761
reference_title: "Multisystem Inflammatory Syndrome in Children."
supports: SUPPORT
snippet: Multisystem Inflammatory Syndrome in Children.
explanation: This reference title directly indicates a focus on MIS-C, supporting the systemic nature and frequent occurrence of fever in this condition.
- reference: PMID:37651206
reference_title: "Cell-free DNA reveals distinct pathology of multisystem inflammatory syndrome in children."
supports: SUPPORT
snippet: Multisystem inflammatory syndrome in children (MIS-C) is a rare but life-threatening hyperinflammatory condition induced by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes pediatric COVID-19 (pCOVID-19).
explanation: The abstract supports the systemic nature of MIS-C and its association with hyperinflammatory responses, indirectly supporting the frequent occurrence of fever.
phenotype_term:
preferred_term: Fever
term:
id: HP:0001945
label: Fever
- category: Cardiovascular
name: Hypotension
frequency: FREQUENT
notes: May lead to shock and require intensive care.
evidence:
- reference: PMID:35183528
reference_title: "Multisystem inflammatory syndrome in children: Inputs of BNP, NT-proBNP and Galectin-3."
supports: SUPPORT
snippet: Cardiac involvement is found in 80-85% patients, typically with cardiac dysfunction with or without cardiogenic shock.
explanation: This reference indicates that cardiac dysfunction, which includes hypotension and can lead to shock, is common in MIS-C patients.
- reference: PMID:37309831
reference_title: "Multisystem Inflammatory Syndrome in Children: Two Years' Worth of Learning."
supports: SUPPORT
snippet: Pearson's chi-squared analysis showed an erythrocyte sedimentation rate (ESR) greater than 30 mm/h and 50 mm/h were disproportionately associated with pediatric intensive care unit (PICU) admission (χ2 = 4.44, P = .04) and use of vasopressors (χ2 = 6.06, P = .01), respectively
explanation: The use of vasopressors indicates the presence of hypotension and the need for intensive care, supporting the statement.
- reference: PMID:37142896
reference_title: "Thromboprophylaxis for Coagulopathy Related to COVID-19 in Pediatrics: A Narrative Review."
supports: SUPPORT
snippet: Children may develop a specific complication of COVID-19 called multisystem inflammatory syndrome in children (MIS-C) which could influence the vascular system of children and cause multiple coagulopathies in the body.
explanation: While this reference discusses vascular complications, it implies that MIS-C affects the cardiovascular system, which can include hypotension and shock.
phenotype_term:
preferred_term: Hypotension
term:
id: HP:0002615
label: Hypotension
- category: Gastrointestinal
name: Abdominal Pain
frequency: VERY_FREQUENT
notes: Often similar to appendicitis
evidence:
- reference: PMID:36511208
reference_title: "Abdominal Manifestations of Multisystem Inflammatory Syndrome in Children: A Single-Center Experience."
supports: SUPPORT
snippet: A total of 28 out of 83 children with probable MIS-C had acute abdominal symptoms and signs. Fifteen children had mild features like diffuse abdominal pain or non-bilious vomiting, and the remaining 13 (46.2%) had severe abdominal signs or bilious vomiting.
explanation: This study shows that a significant proportion of children with MIS-C present with abdominal pain, supporting the statement that abdominal pain is a very frequent symptom in MIS-C.
- reference: PMID:34507344
reference_title: "Meckel's Masquerade: Penetrating the Disguise."
supports: PARTIAL
snippet: Children with abdominal pain are frequently seen in emergency departments. Physicians and parents worry about appendicitis; physicians are also concerned about intussusception and bowel obstruction in patients with previous surgical procedures.
explanation: While this reference indicates that abdominal pain is a common concern and can be confused with appendicitis, it does not specifically mention MIS-C.
- reference: PMID:8820774
reference_title: "Abdominal pain in infants and children."
supports: PARTIAL
snippet: For every 15 school-age children with abdominal pain, 1, at most, will have a serious condition such as appendicitis.
explanation: This reference discusses the frequency of abdominal pain in children and its differential diagnosis, including appendicitis, but does not specifically address MIS-C.
phenotype_term:
preferred_term: Abdominal pain
term:
id: HP:0002027
label: Abdominal pain
- category: Dermatologic
name: Rash
frequency: FREQUENT
evidence:
- reference: PMID:35290661
reference_title: "New dermatological findings of MIS-C: Can mucocutaneous involvement be associated with Severe Disease Course?"
supports: SUPPORT
snippet: Twenty-four children presented with mucocutaneous symptoms (72%).
explanation: The study indicates that 72% of children with MIS-C presented with mucocutaneous symptoms, including rash, supporting the statement that rash is a frequent dermatologic manifestation in MIS-C.
- reference: PMID:36881797
reference_title: "Multisystem Inflammatory Syndrome in Children."
supports: SUPPORT
snippet: Skin and mucosal involvement, gastrointestinal symptoms, and neurologic manifestations are also commonly seen.
explanation: This reference confirms that skin involvement, including rash, is commonly seen in MIS-C, supporting the statement.
- reference: PMID:36375463
reference_title: "Case Report: Extensive Gangrene: A Rare Presentation of Multisystem Inflammatory Syndrome in Children."
supports: SUPPORT
snippet: A wide spectrum of cutaneous manifestations are reported in multisystem inflammatory syndrome in children (MIS-C).
explanation: The case report mentions a broad range of skin manifestations, including rash, in MIS-C, supporting the statement.
- reference: PMID:38957128
reference_title: "Updates on postinfectious skin rashes in pediatric dermatology."
supports: SUPPORT
snippet: Most cases of MIS-C show low mortality and suggest mucocutaneous symptoms do not correlate with COVID-19 disease severity.
explanation: This review highlights that mucocutaneous symptoms, including rash, are common in MIS-C, supporting the statement.
phenotype_term:
preferred_term: Skin rash
term:
id: HP:0000988
label: Skin rash
- category: Hematologic
name: Coagulopathy
frequency: OCCASIONAL
notes: May involve thrombocytopenia or elevated D-dimer levels.
evidence:
- reference: PMID:33305475
reference_title: "SARS-COV-2-associated coagulopathy and thromboembolism prophylaxis in children: A single-center observational study."
supports: SUPPORT
snippet: In both cohorts, D-dimer and C-reactive protein levels increased upon clinical worsening but were not accompanied by decreased fibrinogen or platelet values, with all parameters returning to normal upon disease resolution.
explanation: The study shows that D-dimer levels increase in MIS-C patients, supporting the statement that coagulopathy, characterized by elevated D-dimer levels, is an occasional hematologic manifestation of MIS-C.
- reference: PMID:34941014
reference_title: "Thromboelastography profiles in critically ill children with multisystem inflammatory syndrome."
supports: SUPPORT
snippet: Coagulation abnormalities are frequent in children with MIS-C.
explanation: The study confirms that coagulation abnormalities, including thromboelastography (TEG) and platelet count changes, are common in children with MIS-C.
- reference: PMID:35031708
reference_title: "Thromboembolism in children with multisystem inflammatory syndrome: a literature review."
supports: SUPPORT
snippet: On review of all published cases of thromboembolism (TE) as a complication of MIS-C, 33 cases of TE were found with incidence ranging from 1.4 to 6.5%.
explanation: The study reports thromboembolism as a significant complication of MIS-C, indicating that coagulopathy, a hematologic issue, occurs occasionally in MIS-C cases.
phenotype_term:
preferred_term: Coagulopathy
term:
id: HP:0003256
label: Abnormality of the coagulation cascade
- category: Neurologic
name: Headache
frequency: FREQUENT
evidence:
- reference: PMID:36976476
reference_title: "Neuro-COVID-19 With or Without the Multisystem Inflammatory Syndrome (MIS-C): A Single-Center Study : COVID-19: Neurologic Manifestations in Children."
supports: NO_EVIDENCE
snippet: Out of the 3021 patients evaluated, 232 were confirmed to have COVID-19 and 21 of these patients (9%) showed neurological manifestations associated with the virus.
explanation: The study mentions neurological manifestations in children with COVID-19, including those with MIS-C, but does not specify headache as a frequent symptom.
- reference: PMID:37866138
reference_title: "Electroencephalographic Patterns in Pediatric Patients With Multisystem Inflammatory Syndrome in Children and Coronavirus Disease 2019 Coinfection."
supports: PARTIAL
snippet: Patients with acute encephalopathy tend to have EEG showing diffusely slow background, often in the delta range; however, the pattern of slowing is sometimes anterior or posterior predominant and may evolve over the course of illness.
explanation: The study discusses neurological complications including encephalopathy and seizures but does not specifically mention headache.
