With the end of the COVID-19 pandemic remaining uncertain, the virus continues to spread to new regions previously untouched by the disease. Since March, the U.S. alone has reported more than two million confirmed cases, almost 25 percent of all confirmed cases worldwide. As the pandemic closes in on its sixth month, Feinberg faculty have continued to publish editorials about COVID-19 and its impact on medicine, including new potential drugs targets, the need for more clinical trials and maximizing trainee education during and after the pandemic.
DNA Transcription Shows Potential as COVID-19 Drug Target
Inhibiting DNA transcription, the process by which information from DNA is copied into messenger RNA (mRNA) and carried out by an enzyme called RNA polymerase, may be a promising drug target for treating COVID-19, according to Ali Shilatifard, PhD, the Robert Francis Furchgott Professor and chair of the Department of Biochemistry and Molecular Genetics, and the author of a recent editorial published in Science Advances.
“Based on the detailed molecular studies generated during the past 50 years, scientists are now able to develop specific inhibitors toward viral RNA polymerases that could be used for the treatment of COVID-19, which points to the awesome power of basic molecular research in drug discovery and the medicine used in clinics for the treatment of human disease,” Shilatifard said.
Similar to how the human genome stores genetic information in the form of DNA, viruses store their genetic information in the form of nucleic acid, either as DNA or RNA depending on the virus. In viruses like SARS-CoV2, the virus that causes COVID-19, genetic information is in the form of RNA.
Because human cells don’t contain the enzymes RNA viruses need to replicate genetic information from the genome, these enzymes are potential targets when designing antiviral therapies, according to Shilatifard. One of these targets is SARS-CoV-2’s RNA dependent polymerase (RdRp), which is responsible for replicating the SARS-CoV-2 RNA genome and allowing the virus to adapt, evolve and mutate.
A recent series of clinical trials have found that the viral specific transcriptional inhibitor drug called Remdesivir, which was originally developed to treat Ebola, resulted in accelerated recovery time for hospitalized patients with advanced COVID-19.
Remdesivir and other viral inhibitor-based drugs have demonstrated efficacy in treating SARS-CoV-2 and may also enable scientists to tackle the issue of drug resistance associated with RNA viruses, including SARS-CoV-2, according to Shilatifard.
“These analogs may also allow scientists to tackle the problems of drug resistance associated with RNA viruses given their either high error-prone nature for some RdRp, or high replication rate of the viral genome as the result of a high level of infection,” Shilatifard said.
A Call for More Clinical Trials
Potential therapies recently touted for treating COVID-19 include hydroxychloroquine, which was originally developed to treat malaria and lupus, and is also known for its anti-inflammatory and immunosuppressive properties.
Recent studies, however, have shown that when given to COVID-19 patients, the drug is responsible for changes in a patient’s electrocardiogram. Specifically, it produces QT prolongation — when heart muscle takes longer than normal to recharge between beats. Excessive QT prolongation can also trigger “torsades de pointes,” an abnormal heart rhythm that can cause sudden cardiac death.
While the drug has been viewed as generally safe in patients treated for chronic inflammatory conditions, uncertainties about the drug’s benefits and risks in COVID-19 remain, especially when a patient is already taking additional therapies, according to Robert Bonow, MD, the Max and Lilly Goldberg Distinguished Professor of Cardiology and lead author of a recent editorial published in JAMA Cardiology.
“In the setting of COVID-19, where you have a lot of things going on in really sick patients that can predispose them to heart rhythm problems, when you start adding on drugs such as hydroxychloroquine you might start creating additional problems,” said Bonow, who is also vice chair for Development and Innovation in the Department of Medicine.
The current lack of data on the drug’s effectiveness also underscores the need for more controlled clinical trials, according to Bonow. Until those trials are completed, what is known is that hydroxychloroquine has the potential to cause serious cardiac side effects in COVID-19 patients and treatment decisions will be determined on a case-by-case basis.
“Until then, treatment decisions for this disease will remain based on clinical judgment and, ideally, in the context of enrolling patients into clinical trials to provide definitive answers,” the authors wrote.
Improving COVID-19 Response Efforts with Implementation Science
When the COVID-19 pandemic began to spread across the U.S., national and local responses to the virus drastically varied in regard to the implementation of public health interventions. As the virus continues to spread to new countries and low-income areas with limited resources, knowing how to implement sustainable public health interventions informed by implementation science is needed now more than ever, according to a recent editorial published in The BMJ.
