COVID-19 Research and Innovation

Anschutz Medical Campus COVID-19 Research Consortium

Children's Hospital Colorado and University of Colorado Hospital are collaborating on a new protocol to collect patient electronic health record data and biological samples for analysis. The study is now active at both hospitals, and the first specimens have been collected.

A second collaborative effort is underway to develop a protocol specifically evaluating the risks our own team members face as frontline healthcare providers. The goals are to:

• Determine the incidence of COVID-19 among healthcare workers
• Identify risk factors for severe illness
• Evaluate the humoral and cellular response to SARS-CoV-2
• Characterize the effects of COVID-19 on healthcare workforce capacity

The results of this study will help us protect our team members and guide operational planning into the future. This collaborative approach to understand the clinical characteristics of COVID-19 disease in pediatric and adult populations, as well as the underlying characteristics of patients and their treatment responses, will help us comprehend why children seem better protected from COVID-19. Children are usually one of our most vulnerable populations to viral respiratory infections.

HEROS study

The goal of the HEROS (Human Epidemiology and Response to SARS-CoV-2) study is to learn more about the number of people who may have the coronavirus without knowing it, particularly children. The study will also help us learn how the virus spreads from person to person and the nasal response to the coronavirus. Sponsored by the NIH National Institute of Allergy and Infectious Diseases, the HEROS study is considered mission critical. Andrew Liu, MD, pediatric pulmonologist and Glenn Furuta, MD, pediatric gastroenterologist will lead our participation as one of 11 study sites. National Jewish Hospital is the lead lab for the study.

Airway Inflammation, Resilience and the Environment (AIRE) Research Program updates

Children's Colorado is the clinical performance site for the NHLBI-sponsored program project grant “Defining Molecular Phenotypes of Exacerbation Prone Asthmatics” and is now COMIRB-approved to convert to tele-research and add COVID-19 surveillance. We have long been interested in the determinants of airway inflammation versus resilience to common cold viruses. Molecular phenotyping and translational research can lead us to new therapies and prevention for severe respiratory viral illness, asthma exacerbations and perhaps the common cold.

Age-related airway host factors associated with COVID-19

Age is a primary determinant of COVID-19 disease severity, as are comorbidities including diabetes, obesity, pulmonary and cardiac disease. The receptor for angiotensin converting enzyme 2 (ACE2) expressed by epithelial cells throughout the respiratory tract is recognized as a dominant route for entry of SARS-CoV-2 viral particles into cells lining the airway. Children have lower expression of ACE2 receptors, which may result in age-related differential responses, yet no studies have investigated the expression of ACE2 receptors nor the host response specific to SARS-CoV-2 in children.

This study is among the first to investigate the differential response between asymptomatic carriers and patients with symptomatic COVID-19 in children, and to compare the virus-host interaction between children and adults, to identify potential targets for prevention and therapy.

Lilliam Ambroggio, PhD is the pediatric emergency medicine investigator of the study.

Healthcare worker COVID-19 seroprevalance

This research study is designed to investigate how frequently healthcare workers at Children’s Colorado have antibodies in response to being exposed to patients with SARS-CoV-2 infection. The goals of this research include studying the prevalence and incidence of COVID-19, documented by serology testing, correlated with epidemiologic characteristics in 400 Children’s Colorado healthcare workers. This research is led by pediatrics investigator Steve Berman, MD, FAAP.

COVID-19 prospective observational cohort study and biobank of healthcare workers and other populations

The goal of this research study is to evaluate rates of immunologic responses to SARS-CoV-2 across a variety of occupations, including healthcare workers, first responders, individuals with prior COVID-19 and other campus personnel. A biobank of clinical data and blood samples will be created for future research. Rheumatology investigator Kevin Deane, MD, and pediatric allergy and immunology investigator Elena Hsieh, MD, are leading the study.

