Landmark study of COVID-19 infection among K-12 students debunks early fears about transmission at schools

Debunking a fear that was widespread at the beginning of the COVID-19 pandemic, a novel CHOC- and UC Irvine-led study of SARS-CoV-2 infection rates among the K-12 population concludes that within-school transmission of the virus is limited.

The “Healthy School Restart Study,” one of the first to provide essential research on COVID-19 transmission in children and adolescents as schools started reopening last fall, also concludes that although the compliance rate to such mitigation guidelines as wearing face coverings and practicing social distancing at the four Orange County schools directly observed by investigators varied, it averaged about 90 percent.

The seminal research paper is under review and is expected to be published soon, says Dr. Dan Cooper, who treats kids with lung conditions at CHOC and who serves as director of UC Irvine’s Institute for Clinical & Translational Science. Dr. Cooper is a multiple principal investigator of the study along with Dr. Erlinda Ulloa, a CHOC infectious disease specialist and an assistant professor in the Department of Pediatrics at the UCI School of Medicine.

Dr. Dan Cooper, pediatric pulmonologist at CHOC

“The number one fear was that, just like influenza, children would be a reservoir for COVID-19 and would spread it to each other at schools and then spread it to adults,” Dr. Cooper says. “The data is showing us, fortunately, that that’s not the case. While such spread can occur, it is limited and when schools follow standard mitigation procedures, spread is minimal.”

The study, a joint effort of CHOC, UCI Health and the Orange County Health Care Agency, found that infection rates at schools reflected those of the community, and that neither remote learning nor highly mitigated onsite school attendance could eliminate SARS-CoV-2 infection.

“It would be disingenuous to say it’s 100-percent safe to return to schools – we’re still in a pandemic,” Dr. Cooper says. “It would be wrong to say there’s absolutely no risk in sending your child back to school, but it would also be wrong to say there’s no risk in not sending your child back to school.”

A total of320 students ages 7 to 17, as well as 99 school staff members, participated in the research project by agreeing to nasal swab and blood testing. Two of the schools in the study serve low-income Hispanic learners. One school serves a high proportion of kids with special needs, and the fourth school serves predominately white kids from upper- and middle-class families. The first three schools mainly provided remote instruction, while the fourth school predominantly provided onsite instruction.

“The four participating schools reflected the enormous diversity of income, community COVID-19 case rates, school type (private, charter, public), and learning status (remote vs. onsite) that face learners, school staff, and policy makers across the United States,” the paper states.

The study was done in two phases – in early fall, when there were lower levels of COVID-19 cases, and a second time during the late fall-winter surge, when there was a tenfold increase in COVID-19 cases. Trained observers studied kids four times a day – during classroom learning, at active recess, during PE, and during communal lunch.

During the first testing phase, no kids tested positive for COVID-19. During the second phase, 17 kids tested positive for the virus, along with six staff members.

School A, which primarily serves lower-income Hispanic students and had 97 percent of its students engaged in remote learning, had the highest infection rate, at 12.9 percent. School D, which serves upper- and middle-class students who primarily attended class in person, had the lowest infection rate, at 1.2 percent.

In the aggregate, there was no statistically significant difference in SARS-CoV-2 positive rates among remote or onsite learners, the study found.

In addition, the study found there was a significant relationship between SARS-CoV-2 positivity and presence of symptoms – data that supports the use of limited symptom screening as a mechanism to enhance healthy school reopening.

Investigators also tested for 21 other circulating respiratory pathogens and turned up no signs of the influenza virus – just the common-cold rhinovirus, which stays functional on surfaces such as desktops for much longer intervals than the coronavirus or influenza virus.

“The mitigation procedures and cleanliness procedures that had been put in place got rid of the flu,” Dr. Cooper notes.

He adds: “This study should make parents feel better and prompt them to ask the right questions to their school. Parents should ask, ‘What are your mitigation plans? How are you making sure people are paying attention to your plan? What happens to a child who reports symptoms during the day? Do you have a plan?’ That’s what I would want to know as a parent.”

Mitigation procedures should remain

With widespread implementation of pediatric COVID-19 vaccination still many months away, it’s likely that adherence to COVID-19 mitigation procedures, including physical distancing and face covering, will need to continue for the near future, the study concluded.

Dr. Cooper notes that some students, mostly from lower-income families, are going on a year without in-classroom learning – an unfortunate situation that comes with many disadvantages, such as more sedentary time at home on the computer and increased obesity and depression.

“We have to weigh the damage to kids of keeping schools closed,” he says. “Who is being impacted most? It’s the low-income kids.”