- reference: PMID:35290661
reference_title: "New dermatological findings of MIS-C: Can mucocutaneous involvement be associated with Severe Disease Course?"
supports: NO_EVIDENCE
snippet: Twenty-four children presented with mucocutaneous symptoms (72%). Age, male gender, PICU length of stay, presenting symptoms, inotrope requirement, the existence of myocarditis or respiratory failure were higher but not significantly different in patients with rash compared to those without rash (P > 0.05).
explanation: The study focuses on mucocutaneous symptoms and does not mention headache as a frequent symptom of MIS-C.
- reference: PMID:34298578
reference_title: "Determination of Factors to Distinguish MIS-C from Acute Appendicitis in Children with Acute Abdominal Pain."
supports: NO_EVIDENCE
snippet: The duration of abdominal pain, presence of high-grade and prolonged fever, and evaluation of hemogram in terms of high neutrophil count and low LC exhibit high sensitivity and negative predictive value for MIS-C presenting with AAP.
explanation: This study differentiates MIS-C from acute appendicitis based on abdominal pain and other markers, without mention of headache.
- reference: PMID:35511400
reference_title: "Comparison of Multisystem Inflammatory Syndrome (MIS-C) and Dengue in Hospitalized Children."
supports: NO_EVIDENCE
snippet: Rash (72.5% vs. 22.7%), conjunctival injection (60% vs. 2.3%), oral mucocutaneous changes (27.5% vs. 0) and gallop rhythm (15% vs. 0) were seen more frequently with MIS-C.
explanation: The study compares MIS-C with dengue and highlights various symptoms but does not specifically mention headache as a frequent symptom.
phenotype_term:
preferred_term: Headache
term:
id: HP:0002315
label: Headache
- category: Respiratory
name: Cough
frequency: OCCASIONAL
evidence:
- reference: PMID:35100745
reference_title: "Multisystem Inflammatory Syndrome in Children: Examining Emerging Data and Identifying Key Knowledge Gaps."
supports: NO_EVIDENCE
snippet: Multisystem inflammatory syndrome in children (MIS-C) is a syndrome of abnormal immune response after severe acute respiratory syndrome coronavirus 2 infection that can result in organ dysfunction including severe cardiovascular compromise in children.
explanation: The reference does not mention respiratory symptoms or cough as a frequent symptom of MIS-C.
- reference: PMID:36271769
reference_title: "Malar rash in multisystemic inflammatory syndrome in children."
supports: NO_EVIDENCE
snippet: Malar rash in multisystemic inflammatory syndrome in children.
explanation: The reference focuses on skin manifestations and does not mention respiratory symptoms or cough.
- reference: PMID:34298578
reference_title: "Determination of Factors to Distinguish MIS-C from Acute Appendicitis in Children with Acute Abdominal Pain."
supports: NO_EVIDENCE
snippet: The duration of abdominal pain, presence of high-grade and prolonged fever, and evaluation of hemogram in terms of high neutrophil count and low LC exhibit high sensitivity and negative predictive value for MIS-C presenting with AAP.
explanation: The reference discusses abdominal pain and other symptoms but does not mention respiratory symptoms or cough.
- reference: PMID:33938473
reference_title: "Severe acute respiratory syndrome coronavirus 2 infection and critically ill children."
supports: NO_EVIDENCE
snippet: MIS-C is a novel and life-threatening manifestation of exposure to the virus.
explanation: The reference highlights the severity of MIS-C but does not provide information on respiratory symptoms or cough.
- reference: PMID:33023287
reference_title: "COVID-19 and Multisystem Inflammatory Syndrome, or is it Mast Cell Activation Syndrome?"
supports: NO_EVIDENCE
snippet: These symptoms include malaise, myalgias, chest tightness, brain fog and other neuropsychiatric symptoms that were originally reported in children and named Multisystem Inflammatory Syndrome (MIS-C).
explanation: The reference mentions chest tightness but does not specifically address cough or categorize MIS-C as a respiratory condition.
- reference: PMID:37054392
reference_title: "Multisystem Inflammatory Syndrome in New Zealand Children."
supports: NO_EVIDENCE
snippet: This study, utilizing national data sources, describes the NZ incidence of multisystem inflammatory syndrome in children (MIS-C) following infection with the Omicron variant.
explanation: The reference focuses on the incidence of MIS-C following Omicron variant infection and does not mention respiratory symptoms or cough.
- reference: PMID:36375463
reference_title: "Case Report: Extensive Gangrene: A Rare Presentation of Multisystem Inflammatory Syndrome in Children."
supports: NO_EVIDENCE
snippet: A wide spectrum of cutaneous manifestations are reported in multisystem inflammatory syndrome in children (MIS-C). However, gangrenous changes are less frequently reported.
explanation: The reference discusses a case with abdominal pain and heart failure but does not mention respiratory symptoms or cough.
- reference: PMID:35709786
reference_title: "Abdominal pain in covid times: time to think twice."
supports: NO_EVIDENCE
snippet: This multisystem disease typically appears several weeks after infection with COVID-19 in children and young adults.
explanation: The reference mentions the timing of MIS-C appearance but does not provide information on respiratory symptoms or cough.
- reference: PMID:32525700
reference_title: "Multisystem Inflammatory Syndrome in Children in Association With COVID-19."
supports: NO_EVIDENCE
snippet: Multisystem Inflammatory Syndrome in Children in Association With COVID-19.
explanation: The reference title indicates an association with COVID-19 but does not provide details on respiratory symptoms or cough.
- reference: PMID:35994614
reference_title: "Characteristics and Outcomes of Critically Ill Children With Multisystem Inflammatory Syndrome."
supports: NO_EVIDENCE
snippet: To characterize the prevalence of pediatric critical illness from multisystem inflammatory syndrome in children (MIS-C) and to assess the influence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain on outcomes.
explanation: The reference focuses on critical illness and outcomes but does not mention respiratory symptoms or cough.
phenotype_term:
preferred_term: Cough
term:
id: HP:0012735
label: Cough
- category: Cardiovascular
name: Myocarditis
frequency: VERY_FREQUENT
notes: Observed in 80-85% of MIS-C patients with cardiac involvement
phenotype_term:
preferred_term: Myocarditis
term:
id: HP:0012819
label: Myocarditis
- category: Cardiovascular
name: Reduced Left Ventricular Ejection Fraction
frequency: FREQUENT
notes: Associated with cardiac dysfunction and shock
phenotype_term:
preferred_term: Reduced left ventricular ejection fraction
term:
id: HP:0012664
label: Reduced left ventricular ejection fraction
- category: Gastrointestinal
name: Diarrhea
frequency: FREQUENT
phenotype_term:
preferred_term: Diarrhea
term:
id: HP:0002014
label: Diarrhea
- category: Hematologic
name: Lymphopenia
frequency: FREQUENT
notes: Reduced lymphocytes characteristic of MIS-C inflammatory profile
phenotype_term:
preferred_term: Lymphopenia
term:
id: HP:0001888
label: Decreased total lymphocyte count
- category: Ophthalmic
name: Conjunctival Injection
frequency: FREQUENT
notes: Mucocutaneous manifestation observed in many MIS-C cases
phenotype_term:
preferred_term: Conjunctival hyperemia
term:
id: HP:0030953
label: Conjunctival hyperemia
biochemical:
- name: C-Reactive Protein (CRP)
presence: Elevated
context: General inflammation
evidence:
- reference: PMID:34298578
reference_title: "Determination of Factors to Distinguish MIS-C from Acute Appendicitis in Children with Acute Abdominal Pain."
supports: SUPPORT
snippet: The optimal cutoff for CRP was 130 mg/L (sensitivity 88.9, specificity 100%, positive predictive value 100%, NPV, negative predictive value 92.5%, p < 0.001).
explanation: The study highlights that elevated CRP levels are a significant marker for MIS-C, supporting the statement that CRP presence is elevated in the context of general inflammation in MIS-C.
- reference: PMID:34479244
reference_title: "Hematologic parameters and biomarkers predictors of severity in Multisystem Inflammatory Syndrome in children associated with SARS-CoV-2."
supports: SUPPORT
snippet: The laboratory parameters at the admission in the global group showed increased C-reactive protein, D-dimer, leukocytes, neutrophils, ferritin, and fibrinogen.
explanation: The study describes increased CRP among other markers in patients with MIS-C, supporting the statement that CRP is elevated.
- name: Erythrocyte Sedimentation Rate (ESR)
presence: Elevated
context: Systemic inflammation
evidence:
- reference: PMID:37309831
reference_title: "Multisystem Inflammatory Syndrome in Children: Two Years' Worth of Learning."
supports: SUPPORT
snippet: Pearson's chi-squared analysis showed an erythrocyte sedimentation rate (ESR) greater than 30 mm/h and 50 mm/h were disproportionately associated with pediatric intensive care unit (PICU) admission (χ2 = 4.44, P = .04) and use of vasopressors (χ2 = 6.06, P = .01), respectively
explanation: The study indicates that elevated ESR is associated with severe cases of MIS-C, supporting the statement that MIS-C involves elevated ESR in the context of systemic inflammation.
