COVID-19: Stopgap measure to treat respiratory distress

March 25, 2020

Science Daily/Massachusetts Institute of Technology

Researchers at MIT and the University of Colorado at Denver have proposed a stopgap measure that they believe could help Covid-19 patients who are in acute respiratory distress. By repurposing a drug that is now used to treat blood clots, they believe they could help people in cases where a ventilator is not helping, or if a ventilator is not available.

Three hospitals in Massachusetts and Colorado are developing plans to test this approach in severely ill Covid-19 patients. The drug, a protein called tissue plasminogen activator (tPA), is commonly given to heart attack and stroke victims. The approach is based on emerging data from China and Italy that Covid-19 patients have a profound disorder of blood clotting that is contributing to their respiratory failure.

"If this were to work, which I hope it will, it could potentially be scaled up very quickly, because every hospital already has it in their pharmacy," says Michael Yaffe, a David H. Koch Professor of Science at MIT. "We don't have to make a new drug, and we don't have to do the same kind of testing that you would have to do with a new agent. This is a drug that we already use. We're just trying to repurpose it."

Yaffe, who is also a member of MIT's Koch Institute for Integrative Cancer Research and an intensive care physician at Boston's Beth Israel Deaconess Medical Center/Harvard Medical School, is the senior author of a paper describing the new approach.

The paper, which appears in the Journal of Trauma and Acute Care Surgery, was co-authored by Christopher Barrett, a surgeon at Beth Israel Deaconess and a visiting scientist at MIT; Hunter Moore, Ernest Moore, Peter Moore, and Robert McIntyre of the University of Colorado at Denver; Daniel Talmor of Beth Israel Deaconess; and Frederick Moore of the University of Florida.

Breaking up clots

In one large-scale study of the Covid-19 outbreak in Wuhan, China, it was found that 5 percent of patients required intensive care and 2.3 percent required a ventilator. Many doctors and public health officials in the United States worry that there may not be enough ventilators for all Covid-19 patients who will need them. In China and Italy, a significant number of the patients who required a ventilator went on to die of respiratory failure, despite maximal support, indicating that there is a need for additional treatment approaches.

The treatment that the MIT and University of Colorado team now proposes is based on many years of research into what happens in the lungs during respiratory failure. In such patients, blood clots often form in the lungs. Very small clots called microthrombi can also form in the blood vessels of the lungs. These tiny clots prevent blood from reaching the airspaces of the lungs, where blood normally becomes oxygenated.

The researchers believe that tPA, which helps to dissolve blood clots, may help patients in acute respiratory distress. A natural protein found in our bodies, tPA converts plasminogen to an enzyme called plasmin, which breaks down clots. Larger amounts are often given to heart attack patients or stroke victims to dissolve the clot causing the heart attack or stroke.

Animal experiments, and one human trial, have shown potential benefits of this approach in treating respiratory distress. In the human trial, performed in 2001, 20 patients who were in respiratory failure following trauma or sepsis were given drugs that activate plasminogen (urokinase or streptokinase, but not tPA). All of the patients in the trial had respiratory distress so severe that they were not expected to survive, but 30 percent of them survived following treatment.

That is the only study using plasminogen activators to treat respiratory failure in humans to date, largely because improved ventilator strategies have been working well. This appears not to be the case for many patients with Covid-19, Yaffe says.

The idea to try this treatment in Covid-19 patients arose, in part, because the Colorado and MIT research team has spent the last several years studying the inflammation and abnormal bleeding that can occur in the lungs following traumatic injuries. It turns out that Covid-19 patients also suffer from inflammation-linked tissue damage, which has been seen in autopsy results from those patients and may contribute to clot formation.

"What we are hearing from our intensive care colleagues in Europe and in New York is that many of the critically ill patients with Covid-19 are hypercoagulable, meaning that they are clotting off their IVs, and having kidney and heart failure from blood clots, in addition to lung failure. There's plenty of basic science to support the idea that this concept should be beneficial," Yaffe says. "The tricky part, of course, is figuring out the right dose and route of administration. But the target we are going after is well-validated."

Potential benefits

The researchers will test tPA in patients under the FDA's "compassionate use" program, which allows experimental drugs to be used in cases where there are no other treatment options. If the drug appears to help in an initial set of patients, its use could be expanded further, Yaffe says.

"We learned that the clinical trial will be funded by BARDA [the Biomedical Advanced Research and Development Authority], and that Francis Collins, the NIH director, was briefed on the approach yesterday afternoon," he says. "Genentech, the manufacturer of tPA, has already donated the drug for the initial trial, and indicated that they will rapidly expand access if the initial patient response is encouraging."

Based on the latest data from their colleagues in Colorado, these groups plan to deliver the drug both intravenously and/or instill it directly into the airways. The intravenous route is currently used for stroke and heart attack patients. Their idea is to give one dose rapidly, over a two-hour period, followed by an equivalent dose given more slowly over 22 hours. Applied BioMath, a company spun out by former MIT researchers, is now working on computational models that may help to refine the dosing schedule.

