Clinical trial NCT05172011: Understanding the Long-term Impact of COVID on Children and Families
Official title: NIH RECOVER: A Multi-site Observational Study of Post-acute Sequalae of SARS-CoV-2 Infection in Children
Study type: OBSERVATIONAL
Overall status: ACTIVE_NOT_RECRUITING
Conditions: SARS-CoV-2 Infection
Keywords: Post Acute Sequalae of SARS-CoV-2 (PASC)
Lead sponsor: NYU Langone Health
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2021-12-29
Enrollment: 15028
Sex: ALL
Maximum age (years): 25
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Observational model: OTHER
Time perspective: OTHER
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Infected: Individuals less than 25 years of age meeting WHO criteria for suspected, probable or confirmed SARS-CoV-2 infection on or after March 1, 2020; or those born to a mother meeting these criteria during pregnancy.

Uninfected: Individuals less than 25 years of age who have never met any of the WHO criteria for suspected, probable or confirmed SARS-CoV-2 infection.

Brief summary: This is a combined retrospective and prospective, longitudinal, observational meta-cohort of individuals age 0-25 years who will enter the cohort with and without SARS-CoV-2 infection at varying stages before and after infection. Individuals with and without SARS-CoV-2 infection and with or without PASC symptoms will be followed to identify risk factors and occurrence of PASC. This study will be conducted in the United States and participants will be recruited through inpatient, outpatient, and community-based settings. Study data including age, demographics, social determinants of health, medical history, vaccination history, details of acute SARS-CoV-2 infection, overall health and physical function, and PASC symptoms will be reported by participants or collected from the electronic health record using a case report form at specified intervals. Biologic specimens will be collected at specified intervals, with some tests performed in local clinical laboratories and others performed by centralized research centers or banked in the Biospecimen Repository. Advanced clinical examinations and radiologic examinations will be performed at local study sites with cross-site standardization.

Detailed description: Ambidirectional longitudinal meta-cohort study (combined retrospective and prospective) with nested case-control studies.

Eligibility criteria: Inclusion Criteria:

Infected Cohort:

Patients will be eligible for inclusion according to the following criteria:

1. Ages newborn-25 years
2. Infected individuals will have suspected, probable, or confirmed SARS-CoV-2 infection as defined by WHO criteria within 24 months of enrollment or have been born to a mother meeting these criteria during pregnancy (congenitally exposed)
3. Children/young adults with or without history of MIS-C are eligible
4. Children/young adults with or without history of SARS-CoV-2 vaccination are eligible
5. Children/young adults with evidence of past SARS-CoV-2 infection based on serum antibody profile are eligible (with or without history of acute symptoms)
6. Children/young adults with recurrent SARS-CoV-2 infections and those with post-vaccination (breakthrough) infections are eligible to participate
7. Participants are eligible without exclusion related to sex, race/ethnicity, geography, nationality, severity of disease, or underlying health conditions

Children/Young Adults with Suspected SARS-Cov-2 Infection

Children/young adults who meet these clinical criteria:

At least one of these clinical criteria:

* Acute onset of fever and cough OR
* Acute onset of ANY THREE OR MORE of the following signs or symptoms: fever, cough, general weakness /fatigue, headache, myalgia, sore throat, coryza, dyspnea, anorexia/nausea/vomiting, diarrhea, altered mental status.

AND at least one of these epidemiological criteria:

1. Residing or working in an area with a high risk of transmission of virus: closed residential, school or camp settings anytime within the 14 days before symptom onset; OR
2. Residing or travel to an area with community transmission anytime within the 14 days before symptom onset; OR
3. Any known household contact or any member of the household working in any health care setting, including within health facilities or within the community; anytime within the 14 days before symptom onset.
4. A patient with history of severe acute respiratory illness (SARI):

   - SARI: acute respiratory infection with history of fever or measured fever of ≥ 38 C°; and cough; with onset within the last 10 days; and requires hospitalization
5. An asymptomatic person not meeting epidemiologic criteria with a positive SARS-CoV-2 Antigen-RDT.