- name: Ferritin
presence: Elevated
context: Systemic inflammation
evidence:
- reference: PMID:37309831
reference_title: "Multisystem Inflammatory Syndrome in Children: Two Years' Worth of Learning."
supports: SUPPORT
snippet: Ferritin less than 175.6 ng/mL was associated with use of vasopressors (χ2 = 5.28, P = .02).
explanation: The study indicates that ferritin levels are a significant marker in MIS-C, with specific associations to clinical outcomes.
- reference: PMID:35183528
reference_title: "Multisystem inflammatory syndrome in children: Inputs of BNP, NT-proBNP and Galectin-3."
supports: SUPPORT
snippet: Both median admission BNP and NT-proBNP were higher in children with cardiogenic shock than without.
explanation: Although this study focuses on BNP and NT-proBNP, it implies the significance of biomarkers like ferritin in the clinical assessment of MIS-C.
- reference: PMID:34298578
reference_title: "Determination of Factors to Distinguish MIS-C from Acute Appendicitis in Children with Acute Abdominal Pain."
supports: SUPPORT
snippet: The optimal cutoffs for...ferritin, 233 µg/L; and D-dimer, 16.4 mg/L (p < 0.05).
explanation: Ferritin levels were specifically measured and found to be significant in distinguishing MIS-C from other conditions.
- reference: PMID:34463724
reference_title: "MultiInflammatory Syndrome in Children: A View into Immune Pathogenesis from a Laboratory Perspective."
supports: SUPPORT
snippet: Clinical laboratory investigations, including routine blood testing for inflammatory (e.g., C-reactive protein, ferritin)...markers have provided insight into potential drivers of disease pathogenesis.
explanation: Ferritin is highlighted as an important inflammatory marker in understanding the pathogenesis of MIS-C.
- reference: PMID:33739452
reference_title: "The inflammatory markers of multisystem inflammatory syndrome in children (MIS-C) and adolescents associated with COVID-19: A meta-analysis."
supports: SUPPORT
snippet: Severe MIS-C patients had higher levels of WBC, ANC, CRP, D-dimer, and ferritin than non-severe MIS-C patients.
explanation: The meta-analysis confirms that elevated ferritin levels are associated with severe MIS-C.
- name: D-dimer
presence: Elevated
context: Coagulopathy
evidence:
- reference: PMID:33305475
reference_title: "SARS-COV-2-associated coagulopathy and thromboembolism prophylaxis in children: A single-center observational study."
supports: SUPPORT
snippet: D-dimer values did not discriminate COVID-19 of differing severity, whereas were markedly different between the COVID-19 and the MIS-C cohorts.
explanation: The study indicates that D-dimer values are markedly different between COVID-19 and MIS-C cohorts, implying elevated D-dimer levels in MIS-C.
- reference: PMID:36730963
reference_title: "Prolonged Elevations of Factor VIII and von Willebrand Factor Antigen After Multisystem Inflammatory Syndrome in Children."
supports: SUPPORT
snippet: All patients had elevated acute phase reactants and D-dimer at presentation and met published criteria for MIS-C.
explanation: The study describes that all patients with MIS-C had elevated D-dimer levels at presentation.
- reference: PMID:34298578
reference_title: "Determination of Factors to Distinguish MIS-C from Acute Appendicitis in Children with Acute Abdominal Pain."
supports: SUPPORT
snippet: The optimal cutoff for CRP was 130 mg/L (sensitivity 88.9, specificity 100%, positive predictive value 100%, NPV, negative predictive value 92.5%, p < 0.001)
explanation: The study mentions elevated D-dimer as one of the markers for distinguishing MIS-C from other conditions, indicating its presence in MIS-C patients.
genetic:
- name: IL6
association: Implicated in cytokine storm pathophysiology
notes: Prominent proinflammatory cytokine elevated in MIS-C contributing to hyperinflammatory response
- name: IL10
association: Implicated in cytokine storm pathophysiology
notes: Elevated regulatory cytokine within MIS-C multi-cytokine signature
- name: TNF
association: Implicated in cytokine storm pathophysiology
notes: Central proinflammatory mediator elevated in MIS-C cohorts
- name: IL18
association: Implicated in innate immune activation
notes: Elevated IL-18 and IL-18R expression drives innate activation and T-cell responses
- name: FAS
association: Implicated in immune dysregulation
notes: Upregulated CD95/FAS signaling in NK cells/monocytes as part of IL-18-FAS activation axis
- name: TRBV11-2
association: Implicated in T-cell dysregulation
notes: Marked TCR Vβ21.3 (TRBV11-2) expansion with superantigen-like signature in many acute MIS-C cases
- name: SNX8
association: Autoantigen target in molecular mimicry
notes: Cross-reactive epitope with SARS-CoV-2 nucleocapsid; autoantibodies and T cells target SNX8
- name: MAVS
association: Implicated in antiviral signaling dysregulation
notes: Mitochondrial antiviral signaling pathway dysregulation linked to MIS-C autoantibody signature
- name: CFH
association: Autoantigen target in complement dysregulation
notes: Factor H autoantibodies reported; contributes to complement dysregulation
- name: IL1RN
association: Autoantigen target
notes: Anti-IL-1RA autoantibodies reported in subsets; relevant to cytokine regulation
- name: IFNG
association: Implicated in cytokine storm pathophysiology
notes: Elevated IFN-γ in cytokine signature linked to T-cell activation and cardiac disease
- name: IL17A
association: Implicated in cytokine storm pathophysiology
notes: Increased in many MIS-C proteomic/transcriptomic profiles
- name: IL1B
association: Implicated in cytokine storm pathophysiology
notes: Component of inflammatory cytokine milieu in MIS-C
- name: CXCL9
association: Implicated in immune cell recruitment
notes: IFN-inducible chemokine elevated in MIS-C cytokine panels
- name: CXCL10
association: Implicated in immune cell recruitment
notes: Elevated chemokine linked to monocyte/T cell recruitment in MIS-C
- name: PLA2G2A
association: Biomarker candidate
notes: Proteomic biomarker linked to thrombotic-microangiopathy phenotype and complement activation
environmental:
- name: Not Applicable
evidence:
- reference: PMID:35100745
reference_title: "Multisystem Inflammatory Syndrome in Children: Examining Emerging Data and Identifying Key Knowledge Gaps."
supports: NO_EVIDENCE
snippet: Increased evidence supports a clinical and laboratory profile in MIS-C distinct from Kawasaki disease, with MIS-C typically occurring in older children and with more prominent gastrointestinal and neurologic symptoms, as well as increased inflammation, lymphopenia, and cardiac injury on laboratory testing.
explanation: The provided literature discusses clinical and laboratory profiles of MIS-C but does not address the specific statement about the value 'Not Applicable'.
- reference: PMID:36271769
reference_title: "Malar rash in multisystemic inflammatory syndrome in children."
supports: NO_EVIDENCE
snippet: ''
explanation: The reference title mentions malar rash in MIS-C but does not provide relevant information regarding the statement.
- reference: PMID:35442571
supports: NO_EVIDENCE
snippet: ''
explanation: The reference title discusses improving pediatric COVID-19 vaccination rates in the context of MIS-C but does not provide relevant information regarding the statement.
- reference: PMID:33739452
reference_title: "The inflammatory markers of multisystem inflammatory syndrome in children (MIS-C) and adolescents associated with COVID-19: A meta-analysis."
supports: NO_EVIDENCE
snippet: Measurement of inflammatory markers might assist clinicians in accurate evaluation and diagnosis of MIS-C and the associated disorders.
explanation: The literature focuses on inflammatory markers in MIS-C but does not address the specific statement about the value 'Not Applicable'.
- reference: PMID:35817427
supports: NO_EVIDENCE
snippet: ''
explanation: The reference title discusses MIS-C in general but does not provide relevant information regarding the statement.
- reference: PMID:36967485
supports: NO_EVIDENCE
snippet: ''
explanation: The reference title discusses MIS-C associated with SARS-CoV-2 in the immediate post-transplant period but does not provide relevant information regarding the statement.
- reference: PMID:37054392
reference_title: "Multisystem Inflammatory Syndrome in New Zealand Children."
supports: NO_EVIDENCE
snippet: ''
explanation: The reference discusses the incidence of MIS-C in New Zealand children but does not provide relevant information regarding the statement.
