A possible treatment for COVID-19 and an approach for developing others

March 26, 2020

Science Daily/American Society for Microbiology

SARS-CoV-2, the virus that causes COVID-19 disease is more transmissible, but has a lower mortality rate than its sibling, SARS-CoV, according to a review article published this week in Antimicrobial Agents and Chemotherapy, a journal of the American Society for Microbiology.

In humans, coronaviruses cause mainly respiratory infections. Individuals with SARS-CoV-2 may remain asymptomatic for 2 to 14 days post-infection and some individuals likely transmit the virus without developing disease symptoms.

So far, the most promising compound for treating COVID-19 is the antiviral, remdesivir. It is currently in clinical trials for treating Ebola virus infections.

Remdesivir was recently tested in a non-human primate model of MERS-CoV infection. Prophylactic treatment 24 hours prior to inoculation prevented MERS-CoV from causing clinical disease and inhibited viral replication in lung tissues, preventing formation of lung lesions. Initiation of treatment 12 hours after virus inoculation was similarly effective.

Remdesivir has also shown effectiveness against a wide range of coronaviruses. It has already undergone safety testing in clinical trials for Ebola, thereby reducing the time that would be necessary for conducting clinical trials for SARS-CoV-2.

Nonetheless, much work needs to be done to gain a better understanding of the mechanics of SARS-CoV-2. For example, understanding how SARS-CoV-2 interacts with the host ACE2 receptor -- by which SARS-CoV-2 gains entry into the host (whether human or animal) -- might reveal how this virus overcame the species barrier between animals and humans. This could also lead to design of new antivirals.

Although coronaviruses are common in bats, no direct animal source of the epidemic has been identified to date, according to the report. "It is critical to identify the intermediate species to stop the current spread and to prevent future human SARS-related coronavirus epidemics," the researchers write.

https://www.sciencedaily.com/releases/2020/03/200326124159.htm

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: Low risk of coronavirus spreading through tears

March 25, 2020

Science Daily/American Academy of Ophthalmology

A new study found no virus in tears of COVID-19 infected patients

While researchers are certain that coronavirus spreads through mucus and droplets expelled by coughing or sneezing, it is unclear if the virus is spread through other bodily fluids, such as tears. Today's just-published study offers evidence that it is unlikely that infected patients are shedding virus through their tears, with one important caveat. None of the patients in the study had conjunctivitis, also known as pink eye. However, health officials believe pink eye develops in just 1 percent to 3 percent of people with coronavirus. The study's authors conclude that their findings, coupled with the low incidence of pink eye among infected patients, suggests that the risk of virus transmission through tears is low. Their study was published online today in Ophthalmology, the journal of the American Academy of Ophthalmology.

To conduct the study, Ivan Seah, MBBS, and his colleagues at the National University Hospital in Singapore collected tear samples from 17 patients with COVID-19 from the time they showed symptoms until they recovered about 20 days later. Neither viral culture nor reverse transcription polymerase chain reaction (RT-PCR) detected the virus in their tears throughout the two-week course of the disease.

Dr. Seah also took samples from the back of the nose and throat during the same time period. While the patients' tears were clear of virus, their noses and throats were teeming with COVID-19. Dr. Seah said he hopes their work helps to guide more research into preventing virus transmission through more significant routes, such as droplets and fecal-oral spread.

Despite this reassuring news, it's important for people to understand that guarding your eyes -- as well as your hands and mouth -- can slow the spread of respiratory viruses like the coronavirus.

Here's why:

• When a sick person coughs or talks, virus particles can spray from their mouth or nose into another person's face. You're most likely to inhale these droplets through your mouth or nose, but they can also enter through your eyes.

• You can also become infected by touching something that has the virus on it -- like a table or doorknob -- and then touching your eyes.

Find other ways you can help protect yourself and others on the Academy's EyeSmart website.

 https://www.sciencedaily.com/releases/2020/03/200325143826.htm

Study shows how diligent we have to be to keep surfaces germ-free

Only half of surfaces in animal hospital disinfected

March 25, 2020

Science Daily/Ohio State University

During the COVID-19 pandemic, every frequently touched surface outside our home seems as dangerous as a hot pot right out of the oven. We won't get burned if we touch it, but we might get infected with a potentially dangerous virus.

