Modelling study estimates impact of physical distancing measures on progression of COVID-19 epidemic in Wuhan

March 25, 2020

Science Daily/The Lancet

A new study suggests extending school and workplace closures in Wuhan until April, rather than March, would likely delay a second wave of cases until later in the year, relieving pressure on health services.

New modelling research, published in The Lancet Public Health journal, suggests that school and workplace closures in Wuhan, China have reduced the number of COVID-19 cases and substantially delayed the epidemic peak -- giving the health system the time and opportunity to expand and respond.

Using mathematical modelling to simulate the impact of either extending or relaxing current school and workplace closures, researchers estimate that by lifting these control measures in March, a second wave of cases may occur in late August, whereas maintaining these restrictions until April, would likely delay a second peak until October -- relieving pressure on the health services in the intervening months.

However, the authors caution that given the large uncertainties around estimates of the reproduction number (how many people an individual with the virus is likely to infect), and how long a person is infected on average, the true impact of relaxing physical distancing measures on the ongoing COVID-19 epidemic cannot be precisely predicted.

"The unprecedented measures the city of Wuhan has put in place to reduce social contacts in school and the workplace have helped to control the outbreak," says Dr Kiesha Prem from the London School of Hygiene & Tropical Medicine, UK, who led the research. "However, the city now needs to be really careful to avoid prematurely lifting physical distancing measures, because that could lead to an earlier secondary peak in cases. But if they relax the restrictions gradually, this is likely to both delay and flatten the peak."

In December 2019, a novel coronavirus (SARS-CoV-2) emerged in Wuhan, China. In mid-January 2020, schools and workplace were closed as part of the Lunar New Year holidays. These closures were then extended to reduce person-to-person contact and prevent the spread of SARS-CoV-2.

In the study, researchers developed a transmission model to quantify the impact of school and workplace closures using information about how often people of different ages mix with each other in different locations, and to assess their effects on bringing the outbreak under control.

Using the latest data on the spread of COVID-19 in Wuhan and from the rest of China on the number of contacts per day by age group at school and work, they compared the effect of three scenarios: no interventions and no holidays (a hypothetical scenario); no physical distancing measures but school winter school break and Lunar New Year holidays as normal; and intense control measures with school closed and only about 10% of the workforce -- eg, health-care personnel, police, and other essential government staff -- working during the control measures (as started in Wuhan in mid-January). They also modelled the impact of lifting control measures in a staggered way, and during different stages of the outbreak (in March and April).

The analyses suggest that the normal school winter break and Lunar New Year holidays would have had little impact on the progression of the outbreak had schools and workplaces opened as usual. However, putting extreme measures in place to reduce contacts at school and workplaces, could reduce case numbers and the size of the epidemic peak, whilst also delaying the peak. The effects of these distancing measures seem to vary by age, with the greatest reductions in new cases among school children and the elderly, and lowest among working-aged adults. However, once these interventions are relaxed, case numbers are expected to rise.

Further analysis suggests that physical distancing measures are likely to be most effective if the staggered return to work commences at the beginning of April -- potentially reducing the median number of new infections by 24% up to the end of 2020, and delaying a second peak until October.

"Our results won't look exactly the same in another country, because the population structure and the way people mix will be different. But we think one thing probably applies everywhere: physical distancing measures are very useful, and we need to carefully adjust their lifting to avoid subsequent waves of infection when workers and school children return to their normal routine. If those waves come too quickly, that could overwhelm health systems," says co-author Dr Yang Liu from London School of Hygiene & Tropical Medicine.

Despite these important findings, the study has some limitations, including that it assumed no difference in susceptibility between children, and that the extreme distancing measures used in Wuhan may have increased the transmission within households. Finally, the model did not capture individual-level differences in contact rates, which could be important in super-spreading events, particularly early on in an epidemic.

Writing in a linked Comment, Dr Tim Colbourn from University College London, UK (who was not involved in the study) says: "The study by Kiesha Prem and colleagues in The Lancet Public Health is crucial for policy makers everywhere, as it indicates the effects of extending or relaxing physical distancing control measures on the coronavirus disease 2019 (COVID-19) outbreak in Wuhan, China."

He continues: "Given many countries with mounting epidemics now potentially face the first phase of lockdown, safe ways out of the situation must be identified... New COVID-19 country-specific models should incorporate testing, contract tracing, and localised quarantine of suspected cases as the main alternative intervention strategy to distancing lockdown measures, either at the start of the epidemic, if it is very small, or after the relaxation of lockdown conditions, if lockdown had to be imposed, to prevent health-care system overload in an already mounting epidemic." 

https://www.sciencedaily.com/releases/2020/03/200325212154.htm

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