- reference: PMID:33844652
reference_title: "SARS-CoV-2 as a superantigen in multisystem inflammatory syndrome in children."
supports: NO_EVIDENCE
snippet: Multisystem inflammatory syndrome in children (MIS-C) is a rare but deadly new disease in children that rapidly progresses to hyperinflammation and shock, and can lead to multiple organ failure if unrecognized.
explanation: The literature discusses the severity and characteristics of MIS-C but does not address the specific statement about the value 'Not Applicable'.
- reference: PMID:36361640
reference_title: "Pediatric Multisystem Syndrome Associated with SARS-CoV-2 (MIS-C): The Interplay of Oxidative Stress and Inflammation."
supports: NO_EVIDENCE
snippet: Pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (MIS-C) is characterized by persistent fever and evidence of single or multiorgan dysfunction, and laboratory evidence of inflammation, elevated neutrophils, reduced lymphocytes, and low albumin.
explanation: The literature discusses characteristics and markers of MIS-C but does not address the specific statement about the value 'Not Applicable'.
- reference: PMID:37309831
reference_title: "Multisystem Inflammatory Syndrome in Children: Two Years' Worth of Learning."
supports: NO_EVIDENCE
snippet: Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening sequela of SARS-CoV-2 infection.
explanation: The literature discusses the severity and characteristics of MIS-C but does not address the specific statement about the value 'Not Applicable'.
notes: MIS-C is primarily a post-infectious condition with no strong environmental risk factors identified.
treatments:
- name: Intravenous Immunoglobulin (IVIG)
description: Used to modulate the immune response and reduce inflammation.
evidence:
- reference: PMID:38509432
reference_title: "Treatment of multisystem inflammatory syndrome in children."
supports: SUPPORT
snippet: A variety of treatment approaches, including intravenous immunoglobulins (IVIGs), glucocorticoids (GCs) and biologic agents, such as anakinra and infliximab, have been described for the management of COVID-19-related MIS-C.
explanation: This statement supports the use of IVIG in the treatment of MIS-C, indicating its role in managing the condition.
- reference: PMID:34608458
reference_title: "Unraveling the mechanisms of IVIG immunotherapy in MIS-C."
supports: SUPPORT
snippet: Intravenous immunoglobulin (IVIG) targets IL-1beta(+) neutrophils to exert anti-inflammatory effects in multisystem inflammatory syndrome in children (MIS-C).
explanation: This statement supports the use of IVIG for its anti-inflammatory effects in MIS-C.
- reference: PMID:37830631
reference_title: "Anti-Inflammatory and Immunomodulatory Effect of High-Dose Immunoglobulins in Children: From Approved Indications to Off-Label Use."
supports: SUPPORT
snippet: The large-scale utilization of immunoglobulins in patients with inborn errors of immunity (IEIs) since 1952 prompted the discovery of their key role at high doses as immunomodulatory and anti-inflammatory therapy.
explanation: This statement supports the use of high-dose immunoglobulins, including IVIG, for their immunomodulatory and anti-inflammatory roles, which is relevant to MIS-C treatment.
- reference: PMID:34210761
reference_title: "Multisystem Inflammatory Syndrome in Children."
supports: NO_EVIDENCE
snippet: Multisystem Inflammatory Syndrome in Children.
explanation: This reference does not provide specific information about the use of IVIG in MIS-C.
- reference: PMID:33463100
reference_title: "Intravenous Immunoglobulin Therapy in Myocarditis."
supports: NO_EVIDENCE
snippet: Intravenous Immunoglobulin Therapy in Myocarditis.
explanation: This reference discusses IVIG in the context of myocarditis, not MIS-C.
- reference: PMID:30543921
reference_title: "Intravenous immunoglobulin (IVIG) in the vanguard therapy of Systemic Sclerosis."
supports: NO_EVIDENCE
snippet: Intravenous immunoglobulin (IVIG) in the vanguard therapy of Systemic Sclerosis.
explanation: This reference discusses IVIG in the context of Systemic Sclerosis, not MIS-C.
- reference: PMID:33263756
reference_title: "Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) Antibody Responses in Children With Multisystem Inflammatory Syndrome in Children (MIS-C) and Mild and Severe Coronavirus Disease 2019 (COVID-19)."
supports: NO_EVIDENCE
snippet: Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) Antibody Responses in Children With Multisystem Inflammatory Syndrome in Children (MIS-C) and Mild and Severe Coronavirus Disease 2019 (COVID-19).
explanation: This reference discusses antibody responses in MIS-C but does not specifically address IVIG use.
- reference: PMID:37309831
reference_title: "Multisystem Inflammatory Syndrome in Children: Two Years' Worth of Learning."
supports: NO_EVIDENCE
snippet: 'Multisystem Inflammatory Syndrome in Children: Two Years'' Worth of Learning.'
explanation: This reference discusses MIS-C but does not provide specific information about the use of IVIG.
- reference: PMID:28079913
reference_title: "Intravenous Immunoglobulin in the Treatment of Hematologic Disorders in Pediatrics."
supports: NO_EVIDENCE
snippet: Intravenous Immunoglobulin in the Treatment of Hematologic Disorders in Pediatrics.
explanation: This reference discusses IVIG in the context of hematologic disorders, not MIS-C.
treatment_term:
preferred_term: intravenous immunoglobulin therapy
term:
id: MAXO:0001480
label: immunoglobulin infusion therapy
- name: Corticosteroids
description: Anti-inflammatory medicines to reduce immune system activity and inflammation.
evidence:
- reference: PMID:37534417
reference_title: "Early Treatment of Multisystem Inflammatory Syndrome in Children."
supports: SUPPORT
snippet: The optimal treatment of MIS-C is unknown, although prior studies have indicated benefits of intravenous immunoglobulin (IVIG) and glucocorticoids.
explanation: The term 'glucocorticoids' is used interchangeably with 'corticosteroids' in the context of MIS-C treatment, and the literature supports their use to reduce immune system activity and inflammation.
- reference: PMID:36571257
reference_title: "Multisystem inflammatory syndrome in adults: Characteristics, treatment, and outcomes."
supports: SUPPORT
snippet: Anti-inflammatory agents, including intravenous immunoglobulin and corticosteroids, are commonly used.
explanation: This reference explicitly mentions the use of corticosteroids as anti-inflammatory agents for treating MIS-C.
- reference: PMID:35791863
reference_title: "Biologic disease-modifying antirheumatic drugs to treat multisystem inflammatory syndrome in children."
supports: SUPPORT
snippet: Although intravenous immunoglobulin (IVIg) and glucocorticoids (GCs) are effective therapeutics for most, refractory MIS-C is treated with various biologic disease-modifying antirheumatic drugs (bDMARDs).
explanation: Glucocorticoids (GCs), which are a type of corticosteroid, are mentioned as effective therapeutics for MIS-C.
treatment_term:
preferred_term: systemic corticosteroid therapy
term:
id: NCIT:C122080
label: Systemic Corticosteroid Therapy
- name: Aspirin
description: Used in cases with high risk of blood clots to prevent thrombotic complications.
notes: Dose may vary.
evidence:
- reference: PMID:34941014
reference_title: "Thromboelastography profiles in critically ill children with multisystem inflammatory syndrome."
supports: SUPPORT
snippet: All patients received acetylsalicylic acid (80-100 mg/kg) and none received anticoagulation.
explanation: The study describes the use of acetylsalicylic acid (aspirin) in critically ill children with MIS-C to manage coagulation abnormalities.
- reference: PMID:33305475
reference_title: "SARS-COV-2-associated coagulopathy and thromboembolism prophylaxis in children: A single-center observational study."
supports: PARTIAL
snippet: Universal anticoagulant prophylaxis in hospitalized children with SARS-CoV-2-related manifestations is not warranted, but may be offered to patients with other pro-thrombotic risk factors in the context of a multi-modal therapeutic approach.
explanation: This study indicates that anticoagulant prophylaxis, which may include aspirin, is considered for patients with other pro-thrombotic risk factors, but not universally applied.
- reference: PMID:35791863
reference_title: "Biologic disease-modifying antirheumatic drugs to treat multisystem inflammatory syndrome in children."
supports: NO_EVIDENCE
snippet: Although intravenous immunoglobulin (IVIg) and glucocorticoids (GCs) are effective therapeutics for most, refractory MIS-C is treated with various biologic disease-modifying antirheumatic drugs (bDMARDs).
explanation: The study focuses on the use of IVIg, GCs, and bDMARDs for treating MIS-C but does not mention the use of aspirin.
treatment_term:
preferred_term: cardiovascular agent therapy
term:
id: MAXO:0000181
label: cardiovascular agent therapy
- name: Supportive Care
description: Including fluids, blood pressure support, and respiratory support as needed.
evidence:
- reference: PMID:33760725
reference_title: "Multisystem Inflammatory Syndrome in Children, Chile, May-August 2020."
supports: SUPPORT
snippet: In total, 10 (38.5%) children required mechanical ventilation; 13 (50.0%) required inotropic support.
explanation: This reference provides evidence that children with MIS-C required mechanical ventilation (respiratory support) and inotropic support (blood pressure support), supporting the statement about the need for supportive care.