National COVID Cohort Collaborative

The National COVID Cohort Collaborative, or N3C, is a secure data and computing environment designed to facilitate virtual access to clinical data provided by 72 clinical centers nationwide on more than 374,000 patients with COVID-19. Launched by the National Institutes of Health, it’s the single largest integrated collection of COVID-19 patient data in the nation. Its mission is threefold: make it easier for researchers across the country to access the large data set; expand the number of research studies using the data and analytical supports available to improve our understanding of COVID-19; and demonstrate that aggregating data across centers really does work.

The University of Colorado Anschutz Medical Campus is playing a key role in N3C in part by contributing data from both Children’s Hospital Colorado and neighboring UCHealth University of Colorado Hospital. Additionally, Children’s Colorado critical care physician and informaticist Tell Bennett, MD, MS, is co-leading the N3C’s clinical scenarios and analytics team. His team’s work includes writing code so that future database users will be able to efficiently run algorithms across the database without having to access any patient records.

“One of the reasons this resource is crucial is that each medical center may not have enough patients with different subtypes of the disease to conduct the necessary clinical science,” says Dr. Bennett. “By having a centralized, cloud-based data resource, researchers across the country can easily access the information they need in significant sample sizes.”

For example, in a retrospective cohort study of COVID-19 patients, N3C data and machine learning helped predict clinical severity and risk factors over time (1). “The N3C supports robust evidence-based development of predictive and diagnostic tools and informs critical care and policy,” Dr. Bennett says. Researchers interested in accessing N3C can learn more through covid.cd2h.org/n3c.

Role of SARS-CoV-2 virus in activating the complement immune system

Endothelial cells play a key role in activating complement. Kurt Stenmark, MD, and team are studying whether the SARS-CoV-2 virus, in conjunction with hypoxia, might be acting on endothelial cells to activate complement, and whether anti-complement therapies aimed at the pulmonary vascular endothelium might help. Dr. Stenmark’s team received a $200,000 grant from the American Lung Association to support this research.

“A lot of people who come in with COVID-19 are severely hypoxic,” Dr. Stenmark says. “We’re seeing evidence of vascular involvement, severe endothelial injury and cell death, inflammation and thrombosis. A lot of the same stuff we see in pulmonary hypertension.” Read related research.

Navajo Nation Community Asthma Program Research

We have added COVID-19 surveillance to our current NHLBI-sponsored grant focused on asthma management with a cohort of children from the Navajo Nation and their families. The prevalence of asthma in children from the Navajo Nation is nearly 20%, which is double the U.S. prevalence. National Jewish Hospital is also highly involved in this work, serving as the principal investigator for this study. Our goal is to improve resources to better manage asthma and coronaviruses for the Navajo Nation, where COVID-19 infection and death rates per capita are much higher than surrounding communities.

Defining Molecular Phenotypes of Exacerbation Prone Asthmatics (ENIGMA)

This twelve-month surveillance study was added to an existing study focused on the impact of rhinovirus on asthma severity. The study compares pre-pandemic, current and post-pandemic environmental exposures, lung mechanics and asthma severity among non-infected, symptomatic and symptomatic SARS-CoV-2 infections. Researchers analyze cellular and gene expression responses to SARS-CoV-2 and other common respiratory viruses, enabling the team to investigate factors contributing susceptibility or resilience to these viruses in children with asthma. The allergy and immunology investigator is Andrew Liu, MD.

COVID-19 in type 1 diabetes

The Centers for Disease Control and Prevention reports that individuals with diabetes are at high risk for severe illness and poorer health outcomes with COVID-19. Research suggests this might be due to poor glycemic control or chronic hyperglycemia, yet information on clinical outcomes specifically for patients with type 1 diabetes who have confirmed cases of COVID-19 is limited.

To learn more, the Barbara Davis Center for Childhood Diabetes at the University of Colorado, the primary type 1 diabetes service provider for Children’s Colorado, helped rapidly form a national COVID-19 registry. “In partnership with other U.S. pediatric and adult diabetes clinics, the registry helps pinpoint factors associated with poorer outcomes,” says pediatric endocrinologist Todd Alonso, MD.

An early publication from the registry last August demonstrated poor outcomes and symptoms in patients with type 1 diabetes. A third of patients in the study developed diabetic ketoacidosis, or DKA, a life-threatening illness often precipitated by other illnesses. Subsequent studies showed clear inequities in those who were hospitalized and developed DKA, particularly Black and Hispanic patients, mirroring observations in other patient populations. The registry has also studied new onset diabetes during the COVID-19 pandemic. It found that patients were very sick at onset, suggesting healthcare access has significantly suffered. “These papers show that DKA is a big risk for this patient population,” Dr. Alonso says. “It’s more important than ever to optimize blood sugar management.”

Sniffing out COVID-19

Basic science research on SARS-CoV-2 in adults shows that the virus attacks nerves in the nose called the olfactory bulb, causing a dramatic change in sense of taste and smell. It seems to be an early sign of infection, developing sooner than more severe symptoms. Little is known about how the virus affects kids. But, if kids’ symptoms are similar to adults’ symptoms, could sense of smell be an effective way to screen kids before they start their school day?

That’s a question that researchers at Children’s Colorado are asking, and they’ve secured $150,000 over two years to find out. Led by pediatric otolaryngologist Sarah Gitomer, MD, the study is administering a 40-question scratch-and-sniff quiz to a sample of patients who’ve received a COVID-19 test from Children’s Colorado, regardless of whether that test was positive or negative. Researchers are hoping to learn:

• how the virus affects kids compared to adults
• whether scratch-and-sniff tests can be an effective screening tool
• if certain smells are more effective than others

This collaborative effort has been made possible with essential contributions from across the Anschutz Medical Campus.

Treating COVID-19 lymphatic clots and airway plugs

Patients with severe COVID-19 have small clots in their blood vessels and fibrin plugs in their airways. Through work with the Airway Research Center, Livia Veress, MD, has shown in animal models that using a clot-busting drug (alteplase) can treat the airway plugs that develop after sulfur mustard gas exposure. Dr. Veress and Deborah Liptzin, MD, have also used alteplase to treat children with plastic bronchitis (small lymphatic clots in the airways). They are developing protocols to treat patients with severe COVID-19 disease with alteplase both in the lungs and intravenously. They are also providing guidance to adult and pediatric providers throughout the country on how to use these drugs.

Long-Term Outcomes after the Multisystem Inflammatory Syndrome in Children (MUSIC) Trial

In collaboration with the NIH and Pediatric Heart Network (PHN), this multicenter trial will evaluate the cardiac outcomes of patients with multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19. The goal of the study is to determine the spectrum and time course of coronary artery involvement, left ventricular function and conduction disturbances within the first year from illness onset.

To accurately diagnose and differentiate MIS-C from Kawasaki disease and other more common conditions, a multidisciplinary team of infectious disease specialists, rheumatologists and critical care experts have developed a treatment pathway that helps doctors take a standardized approach. Combining recommendations from the Centers for Disease Control and Prevention, World Health Organization and European Center for Disease Prevention and Control, the team also recommended clinical criteria and sophisticated decision trees leading to further labs and testing without delaying necessary treatments. Pei-Ni Jone, MD, is the pediatric cardiology investigator.

See “A Pathway for MIS-C.”

Healthcare Worker Exposure Response & Outcomes Study (HERO-HCW)

The research program, HeroesResearch.org, is designed by and for healthcare workers to help develop real-time, evidence-based strategies to protect the health and well-being of frontline workers fighting COVID-19. The program includes a preventive medications trial and vaccine study. The lead site clinical research investigator and pediatric infectious disease investigator is Suchitra Rao, MD.

Pediatric nurses’ experiences to the COVID-19 response case study research

The goal of this qualitative study is to describe and document an in-depth understanding and meaning of the experiences and responses of pediatric nurses working for Children’s Colorado during the COVID-19 pandemic. This study also seeks to identify issues important to pediatric nurses and to outline future practices considerations. Lindsey Tarasenko, RN, PhD, is the pediatric nursing investigator.