A recent study suggests that even organized efforts to clean surfaces can fall short, a reminder for us all that keeping our surroundings clean may require some additional work.

For 5 ½ weeks, researchers tagged surfaces of a small-animal veterinary practice daily with a fluorescent dye visible only under black light. They checked tagged surfaces 24 hours later to see if the marks were showing. Surfaces were considered cleaned if the dye was completely removed.

Results showed that overall, only half of all surfaces were adequately cleaned during the study period. Human-touch surfaces -- such as medical instruments, dog run handles, and computer mice and keyboards -- were cleaned less frequently than areas touched primarily by animals. The results were similar to studies from other veterinary clinics.

The researchers recommended creating checklists of surfaces that need to be regularly cleaned and educating all staff on the importance of proper cleaning to protect animal and human health.

"The concept of infectious diseases is around us all the time, but now it's more important than ever to take steps to protect ourselves," said senior study author Jason Stull, assistant professor of veterinary preventive medicine at The Ohio State University.

"A recent study concluded the coronavirus causing COVID-19 has the ability to survive on certain types of surfaces for hours to a few days. At veterinary practices, other businesses and certainly human hospitals, surface cleaning and disinfection is extremely important. People come in and may contaminate an area and that area potentially can serve as a source of infection for other people."

The study is published in the February issue of the Journal of Small Animal Practice.

Stull specializes in veterinary infection control, including prevention of diseases that animals can share with each other or pass to humans -- such as Salmonella, E. coli and parasites.

For the current work, Stull and colleagues assessed almost 5,000 surfaces over the course of the study. On average, 50 percent of surfaces were cleaned, with broad variations by type of surface and hospital location. The human-touch surfaces were the least likely to be cleaned.

The study assessed everyday cleaning practices in a place where people spend lots of time with different animals and different people. It's not too much of a stretch to apply some lessons to what we're experiencing now with COVID-19, Stull said.

"Plenty of industries and groups outside of human health care have ramped up their efforts to clean and disinfect common-touch surfaces. The take-home messages from our study can have important parallels for others, such as other veterinary clinics, but also groups such as grocery stores.

"Our study also highlights that, despite our best efforts, 100 percent cleaning and disinfection is unlikely to occur. This is important to remember, as regardless of where you visit, it's also best to assume surfaces may be contaminated -- and before you come back into your home, you should follow the recommendations to clean your hands and clean items you've handled."

At home, Stull said, it makes sense to concentrate on cleaning common-touch surfaces like doorknobs and countertops.

"For the average person, it's thinking about your list of things in your own home and ensuring that in some way that you're actually hitting those pieces with reasonable effort," he said.

On a normal day, people who have touched commonly shared surfaces should wash their hands before eating or scratching their noses. But will we remain diligent about this level of personal cleanliness -- and community health -- once the worst of the coronavirus threat is behind us?

"People have a tendency to swing from extremes," Stull said. "Changing the innate behaviors of people is always difficult, and we've struggled in human and veterinary health care to change these everyday practices.

"The hard part is continuing these efforts. When we get to the end of this, and at some point that will happen, you will likely see people revert back to their norm. What we need is a culture shift, so people recognize that infection control through hand-washing and thorough cleaning of shared surfaces is a critically important thing we can all do all the time, and it has measurable impact."

Armando Hoet of Ohio State's College of Veterinary Medicine and Gregory Langdon of the College of Public Health also worked on the study.

https://www.sciencedaily.com/releases/2020/03/200325120849.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

Wuhan study shows lying face down improves breathing in severe COVID-19

March 24, 2020

Science Daily/American Thoracic Society

In a new study of patients with severe COVID-19 (SARS-CoV-2) hospitalized on ventilators, researchers found that lying face down was better for the lungs. The research letter was published online in the American Thoracic Society's American Journal of Respiratory and Critical Care Medicine.

In "Lung Recruitability in SARS -- CoV-2 Associated Acute Respiratory Distress Syndrome: A Single-Center, Observational Study," Haibo Qiu, MD, Chun Pan, MD, and co-authors report on a retrospective study of the treatment of 12 patients in Wuhan Jinyintan Hospital, China, with severe COVID-19 infection-related acute respiratory distress syndrome (ARDS) who were assisted by mechanical ventilation. Drs. Qiu and Pan were in charge of the treatment of these patients, who were transferred from other treatment centers to Jinyintan Hospital.