- reference: PMID:34034587
reference_title: "Extracorporeal membrane oxygenation for multisystem inflammatory syndrome in children."
supports: SUPPORT
snippet: These children developed severely depressed myocardial function with end-organ injury and were cannulated to veno-arterial extracorporeal membrane oxygenation (VA-ECMO) due to cardiogenic shock with arrhythmia.
explanation: The necessity of VA-ECMO (a type of respiratory and cardiovascular support) in severe MIS-C cases supports the statement about the need for supportive care measures including fluids, blood pressure support, and respiratory support.
treatment_term:
preferred_term: supportive care
term:
id: MAXO:0000950
label: supportive care
disease_term:
preferred_term: multisystem inflammatory syndrome in children
term:
id: MONDO:0100163
label: COVID-19–associated multisystem inflammatory syndrome in children
references:
- reference: DOI:10.1038/s41467-024-48699-y
title: Enhanced CD95 and interleukin 18 signalling accompany T cell receptor Vβ21.3+ activation in multi-inflammatory syndrome in children
findings: []
- reference: DOI:10.1038/s41586-024-07722-4
title: Molecular mimicry in multisystem inflammatory syndrome in children
findings: []
- reference: DOI:10.1084/jem.20221518
title: 'SARS-CoV-2 infection and recovery in children: Distinct T cell responses in MIS-C compared to COVID-19'
findings: []
- reference: DOI:10.1111/pai.13900
title: 'Pathogenesis, immunology, and immune‐targeted management of the multisystem inflammatory syndrome in children (MIS‐C) or pediatric inflammatory multisystem syndrome (PIMS): EAACI Position Paper'
findings: []
- reference: DOI:10.1136/bmjpo-2023-002344
title: 'Clinical presentation, diagnosis and management of multisystem inflammatory syndrome in children (MIS-C): a systematic review'
findings: []
- reference: DOI:10.1186/s10020-024-00806-x
title: The plasma proteome differentiates the multisystem inflammatory syndrome in children (MIS-C) from children with SARS-CoV-2 negative sepsis
findings: []
- reference: DOI:10.3389/fimmu.2022.841126
title: Autoantibodies Against Proteins Previously Associated With Autoimmunity in Adult and Pediatric Patients With COVID-19 and Children With MIS-C
findings: []
- reference: DOI:10.3390/children11101174
title: 'Proteomic Signatures of Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with COVID-19: A Narrative Review'
findings: []
- reference: DOI:10.3390/ijms24065711
title: 'Immunology of Multisystem Inflammatory Syndrome after COVID-19 in Children: A Review of the Current Evidence'
findings: []
Disease Pathophysiology Research Report
Target Disease - Disease Name: Multisystem Inflammatory Syndrome in Children (MIS-C) - MONDO ID: Not established in retrieved sources - Category: Complex, post-infectious hyperinflammatory syndrome temporally associated with SARS‑CoV‑2 exposure
Pathophysiology description (current understanding) MIS‑C typically presents 2–6 weeks after SARS‑CoV‑2 infection with systemic hyperinflammation, shock, and prominent gastrointestinal and cardiovascular involvement. Mechanistically, converging 2023–2024 evidence supports: (i) expansion of TRBV11‑2 (Vβ21.3)+ T cells with features consistent with superantigen-like activation; (ii) innate immune activation involving IL‑18 signaling and upregulated FAS (CD95) on NK cells/monocytes that accompanies activation of Vβ21.3+ T cells; (iii) molecular mimicry linking antibody/T‑cell responses to a SARS‑CoV‑2 nucleocapsid epitope and the host protein SNX8, with cross‑reactive T cells; (iv) persistent viral antigens in gut and mucosal barrier dysfunction leading to antigenemia and elevated IgA; (v) endothelial injury with complement activation and occasional autoantibodies (e.g., anti–factor H, reports of anti–IL‑1RA) contributing to vasculopathy; and (vi) multi‑omic proteomic signatures that distinguish MIS‑C from sepsis and acute pediatric COVID‑19, with markers correlating to illness severity. These processes culminate in a cytokine milieu enriched for IL‑6, IL‑10, IL‑17A, IL‑18, IL‑1β, TNF, IFN‑γ, and IFN‑inducible chemokines (CXCL9/10), and correlate with cardiac dysfunction. (https://doi.org/10.1038/s41467-024-48699-y, May 2024; https://doi.org/10.1038/s41586-024-07722-4, Aug 2024; https://doi.org/10.1186/s10020-024-00806-x, Apr 2024; https://doi.org/10.1084/jem.20221518, May 2023; https://doi.org/10.1111/pai.13900, Jan 2023) (zhang2024enhancedcd95and pages 1-2, bodansky2024molecularmimicryin pages 1-2, patel2024theplasmaproteome pages 1-2, rybkina2023sarscov2infectionand pages 1-2, feleszko2023pathogenesisimmunologyand pages 22-23)
Embed: mechanisms and ontology mapping | Mechanism | Key findings (concise) | Principal molecules/genes (HGNC) | Cells (CL) | Tissues/organs (UBERON) | Pathways/Processes (GO) | Key evidence (journal, year, URL) | |---|---|---|---|---|---|---| | Superantigen/TCR Vβ21.3 (TRBV11-2) skewing with IL-18–FAS signaling | Expansion of TRBV11-2 / Vβ21.3+ T cells with skewed differentiation; NK/monocyte IL-18 and FAS (CD95) upregulation promotes pathogenic T-cell activation and distinct cytokine signature | TRBV11-2, IL18, FAS, ICOS, CD28 | CL:0000084 T cell; CL:0000576 NK cell; CL:0000623 monocyte | UBERON:0000948 heart; UBERON:0002107 small intestine | GO:0006954 inflammatory response; GO:0002757 immune response-activating signal transduction | Zhang et al., Nature Communications, May 2024 (https://doi.org/10.1038/s41467-024-48699-y) (zhang2024enhancedcd95and pages 1-2); Rybkina et al., J Exp Med, May 2023 (https://doi.org/10.1084/jem.20221518) (rybkina2023sarscov2infectionand pages 1-2) | | Molecular mimicry: SNX8–SARS‑CoV‑2 nucleocapsid cross-reactivity | Proteome-wide screens identify autoantibodies to host SNX8 and enriched reactivity to a SARS‑CoV‑2 nucleocapsid domain with sequence similarity; cross-reactive T cells implicate molecular mimicry and MAVS pathway dysregulation | SNX8, MAVS, (SARS‑CoV‑2 N) | CL:0000084 T cell; CL:0000236 B cell | UBERON:0000178 blood; UBERON:0000948 heart | GO:0006954 inflammatory response; GO:0009615 response to virus | Bodansky et al., Nature, Aug 2024 (https://doi.org/10.1038/s41586-024-07722-4) (bodansky2024molecularmimicryin pages 1-2) | | Gut antigen persistence and mucosal barrier dysfunction with elevated IgA | Persistent SARS‑CoV‑2 antigen in gut, elevated markers of permeability (zonulin, LBP), increased mucosal IgA and GI-dominant proteome signals; supports gut-to-systemic antigen leak model | IGHA1, LBP, (S1 spike antigen) | CL:0000236 B cell; CL:0000657 enterocyte (intestinal epithelial cell) | UBERON:0002107 small intestine | GO:0006954 inflammatory response; GO:0007155 cell adhesion | Filippatos et al., Int J Mol Sci, Mar 2023 (https://doi.org/10.3390/ijms24065711) (filippatos2023immunologyofmultisystem pages 5-6); EAACI position paper, Pediatr Allergy Immunol, Jan 2023 (https://doi.org/10.1111/pai.13900) (feleszko2023pathogenesisimmunologyand pages 22-23) | | Endothelial injury, complement activation, and autoantibodies (Factor H, IL‑1RA) | Elevated soluble C5b-9 and evidence of alternative complement activation; reports of anti‑CFH and anti‑IL1RN (anti‑IL‑1RA) autoantibodies; endothelial markers (VEGF, angiopoietin-2) and PLA2G2A associate with complement/TMA phenotype | CFH, IL1RN, C5 (C5b-9), PLA2G2A, CFB | CL:0000115 endothelial cell; CL:0000623 monocyte | UBERON:0000948 heart; UBERON:0001981 blood vessel | GO:0006956 complement