A previously validated gene profile in blood that predicts idiopathic pulmonary fibrosis mortality was repurposed to assess the likelihood of COVID-19 survival, a USF Health-led study reports

Tampa, FL (June 20, 2021) — A blood gene profile associated with a high risk of dying from a severe lung disease can also predict poor outcomes in patients with COVID-19, a multicenter retrospective study led by the University of South Florida Health (USF Health) demonstrated. The risk profile based on 50 genes could help customize how COVID-19 is treated, improve allocation of limited health care resources such as intensive care beds and ventilators, and potentially save lives.

Idiopathic pulmonary fibrosis (IPF), a disease of unknown cause, affects the lung interstitium or the space between the lung sacs and the bloodstream, leading to severe lung scarring. Severe COVID-19 can also damage the lung interstitium leading to severe lung scarring.

“Our study identified at the molecular level, a gene risk profile that predicts worse COVID-19 outcomes before the patient becomes severely ill,” said principal investigator Jose Herazo-Maya, MD, an associate professor and associate chief of pulmonary, critical care and sleep medicine at the USF Health Morsani College of Medicine. “That means every patient with COVID-19 could potentially get a blood test that could tell us if they are at high or low risk of dying… And if we know in advance who will likely end up in the ICU and who will likely do well recovering at home with appropriate monitoring, we can tailor our interventions to individual patients based on their level of risk.”

The USF Health study appeared online June 20 in EBioMedicine, a publication of THE LANCET. It builds upon previous genomic research by Dr. Herazo-Maya and colleagues at Yale School of Medicine. In 2017, they led an international team that studied and validated a gene expression signature in the blood that reliably forecasts the likelihood of IPF mortality. (Certain patients with lung scarring can live well for years, while others develop worsening disease and die quickly from IPF.)

The study’s principal investigator was Jose Herazo-Maya, MD, associate professor of medicine and associate division chief of USF Health Pulmonary, Critical Care and Sleep Medicine. | Photo by Allison Long,  USF Health Communications and Marketing

As the COVID-19 pandemic unfolded, “the basic question we had was ‘Can we repurpose the gene signature known to predict mortality in a fibrotic lung disease to predict mortality in those infected with a new coronavirus that can cause lung fibrosis as well?” said the EBioMedicine paper lead author Brenda Juan-Guardela, MD, assistant professor of medicine at the USF Health Morsani College of Medicine and medical director of Respiratory Care Services at Tampa General Hospital (TGH). “To the best of our knowledge, this study is the first to compare overlapping immune gene profiles in COVID-19 and IPF, which were remarkably similar.”

The USF Health-led team analyzed gene expression patterns of 50 genes known to predict IPF mortality in three COVID-19 cohorts and two IPF cohorts. The researchers used a molecular scoring system to distinguish between high versus low-risk gene profiles in all five cohorts.

Among their findings:

• In the COVID-19 validation cohorts, a 50-gene high risk profile was linked to greater risk of ICU admission, mechanical ventilation, and in-hospital death.
• The researchers also performed single-cell, gene expression analyses and identified specific immune cells — monocytes, neutrophils, and dendritic cells – as the primary source of gene expression changes in the high-risk, COVID-19 gene profile. This finding suggests COVID-19 and IPF may share common innate and adaptive immune responses that trigger lung scarring.
• The 50-gene risk profile in COVID-19 can also predicts mortality in IPF at the exact same threshold.

Lead author Brenda Juan-Guardela, MD, assistant professor of medicine at the USF Health Morsani College of Medicine and medical director of Respiratory Care Services at TGH

At TGH, Dr. Herazo-Maya treats previously hospitalized COVID-19 patients who come to the Center for Advanced Lung Disease with severe lung fibrosis; some are being evaluated for lung transplantation. “Even though coronavirus cases are dropping, that doesn’t mean all the patients will recover without complications,” he said. “We’re starting to see the damaging, long-term effects in the lungs of some COVID-19 survivors.”

While more studies are needed, researchers and clinicians may soon be able to apply the gene risk profiles to help advance the care of both COVID-19 and IPF patients, Dr. Herazo-Maya said. His laboratory is currently developing a blood test, based on these genes, that can be easily applied in clinical practice to predict poor disease outcomes.

