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

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.

Study Overview

• Status: Recruiting
• Conditions: COVID-19; Post-Acute COVID19 Syndrome; Post-COVID-19 Syndrome; Post-Acute COVID-19; Post COVID-19 Condition; Multi-System Inflammatory Syndrome in Children; Pediatric Inflammatory Multisystem Syndrome
• Intervention / Treatment: Genetic: Saliva collection at home

Detailed Description

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:

1. 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
2. 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

• Study Type: Observational
• Enrollment (Anticipated): 400

Contacts and Locations

• Study Contact: Name: Adam J Tulling, MD; Phone Number: +31 629843439; Email: a.j.tulling@lumc.nl
• Study Contact Backup: Name: Emmeline P Buddingh, MD, PhD; Phone Number: +31 715262822; Email: E.P.Buddingh@lumc.nl

Study Locations

• Netherlands
  • Zuid-Holland
    • Leiden, Zuid-Holland, Netherlands, 2333ZA
      • Recruiting
      • Leiden University Medical Center
      • Contact: Adam Tulling, MD; Phone Number: +31629843439; Email: a.j.tulling@lumc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 second to 19 years (ADULT, CHILD)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Children with a history of MIS-C or Post-COVID Condition and children with a known SARS-CoV-2 infection without severe disease course.

Description

Inclusion Criteria:

1. Children (<19 years) with a history of MIS-C: as defined according to WHO criteria.
2. 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.
3. '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:

1. No informed consent
2. Group 1 (MIS-C): no specific exclusion criteria

3. 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.

4. 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.

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
MIS-C; 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; Children (with help of their parents) collect their saliva with a saliva collection kit which they send to our research center.
Post COVID-Condition; 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; Children (with help of their parents) collect their saliva with a saliva collection kit which they send to our research center.
Control; '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; Children (with help of their parents) collect their saliva with a saliva collection kit which they send to our research center.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Leiden University Medical Center
• Collaborators: University Medical Center Groningen; UMC Utrecht; Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA); ZonMw: The Netherlands Organisation for Health Research and Development
• Investigators: Principal Investigator: Emmeline P Buddingh, MD, PhD, Leiden University Medical Center

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 28, 2022
• Primary Completion (ANTICIPATED): January 31, 2024
• Study Completion (ANTICIPATED): January 31, 2024

Study Registration Dates

• First Submitted: February 9, 2023
• First Submitted That Met QC Criteria: February 9, 2023
• First Posted (ACTUAL): February 10, 2023

Study Record Updates

• Last Update Posted (ACTUAL): February 10, 2023
• Last Update Submitted That Met QC Criteria: February 9, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: COVID-19; MIS-C; PIMS-TS; Post-COVID Condition
• Additional Relevant MeSH Terms: Pathologic Processes; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Syndrome; Disease
• Other Study ID Numbers: NL80853.058.22

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No