activation; GO:0007596 blood coagulation | Proteomics review (PLA2G2A–SC5b-9 link), Children, Sep 2024 (https://doi.org/10.3390/children11101174) (dourdouna2024proteomicsignaturesof pages 12-14); Filippatos et al., Int J Mol Sci, Mar 2023 (https://doi.org/10.3390/ijms24065711) (filippatos2023immunologyofmultisystem pages 5-6) | | Proteomic/transcriptomic classifiers distinguishing MIS‑C from sepsis | High‑dimensional plasma proteomics identified 58‑ and 15‑protein classifiers (AUC ~1.00) that discriminate MIS‑C from SARS‑CoV‑2‑negative sepsis; severity‑linked proteins (LTA4H, PTN, PPBP, EGF); signatures map strongly to digestive system and immune cells | PLA2G2A, LTA4H, PTN, PPBP, EGF, IL10RB | CL:0000236 B cell; CL:0000623 monocyte; CL:0000576 NK cell; platelets | UBERON:0002107 small intestine; UBERON:0000178 blood | GO:0006954 inflammatory response; GO:0002682 regulation of immune system process | Patel et al., Molecular Medicine, Apr 2024 (https://doi.org/10.1186/s10020-024-00806-x) (patel2024theplasmaproteome pages 1-2); Proteomics review, Children, Sep 2024 (https://doi.org/10.3390/children11101174) (dourdouna2024proteomicsignaturesof pages 12-14) | | Distinct T‑cell activation and cardiac correlation | Acute MIS‑C T cells show transient activation, tissue‑resident signatures that correlate with myocardial dysfunction; convalescent memory T cells retain pro‑inflammatory features | IFNG, CX3CR1, TRBV11-2, TNF | CL:0000084 T cell; CL:0000106 cardiomyocyte | UBERON:0000948 heart | GO:0006954 inflammatory response; GO:0006656 cardiac muscle cell action potential/heart processes | Rybkina et al., J Exp Med, May 2023 (https://doi.org/10.1084/jem.20221518) (rybkina2023sarscov2infectionand pages 1-2); Zhang et al., Nat Commun, May 2024 (https://doi.org/10.1038/s41467-024-48699-y) (zhang2024enhancedcd95and pages 1-2) | | Broad cytokine/chemokine signature and neutrophil/NK/monocyte activation | Multi‑cytokine elevation (IL‑6, IL‑10, IL‑17A, IL‑18, IL‑1β, TNF, IFNs, CXCL9/10), prominent neutrophil activation/NETosis and monocyte/NK activation with apoptosis signals | IL6, IL10, IL17A, IL18, IL1B, TNF, CXCL9, CXCL10, PLA2G2A | CL:0000775 neutrophil; CL:0000623 monocyte; CL:0000576 NK cell | UBERON:0000178 blood; UBERON:0000948 heart; UBERON:0002107 small intestine | GO:0006954 inflammatory response; GO:0043312 neutrophil activation | EAACI position paper, Pediatr Allergy Immunol, Jan 2023 (https://doi.org/10.1111/pai.13900) (feleszko2023pathogenesisimmunologyand pages 22-23); Zhang et al., Nat Commun, May 2024 (https://doi.org/10.1038/s41467-024-48699-y) (zhang2024enhancedcd95and pages 1-2) |
Table: Concise 2023–2024 evidence table summarizing proposed MIS‑C mechanisms, ontology‑ready molecules/cells/tissues, key GO processes, and primary citations with DOI links for rapid knowledge‑base ingestion. | Entity type | Preferred label | Ontology ID | Notes / role in MIS-C | Key evidence (year, URL, context) | |---|---|---|---|---| | Disease | Multisystem Inflammatory Syndrome in Children (MIS-C) | MONDO: not available | Post-infectious hyperinflammatory syndrome temporally linked to SARS-CoV-2 infection | 2023 EAACI position paper: https://doi.org/10.1111/pai.13900 (feleszko2023pathogenesisimmunologyand pages 22-23); 2023 J Exp Med cohort: https://doi.org/10.1084/jem.20221518 (rybkina2023sarscov2infectionand pages 1-2) | | Gene / Protein | FAS (CD95) | HGNC:FAS | Upregulated CD95/FAS signaling in NK cells/monocytes; part of IL-18–FAS activation axis | 2024 Nat Commun: https://doi.org/10.1038/s41467-024-48699-y (zhang2024enhancedcd95and pages 1-2) | | Gene / Protein | IL18 | HGNC:IL18 | Elevated IL-18 and IL-18R expression (innate activation driving T-cell responses) | 2024 Nat Commun: https://doi.org/10.1038/s41467-024-48699-y (zhang2024enhancedcd95and pages 1-2) | | Gene / Protein | TRBV11-2 (TCR Vβ21.3) | TRBV11-2 | Marked TCR Vβ skewing/expansion (superantigen-like signature) in many acute MIS-C cases | 2024 Nat Commun: https://doi.org/10.1038/s41467-024-48699-y (zhang2024enhancedcd95and pages 1-2); 2023 J Exp Med: https://doi.org/10.1084/jem.20221518 (rybkina2023sarscov2infectionand pages 1-2) | | Gene / Protein | SNX8 | HGNC:SNX8 | Autoantigen targeted by MIS-C autoantibodies; cross-reactive epitope with SARS-CoV-2 nucleocapsid (molecular mimicry) | 2024 Nature: https://doi.org/10.1038/s41586-024-07722-4 (bodansky2024molecularmimicryin pages 1-2) | | Gene / Protein | MAVS | HGNC:MAVS | MAVS / mitochondrial antiviral signaling dysregulation linked to MIS-C autoantibody signature | 2024 Nature: https://doi.org/10.1038/s41586-024-07722-4 (bodansky2024molecularmimicryin pages 1-2) | | Gene / Protein | CFH (Factor H) | HGNC:CFH | Factor H autoantibodies reported; contributes to complement dysregulation in MIS-C | 2024 proteomics review: https://doi.org/10.3390/children11101174 (dourdouna2024proteomicsignaturesof pages 12-14); 2023 review: https://doi.org/10.3390/ijms24065711 (filippatos2023immunologyofmultisystem pages 5-6) | | Gene / Protein | IL1RN (IL-1RA) | HGNC:IL1RN | Anti–IL-1RA autoantibodies reported in subsets; relevant to cytokine regulation | 2023 EAACI: https://doi.org/10.1111/pai.13900 (feleszko2023pathogenesisimmunologyand pages 22-23); 2023 review: https://doi.org/10.3390/ijms24065711 (filippatos2023immunologyofmultisystem pages 5-6) | | Gene / Protein | PLA2G2A | HGNC:PLA2G2A | Proteomic biomarker candidate linked to thrombotic-microangiopathy phenotype and complement (SC5b-9) | 2024 proteomics review: https://doi.org/10.3390/children11101174 (dourdouna2024proteomicsignaturesof pages 12-14) | | Gene / Protein | LTA4H | HGNC:LTA4H | Identified in proteomic classifier; correlates with illness severity | 2024 Mol Med (proteomics classifier): https://doi.org/10.1186/s10020-024-00806-x (patel2024theplasmaproteome pages 1-2) | | Gene / Protein | PTN | HGNC:PTN | Severity-linked protein in MIS-C proteomic classifier | 2024 Mol Med: https://doi.org/10.1186/s10020-024-00806-x (patel2024theplasmaproteome pages 1-2) | | Gene / Protein | PPBP (CXCL7) | HGNC:PPBP | Severity-linked platelet/chemokine signal in proteomic classifier | 2024 Mol Med: https://doi.org/10.1186/s10020-024-00806-x (patel2024theplasmaproteome pages 1-2) | | Gene / Protein | EGF | HGNC:EGF | Correlated with clinical outcomes in proteomic analyses | 2024 Mol Med: https://doi.org/10.1186/s10020-024-00806-x (patel2024theplasmaproteome pages 1-2) | | Gene / Protein | CX3CR1 | HGNC:CX3CR1 | Marker of tissue-associated / cytotoxic T cells noted in MIS-C profiling | 2023 J Exp Med: https://doi.org/10.1084/jem.20221518 (rybkina2023sarscov2infectionand pages 1-2) | | Gene / Protein | IFNG | HGNC:IFNG | Elevated IFN-γ in cytokine signature linked to T-cell activation and cardiac disease | 2023 J Exp Med: https://doi.org/10.1084/jem.20221518 (rybkina2023sarscov2infectionand pages 1-2) | | Gene / Protein | IL6 | HGNC:IL6 | Prominent proinflammatory cytokine elevated in MIS-C | 2023 EAACI: https://doi.org/10.1111/pai.13900 (feleszko2023pathogenesisimmunologyand pages 22-23) | | Gene / Protein | IL10 | HGNC:IL10 | Elevated regulatory cytokine within MIS-C multi-cytokine signature | 2023 EAACI: https://doi.org/10.1111/pai.13900 (feleszko2023pathogenesisimmunologyand pages 22-23) | | Gene / Protein | IL17A | HGNC:IL17A | Increased in many MIS-C proteomic/transcriptomic profiles | 2024 Nat Commun / reviews: https://doi.org/10.1038/s41467-024-48699-y (zhang2024enhancedcd95and pages 1-2) | | Gene / Protein | IL1B | HGNC:IL1B | Component of inflammatory cytokine milieu in MIS-C | 2024 Nat Commun: https://doi.org/10.1038/s41467-024-48699-y (zhang2024enhancedcd95and pages 1-2) | | Gene / Protein | TNF | HGNC:TNF | Central proinflammatory mediator elevated in MIS-C cohorts | 2023 EAACI: https://doi.org/10.1111/pai.13900 (feleszko2023pathogenesisimmunologyand pages 22-23) | | Gene / Protein | CXCL9 | HGNC:CXCL9 | IFN-inducible chemokine elevated in MIS-C cytokine panels | 2024 Nat Commun: https://doi.org/10.1038/s41467-024-48699-y (zhang2024enhancedcd95and pages 1-2) | | Gene / Protein | CXCL10 | HGNC:CXCL10 | Elevated chemokine linked to monocyte/T cell recruitment in MIS-C | 2024 Nat Commun: https://doi.org/10.1038/s41467-024-48699-y (zhang2024enhancedcd95and pages 1-2) | | Cell type | T cell | CL:0000084 | Central adaptive effector showing Vβ skewing, activation/exhaustion, tissue-residency signatures correlated with cardiac disease | 2023 J Exp Med: https://doi.org/10.1084/jem.20221518 (rybkina2023sarscov2infectionand pages 1-2) | | Cell type | Natural killer cell (NK cell) | CL:0000576 | NKs show altered IL-18 expression and activation markers in MIS-C | 2024 Nat Commun: https://doi.org/10.1038/s41467-024-48699-y (zhang2024enhancedcd95and pages 1-2) | | Cell type | Monocyte | CL:0000623 | Monocyte activation, caspase-8 activity and cytokine production drive innate inflammation | 2024 Nat Commun: https://doi.org/10.1038/s41467-024-48699-y (zhang2024enhancedcd95and pages 1-2) | | Cell type | Neutrophil | CL:0000775 | Neutrophil activation / NETosis implicated in endothelial injury and thrombosis | 2023 EAACI: https://doi.org/10.1111/pai.13900 (feleszko2023pathogenesisimmunologyand pages 22-23) | | Cell type | Endothelial cell | CL:0000115 | Target of immune/complement injury; endothelial markers (VEGF, Ang-2) elevated | 2024 proteomics review: https://doi.org/10.3390/children11101174 (dourdouna2024proteomicsignaturesof pages 12-14) | | Cell type | B cell | CL:0000236 | Plasmablast expansions and autoantibody production (IVIG can confound measurements) | 2023 EAACI: https://doi.org/10.1111/pai.13900 (feleszko2023pathogenesisimmunologyand pages 22-23) | | Cell type | Cardiomyocyte | CL:0000106 | Cardiac myocyte dysfunction (myocarditis, reduced LVEF) correlates with immune signatures | 2023 J Exp Med: https://doi.org/10.1084/jem.20221518 (rybkina2023sarscov2infectionand pages 1-2) | | Cell type | Intestinal epithelial cell (enterocyte) | CL:0000657 | Enteric epithelium implicated in SARS-CoV-2 antigen persistence and gut barrier leak | 2023 Int J Mol Sci review: https://doi.org/10.3390/ijms24065711 (filippatos2023immunologyofmultisystem pages 5-6); 2024 proteomics review: https://doi.org/10.3390/children11101174 (dourdouna2024proteomicsignaturesof pages 12-14) | | Anatomical structure | Heart | UBERON:0000948 | Primary organ affected (myocarditis, ventricular dysfunction, occasional coronary changes) | 2023 J Exp Med: https://doi.org/10.1084/jem.20221518 (rybkina2023sarscov2infectionand pages 1-2) | | Anatomical structure | Small intestine | UBERON:0002107 | Site of antigen persistence / gut leak implicated in MIS-C pathogenesis | 2023 Int J Mol Sci: https://doi.org/10.3390/ijms24065711 (filippatos2023immunologyofmultisystem pages 5-6) | | Anatomical structure | Blood vessel | UBERON:0001981 | Vasculitis / endothelial injury and coagulopathy observed in MIS-C | 2024 proteomics review: https://doi.org/10.3390/children11101174 (dourdouna2024proteomicsignaturesof pages 12-14) | | Anatomical structure | Blood | UBERON:0000178 | Source of proteomic classifiers and systemic biomarkers; plasma proteome discriminates MIS-C from sepsis | 2024 Mol Med: https://doi.org/10.1186/s10020-024-00806-x (patel2024theplasmaproteome pages 1-2) | | Chemical (CHEBI) | Leukotriene A4 (LTA4 product) | CHEBI:17012 | Inferred involvement via LTA4H elevation in proteomic severity signatures (inflammatory lipid mediator) | 2024 Mol Med: https://doi.org/10.1186/s10020-024-00806-x (patel2024theplasmaproteome pages 1-2) | | Chemical (CHEBI) | Complement C5b-9 (terminal complement complex) | CHEBI: not specified | Elevated soluble C5b-9 (SC5b-9) links complement activation to TMA-like features in MIS-C | 2024 proteomics review: https://doi.org/10.3390/children11101174 (dourdouna2024proteomicsignaturesof pages 12-14) | | Chemical (CHEBI) | Immunoglobulin A (IgA) | CHEBI:16412 | Elevated mucosal IgA responses and persistence associated with GI symptoms and potential antigen translocation | 2023 Int J Mol Sci review: https://doi.org/10.3390/ijms24065711 (filippatos2023immunologyofmultisystem pages 5-6) |
Table: A structured ontology-ready table mapping key MIS-C entities (disease, genes/proteins, cell types, anatomical structures, chemicals) to ontology identifiers and concise roles in MIS-C, with 2023–2024 primary-source evidence (DOI + context IDs) for knowledge-base integration.
Distinct proteomic signature vs sepsis: A 2,870‑protein PEA study identified 58‑ and 15‑protein classifiers with AUC ≈ 1.00 differentiating MIS‑C from SARS‑CoV‑2–negative sepsis; severity associated with LTA4H, PTN, PPBP, EGF; expression mapped across organ systems, highest in digestive tract, and in leukocytes/lymphocytes/macrophages/platelets. URL: https://doi.org/10.1186/s10020-024-00806-x (Apr 2024) (patel2024theplasmaproteome pages 1-2).
Dysregulated molecular pathways
Antiviral sensing (MAVS) implicated via autoantibody targets in Nature 2024. URL: https://doi.org/10.1038/s41586-024-07722-4 (Aug 2024) (bodansky2024molecularmimicryin pages 1-2).
Affected cellular processes
T‑cell activation/exhaustion and tissue residency; NK and monocyte activation with IL‑18R/CD95 upregulation; neutrophil activation/NETosis; endothelial activation/dysfunction; complement activation; mucosal antibody production (IgA). URLs as above (zhang2024enhancedcd95and pages 1-2, feleszko2023pathogenesisimmunologyand pages 22-23, dourdouna2024proteomicsignaturesof pages 12-14, filippatos2023immunologyofmultisystem pages 5-6).
Key Molecular Players
Heart (myocarditis/ventricular dysfunction), small intestine (antigen persistence/gut leak), blood vessels (vasculitis/endothelium), blood (systemic biomarkers). Evidence: JEM 2023; IJMS 2023; Children 2024; Mol Med 2024 (rybkina2023sarscov2infectionand pages 1-2, filippatos2023immunologyofmultisystem pages 5-6, dourdouna2024proteomicsignaturesof pages 12-14, patel2024theplasmaproteome pages 1-2).
Biological Processes (GO) for annotation
GO:0006954 inflammatory response (broad cytokine storm features); GO:0006956 complement activation; GO:0002757 immune response‑activating signal transduction (TCR/co‑stimulation); GO:0043312 neutrophil activation; GO:0009615 response to virus; GO:0002682 regulation of immune system process. Evidence: EAACI 2023; Nat Commun 2024; proteomics review 2024 (feleszko2023pathogenesisimmunologyand pages 22-23, zhang2024enhancedcd95and pages 1-2, dourdouna2024proteomicsignaturesof pages 12-14).
Cellular Components (where processes occur)
Plasma membrane (FAS, IL‑18R on NK/monocytes/T cells); extracellular region/plasma (cytokines, complement C5b‑9, PLA2G2A); mitochondrion (MAVS); vascular endothelium. Evidence: Nat Commun 2024; Nature 2024; Children 2024 (zhang2024enhancedcd95and pages 1-2, bodansky2024molecularmimicryin pages 1-2, dourdouna2024proteomicsignaturesof pages 12-14).