In addition to Dr. Cooper and Dr. Ulloa, other CHOC and UCI personnel who participated in the “Healthy School Restart Study” included Jessica Ardo, Kirsten Casper, Andria Meyer, and Diana Stephens, clinical research coordinators; Dr. Charles Golden, vice president and executive medical director of the CHOC Primary Care Network; and Dr. Michael Weiss, vice president of population health at CHOC.

The authors of the research paper also acknowledged the “outstanding management” of the complex study by Phuong Dao, director of research operations; Brent Dethlefs, executive director of research; and other staff members of the CHOC Research Institute.

In another research paper, published in late February 2021 in the journal Pediatric Research, Dr. Cooper and Dr. Ulloa addressed the biologic, ethical, research and implementation challenges of SARS-CoV-2 vaccine testing and trials in the pediatric population.

Among others, the paper was co-authored by Dr. Coleen Cunningham, CHOC’s new senior vice president and pediatrician-in-chief, as well as chair of the UCI Department of Pediatrics, and Dr. Jasjit Singh, a CHOC infectious disease specialist.

Children under the age of 12, this paper notes, have yet to be enrolled in COVID-19 vaccine trials.

The paper states that enrolling children in medical research involves a balance between access to experimental but potentially life-saving therapeutics and protection from unsafe or ineffective therapeutics.

The paper notes that in the early stages of the pandemic, a national working group convened and published a commentary outlining the challenges ahead that would inevitably need to be addressed as schools reopened. That commentary, the paper says, included a message that resonates with the immediate challenge of pediatric SARS-CoV-2 vaccine testing and clinical trials:

“This could be accomplished by building public health-focused collaboratives capable of continuous learning and rapid cycles of implementation, as COVID-19 information evolves at breakneck speed. Otherwise, we risk further compounding the incalculable damage already incurred by COVID-19 among children across our country and the world.”

Read more about the Healthy School Restart Study.

CHOC awarded $2.3-million grant to study how toxic stress and unpredictability in the early environment affects neurodevelopment

The state of California has awarded CHOC, in partnership with UC Irvine and Chapman University, a $2.3-million grant to screen patients for adverse childhood experiences (ACEs) and childhood unpredictability to assess how such high-stress events affect the brain and put kids at increased risk of later developing physical and mental illnesses.

In a novel aspect of the study, researchers also will determine if there are epigenetic markers on the DNA that predict whether any given child will be more adversely affected than another.

The team is among four awardees statewide that have been given a total of $9 million to assess which children are most vulnerable to the effects of ACEs and unpredictability in the home environment, and to design medical care to improve the outcomes for this particular group of patients – a model known as “precision medicine,” which eschews a one-therapy-fits-all approach to healthcare.

“The whole concept here is that kids who grow up in environments with frequent exposures to toxic levels of stress can have all kinds of internal things happen in their bodies related to prolonged or extensive stress hormone response – their brains can develop differently, and when they become adults, research has shown that they have a higher risk of developing medical conditions such as heart disease, asthma and cancer,  among other physical diseases, as well as mental disorders,” says Dr. Charles Golden, a co-investigator on the study and executive medical director of the CHOC Primary Care Network (PCN).

Dr. Charles Golden, executive medical director of the CHOC Primary Care Network (PCN)

The California Governor’s Office of Planning & Research, in partnership with the Office of the California Surgeon General, awarded the three-year research project as part of the California Initiative to Advance Precision Medicine (CIAPM). The other three recipients were Children’s Hospital Los Angeles, University of California, San Francisco, and Loma Linda University.

The CHOC-UCI-Chapman research project begins in July 2021, with screening expected to start in CHOC PCN clinics by November 2021. Lead principal investigator on the project is Dr. Tallie Baram, Bren Distinguished Professor and director of the Conte Center at UCI. The National Institute of Mental Health-funded Conte Center also addresses how early-life experiences influence the brain and contribute to mental illnesses.

Results of the study are expected by the end of 2024, says Laura Glynn, PhD, a Professor of Psychology and Associate Dean for Research at Chapman University and one of the principal investigators on the study.

CHOC’s PCN has been screening its Medi-Cal patient population for ACEs since February 2020, and expanded such screening – using a tool called PEARLS, for Pediatric ACEs and Related Life Events Screener – to all patients in November 2020, Dr. Golden says.

The 17-question PEARLS tool screens for such experiences as a parent being jailed, the prevalence of alcohol or drug abuse in the household, and whether the child has been a victim of violence in his or her neighborhood, in the community at large, or at school.

“This existing infrastructure at CHOC was a very important part of the application for this grant,” Glynn says.

The CHOC-UCI-Chapman study, “Using Precision Medicine to Tackle Impacts of Adverse and Unpredictable Experiences on Children’s Neurodevelopment,” will dig deeper than standard PEARLS screening.

The children will be asked an additional five questions to assess exposure to unpredictability in the social, emotional, and physical domains. Such questions are an attempt by researchers to develop an instrument that will predict this population of kids’ resilience to, or risk of developing, physical or mental illnesses. Children from low socioeconomic and racial/ethnic minority communities are at greater risk of exposure to ACEs.

“This study will involve looking at whether routine, or lack of routine, in a child’s life contribute as an ACE,” Dr. Golden explains. “In other words, do they eat dinner every night at 6 p.m., do they have a routine bedtime, do they have a stable household versus a family with no routine or little structure.”

Such factors of unpredictability potentially are amenable to intervention, Glynn notes.

Emerging evidence from experiments with rodents show that fragmented or unpredictable maternal signals influence the maturation of systems governing emotional and cognitive function in the developing brain. In preclinical work led by Dr. Baram, the group has shown that rats exhibited diminished memory function when exposed to unpredictable maternal signals early in life, as well as anhedonia (reduced ability to experience pleasure) beginning in adolescence.

Also, as part of the study, DNA swabs will be performed on a cohort of 120 children who experience high levels of ACEs to determine if genetic expression patterns indicate a vulnerability to chaos and unpredictability in their lives. The team also will be examining whether epigenetics – the process of how genes may be altered based on environmental events – may play a role in the development of ACE-related medical conditions.

“We think potentially we can look at these epigenetic profiles to predict neurodevelopmental outcomes,” Glynn says.

Dr. Michael Weiss, vice president of population health at CHOC and a primary investigator on the study, says such information may make it easier for doctors to identify a child who has a genetic predisposition to experiencing a bad outcome from being exposed to ACEs – thus leading to targeted interventions to kids who need them the most.

“This project is a great demonstration of a collaboration between CHOC and UCI and Chapman University involving primary care research,” Dr. Weiss says.

Other CHOC researchers who will participate in the research project are Dr. Dan Cooper, who treats kids with lung conditions at CHOC and who serves as director of UC Irvine’s Institute for Clinical & Translational Science; Dr. Candice Taylor Lucas, co-director of LEAD-ABC (Leadership Education to Advance Diversity–African, Black and Caribbean) at UCI/CHOC; Louis Ehwerhemuepa, PhD, a senior data scientist; and Dr. Mary Zupanc, co-medical director of the Neuroscience Institute.

Seminal study of COVID-19 infections at Orange County schools nears completion

Two doctors – one a rising star in infectious disease research, the other a nationally known pediatric pulmonologist – are nearing completion of a seminal study on COVID-19 transmission at four Orange County schools and how closely students and staff are following mitigation procedures such as wearing face coverings.

The doctors believe the study is the first of its kind in the country, and that it could shed light on such critical issues such as the role that kids play in the spread of SARS-CoV-2, the novel coronavirus that has led to the deaths of some 300,000 Americans and counting.

“We’ll never understand COVID-19 disease until we understand it in children,” says Dr. Dan Cooper, who treats kids with lung conditions at CHOC and who serves as director of UC Irvine’s Institute for Clinical & Translational Science.

Dr. Cooper was reiterating a comment made by UCI colleague Dr. Donald Forthal, chief of the Division of Infectious Diseases at the university, in the early stages of the pandemic.

Dr. Cooper is a multiple principal investigator of the O.C. school study along with Dr. E.R. Chulie Ulloa, a CHOC infectious disease specialist and an assistant professor in the Department of Pediatrics at the UCI School of Medicine.

Drs. Coopers and Ulloa provided an update on their novel study of four O.C. middle and high schools during a recent presentation on Research Day. The study, a partnership of CHOC, UCI Health and the Orange County Health Care Agency, began at the end of October and will conclude before Christmas.

Results are expected during the first quarter of 2021.

“We understand little about the immune responses to COVID-19 in children, but hopefully we’ll be able to shed some light with this study,” Dr. Ulloa says.

Vaccinations in adult U.S. healthcare workers began in mid-December at a time when the country remains in the grips of a terrible increase in COVID-19 infections and deaths – the dreaded “second surge” healthcare experts predicted would happen this winter.

“We’re just beginning to understand and accumulate the knowledge we need to eventually make definitive statements about SARS-CoV-2 transmission in children,” Dr. Cooper says. “This information will ultimately inform decisions around vaccinations in the pediatric population.”

PRELIMINARY RESULTS

Although the numbers continue to increase as the study nears completion, as of mid-November — when Drs. Cooper and Ulloa provided their update on Research Day — 187 students and 100 staff members at four demographically diverse schools had undergone nasal-swab tests, with none testing positive for COVID-19, Dr. Ulloa reported.