Besides outcome prediction, the identification of 50-gene risk profiles may also have significant therapeutic potentials.  For example, a 10-day regimen of the steroid dexamethasone, a drug that suppresses the immune system, has been shown to increase survival of patients hospitalized with COVID-19. Immunosuppressant drugs have been essentially discontinued for IPF treatment because they increase mortality when given at high doses and in combination over long periods, Dr. Herazo-Maya said. “But perhaps we could investigate the use of dexamethasone or a similar steroid treatment for a short period of time in a subgroup of IPF patients with a 50-gene high risk profile, using the principle of precision or personalized medicine.”

The 50-gene high risk profile may also support the rationale to investigate the use of targeted IPF antifibrotic medications, which slow the rate of lung scarring, to prevent short and long-term sequelae of COVID-19, he added.

Heat maps depict clustering of COVID-19 subjects based on 50-gene risk profiles (High versus Low) determined by SAMS in Discovery (a) and Validation cohorts (b). The image, courtesy of Jose Herazo-Maya, first appeared online 20 June 2021 in EBioMedicine, Vol. 69. Full caption available for this Figure 1 at: www.sciencedirect.com/science/article/pii/S2352396421002322

USF Health’s Gaetane Michaud, MD, professor of medicine and chief of pulmonary, critical care and sleep medicine, was a paper coauthor. The research was supported by the Ubben Pulmonary Fibrosis Fund-USF Foundation, National Institute for Health Clinician Scientist Fellowship, Action for Pulmonary Fibrosis Mike Bray Fellowship, and the National Heart, Lung, and Blood Institute.

Dr Kapil Patel was recruited from Stanford University known for its preeminent center

Pulmonologist Kapil Patel, MD, arrived at USF Health full-time Sept. 1 with one overarching goal in mind: to help lead and strengthen the Lung Transplant Program at Tampa General Hospital while strategically working to create a Center of Excellence for Advanced Lung Disease.

He came from Stanford University Medical Center, home to one the few such specialty pulmonology centers in the United States, which is known for its exceptional patient outcomes and consistently ranked by U.S. News & World Report as one of the best in the nation.

Pulmonologist Dr. Kapil Patel was recruited to the USF Health Morsani College of Medicine from Stanford University Medical Center.

“Dr. Patel’s recruitment is significant for USF Internal Medicine, the patients of USF Health and Tampa General Hospital and the community at large. His move from Stanford University to head the lung transplantation program is a landmark, making this the first solid organ transplant program to be part of USF in 35 years,” said John Sinnott, MD, chair of the Department of Internal Medicine, USF Health Morsani College of Medicine. “Dr. Patel’s vision for a center for advanced lung disease will place USF and Tampa General at the forefront of caring for patients with lung diseases in the United States.”

A center like the one at Stanford promotes continuity of care, allowing patients to be conveniently treated in one place by physicians who subspecialize in complex lung disorders, while cohesively providing the latest advances in medical and surgical care, said Dr. Patel, assistant professor of medicine in the Morsani College of Medicine’s Division of Pulmonary, Critical Care and Sleep Medicine and medical director for lung transplant, interstitial lung disease and adult cystic fibrosis.

“As you bring academic research to the forefront, it also opens opportunities for patients to participate in clinical trials that can afford alternatives to treatment they may not otherwise receive elsewhere,” he said.

Dr. Patel most recently directed the Stanford’s Interstitial Lung Disease (ILD) Program, one of the arms of the medical school’s Center for Advanced Lung Disease. He helped build physician referrals to Stanford’s ILD program from 100 to more than 200 in just over two years.

Providing integrated subspecialty care for complex lung diseases

Dr. Patel says he was attracted to USF Health by the opportunity to serve as medical director of an academic-affiliated lung transplant program and to build upon the solid foundation laid by Tampa General’s transplant team to create what could be Florida’s first center for advanced lung disease.

He plans to work with colleagues in USF Health Internal Medicine and Tampa General over the next several years to develop a center of excellence serving as the umbrella for four interconnected programs:

• Lung Transplantation: Tampa General already has an active program accredited by the United Network of Organ Sharing – one of five in Florida – and has performed more than 480 total adult lung transplants (single and double) since 2002. The program’s one-year patient survival rate of more than 91 percent and three-year survival rate of more than 71 percent both exceed national survival rate statistics. Dr. Patel plans to selectively grow a larger program.

“Selective is the way to go to do the right thing for patients. It is critical to identify appropriate candidates in need of transplant and to understand the limitations to transplant, so you do not push the limits too far,” he said. “We want to be confident that the surgery will go well, so the patient leaves the hospital with a new life.”