Disease Progression (sequence of events)
Initial trigger: SARS‑CoV‑2 infection with subsequent convalescence; in a minority of children, intestinal persistence of viral antigens (especially nucleocapsid/spike fragments) and barrier disruption leads to sustained antigen exposure and heightened mucosal IgA responses. A superantigen‑like effect and/or mimicry drive Vβ‑skewed T‑cell activation (TRBV11‑2). Innate cells (NK/monocytes) with elevated IL‑18R and CD95 amplify adaptive activation and cytokine production. Endothelial injury with complement activation and occasional autoantibody effects contributes to shock and myocardial involvement. With immunomodulation (IVIG, corticosteroids), most children recover rapidly and cardiac function normalizes in weeks. URLs: IJMS 2023; EAACI 2023; Nat Commun 2024; Nature 2024 (filippatos2023immunologyofmultisystem pages 5-6, feleszko2023pathogenesisimmunologyand pages 22-23, zhang2024enhancedcd95and pages 1-2, bodansky2024molecularmimicryin pages 1-2).
Phenotypic Manifestations (HP terms) and relation to mechanisms
Recent developments (2023–2024) - Molecular mimicry: Nature 2024 demonstrates SNX8–SARS‑CoV‑2 nucleocapsid cross‑reactivity with both autoantibodies and T cells, providing a mechanistic link from infection to MIS‑C. URL: https://doi.org/10.1038/s41586-024-07722-4 (Aug 2024) (bodansky2024molecularmimicryin pages 1-2). - Innate–adaptive axis: Nature Communications 2024 reveals IL‑18–CD95 signaling and monocyte/NK activation accompanying Vβ21.3+ T‑cell expansions, refining the superantigen hypothesis toward a broader innate‑driven activation context. URL: https://doi.org/10.1038/s41467-024-48699-y (May 2024) (zhang2024enhancedcd95and pages 1-2). - Proteomic classifiers: Molecular Medicine 2024 reports 58‑ and 15‑protein panels distinguishing MIS‑C from sepsis with AUC ~1.00 and severity correlations (LTA4H, PTN, PPBP, EGF), highlighting translational diagnostic potential and digestive‑system enrichment. URL: https://doi.org/10.1186/s10020-024-00806-x (Apr 2024) (patel2024theplasmaproteome pages 1-2). - Systematic characterization and guidance: EAACI Position Paper (2023) and updated reviews consolidate evidence on gut leak, neutrophil activation/NETs, complement and cytokine signatures, and management algorithms. URL: https://doi.org/10.1111/pai.13900 (Jan 2023) (feleszko2023pathogenesisimmunologyand pages 22-23).
Current applications and real‑world implementations - Diagnostics/biomarkers: High‑dimensional plasma proteomics classifiers (58‑ and 15‑protein) distinguishing MIS‑C from sepsis with excellent performance; individual markers correlate to severity and interventions (e.g., LTA4H, PTN, PPBP, EGF). URL: https://doi.org/10.1186/s10020-024-00806-x (Apr 2024) (patel2024theplasmaproteome pages 1-2). - Immunomodulation: Clinical responses to IVIG and corticosteroids remain standard; cytokine findings (e.g., IL‑18, IL‑1 axis) support rationale for targeted biologics in select cases, though robust randomized evidence remains limited (EAACI algorithm). URL: https://doi.org/10.1111/pai.13900 (Jan 2023) (feleszko2023pathogenesisimmunologyand pages 22-23).
Expert opinions and analysis - The multi‑hit model (antigen persistence + superantigen/mimicry + innate amplification) best explains the breadth of MIS‑C features. Nature/Nat Commun studies provide mechanistic clarity on TCR skewing, IL‑18–FAS axis, and mimicry, while proteomics/transcriptomics define disease‑specific signatures and differentiate MIS‑C from sepsis. EAACI 2023 synthesizes consensus statements on immunopathology and management. URLs as above (zhang2024enhancedcd95and pages 1-2, bodansky2024molecularmimicryin pages 1-2, patel2024theplasmaproteome pages 1-2, feleszko2023pathogenesisimmunologyand pages 22-23).
Relevant statistics and data (recent) - Systematic review/meta‑analysis (120 studies; 20,881 cases): fever 99%, GI symptoms 76.7%, dermatologic 63.3%, PICU admission 53.1%, mortality 3.9%; greater severity and mortality reported in MIC vs HIC settings. URL: https://doi.org/10.1136/bmjpo-2023-002344 (Jun 2024) (patel2024theplasmaproteome pages 1-2) (patel2024theplasmaproteome pages 1-2).
Structured annotations for a knowledge base - Gene/protein (HGNC): FAS, IL18, TRBV11‑2, ICOS, CD28, IFNG, IL6, IL10, IL17A, IL1B, TNF, CXCL9, CXCL10, SNX8, MAVS, CFH, IL1RN, PLA2G2A, LTA4H, PTN, PPBP, EGF, CX3CR1. (zhang2024enhancedcd95and pages 1-2, bodansky2024molecularmimicryin pages 1-2, patel2024theplasmaproteome pages 1-2, feleszko2023pathogenesisimmunologyand pages 22-23) - Biological processes (GO): inflammatory response (GO:0006954); complement activation (GO:0006956); immune response‑activating signal transduction (GO:0002757); neutrophil activation (GO:0043312); response to virus (GO:0009615); regulation of immune system process (GO:0002682). (feleszko2023pathogenesisimmunologyand pages 22-23, zhang2024enhancedcd95and pages 1-2, dourdouna2024proteomicsignaturesof pages 12-14) - Cellular components: plasma membrane (FAS/IL‑18R), extracellular region (cytokines, complement), mitochondrion (MAVS), endothelium. (zhang2024enhancedcd95and pages 1-2, bodansky2024molecularmimicryin pages 1-2, dourdouna2024proteomicsignaturesof pages 12-14) - Cell types (CL): T cell (CL:0000084), NK cell (CL:0000576), monocyte (CL:0000623), neutrophil (CL:0000775), B cell (CL:0000236), endothelial cell (CL:0000115), cardiomyocyte (CL:0000106), intestinal epithelial cell/enterocyte (CL:0000657). (zhang2024enhancedcd95and pages 1-2, feleszko2023pathogenesisimmunologyand pages 22-23) - Anatomical locations (UBERON): heart (UBERON:0000948), small intestine (UBERON:0002107), blood vessel (UBERON:0001981), blood (UBERON:0000178). (rybkina2023sarscov2infectionand pages 1-2, filippatos2023immunologyofmultisystem pages 5-6, dourdouna2024proteomicsignaturesof pages 12-14, patel2024theplasmaproteome pages 1-2) - Chemical entities (CHEBI): leukotriene A4 (CHEBI:17012), immunoglobulin A (CHEBI:16412); soluble C5b‑9 complex reported (proteomics literature). (patel2024theplasmaproteome pages 1-2, dourdouna2024proteomicsignaturesof pages 12-14, filippatos2023immunologyofmultisystem pages 5-6)
Direct quotes (supporting key statements) - “In MIS‑C, the natural killer cell and monocyte population demonstrate heightened CD95 (Fas) and Interleukin 18 receptor expression… TCR Vβ21.3+ CD4+ T‑cells exhibit skewed differentiation towards T helper 1, 17 and regulatory T cells.” URL: https://doi.org/10.1038/s41467-024-48699-y (May 2024) (zhang2024enhancedcd95and pages 1-2). - “We found that many children with anti‑SNX8 autoantibodies also have cross‑reactive T cells engaging both the SNX8 and the SARS‑CoV‑2 nucleocapsid protein epitopes.” URL: https://doi.org/10.1038/s41586-024-07722-4 (Aug 2024) (bodansky2024molecularmimicryin pages 1-2). - “Of the 2,870 unique blood proteins, 58 proteins were identified… [classifier] accuracy = 0.96, AUC = 1.00…” URL: https://doi.org/10.1186/s10020-024-00806-x (Apr 2024) (patel2024theplasmaproteome pages 1-2).
Notes on evidence limitations - Autoantibody measurements can be confounded by IVIG administration; careful timing/controls are required for interpretation. Evidence: Frontiers Immunology 2022 shows IVIG‑derived autoantibodies may explain many signals in MIS‑C/KD cohorts, with only rare endogenous specificities detected pre‑IVIG. URL: https://doi.org/10.3389/fimmu.2022.841126 (Mar 2022) (filippatos2023immunologyofmultisystem pages 8-9).
URLs and dates are provided inline above with each citation.
References
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