Pulmonologist Develops Test To Predict Covid-19 Severity
Of the various hurdles Dr. Sean Agbor-Enoh faced during the pandemic, one of the biggest was personal. For 2 months, he couldn’t go home.
An NIH principal investigator, Agbor-Enoh is also a pulmonologist. When everything shut down in spring 2020, he still headed to work at the Johns Hopkins Hospital in Baltimore and at NIH, where he’s on a pulmonary consult clinical team. His wife Juul is a pharmacist who also couldn’t work from home.
“In health care, in a pandemic, all of us have to pull up our boots together and just jump in,” said Agbor-Enoh.
With 4 kids at home between ages 3 and 18, he didn’t want to risk potentially exposing them to Covid, so he stayed at a hotel for 6 weeks, then quarantined for 2 more. “It was a trying experience for my family,” he recounted.
Originally from Cameroon in central Africa, Agbor-Enoh first came to NIH on a fellowship. His mentor, former NHLBI investigator Dr. Hannah Valantine, soon invited him to join her team studying transplant rejection.
In 2015, newly hired as an NHLBI staff clinician, Agbor-Enoh set out to adapt a technology Valantine co-developed with a Stanford colleague to diagnose lung transplant rejection. That technology is a blood test called cell-free DNA, which—since dying cells release their content, including DNA—can measure cell death and injury.
Photo: NHLBI
But NIH doesn’t have a lung transplant program, so Agbor-Enoh established GRAFT, the Genomic Research Alliance for Transplantation. By partnering with five local extramural hospitals, he could obtain patient samples to develop and validate this test.
Since getting his own lab in 2019, “[Our team] developed a method which, with a patient’s blood sample, we can measure what tissues or organs are affected in any disease, not just in transplant,” he said. “You can almost draw a whole-body injury map with this test.”
When the pandemic struck, he wondered whether they could adapt this same testing to predict the trajectory of Covid-19 infections. But this was beyond the scope of their approved project and they needed resources. “We don’t just have money sitting somewhere when you want to study [something new].”
With funding from ITAC (intramural targeted anti-Covid award), he obtained Covid-positive samples from GRAFT collaborators. Then, he and Drs. Moon Kong and Hyesik Kong, along with colleagues in Dr. Mehdi Pirooznia’s and Dr. Robert Star’s lab, made remarkable discoveries. They hypothesized that cell-free DNA analysis, which measures tissue damage, would identify Covid-19 patients at high risk of poor outcomes.
“We concurrently worked to develop the test and apply it to the Covid-19 samples and, boom, we found our hypothesis was correct,” Agbor-Enoh said. “This virus is bad!”
The team saw injury in blood vessels, multiple organs and different tissue types. “It causes more injury than other viruses that we know,” he observed.
Looking at their data in summer 2020, the team was stunned at the amount of injury they found. “Our tests showed the virus was causing tissue injury 100 times higher than in a healthy person,” Agbor-Enoh said.
Photo: NHLBI's Laboratory of Applied Precision Omics
In fact, he was so astounded that he halted his lab’s research to recheck their experiments. Several months later, they confirmed their initial results. “The strangeness of the virus made us unable to accept the results that we were seeing in front of us, because we’d never seen anything like this.”
Agbor-Enoh wondered if the test also could predict which Covid patients would become hospitalized. “If we could use this test to identify patients who would need the ICU,” he said, “we could really help with health care resource adjudication for this pandemic.”
Sure enough, the test also allowed them to stratify patients who would need critical care versus those who had milder cases. They found far greater injury among hospitalized patients, even more so among those who needed the ICU.
Meanwhile, the pandemic created an unexpected opportunity to further his original research project.
Normally, to prevent organ rejection, patients get biopsies—removing tissue samples for inspection. When the pandemic hit, patients especially didn’t want to come in for these invasive, costly tests.
With a company already on board to produce the transplant test, Agbor-Enoh teamed up with his clinical fellow Dr. Michael Keller to set up the ALARM [Analysis of Lung Allograph Remote Monitoring] study to bring cell-free DNA blood tests to patients’ homes. Only patients who tested positive for cell-free DNA would come into the hospital for a confirmatory biopsy.
“With this approach and with FDA compassionate-use authorization,” said Agbor-Enoh, “a company produced the tests, which turned out to be 90 percent accurate. And, we were able to avoid 85 percent of [unnecessary] biopsies.”
What’s more, these tests can detect whether a patient will develop transplant rejection 2-3 months before they show any signs of rejection.
“This experience really gives us hope,” he said. “There seem to be NIH processes in place and companies ready to take these technologies and make them become clinically available very quickly.”
While Agbor-Enoh is staying involved in Covid-19 research, his focus has returned to lung transplantation.
“I think I owe it to my lung transplant patients to continue that work,” he concluded.