Children/Young Adults with Probable SARS-Cov-2 Infection

1. A patient who meets clinical criteria above AND is a contact of a probable or confirmed case or linked to a COVID-19 cluster; OR
2. A suspect case with chest imaging showing findings suggestive of COVID-19 disease; OR
3. A person with recent onset of anosmia (loss of smell) or ageusia (loss of taste) in the absence of any other identified cause

Children/Young Adults with Confirmed SARS-Cov-2 Infection

1. A person with a positive Nucleic Acid Amplification Test (NAAT); OR
2. A person with a positive SARS-CoV-2Antigen-RDT AND meeting either the probable case definition or suspect criteria A OR B; OR
3. An asymptomatic person with a positive SARS-CoV-2 Antigen-RDT who is a contact of a probable or confirmed case

Children/Young Adults with Asymptomatic SARS-CoV-2 Infection

1. A person without history of acute COVID-19 symptoms who has one or more of the epidemiological exposures for suspected infection and who also meets criteria b or c for suspected or probable infection, or who meets any of the criteria for confirmed infection
2. A person without history of acute COVID-19 symptoms who has positive nucleocapsid antibody test result in medical history or Tier 1 testing with or without NAAT or RDT testing or known contact to a probable or confirmed case.

Non-Infected Cohort

A person who meets the following criteria will qualify for enrollment as a non-infected control subject:

1. Does not meet WHO criteria for a suspected, probable, or confirmed case of SARS-CoV-2 infection AND
2. Does not have serological evidence of past asymptomatic SARS-CoV-2 infection in medical history or Tier 1 testing, AND
3. Lives in the same communities or recruited from the same sources as those in the SARS-CoV-2 infected cohort, AND
4. Either not hospitalized for any reason in prior 3 months, or hospitalized (with or without ICU stay) within the prior 3 months
5. Uninfected individuals may participate independent of their vaccination status
6. Uninfected individuals who develop SARS-CoV-2 infection during the study period will be reassigned to the SARS-Cov-2 infected group and will be considered to have been enrolled prior to SARS-CoV-2 infection.

Children (≤3 years of age) born in and out of the context of maternal SARS-CoV-2 infection during pregnancy.

1. Children ≤3 years of age born to a childbearing parent with history of suspected, probable, or confirmed SARS-COV-2 infection during pregnancy (according the same criteria listed for the infected child cohort) will be enrolled in the study from existing research cohorts at the maternal fetal medicine sites in the RECOVER. network.
2. Children ≤3 years of age born to a childbearing parent without history of SARS-COV-2 infection during pregnancy (according to the same criteria listed for the non-infected child cohort) will also be enrolled from the same existing research cohorts at maternal fetal medicine sites in the RECOVER network.

Children with MIS-C

Children/young adults with SARS-CoV-2 infection who have history of MIS-C meeting the CDC definition:

1. An individual aged \<21 years presenting with fever\*, laboratory evidence of inflammation\*\*, and evidence of clinically severe illness requiring hospitalization, with multisystem (\>2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurological); AND
2. No alternative plausible diagnoses; AND
3. Positive for current or recent SARS-CoV-2 infection by RT-PCR, serology, or antigen test; or exposure to a suspected or confirmed COVID-19 case within the 4 weeks prior to the onset of symptoms.

   * Fever \>38.0°C for ≥24 hours, or report of subjective fever lasting ≥24 hours \*\*Including, but not limited to, one or more of the following: an elevated C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), fibrinogen, procalcitonin, d-dimer, ferritin, lactic acid dehydrogenase (LDH), or interleukin 6 (IL-6), elevated neutrophils, reduced lymphocytes and low albumin Young adults with past history of MIS-C with current ages 22-25 years are eligible to participate.

Children/Young Adults with Post-Vaccine Myocarditis

1. Age 3-25 years
2. Recipient of mRNA COVID-19 vaccination within last 4 weeks
3. Children or young adults with or without history of SARS-CoV-2 infection are eligible
4. Children or young adults with or without history of MIS-C are eligible (if any prior MIS-C-related cardiac abnormalities are known to have resolved pre-vaccination)
5. No other known auto-immune or other immune dysregulation disease
6. Participants are eligible without exclusion related to sex, race/ethnicity, geography, nationality, severity of disease, or underlying health conditions
7. Clinical evidence of probable or confirmed myocarditis based on the following criteria:

Children and young adults ages 3-25 years with presence of ≥1 new or worsening of the following clinical symptoms:

* chest pain, pressure, or discomfort
* dyspnea, shortness of breath, or pain with breathing
* palpitations
* syncope

OR, children aged 3-12 years might instead have ≥2 of the following symptoms:

* irritability
* vomiting
* poor feeding
* tachypnea
* lethargy AND

  ≥1 new finding of:
* troponin level above upper limit of normal (any type of troponin)
* abnormal electrocardiogram (ECG or EKG) or rhythm monitoring findings consistent with myocarditis
* abnormal cardiac function or wall motion abnormalities on echocardiogram
* cardiac MRI findings consistent with myocarditis
* histopathologic confirmation of myocarditis (Definite myocarditis)¶ AND
* No other identifiable cause of the symptoms and finding

Entry criteria are adapted from the CDC definition based on the assumptions that COVID-19 vaccines will be available in the future to children \<5 years of age.