A majority of patients admitted to the ICU with confirmed COVID-19 developed ARDS.

The observational study took place during a six-day period the week of Feb. 18, 2020.

"This study is the first description of the behavior of the lungs in patients with severe COVID-19 requiring mechanical ventilation and receiving positive pressure," said Dr. Qiu, professor, Department of Critical Care Medicine, Zhangda Hospital, School of Medicine, Southeast University, Nanjing, China. "It indicates that some patients do not respond well to high positive pressure and respond better to prone positioning in bed (facing downward)."

The clinicians in Wuhan used an index, the Recruitment-to-Inflation ratio, that measures the response of lungs to pressure (lung recruitability). Members of the research team, Lu Chen, PhD, and Laurent Brochard, PhD, HDR, from the University of Toronto, developed this index prior to this study.

The researchers assessed the effect of body positioning. Prone positioning was performed for 24-hour periods in which patients had persistently low levels of blood oxygenation. Oxygen flow, lung volume and airway pressure were measured by devices on patients' ventilators. Other measurements were taken, including the aeration of their airway passages and calculations were done to measure recruitability.

Seven patients received at least one session of prone positioning. Three patients received both prone positioning and ECMO (life support, replacing the function of heart and lungs). Three patients died.

Patients who did not receive prone positioning had poor lung recruitability, while alternating supine (face upward) and prone positioning was associated with increased lung recruitability.

"It is only a small number of patients, but our study shows that many patients did not re-open their lungs under high positive pressure and may be exposed to more harm than benefit in trying to increase the pressure," said Chun Pan, MD, also a professor with Zhongda Hospital, School of Medicine, Southeast University. "By contrast, the lung improves when the patient is in the prone position.

Considering this can be done, it is important for the management of patients with severe COVID-19 requiring mechanical ventilation."

The team consisted of scientists and clinicians affiliated with four Chinese and two Canadian hospitals, medical schools and universities.

https://www.sciencedaily.com/releases/2020/03/200324202056.htm

Anxious about COVID-19? Stress can have lasting impacts on sperm and future offspring

Study identifies biological mechanism by which stress alters sperm and impacts brain development in next generation

March 23, 2020

Science Daily/University of Maryland School of Medicine

Prolonged fear and anxiety brought on by major stressors, like the coronavirus pandemic, can not only take a toll on a person's mental health, but may also have a lasting impact on a man's sperm composition that could affect his future offspring. That is the finding of a provocative new study published in the journal Nature Communications by researchers at the University of Maryland School of Medicine.

The research outlines a biological mechanism for how a father's experience with stress can influence fetal brain development in the womb. The effects of paternal stress can be transferred to offspring through changes in the extracellular vesicles that then interact with maturing sperm. Extracellular vesicles are small membrane-bound particles that transport proteins, lipids, and nucleic acids between cells. They are produced in large amounts in the reproductive tract and play an integral role in sperm maturation.

"There are so many reasons that reducing stress is beneficial especially now when our stress levels are chronically elevated and will remain so for the next few months," said study corresponding author Tracy Bale, PhD, Professor of Pharmacology and Director of the Center for Epigenetic Research in Child Health & Brain Development at the University of Maryland School of Medicine. "Properly managing stress can not only improve mental health and other stress-related ailments, but it can also help reduce the potential lasting impact on the reproductive system that could impact future generations."

She and her colleagues did not specifically study those who were under stress due to the coronavirus pandemic.

To examine a novel biological role for extracellular vesicles in transferring dad's stress to sperm, the researchers examined extracellular vesicles from mice following treatment with the stress hormone corticosterone. After treatment, the extracellular vesicles showed dramatic changes in their overall size as well as their protein and small RNA content.

When sperm were incubated with these previously "stressed" extracellular vesicles prior to fertilizing an egg, the resulting mouse pups showed significant changes in patterns of early brain development, and as adults these mice were also significantly different than controls for how they responded to stress themselves.

To see if similar differences occurred in human sperm, the researchers recruited students from the University of Pennsylvania to donate sperm each month for six months, and complete questionnaires about their perceived stress state in the preceding month. They found that students who had experienced elevated stress in months prior showed significant changes in the small RNA content of their sperm, while those who had no change in stress levels experienced little or no change. These data confirm a very similar pattern found in the mouse study.

"Our study shows that the baby's brain develops differently if the father experienced a chronic period of stress before conception, but we still do not know the implications of these differences," said Dr. Bale. "Could this prolonged higher level of stress raise the risk for mental health issues in future offspring, or could experiencing stress and managing it well help to promote stress resilience? We don't really know at this point, but our data highlight why further studies are necessary."

The research team did find that stress-induced changes in the male reproductive system take place at least a month after the stress is attenuated and life has resumed its normal patterns. "It appears the body's adaptation to stress is to return to a new baseline," Dr. Bale said, "a post-stress physiological state -- termed allostasis."

This research was funded by the National Institute of Mental Health and included co-authors from the Institute for Genome Sciences at the University of Maryland School of Medicine and the Department of Pharmaceutical Science at the University of Maryland School of Pharmacy, as well as the University of Pennsylvania.

"This research represents a critical step in understanding important mechanisms that underlie the field of intergenerational epigenetics," said UMSOM Dean E. Albert Reece, MD, PhD, MBA, who is also the Executive Vice President for Medical Affairs, University of Maryland, and the John Z. and Akiko K. Bowers Distinguished Professor. "Such knowledge is crucial to identify early interventions to improve reproduction and early childhood development down the road."

While the study did not test stress management interventions to determine what effects they might have on attenuating the changes in sperm composition, Dr. Bale, who goes for regular runs to reduce the stress of the current COVID-19 pandemic, contends that any lifestyle habits that are good for the brain are likely good for the reproductive system.

"It is important to realize that social distancing does not have to mean social isolation, especially with modern technologies available to many of us," said Joshua Gordon, Director of the National Institute of Mental Health in his web message about coping with coronavirus. "Connecting with our friends and loved ones, whether by high tech means or through simple phone calls, can help us maintain ties during stressful days ahead and will give us strength to weather this difficult passage."

The Centers for Disease Control and Prevention has tips on "stress and coping" page on their COVID-19 site that recommends the following to "support yourself":

• Take breaks from watching, reading, or listening to news stories, including social media. Hearing about the pandemic repeatedly can be upsetting.

• Take care of your body. Take deep breaths, stretch, or meditate. Try to eat healthy, well-balanced meals, exercise regularly, get plenty of sleep, and avoid alcohol and drugs.

• Make time to unwind. Try to do some other activities you enjoy.

• Connect with others. Talk with people you trust about your concerns and how you are feeling.

https://www.sciencedaily.com/releases/2020/03/200323132410.htm

ACE inhibitors and angiotensin receptor blockers may increase the risk of severe COVID-19

March 23, 2020

Science Daily/Louisiana State University Health Sciences Center

James Diaz, MD, MHA, MPH & TM, Dr PH, Professor and Head of Environmental Health Sciences at LSU Health New Orleans School of Public Health, has proposed a possible explanation for the severe lung complications being seen in some people diagnosed with COVID-19. The manuscript was published by Oxford University Press online in the Journal of Travel Medicine.

The SARS beta coronaviruses, SARS-CoV, which caused the SARS (Severe Acute Respiratory Syndrome) outbreak in 2003 and the new SARS-CoV-2, which causes COVID-19, bind to angiotensin converting enzyme 2 (ACE2) receptors in the lower respiratory tracts of infected patients to gain entry into the lungs. Viral pneumonia and potentially fatal respiratory failure may result in susceptible persons after 10-14 days.

"Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are highly recommended medications for patients with cardiovascular diseases including heart attacks, high blood pressure, diabetes and chronic kidney disease to name a few," notes Dr. Diaz. "Many of those who develop these diseases are older adults. They are prescribed these medications and take them every day."

Research in experimental models has shown an increase in the number of ACE2 receptors in the cardiopulmonary circulation after intravenous infusions of ACE inhibitors.

"Since patients treated with ACEIs and ARBS will have increased numbers of ACE2 receptors in their lungs for coronavirus S proteins to bind to, they may be at increased risk of severe disease outcomes due to SARS-CoV-2infections," explains Diaz.

Diaz writes, this hypothesis is supported by a recent descriptive analysis of 1,099 patients with laboratory-confirmed COVID-19 infections treated in China during the reporting period, December 11, 2019, to January 29, 2020. This study reported more severe disease outcomes in patients with hypertension, coronary artery disease, diabetes and chronic renal disease. All patients with the diagnoses noted met the recommended indications for treatment with ACEIs or ARBs. Diaz says that two mechanisms may protect children from COVID-19 infections -- cross-protective antibodies from multiple upper respiratory tract infections caused by the common cold-causing alpha coronaviruses, and fewer ACE2 receptors in their lower respiratory tracts to attract the binding S proteins of the beta coronaviruses.

He recommends future case-control studies in patients with COVID-19 infections to further confirm chronic therapy with ACEIs or ARBs may raise the risk for severe outcomes.

In the meantime he cautions, "Patients treated with ACEIs and ARBs for cardiovascular diseases should not stop taking their medicine, but should avoid crowds, mass events, ocean cruises, prolonged air travel, and all persons with respiratory illnesses during the current COVID-19 outbreak in order to reduce their risks of infection."

https://www.sciencedaily.com/releases/2020/03/200323101354.htm

Study reveals how long COVID-19 remains infectious on cardboard, metal and plastic

People may acquire coronavirus through air and by touching contaminated surfaces

March 20, 2020

Science Daily/University of California - Los Angeles

The virus that causes COVID-19 remains for several hours to days on surfaces and in aerosols, a new study published in the New England Journal of Medicine found.

The study suggests that people may acquire the coronavirus through the air and after touching contaminated objects. Scientists discovered the virus is detectable for up to three hours in aerosols, up to four hours on copper, up to 24 hours on cardboard and up to two to three days on plastic and stainless steel.

"This virus is quite transmissible through relatively casual contact, making this pathogen very hard to contain," said James Lloyd-Smith, a co-author of the study and a UCLA professor of ecology and evolutionary biology. "If you're touching items that someone else has recently handled, be aware they could be contaminated and wash your hands."

The study attempted to mimic the virus being deposited onto everyday surfaces in a household or hospital setting by an infected person through coughing or touching objects, for example. The scientists then investigated how long the virus remained infectious on these surfaces.

The study's authors are from UCLA, the National Institutes of Health's National Institute of Allergy and Infectious Diseases, the Centers for Disease Control and Prevention, and Princeton University. They include Amandine Gamble, a UCLA postdoctoral researcher in Lloyd-Smith's laboratory.

In February, Lloyd-Smith and colleagues reported in the journal eLife that screening travelers for COVID-19 is not very effective. People infected with the virus -- officially named SARS-CoV-2 -- may be spreading the virus without knowing they have it or before symptoms appear. Lloyd-Smith said the biology and epidemiology of the virus make infection extremely difficult to detect in its early stages because the majority of cases show no symptoms for five days or longer after exposure.

"Many people won't have developed symptoms yet," Lloyd-Smith said. "Based on our earlier analysis of flu pandemic data, many people may not choose to disclose if they do know."

The new study supports guidance from public health professionals to slow the spread of COVID-19:

• Avoid close contact with people who are sick.

• Avoid touching your eyes, nose and mouth.

• Stay home when you are sick.

• Cover coughs or sneezes with a tissue, and dispose of the tissue in the trash.

• Clean and disinfect frequently touched objects and surfaces using a household cleaning spray or wipe.

https://www.sciencedaily.com/releases/2020/03/200320192755.htm

Understanding how COVID-19 affects children vital to slowing pandemic

March 19, 2020

Science Daily/University of Virginia Health System

Though COVID-19 so far appears to be largely sparing children, researchers are cautioning that it is critical to understand how the virus affects kids to model the pandemic accurately, limit the disease's spread and ensure the youngest patients get the care they need.The warning comes from Steven L. Zeichner, MD, PhD, the head of UVA Health's Division of Pediatric Infectious Diseases, and Andrea T. Cruz, MD, MPH, a pediatric emergency medicine physician at Houston's Baylor College of Medicine. They have authored a commentary in the journal Pediatrics accompanying a new article that reveals a small percentage of infected children become seriously ill. Those at greatest risk include babies and preschoolers.

"Many infectious diseases affect children differently than adults and understanding those differences can yield important insights," the commentary authors write. "This will likely be true for COVID-19, just as it was for older infectious diseases."

Assessing COVID-19 Risks

Zeichner and Cruz note that there are subgroups of children who appear to be at greater risk of COVID-19 complications, particularly those who are younger, immunocompromised or have other pulmonary health problems.

However, the presence of other viral infections in up to two-thirds of childhood coronavirus cases makes it very difficult to assess the true effect of COVID-19 on children, they state. (This figure is based on prior studies of children with coronaviruses detectable in the respiratory tract.)

While much remains unknown, Cruz and Zeichner caution that children, even asymptomatic children, could play a "major role" in disease transmission. For example, they cite a study that found the virus remained in children's stool for several weeks after diagnosis. That, combined with other routes of transmission such as nasal secretions, could pose a major challenge for schools, day care centers and the children's families, they note.

"Since many children infected with COVID-19 appear to have have mild symptoms, or even no symptoms at all, it is important to practice all the social distancing, hygiene and other precautions being recommended by public health authorities to minimize transmission from children to others, including family members who may be at greater risk from the infection, such as grandparents or family members with chronic medical conditions," said Zeichner, who is working on innovative potential COVID-19 vaccines in his lab. "In addition, studies of the reasons why children are affected differently than adults by the infection may yield insights that can be helpful in understanding the disease and ways to treat or prevent it."

https://www.sciencedaily.com/releases/2020/03/200319125201.htm

Median incubation period for COVID-19

March 17, 2020

Science Daily/University of Massachusetts Amherst

A new study calculates that the median incubation period for COVID-19 is just over 5 days and that 97.5% of people who develop symptoms will do so within 11.5 days of infection.

A University of Massachusetts Amherst biostatistician who directs the UMass-based Flu Forecasting Center of Excellence was invited by the White House Coronavirus Task Force to participate Wednesday morning in a coronavirus modeling webinar.

The four-hour, virtual gathering will include 20 of the world's leading infectious disease and pandemic forecasting modelers, from researchers at Harvard, Johns Hopkins and the Centers for Disease Control and Prevention (CDC) in the U.S. to those based at institutions in England, Hong Kong, South Africa and the Netherlands.

According to the White House Coronavirus Task Force coordinator Dr. Charles Vitek, "This webinar is designed to highlight for the Task Force what modeling can tell us regarding the potential effects of mitigation measures on the coronavirus outbreak. The unprecedented speed and impact of the nCoV-19 epidemic requires the best-informed public health decision-making we can produce."

Nicholas Reich, associate professor in the School of Public Health and Health Sciences, heads a flu forecasting collaborative that has produced some of the world's most accurate models in recent years. He and postdoctoral researcher Thomas McAndrew have been conducting weekly surveys of more than 20 infectious disease modeling researchers to assess their collective expert opinion on the trajectory of the COVID-19 outbreak in the U.S. The researchers and modeling experts design, build and interpret models to explain and understand infectious disease dynamics and the associated policy implications in human populations.

Reich is co-author of a new study in the Annals of Internal Medicine that calculates that the median incubation period for COVID-19 is just over five days and that 97.5 percent of people who develop symptoms will do so within 11.5 days of infection. The incubation period refers to the time between exposure to the virus and the appearance of the first symptoms.

The study's lead author is UMass Amherst biostatistics doctoral alumnus Stephen Lauer, a former member of the Reich Lab and current postdoctoral researcher at the Johns Hopkins Bloomberg School of Public Health.

The researchers examined 181 confirmed cases with identifiable exposure and symptom onset windows to estimate the incubation period of COVID-19. They conclude that "the current period of active monitoring recommended by the U.S. Centers for Disease Control and Prevention [14 days] is well supported by the evidence."

https://www.sciencedaily.com/releases/2020/03/200317175438.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

Breakthrough in coronavirus research results in new map to support vaccine design

February 19, 2020

Science Daily/University of Texas at Austin

Researchers have made a critical breakthrough toward developing a vaccine for the 2019 novel coronavirus by creating the first 3D atomic scale map of the part of the virus that attaches to and infects human cells. Mapping this part, called the spike protein, is an essential step so researchers around the world can develop vaccines and antiviral drugs to combat the virus.

Mapping this part, called the spike protein, is an essential step so researchers around the world can develop vaccines and antiviral drugs to combat the virus. The paper is publishing Wednesday, Feb. 19 in the journal Science.

The scientific team is also working on a related viable vaccine candidate stemming from the research.

Jason McLellan, associate professor at UT Austin who led the research, and his colleagues have spent many years studying other coronaviruses, including SARS-CoV and MERS-CoV. They had already developed methods for locking coronavirus spike proteins into a shape that made them easier to analyze and could effectively turn them into candidates for vaccines. This experience gave them an advantage over other research teams studying the novel virus.

"As soon as we knew this was a coronavirus, we felt we had to jump at it," McLellan said, "because we could be one of the first ones to get this structure. We knew exactly what mutations to put into this, because we've already shown these mutations work for a bunch of other coronaviruses."

The bulk of the research was carried out by the study's co-first authors, Ph.D. student Daniel Wrapp and research associate Nianshuang Wang, both at UT Austin.

Just two weeks after receiving the genome sequence of the virus from Chinese researchers, the team had designed and produced samples of their stabilized spike protein. It took about 12 more days to reconstruct the 3D atomic scale map, called a molecular structure, of the spike protein and submit a manuscript to Science, which expedited its peer review process. The many steps involved in this process would typically take months to accomplish.

Critical to the success was state-of-the-art technology known as cryogenic electron microscopy (cryo-EM) in UT Austin's new Sauer Laboratory for Structural Biology. Cryo-EM allows researchers to make atomic-scale 3D models of cellular structures, molecules and viruses.

"We ended up being the first ones in part due to the infrastructure at the Sauer Lab," McLellan said. "It highlights the importance of funding basic research facilities."

The molecule the team produced, and for which they obtained a structure, represents only the extracellular portion of the spike protein, but it is enough to elicit an immune response in people, and thus serve as a vaccine.

Next, McLellan's team plans to use their molecule to pursue another line of attack against the virus that causes COVID-19, using the molecule as a "probe" to isolate naturally produced antibodies from patients who have been infected with the novel coronavirus and successfully recovered. In large enough quantities, these antibodies could help treat a coronavirus infection soon after exposure. For example, the antibodies could protect soldiers or health care workers sent into an area with high infection rates on too short notice for the immunity from a vaccine to take effect.

https://www.sciencedaily.com/releases/2020/02/200219152850.htm

To predict an epidemic, evolution can't be ignored

March 2, 2020

Science Daily/College of Engineering, Carnegie Mellon University

Whether it's coronavirus or misinformation, scientists can use mathematical models to predict how something will spread across populations. But what happens if a pathogen mutates, or information becomes modified, changing the speed at which it spreads? Researchers now show for the first time how important these considerations are.

When scientists try to predict the spread of something across populations -- anything from a coronavirus to misinformation -- they use complex mathematical models to do so. Typically, they'll study the first few steps in which the subject spreads, and use that rate to project how far and wide the spread will go.

But what happens if a pathogen mutates, or information becomes modified, changing the speed at which it spreads? In a new study appearing in this week's issue of Proceedings of the National Academy of Sciences (PNAS), a team of Carnegie Mellon University researchers show for the first time how important these considerations are.

"These evolutionary changes have a huge impact," says CyLab faculty member Osman Yagan, an associate research professor in Electrical and Computer Engineering (ECE) and corresponding author of the study. "If you don't consider the potential changes over time, you will be wrong in predicting the number of people that will get sick or the number of people who are exposed to a piece of information."

Most people are familiar with epidemics of disease, but information itself -- nowadays traveling at lightning speeds over social media -- can experience its own kind of epidemic and "go viral." Whether a piece of information goes viral or not can depend on how the original message is tweaked.

"Some pieces of misinformation are intentional, but some may develop organically when many people sequentially make small changes like a game of 'telephone,'" says Yagan. "A seemingly boring piece of information can evolve into a viral Tweet, and we need to be able to predict how these things spread."

In their study, the researchers developed a mathematical theory that takes these evolutionary changes into consideration. They then tested their theory against thousands of computer-simulated epidemics in real-world networks, such as Twitter for the spread of information or a hospital for the spread of disease.

In the context of spreading of infectious disease, the team ran thousands of simulations using data from two real-world networks: a contact network among students, teachers, and staff at a US high school, and a contact network among staff and patients in a hospital in Lyon, France.

These simulations served as a test bed: the theory that matches what is observed in the simulations would prove to be the more accurate one.

"We showed that our theory works over real-world networks," says the study's first author, Rashad Eletreby, who was a Carnegie Mellon Ph.D. student when he wrote the paper. "Traditional models that don't consider evolutionary adaptations fail at predicting the probability of the emergence of an epidemic."

While the study isn't a silver bullet for predicting the spread of today's coronavirus or the spread of fake news in today's volatile political environment with 100% accuracy -- one would need real-time data tracking the evolution of the pathogen or information to do that -- the authors say it's a big step.

"We're one step closer to reality," says Eletreby.

https://www.sciencedaily.com/releases/2020/03/200302153551.htm

COVID-19 vaccine development

February 26, 2020

Science Daily/Hong Kong University of Science and Technology

Scientists have recently identified a set of potential vaccine targets for SARS-CoV-2 coronavirus, to guide experimental efforts towards vaccine development against novel pneumonia (COVID-19).

A team of scientists at the Hong Kong University of Science and Technology (HKUST) has recently made an important discovery in identifying a set of potential vaccine targets for the SARS-CoV-2 coronavirus, providing crucial leads for guiding experimental efforts towards the vaccine development against the novel pneumonia (COVID-19) caused by the virus.

Like SARS-CoV, which caused the SARS (Severe Acute Respiratory Syndrome) outbreak in 2003, SARS-CoV-2 belongs to the same Betacoronavirus genus. By considering the genetic similarity between SARS-CoV-2 and SARS-CoV, the team leveraged experimentally-determined immunological data to identify a set of SARS-CoV- derived B cell and T cell epitopes that exactly match to SARS-CoV-2. Epitopes are biomarkers recognized by the immune system to trigger actions against the virus. As no mutation has been observed in the identified epitopes among the available SARS-CoV-2 genetic sequences, immune targeting of these epitopes may potentially offer protection against the novel pneumonia COVID-19.

The team, led by data scientists Prof. Matthew McKay and Dr. Ahmed Abdul Quadeer, expected that their work can assist in guiding experimental research towards the development of effective vaccines against SARS- CoV-2.

Prof. McKay highlighted that "Despite similarities between SARS-CoV and SARS-CoV-2, there is genetic variation between the two, and it is not obvious if epitopes that elicit an immune response against SARS-CoV will likely be effective against SARS-CoV-2. We found that only roughly 20% of the SARS-CoV epitopes map identically to SARS-CoV-2, and believe these are promising candidates."

"For the identified T cell epitopes, we also performed a population coverage analysis and determined a set of epitopes that is estimated to provide broad coverage globally as well as in China" said Dr. Quadeer. The estimated population coverage represents the percentage of individuals within the selected population that are likely to elicit an immune response to at least one epitope from the identified set.

Prof. McKay is a Professor in the Departments of Electronic & Computer Engineering and Chemical & Biological Engineering; Dr. Quadeer is a post-doctoral fellow in the Department of Electronic & Computer Engineering. Their findings were recently published in the scientific journal Viruses this month.

"Our objective was to try to assist with the initial phase of vaccine development, by providing recommendations of specific epitopes that may potentially be considered for incorporation in vaccine designs" Prof. McKay added. "More generally, our work is part of a global effort seeking to capitalize on data for COVID-19, made available and rapidly shared by the scientific community, to understand this new virus and come up with effective interventions."

The beginning of 2020 has seen the emergence of SARS-CoV-2 outbreak in mainland China, which has quickly spread to over 30 countries around the world, infecting over 80,000 people and causing over 2,600 deaths as of late February 2020.

https://www.sciencedaily.com/releases/2020/02/200226091227.htm