Implementation research involves measuring and studying why and how interventions are implemented in real world settings and tests these strategies to improve their impact. This work can help policymakers and stakeholders, for example, understand existing and emerging evidence-based interventions and implement the most effective strategies to improve patient outcomes and overall public health.
For countries newly hit by COVID-19, they must identify, understand and incorporate knowledge gained throughout the course of the pandemic to implement data driven strategies for effective outcomes, according to Lisa Hirschhorn, MD, MPH, professor Medical Social Sciences and Psychiatry and Behavioral Sciences, and lead author of the editorial written with colleagues from the University of Global Health Equity in Rwanda.
Utilizing an implementation science approach to design and improve the response to COVID-19, according to Hirschhorn, allows countries to build on previous success and ensure new evidence-based public health interventions are applied and spread faster than the pandemic itself.
At the same time, public health efforts to stop the pandemic must be sustained without neglecting other evidence-based interventions in order to maintain demand, access and availability of other health services.
“As more effective treatments and ultimately vaccines become available, having this knowledge which can be produced by applying implementation science will be critical to also ensure the rapid and equitable delivery of care to everyone everywhere,” Hirschhorn said.
Heart Failure Support for COVID-19 Patients
Recent studies have shown that 20 percent of COVID-19 patients present with some degree of cardiac injury or failure. While the prognosis for these abnormalities in stable patients remains poorly understood, extra-corporeal membrane oxygenation (ECMO) therapy may provide extra support for patients with COVID-19-related heart failure, according to a recent editorial published in Circulation.
“We hope to provide a broader understanding of the utility of ECMO and mechanical circulatory support in dealing with severe lung and heart failure, as well as awareness that there are therapies available for extremely sick COVID-19 patients that provide a realistic chance of survival,” said Duc Thinh Pham, MD, ’05 GME, associate professor of Surgery in the Division of Cardiac Surgery and first author of the editorial.
In cases of COVID-19-related myocardial injury, support for patients includes inotropic therapy, vasoconstrictor therapy, or both, as well as early intubation with ventilatory support and other first-line therapies. However, patient selection, treatment algorithm, inflow and outflow configuration, resource allocation and overall effectiveness of ECMO for such patients has remained undefined, according to the authors.
In response, the authors discussed the following therapy options for COVID-19-related myocardial injury: veno-venous extracorporeal membrane oxygenation for isolated respiratory failure, mechanical circulatory support (including veno-arterial ECMO) for isolated cardiogenic shock, or veno-arterial ECMO for cardiorespiratory failure.
Nonetheless, utilizing ECMO during a pandemic presents serious technical, management, resource and ethical challenges, as it requires significant manpower and resources. Deciding whether to use ECMO should be a case-by-case consideration made by a multidisciplinary team and using risk scores can help determine when it will be the most effective.
“As our collective experience with ECMO in COVID-19 grows, we urge judicious use of this treatment option until further outcomes data are accumulated and the ultimate role of ECMO is better delineated during this pandemic,” according to the authors.
Maximizing Gastroenterology Trainee Education
The COVID-19 pandemic has pushed healthcare systems around the world to their limits and altered the practice of medicine. As the need to preserve personal protective equipment and conserve healthcare professionals for the critically ill became a top priority, training in procedure-intensive specialties including gastroenterology was severely impacted. With its heavy focus on endoscopy training, gastroenterology programs have had to incorporate new teaching methods in response to the pandemic, according to an editorial published the journal Gastroenterology.
As the COVID-19 pandemic continues to spread, gastroenterology training and education must evolve, according to Rajesh Keswani, MD, MS, associate professor of Medicine in the Division of Gastroenterology and Hepatology, and lead author of the editorial.
“For too long, gastroenterology has primarily relied upon the apprenticeship model of training, wherein the majority of learning is done by watching and performing procedures, as well as passive learning through didactics,” Keswani said.
The COVID-19 pandemic, according to the authors, provides an opportunity to reimagine what it means to be a gastroenterology trainee and to rebuild existing approaches to training, such as utilizing simulation, social media, online didactics and video-based education. The authors also suggest that trainees should be encouraged to make weekly lists of educational opportunities and individualized goals both during and after the pandemic. Additionally, attending physicians must adapt to implement new training methods in order to meet these changes and sustain them.
“Too often during a disruptive time, such as the pandemic, we wait for things to return back to ‘normal’. Instead, I think it’s important to think about how we can maximize the current time and plan for a new future,” Keswani said.