Additionally, nearly 90 percent of those students agreed to have their blood drawn to check for antibodies that showed they had been exposed to the novel coronavirus. The positivity rate for those tests came back at 8.5 percent.

This number is encouraging, Dr. Ulloa says. She explains that nearly all these COVID-19 antibody-positive students were completely asymptomatic or mildly symptomatic.

“We’re not sure yet if this positivity rate shows that children do indeed have protection (against COVID-19), but it’s certainly a positive sign,” Dr. Ulloa says. “We will conduct more research in the lab to see if those antibodies are able to neutralize or inhibit the replication of the virus.”

The preliminary results of the study – which involves students from a charter school and a public school in Santa Ana, a charter school in another city that primarily serves students with special needs and a private school elsewhere whose students come from middle- to upper-class families – suggests that children likely are not super-spreaders of COVID-19, Dr. Cooper says.

“We still don’t know why that appears to be the case,” he says.

In addition to testing for COVID-19 with the nasal swabs, the school project team – which includes a total of nearly two-dozen people – also is testing for 21 other respiratory infections, such as the common cold, in the students. The thinking is that these additional tests will help determine how well students are following COVID-19 mitigation measures such as social distancing and frequent washing of hands – which should help prevent them from catching many viral diseases.

“We hope to be able to see if there’s a relationship between how well the school is able to put into place mitigation procedures and the degree of viral infection,” Dr. Cooper notes.

The pool of students involved in the research project has expanded to kids ages 7 to 17, from ages 10-15 at the onset. Dr. Cooper points out although data are accumulating through public health agencies on SARS-CoV-2 in school-aged children, there are few, if any studies like this one that involves students and school staff as research volunteers and who must consent to participate. These types of studies can often add to our knowledge of disease to a much greater extent than simple descriptions of ongoing data, he says.

“In addition, we’re capturing data from an age group that hasn’t been involved in vaccine clinical trials before,” Dr. Ulloa adds, “and these data may shed light on efforts to test COVID-19 vaccines in the future.”

Drs. Cooper and Ulloa both praised the cooperation of school officials and students in allowing them to carry out this seminal study, in which participants also receive free of charge a complete blood count to check for anemia and a full lipid screening to check the amount of cholesterol and triglycerides in their blood.

“In order to pull this off,” Dr. Cooper says, “we had to have very close relationships with the schools, with the parents, and with the kids.”

Dr. Ulloa’s fluency in Spanish and leadership has helped a lot, he says. So has her serving as a strong pediatrician-scientist role model for the children.

“We’ve really been active in the community for a while, which has helped establish trust,” Dr. Ulloa says.

Dr. Cooper notes that the school research team already is talking to the National Institutes of Health about putting together a project to follow middle- and high-school kids who are infected with the coronavirus over the next five years to determine the long-term effects on such things as cognitive development and the role of exercise in keeping the disease in check.

CHOC Researchers to Present at Upcoming Conference

CHOC will be well represented at a prestigious upcoming pediatrics conference, with two research projects set to be presented.

At the 2015 Pediatric Academic Societies annual meeting later this month, CHOC infectious disease physicians will present the outcomes of a study that examined the efficacy of the pneumococcal disease vaccine in Orange County youth.

The study shows that the incidence of invasive pneumococcal disease has decreased in Orange County children every year since the 13-valent pneumococcal conjugate vaccine (PCV-13) was introduced in 2010, says Dr. Antonio Arrieta, chief of infectious disease at CHOC.

CHOC Children's Research Institute

Researchers looked at all Orange County children who developed invasive pneumococcal disease, found each case’s bacteria serotype, and determined whether it was a vaccine type.

“We were able to show that the difference was for the whole population and more noticeable in children 5 and younger, who are more susceptible,” Dr. Arrieta says. “The vaccine is doing its job.”

The results show that PCV-13 has improved upon the already good outcomes from the vaccine’s previous incarnation, PCV-7, which was released in 2000.

“The vaccine is very expensive, so we are putting our money on something that is working,” Dr. Arrieta says. “It was very important to ascertain that the vaccine worked because when this was approved, it was approved without clinical trials. It was approved only with immunogenicity data.”

Drs. Michele Cheung, Delma Nieves and Jasjit Singh, as well as Stephanie Osborne, a CHOC clinical research nurse, also authored the study, which was conducted in partnership with the Orange County Health Care Agency and Kaiser.

Also, the conference will feature a project co-led by Dr. Dan Cooper, CHOC’s chief academic officer, on exercise biomarkers and translational research in child health.

The annual meeting will be held April 25-28 in San Diego.