In the past year, the COVID-19 pandemic has delivered unprecedented challenges to the world’s health care systems. Even with a burgeoning vaccination effort, the disease continues to take an enormous human toll measured in deaths, hospitalizations, and long-term physical and mental effects. COVID-19 has also left many questions in its wake, notably why the SARS-CoV-2 virus that causes it affects people so differently.
Much is known about the factors that increase the risk of contracting severe COVID-19: age, race and a host of underlying conditions. Yet some people in these categories escape serious illness and death while some young, otherwise healthy people fall prey to the disease. Even among hospitalized COVID-19 patients there are considerable differences in the effects. Why?
Researchers link antibody production to COVID-19 progression
A new paper by a team of researchers on the University of Colorado Anschutz Medical Campus suggests that one clue lies in the amount of antibodies produced to fight the infection. The researchers found that the amount of these infection-fighters and the time it takes to produce them could help to explain the vastly different tolls COVID-19 exacts on patients. That information could be used to tailor treatments that target specific symptoms.
The study, published March 16 in the journal eLife, relied on analysis of blood samples from COVID-19-positive patients and controls collected from patients at UCHealth University of Colorado Hospital and Children’s Hospital Colorado on the Anschutz Medical Campus and deposited in the University of Colorado COVID-19 Biobank, overseen by the Vice Chancellor for Research Dr. Thomas Flaig. These samples, in turn, provided the raw material for the COVIDome, a large data set that is shared broadly through the COVIDome Explorer, an online portal investigators use to analyze the data and probe the mysteries of the disease.
The crux of the study is that COVID-19 patients can be “staged” according to a “seroconversion index”: that is, the amount of antibodies produced as the body battles the viral infection, said Dr. Joaquin Espinosa, Professor of Pharmacology and executive director of the Linda Crnic Institute for Down Syndrome at the University of Colorado School of Medicine. Espinosa is the senior author of the study.
Different stages, different disease characteristics
Patients in each stage exhibit specific characteristics that drive their disease, Espinosa explained. In stage 1, when the amount of antibodies against the virus is low, the body’s immune system goes into high gear, unleashing T cells, NK (natural killer) cells and monocytes – white blood cells that are the “front-line commando infantry” of the attack on foreign invaders, like the SARS-CoV-2 virus, he said. The immune cell attack, however, is associated with markers of hyperinflammation that can cause severe tissue and organ damage if they are untamed.
As the body makes more antibodies to combat the virus, patients transition to stage 2. In this phase, the researchers said, inflammation decreases, but signs of liver damage, blood vessel injury and blood clotting increase.
Espinosa said understanding the transition between stages 1 and 2 offers clinicians and researchers a tool to tailor COVID-19 treatments. For example, patients in stage 1 could benefit from anti-inflammatory medications. In contrast, patients in stage 2 could be monitored closely to guard against blood clots and for signs of liver problems or leaking blood vessels injured in stage 1.
“Moving from stage 1 to stage 2 is like walking from a forest fire into an urban fire,” Espinosa said. “Treatments and medications should be different, according to each stage.”
Findings open door to further research
Espinosa emphasized that the signs of stages 1 and 2 are also being observed in much larger studies of hospitalized COVID-19 patients, such as those carried out by the National COVID Cohort Collaborative (N3C).
The new study opens the door to further investigation that will be possible as the number of COVIDome samples grows, Espinosa added. For example, researchers could look into factors that might increase the length and intensity of stage 1 versus stage 2, such as age, body mass index, diabetes, prior chemotherapy treatment and so on, he said.
“As we add more batches of samples, we will be able to continue to map the trajectory of COVID-19 and ask more questions,” Espinosa said.
Down syndrome research drives COVID-19 studies
The COVIDome project builds on previous work at the Linda Crnic Institute for Down Syndrome, where Espinosa and his colleagues created the Crnic Institute Human Trisome Project (HTP). The idea was to methodically address the radically different disease profiles of people with Down syndrome, a genetic condition caused by an extra chromosome 21 that leads to a host of clinical and developmental problems.
The HTP is the intellectual forebear of COVIDome and the COVIDome Explorer. Researchers collect biospecimens from people with Down syndrome and analyze them through the TrisomExplorer researcher portal.
But the connections between COVID-19 and Down syndrome run deeper, noted Michelle Sie Whitten, president and CEO of the Denver-based non-profit Global Down Syndrome Foundation (GLOBAL), which helped to fund the seroconversion study. The organization, which recently joined with other Down syndrome organizations to publish the COVID-19 and Down Syndrome Resource, aims to improve the lives of people with Down Syndrome. For Whitten, the mission is also personal: her daughter, Sophia, has Down syndrome.
GLOBAL’s mission rests on four pillars, Whitten said. They include government advocacy, medical care, education and research. “As affiliates under one umbrella, GLOBAL and the Crnic Institute work closely together to help drive the national agenda for Down syndrome research,” she added.
Down syndrome and COVID-19 both tied to hyperinflammation
Whitten pointed out that the HTP produced key studies that established Down syndrome as an immune system disorder that is tied to proteins called interferons. These proteins are part of the body’s inflammatory reaction to infections. That response is essential to fighting off disease, but in people with Down syndrome, Espinosa and fellow researchers found, the interferon response is hyperactive, producing a steady flame of chronic inflammation.
That discovery has parallels with the new COVIDome study. The heightened interferon response that affects individuals with Down syndrome has many similarities to the hyperinflammatory response of COVID-19 patients who produce low numbers of antibodies. In essence, people with Down syndrome are inherently at risk of dangerous complications from a COVID-19 infection. Espinosa previously discussed the Down syndrome-COVID-19 connection in a May 2020 study.
The Centers for Disease Control and Prevention list Down syndrome as a condition that puts adults of any age at increased risk for COVID-19. That is true in part because of underlying conditions they are prone to, including obesity, cardiovascular disease, diabetes and sleep apnea. But, Whitten said, in her view, the root of the risk traces back to the disruption of the immune system.
Human Trisome Project and COVIDome could drive research around the globe
The HTP and the COVIDome initiative aim to answer important unanswered questions related to Down syndrome and COVID-19, Whitten said. But she also sees potential benefits in better care for the subset of COVID-19 patients who also have Down syndrome, with research into Down syndrome yielding additional clues about the biological processes of COVID-19.
“The Human Trisome Project has definitively become the gold standard for research into Down syndrome for scientists at the University of Colorado and across the globe,” Whitten said. “Now the COVIDome is applying that concept to COVID-19.”
Her point is echoed by Dr. Matthew Galbraith of the Crnic Institute and the Department of Pharmacology at the CU School of Medicine. Galbraith served as lead bioinformatics data analyst for the seroconversion study and wrote the manuscript with Espinosa.
“The intention all along has been to make these data as freely available as possible to other interested scientists and the general public, similarly to our Human Trisome Project,” Galbraith said.
A second paper currently under review co-authored by Galbraith, Espinosa and a host of CU Anschutz collaborators makes a similar observation. “We expect that the COVIDome Explorer will rapidly accelerate data sharing, hypothesis testing, and discoveries worldwide,” the authors asserted.
More research lies ahead
What is next for COVIDome? If the past is any indication, the pace of new discoveries will be swift. Galbraith noted that the COVIDome team collected, integrated, produced and analyzed an array of complex biological data sets in less than six months – a comparative blur for such a massive undertaking.
For his part, Espinosa said he wants to see the number of Biobank samples available to COVIDome researchers grow. This would extend their ability to probe cellular and molecular differences in COVID-19 patients based on the severity of their disease, preexisting conditions, race, and so on. He would also like to use COVIDome Explorer to study so-called “long-hauler” patients who struggle after surviving COVID-19 – a phenomenon Dr. Anthony Fauci recently referred to as “post-acute sequelae of SARS-CoV-2 infection,” or PASC, in announcing the government’s recognition of its importance. Espinosa further emphasized the need to study other “dysregulated processes,” such as blood-clotting problems, in the development of severe COVID-19.
Whatever the course of future research, COVIDome Explorer exists to prod development of treatments and therapies that target individuals’ specific biologic characteristics, Espinosa concluded.
“Our goal is to empower and enable a precision medicine approach to COVID-19,” he said.