Months ago, when news came flooding in about the dire toll the novel coronavirus can take on the body, so did the phone calls to Beth Kozel, M.D., Ph.D. A clinical geneticist in the Division of Intramural Research (DIR) at the National Heart, Lung, and Blood Institute (NHLBI), Kozel cares for adult and pediatric patients with rare connective tissue disorders. And they weren’t shy about making their worries known.
Kozel listened intently and, like other physician-scientists across the internal research program at the National Institutes of Health (NIH), quickly began using her expertise to find answers to some of the more vexing questions posed by COVID-19, the disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). As of Sept. 16, the virus has caused the deaths of more than 195,000 Americans and affected the health of 6.5 million others. Kozel’s work, along with that of other researchers, such as Richard Childs, M.D., NHLBI’s clinical director, has been pointing the way to the kind of progress many hope will turn this tide, especially for the most vulnerable Americans.
“Our patients are looking to us for guidance about what to do during this situation,” said Kozel, director of the Laboratory of Vascular and Matrix Genetics at NHLBI. “Unfortunately we don’t have the data yet to be able to tell them what to do or what to expect.”
While data about possible COVID-19 risk factors, such as age and sex, continue to emerge for the general population, the data on rare diseases and COVID-19 are negligible. And larger surveying efforts have not accounted for people with rare diseases.
So Kozel took matters into her own hands and developed a 30-minute survey that might reveal whether rare diseases that affect the heart, lung, vascular and immune systems enhance or change a person’s risk of severe outcomes with COVID-19. Kozel has teamed up with Tiffany Powell-Wiley, M.D., M.P.H., a tenure-track investigator in NHLBI’s Cardiovascular Branch, to make sure the survey also takes into account exposure differences if a person lives in a city or a rural community and racial disparities of COVID-19. Kozel is also partnering with Robert Hufnagel, MD, Ph.D., of the National Eye Institute, investigators across six other Institutes and family advocacy groups to tap up to 100,000 survey participants from various rare disease communities.
The survey will ask questions about demographics, general health and chronic conditions, as well as potential symptoms, exposure, and testing for COVID-19. For participants who have had a positive test, it will ask how the disease has impacted their well-being, finances, and access to services. After compiling the survey results, Kozel will inform participants about how their biological risk, based on their particular rare disease, compares to the general population.
“If the data points us to a particular rare condition, we can then work with experts who understand the genes and pathways of that condition and determine what mechanism(s) could be making COVID-19 mild or severe for people,” Kozel said. “If the worst case scenario will be telling people that their risk is similar to relatively healthy people in their communities, I think that will give them valuable information where there previously wasn’t any.”
Kozel said that her rare disease patients and their loved ones have done a good job practicing social distancing. But with a resurgence of COVID-19 cases in many parts of the United States, she knows how tenuous these efforts can be. That’s why Childs is working to stop the virus and develop effective therapies to treat those with severe and life-threatening symptoms.
Childs, who also is a Rear Admiral in the U.S. Public Health Service Commissioned Corps and an Assistant U.S. Surgeon General, successfully treated several critically ill Americans who were infected with COVID-19 on the Diamond Princess cruise ship with the antiviral drug remdesivir during a deployment in Japan this past February. Remdesivir is now part of the standard of care for treating hospitalized COVID-19 patients. Working alongside colleagues in the Critical Care Medicine Department in the NIH Clinical Center, Childs has now turned his attention to fostamatinib, a drug that could be the next major development in the fight against the pandemic.
“There is encouraging data that highlights the potential of fostamatinib to specifically treat the immunological complications seen in COVID-19 patients,” said Childs, who is also an investigator on the new trial being conducted at the NIH Clinical Center and local hospitals.
Fostamatinib treats adults with immune thrombocytopenia—a condition leading to chronically low platelets—when a prior treatment has not worked well enough. The trial will evaluate the efficacy and safety of fostamatinib for the treatment of hospitalized COVID-19 patients.
Severe SARS-CoV-2 infection can lead to acute respiratory distress syndrome, organ dysfunction, and clots in the smallest blood vessels. Much of the underlying disease process, researchers think, is driven by an unregulated immune response and “hyperactivity” in blood-clotting cells.
To treat COVID-19, fostamatinib is thought to work by preventing immune cells and platelets from reacting to immune complexes formed when antibodies bind to the virus, and reducing blood clots in the smallest blood vessels. The hope, said Jeffrey Strich, M.D., lead investigator for the trial, is that blocking this mechanism will reduce the inflammation and thrombotic complications that have been linked to the long-term complications of COVID-19.
“We want to get patients over this acute illness, this hump, and into a phase of recovery where their body can essentially take over and clear the virus on its’ own,” said Strich, who also is a staff clinician in the Critical Care Medicine Department at the NIH Clinical Center and Lieutenant Commander in the U.S. Public Health Service Commissioned Corps.
The 60 participants in the study will be randomly assigned to receive either fostamatinib or a placebo twice daily for 14 days.
Like many drugs, fostamatinib has side effects, such as hypertension, liver toxicity, diarrhea, low count of white blood cells, and respiratory infection, Strich said. But the risks are low, he added, given the specificity of the drug target and the short use of the drug.
Participants who enroll in the trial will also have the option to enroll in a natural history study of COVID-19 so that researchers can better understand the vast differences in disease severity. Anthony Suffredini, M.D., senior investigator in the Critical Care Medicine Department at the NIH Clinical Center, plans to enroll 75 patients with a broad representation of the illness: 25 with mild disease who do not require hospitalization, 25 who might be hospitalized but are not critically ill, and 25 who are seriously ill in the intensive care unit and require supplemental oxygen or mechanical ventilation. He also aims to enroll an additional 75 patients from outlying hospitals after their acute illness for follow-up study.
Suffredini is teaming up with Marcus Chen, M.D., Adrienne Campbell-Washburn, Ph.D., and Han Wen, Ph.D., NHLBI’s experts in MRI and CT imaging of the heart and lungs. This partnership, Suffredini said, will make it easy to ask questions about how a patient’s organs have been affected by COVID-19.
By collaborating with experts in other Institutes, researchers will be able to request MRI scans of a patient’s brain, as well as heart and lung function tests and ultrasounds of the kidneys and heart. Participants will also be asked to provide blood and urine samples and have a bronchoscopy to collect cells from the lower respiratory tract. In some instances, participants may need to provide a spinal fluid sample.
“We really want to know what are the long-term consequences of COVID-19, and if there is something we can do to recognize it early and intervene,” Suffredini said. “These are wide open areas of research, and we are fortunate to have a wealth of resources and expertise at NIH. Let’s take advantage of this and contribute to the understanding of this illness.”