"If it were to work, and we don't yet know if it will, it has a lot of potential for rapid expansion," Yaffe says. "The public health benefits are obvious. We might get people off ventilators quicker, and we could potentially prevent people from needing to go on a ventilator."

The hospitals planning to test this approach are Beth Israel Deaconess, the University of Colorado Anschultz Medical Campus, and Denver Health. The research that led to this proposal was funded by the National Institutes of Health and the Department of Defense Peer Reviewed Medical Research Program.

https://www.sciencedaily.com/releases/2020/03/200325120845.htm

COVID-19 infections in U.S. may be much higher, new estimates show

But even moderate interventions can help reduce spread, according to study

March 9, 2020

Science Daily/Cedars-Sinai Medical Center

By March 1, 2020, between 1,043 and 9,484 people in the U.S. may have already been infected by the COVID-19 coronavirus, far more than the number that had been publicly reported, according to a new Cedars-Sinai study.

"This suggests that the opportunity window to contain the epidemic of COVID-19 in its early stage is closing," the researchers stated in their paper, which is posted online on a forum where physicians and researchers share information.

The range of possible patients is significantly higher than the number of confirmed and presumptive U.S. cases reported by the federal Centers for Disease Control and Prevention, which stood at 164 as of March 7. Some news media on March 8 were reporting more than 500 total cases. [Editor's note: as of its March 9 update, the CDC put the total number of COVID-19 cases in the U.S. at 423, including both confirmed and presumptive positive cases.]

Cedars-Sinai investigators, who led the study, said they chose "very conservative" methods to estimate the number of coronavirus cases. "This makes our current estimation likely to be an underestimation of the true number of infected individuals in the U.S.," they wrote.

Shlomo Melmed, MB, ChB, executive vice president of Academic Affairs and dean of the medical faculty at Cedars-Sinai, added: "Cedars-Sinai is committed to the global efforts to combat COVID-19 and we believe that early dissemination of this study and the free sharing of the code that underlies the model will help in those efforts."

To arrive at infection estimates for their new study, the researchers modeled only COVID-19 coronavirus cases "imported" directly to the U.S. from the area of Wuhan, China, before Jan. 23, when the Chinese government locked down the city, and they assumed the lockdown stopped all outbound traffic. Potential cases arriving in the U.S. from other parts of China, or other heavily affected countries such as South Korea, Italy or Iran, were not included in the estimate.

The scale of the COVID-19 epidemic in the U.S. was calculated based on: air traffic data between Wuhan and the U.S., totals of confirmed cases publicly released by the CDC and transmission dynamics as estimated from previous research. The study took into account the identification and quarantine of individual domestic cases in the U.S. Among other considerations, the research team assumed the imported cases were no longer spreading infection.

Based on all these assumptions and methods, the investigators estimated the total number of people in the U.S. infected with coronavirus as of March 1 to be between 1,043 and 9,484. The first figure assumed current preventive procedures -- such as quarantines and screening international travelers at airports -- had reduced as much as 25% of the transmissibility in unidentified cases. The second figure assumed no intervention procedures had been undertaken to reduce the transmissibility.

The disparity between the lowest and highest estimates has important implications for controlling the COVID-19 epidemic, said Dermot P. McGovern, MD, PhD, professor of Medicine and Biomedical Sciences at Cedars-Sinai and senior author of the new study.

"Our model suggests that even moderately effective population interventions to reduce transmission can have a profound impact on the scale of the epidemic," McGovern explained. "This finding supports the role of public health interventions in controlling this disease."

But slowing transmission is not an easy task, given that most COVID-19 cases appear to be mild or even asymptomatic, the researchers noted, which can make it difficult to identify infected individuals who may be spreading the virus.

Despite these obstacles, McGovern said, it may still be possible to mitigate the COVID-19 outbreak through steps already suggested by public health experts.These include promoting social distancing and personal hygiene and restricting large-scale gatherings for occasions such as sporting events.

Additionally, performing mass screening for infected individuals, while expensive and logistically challenging, also would potentially help to control the epidemic, said McGovern, who also is director of Translational Research in the Inflammatory Bowel and Immunobiology Research Institute at Cedars-Sinai.

Dalin Li, PhD, the new study's first author and co-corresponding author with McGovern, said the research team is releasing the just-completed study data online before the full study has been accepted in a journal due to the urgency of the COVID-19 outbreak.

"We are making the results public before peer review as it will be important for timely and informed public health decision-making. We are also making the model available to the research community so that others can build upon it." said Li, a research scientist in the Inflammatory Bowel and Immunobiology Research Institute.

The other co-authors of the study were Jonathan Braun, MD, PhD, professor of Medicine, and research operations associate Gregory Botwin from the Inflammatory Bowel and Immunobiology Research Institute at Cedars-Sinai; and Jun Lv, Weihua Cao and Liming Li, all from Peking University Health Science Center in Beijing.

Funding: Research reported in this publication was supported by the National Institutes of Health, the Helmsley Charitable Trust and the F. Widjaja Foundation.

https://www.sciencedaily.com/releases/2020/03/200309110456.htm