Primary Caregiver Entry Criteria

1. A primary caregiver is defined as an individual, such as a family member (biological or nonbiological) or legal guardian, who is responsible for the care of the enrolled child and resides in the same household as the child. When possible, the primary caregiver identified at study entry will remain in the same role throughout the study.
2. The primary caregiver is the caregiver who spends the most time with the child or young adult, has substantial responsibility for taking care of him/her on a daily basis, and is most knowledgeable about him/her.
3. If two or more persons share equally in the caregiver responsibilities for the child or young adult, the person selected by the family to fill out study forms both about themselves and the child will be considered the primary caregiver.
4. If a biological family member primary caregiver has not reached the legal age of majority in their jurisdiction, the parent/legal guardian for the minor primary caregiver will provide consent for participation, with assent provided by the minor caregiver.
5. A nonbiological primary caregiver or legal guardian serving as primary caregiver must be above the legal age of majority in their jurisdiction.
6. The primary caregiver cannot be a babysitter or other childcare provider who receives money to care for the child.

Biological Parent Entry Criteria

- If the primary caregiver is a biological parent of the child or young adult who is participating in the study, the other biological parent may be enrolled to provide a home sample of saliva for DNA analysis.

Exclusion Criteria

An individual who meets any of the following criteria will be excluded from participation in this study:

1. Any child, young adult, caregiver, or other biological parent who in the opinion of the site investigator may be at increased risk of adverse events during participation in the study, or who may not be able to complete study procedures due to co-morbid disease or disability.
2. Any young adult age above the age of majority who lacks capacity to provide consent
3. Nonviable neonates and neonates of uncertain viability as determined by the treating physician
4. Any child, young, adult, or caregiver with co-morbid illness with expected survival \<2 years
5. Any child who is being given up for adoption or is a ward of the state
6. Any caregiver or other biological parent who is incarcerated, or who lacks capacity to provide consent
7. Currently enrolled in the study Understanding the Long-term Impact of COVID-19 in Adults