Since arriving here, Dr. Patel has worked closely with USF Health-affiliated cardiothoracic surgeon Christiano Caldeira, MD, of Florida Advanced Cardiothoracic Surgery, who serves as surgical director of the heart and lung transplant programs at TGH. They take donor calls together, jointly decide which donor organs are the healthiest for recipients, and co-manage lung transplant patients in the intensive care unit (ICU).

Dr. Patel with Nicole Davis, RN, a lung transplant coordinator at Tampa General Hospital.

• Interstitial Lung Disease, or ILD (also known as pulmonary fibrosis): This new program would manage the care of patients with a group of lung disorders causing tissue deep in the lungs to progressively stiffen and scar, which affects the ability to get enough oxygen into the bloodstream. Currently, Dr. Patel said, Florida has no ILD program certified by the Pulmonary Fibrosis Foundation (PFF) Care Center Network. Dr. Patel will lead an initiative by USF and TGH to establish the first.

• Cystic Fibrosis: Cystic fibrosis is an inherited disease that causes thick mucus to build up in the lungs, leading to repeated, serious lung infections. The Cystic Fibrosis Program at TGH is the largest adult program in the state certified and supported by the Cystic Fibrosis Foundation.

• Pulmonary Hypertension: USF Health pulmonologist Ricardo Restrepo-Jaramillo,MD, assistant professor of medicine, specializes in pulmonary hypertension – high blood pressure that occurs in the arteries that go from the heart to the lungs and may eventually lead to heart failure. He will become director of the new USF pulmonary hypertension program at TGH, Dr. Patel said.

Lung transplants are typically performed for people likely to die from lung disease within one to two years, when other treatments like medications or breathing devices no longer work, according to the National Heart, Lung and Blood Institute. ILD and cystic fibrosis are both conditions accounting for the most lung transplants nationwide, Dr. Patel said, with pulmonary hypertension affecting a smaller population of patients needing transplants.

Collaborating with community physicians

To create an integrated center, Dr. Patel plans to bring several pulmonologists with research as well as clinical expertise into the lung transplant program he directs, as well as recruit subspecialty directors for the ILD and cystic fibrosis programs. He will also add nurse practitioners to a team already supported by TGH nurse coordinators, respiratory therapists, social workers, dietitians and a pharmacist.

“When you manage patients with advanced lung disease, it takes a multidisciplinary team of professionals skilled in pre and post-transplant,” he said. “These are patients with complex conditions who need a lot of support and coordination,”

Dr. Patel sees patients at the Cardiac and Lung Transplant Clinic based at Harbourside Medical Tower.

More immediately, though, he is focusing on selectively increasing the referral base of patients by meeting with community physicians across the Tampa Bay region and seeing established pre-transplant patients in the clinic at Harbourside Medical Tower, Tampa General campus.

“I want doctors in the community to know that we are here to collaborate in the care of patients with advanced lung diseases,” Dr. Patel said. “Our availability is a priority, and ensuring the shortening of turn-around times for initial clinic visits is crucial, so that patients referred to the USF-TGH program are evaluated for medical care or transplant within weeks, not months. When someone needs a transplant, they need to be seen yesterday, and we work to intervene early.”

Advances in pulmonary transplant treatment

Over the last decade, advances in surgical techniques and significant improvements in post-operative care have contributed to improved survival of pulmonary transplant patients.

“We’ve gotten better at understanding what it takes to get these patients through transplants with fewer complications,” Dr. Patel said. “Once you get patients through the ICU following transplant, their chances of recovery and surviving a year or more out are much better.”

Medical therapy has also improved. For example, in 2014 the FDA approved the first medications (pirfenidone and nintedanib) to treat the most common type of pulmonary fibrosis, known as idiopathic pulmonary fibrosis (IPF). Until then, lung transplant was the only option for these patients, said Dr. Patel, who at Stanford led several site clinical trials testing the effectiveness of drugs for IPF.

Dr. Patel received his MD degree from the Medical University of Lublin in Poland. He completed a fellowship in pulmonary and critical care medicine at the University of Vermont and a dual heart-lung and lung fellowship at Stanford University Medical Center. He worked in private practice in Baltimore as well as holding faculty positions at the University of Vermont College of Medicine, the University of Maryland Medical Center, and Stanford.

Dr. Patel is a member of the American College of Chest Physicians and the International Society for Heart and Lung Transplantation.

A USF-TGH Center for Advanced Lung Disease won’t happen overnight. But Dr. Patel is confident that the vision can become a reality one purposeful step at a time.

“That’s why I came here,” he said. “We have a strong foundation and the pieces to grow.”

Photos by Eric Younghans, USF Health Communications and Marketing