Genetic Risk Factors for Multi-system Inflammatory Syndrome in Children and Pediatric Post COVID Condition

Study Overview
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Brief Summary
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We will perform Whole Exome Sequencing on DNA from saliva. We will include: Children with a history of MIS-C; children with post-COVID condition; and controls in order to identify rare, high impact genetic variants in immunological genes and pathways in children with a history of MIS-C or pediatric post-COVID condition.

Detailed Description
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Rationale: Following infection with SARS-CoV-2, some children develop the potentially life-threatening disease Multi-System Inflammatory Syndrome in Children (MIS-C) and some children develop post-COVID condition (formerly 'long COVID'). It is unknown why some children develop severe or prolonged symptoms after SARS-CoV-2 infection, while most children have asymptomatic or mild disease. We hypothesize that rare variants in genes associated with the immune system predispose children to develop MIS-C or post-COVID condition after infection with SARS-CoV-2. Objective: Primary objective: To identify rare, high impact genetic variants in immunological genes and pathways in children with a history of MIS-C or pediatric post-COVID condition. Secondary objectives: To analyze the clinical characteristics and long-term effects of pediatric COVID-19 and MIS-C. To characterize the functional and clinical impact of genetic variants in MIS-C and post-COVID condition and identify targets for therapy. Study design: We will do an observational study. We will perform Whole Exome Sequencing (WES) using Next Generation Sequencing (NGS) on DNA from blood or saliva. We will include: (1) MIS-C cases: Children with a history of MIS-C; (2) post-COVID condition cases: Children with post-COVID condition; and (3) Controls: SARS-CoV-2 exposed age-matched control group: children who were infected with SARS-CoV-2 but did not develop moderate to severe COVID-19, MIS-C or post-COVID condition. Study population: Children 0-19 years old with a history of MIS-C (n=100), post-COVID condition (n=100), or uncomplicated SARS-CoV-2 infection (n=200). Main study parameters/endpoints: To evaluate if some children with MIS-C or post-COVID condition have an inborn error of immunity by determining the presence of pathogenic or likely pathogenic variants in immunological genes To evaluate if a larger proportion of cases with MIS-C or post-COVID condition have rare and presumably deleterious variants in immunological genes than children with an asymptomatic or mild infection

Official Title
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Genetic Risk Factors for Multi-system Inflammatory Syndrome in Children and Pediatric Post COVID Condition

Conditions
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COVID-19, Post-Acute COVID-19, Post-Acute COVID19 Syndrome, Multi-System Inflammatory Syndrome in Children, Pediatric Inflammatory Multisystem Syndrome, Post COVID-19 Condition, Post-COVID-19 Syndrome

Intervention / Treatment
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* Genetic: Saliva collection at home


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children (<19 years) with a history of MIS-C: as defined according to WHO criteria. Children (<19 years) with post-COVID condition: as defined according to the WHO case definition. This includes a history of probable or confirmed prior SARS-CoV-2 infection, with signs and symptoms (including fatigue, shortness of breath, cognitive dysfunction) that are present after 12 weeks, last at least 2 months, have an impact on daily functioning and are not explained by an alternative diagnosis. 'Exposed' control group: children (<19 years of age): a history of proven SARS-CoV-2 infection (RT-PCR, antigen test or serology positive). If the child has been vaccinated against SARS-CoV-2, the first documented infection must have been prior to the vaccination. Exclusion Criteria: No informed consent Group 1 (MIS-C): no specific exclusion criteria Group 2 (post-COVID condition): other plausible cause of symptoms AND/OR a history compatible with chronic fatigue syndrome prior to infection with SARS-CoV-2. Children with a history of MIS-C who suffer prolonged signs and symptoms will be included in the MIS-C group. Group 3 ('exposed' control group): MIS-C or post-COVID condition; AND/OR Moderate or severe course of COVID-19, as defined in the COPP-study (N20.043) (need for supplemental oxygen and/or intensive care admission because of COVID-19 and/or death) AND/OR first degree relative with long COVID or MIS-C.

Ages Eligible for Study
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Minimum Age: 0 Months
Maximum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| MIS-C<br>Children with a history of MIS-C: as defined according to WHO criteria, who were 0-18 at the time of MIS-C. | Genetic: Saliva collection at home<br>* Children (with help of their parents) collect their saliva with a saliva collection kit which they send to our research center.<br>|
| Post COVID-Condition<br>Children with post-COVID condition who were 0-18 at the time of SARS-CoV-2 infection: as defined according to the WHO case definition. | Genetic: Saliva collection at home<br>* Children (with help of their parents) collect their saliva with a saliva collection kit which they send to our research center.<br>|
| Control<br>'Exposed' control group: children with a history of proven SARS-CoV-2 infection (RT-PCR, antigen test or serology positive) who were 0-18 at the time of SARS-CoV-2 infection. | Genetic: Saliva collection at home<br>* Children (with help of their parents) collect their saliva with a saliva collection kit which they send to our research center.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quantity and quality of genetic variants in immunological genes between study groups. | We want to quantify how many immunogenic variants are found between the groups and identify which variants/genes these are. | 2 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlate genetic findings with clinical characteristics | We want to connect the data found during genetic testing with multiple clinical characteristics already collected in previous studies. | 2 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, Post-COVID Condition, MIS-C, PIMS-TS