Primary outcomes:
measure: Caregiver SARS-CoV-2 Infection Status
timeFrame: Baseline
measure: Child SARS-CoV-2 Infection Status
timeFrame: Baseline
measure: Caregiver Severity of SARS-CoV-2 Infection
timeFrame: Baseline
measure: Child Severity of SARS-CoV-2 Infection
timeFrame: Baseline
measure: Caregiver Previous In-Hospital SARS-CoV-2 Treatment Record
timeFrame: Baseline
measure: Child Previous In-Hospital SARS-CoV-2 Treatment Record
timeFrame: Baseline
measure: Caregiver Symptoms
timeFrame: Baseline, up to Month 48
measure: Child Symptoms
timeFrame: Baseline, up to Month 48
measure: Caregiver SARS-CoV-2 Vaccination Status
timeFrame: Baseline, up to Month 48
measure: Change in Child SARS-CoV-2 Vaccination Status
timeFrame: Week 8, up to Month 48
measure: Change in Caregiver SARS-CoV-2 Treatment Record
timeFrame: Month 12, up to Month 48
measure: Change in Child SARS-CoV-2 Treatment Record
timeFrame: Week 8, up to Month 48
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham (Pregnancy Cohort)
state: Alabama
city: Little Rock
country: United States
facility: Arkansas Children's Hospital and Research Institute
state: Arkansas
city: La Jolla
country: United States
facility: University of California San Diego
state: California
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: San Diego
country: United States
facility: University of California San Diego Health - Rady Children's Hospital
state: California
city: San Francisco
country: United States
facility: University of California San Francisco (Pregnancy Cohort)
state: California
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Hartford
country: United States
facility: Connecticut Children's Medical Center
state: Connecticut
city: New Haven
country: United States
facility: Yale School of Medicine (YSM)
state: Connecticut
city: Newark
country: United States
facility: ChristianaCare Health System
state: Delaware
city: Wilmington
country: United States
facility: Nemours Children's Health
state: Delaware
city: Washington
country: United States
facility: George Washington University
state: District of Columbia
city: Honolulu
country: United States
facility: Kapi'olani Medical Center for Women & Children
state: Hawaii
city: Evanston
country: United States
facility: Northwestern University
state: Illinois
city: Glenview
country: United States
facility: Northshore University HealthSystem
state: Illinois
city: Itasca
country: United States
facility: American Academy of Pediatrics
state: Illinois
city: Leawood
country: United States
facility: American Academy of Family Physicians
state: Kansas
city: Louisville
country: United States
facility: University of Louisville - Norton Children's Hospital
state: Kentucky
city: Baton Rouge
country: United States
facility: Louisiana State University (LSU) - Pennington Biomedical Research Center
state: Louisiana
city: New Orleans
country: United States
facility: Tulane University
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Mass General Brigham - Harvard University
state: Massachusetts
city: Boston
country: United States
facility: Harvard Medical School
state: Massachusetts
city: Boston
country: United States
facility: Harvard School Of Public Health
state: Massachusetts
city: Boston
country: United States
facility: Northeastern University
state: Massachusetts
city: Detroit
country: United States
facility: Central Michigan University - College of Medicine
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Omaha
country: United States
facility: University Of Nebraska Medical Center
state: Nebraska
city: Lebanon
country: United States
facility: Dartmouth-Hitchcock
state: New Hampshire
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: New Brunswick
country: United States
facility: Rutgers University
state: New Jersey
city: New Brunswick
country: United States
facility: Saint Peter's University Hospital
state: New Jersey
city: West Orange
country: United States
facility: The Pediatric Specialty Center at Saint Barnabas
state: New Jersey
city: Albuquerque
country: United States
facility: University of New Mexico Health Sciences Center
state: New Mexico
city: New York
country: United States
facility: NYU Langone Health
state: New York
city: New York
country: United States
facility: Columbia University
state: New York
city: New York
country: United States
facility: Columbia University (Pregnancy)
state: New York
city: Queens
country: United States
facility: NewYork-Presbyterian Hospital
state: New York
city: Valhalla
country: United States
facility: New York Medical College
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina (UNC) at Chapel Hill
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Raleigh
country: United States
facility: WakeMed Health & Hospitals
state: North Carolina
city: Cincinnati
country: United States
facility: Good Samaritan Hospital
state: Ohio
city: Cleveland
country: United States
facility: University Hospitals MacDonald's Women's Hospital
state: Ohio
city: Cleveland
country: United States
facility: Metrohealth System
state: Ohio
city: Cleveland
country: United States
facility: The MetroHealth System (Pregnancy Cohort)
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University - Wexner Medical Center
state: Ohio
city: Dayton
country: United States
facility: Miami Valley Hospital
state: Ohio
city: Fairfield
country: United States
facility: Children's Mercy Hospital
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center (OUHSC)
state: Oklahoma
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center (UPMC)
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Providence
country: United States
facility: Women & Infants Hospital
state: Rhode Island
city: Charleston
country: United States
facility: Medical University of South Carolina (MUSC)
state: South Carolina
city: Greenville
country: United States
facility: Prisma Health Upstate
state: South Carolina
city: Sioux Falls
country: United States
facility: Avera Research Institute
state: South Dakota
city: Galveston
country: United States
facility: University of Texas Medical Branch (UTMB) Galveston
state: Texas
city: Houston
country: United States
facility: University of Texas Health Science Center at Houston
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Health
state: Utah
city: Burlington
country: United States
facility: University of Vermont (UVM) Children's Hospital
state: Vermont
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Morgantown
country: United States
facility: West Virginia University
state: West Virginia
city: Milwaukee
country: United States
facility: Medical College Of Wisconsin
state: Wisconsin
Study officials:
affiliation: NYU Langone Health
name: Stuart Katz, MD, MS
role: PRINCIPAL_INVESTIGATOR
affiliation: NYU Langone Health
name: Andrea Troxel, ScD
role: PRINCIPAL_INVESTIGATOR
affiliation: NYU Langone Health
name: Leora Horwitz, MD
role: PRINCIPAL_INVESTIGATOR
References: