August 7, 2020 |  Healthcare systems in five states have reported a decrease in the number of emergency department (ED) visits since April, while hospital admission rates have increased in the same timeframe. A recent study urges public health officials to emphasize the importance of visiting the ED during the COVID-19 pandemic. This, plus more, is included in this week’s announcements and updates from the clinical research industry.

Literature Updates

Patients with COVID-19 presenting with acute neurologic symptoms warrant a lower threshold for suspicion of large vessel occlusion (LVO) stroke, thus necessitating prompt workup, according to a retrospective, case-control study by Mount Sinai researchers that published in the American Journal of Roentgenology. The study included 329 patients for whom a code for stroke was activated during March 16 to April 30, 2020 at a single system of six hospitals in New York City; for 21.6% is was determined to be a LVO stroke, the most common type being middle cerebral artery segment M1-M2 occlusion. Multifocal LVOs were observed in only 9.9% of patients with LVO stroke. LVO stroke was present in 31.7% of patients with COVID-19, compared with 15.3% of patients without COVID-19. The figures were 1.9% and 13.8%, respectively, for SVO stroke. DOI: 10.2214/AJR.20.23847

Researchers from Children's Hospital of Philadelphia have identified lab profiles that differentiate Multisystem Inflammatory Syndrome in Children (MIS-C) from severe COVID-19 in children and suggest that MIS-C is a post-infectious syndrome that is distinct from Kawasaki disease (KD). Their findings published in The Journal of Clinical Investigation. The study analyzed 20 patients with SARS-CoV-2 and found that patients with MIS-C had elevated levels of two cytokines—IL-10 and TNF-α—whereas patients with severe or mild COVID-19 had no or minimally elevated levels of these cytokines. In previous reports, KD profiles tend to be associated with mild elevations of other cytokines and not IL-10. An additional finding was that severe COVID-19 is easily detectable and active, while patients with MIS-C had been infected with the virus at some point in the distant past and cleared most of the active virus. Simple peripheral blood smears could also help distinguish severe COVID-19, mild COVID-19 and MIS-c. DOI: 10.1172/JCI140970

In The BMJ, a panel of international experts make a weak recommendation for the use of remdesivir in patients with severe COVID-19, and strongly support continued enrollment of patients into ongoing clinical trials of the antiviral medication. Their recommendation is based on a new evidence review comparing the effects of several drug treatments for COVID-19 through July 20. They suggest that future research focus on optimal dose and duration of therapy, and whether there are specific groups of patients most likely to benefit from remdesivir, which has been associated with a reduction in time to clinical improvement. DOI: 10.1136/bmj.m2980

Investigators have initiated a first-in-human phase 1/2 clinical trial of the Ad26.COV2.S vaccine in healthy volunteers, which is being funded by Janssen Vaccines & Prevention, B.V. (pharmaceutical research arm of Johnson & Johnson). The vaccine uses a common cold virus (adenovirus serotype 26) to deliver the SARS-CoV-2 spike protein into host cells, where it stimulates the body to raise immune responses against the coronavirus. In preclinical studies, the vaccine raised neutralizing antibodies and robustly protected non-human primates against SARS-CoV-2, as reported in Nature. Principal investigator for the trial is at Beth Israel Deaconess Medical Center. Pending clinical trial outcomes, the vaccine is on track to start a phase 3 efficacy trial in 30,000 participants in September. DOI: 10.1038/s41586-020-2607-z

From January through April 2020, emergency department (ED) visits decreased while hospital admission rates increased at five healthcare systems in five states (Colorado, Connecticut, Massachusetts, New York and North Carolina), according to a study that published in JAMA Internal Medicine. The findings suggest that practitioners and public health officials should emphasize the importance of visiting the ED during the COVID-19 pandemic for serious symptoms, illnesses, and injuries that cannot be managed in other settings. DOI: 10.1001/jamainternmed.2020.3288

Scientists at the University of Michigan report in Science Advances that countries with mandatory Bacillus Calmette-Guérin (BCG) vaccination (typically given at birth or during childhood to prevent tuberculosis) until at least the year 2000 tended to exhibit slower infection and death rates during the first 30 days of the outbreak of COVID-19 in their country. By applying a statistical model based on their findings, the researchers further estimated that only 468 people would likely have died from COVID-19 in the U.S. as of March 29, 2020—19% of the actual figure by that date—if the U.S. had instituted mandatory BCG vaccination several decades ago. The association merits clinical investigation and would requires accounting for the effects of several biases and variables across countries, the authors say. For this study, they focused on changes in the growth rates of COVID-19 cases and deaths while controlling for variables such as diagnostic test availability, median age, per capita GDP, population size and density, net migration rate, and various cultural differences such as individualism. DOI: 10.1126/sciadv.abc1463

A study authored by representatives of Quest Diagnostics has found a significant decline in newly identified patients in the U.S. with six common types of cancer before and during the COVID-19 pandemic, mirroring findings from other countries. The study included 278,778 patients, 92.8% from the baseline period (Jan. 6, 2019 to Feb. 29, 2020) and the remainder from the COVID-19 period (March 1 to April 18, 2020). During the pandemic, the weekly number of newly identified patients fell 46.4% overall, with significant declines in all cancer types—ranging from 24.7% for pancreatic cancer to 51.8% for breast cancer. Results published in JAMA Open Network. DOI: 10.1001/jamanetworkopen.2020.17267

Despite recent reports of lower COVID-19 incidence among high-altitude populations, current data is insufficient to conclude that high altitude is protective against the SARS-CoV-2 virus, write researchers from Italy, the U.S. and Canada in an article appearing online in High Altitude Medicine & Biology. They say epidemiological observations presented to date from high-altitude regions, suggesting a protective benefit of genetic or nongenomic adaptation to high-altitude hypoxia, are preliminary. DOI: 10.1089/ham.2020.0114

The death rate for patients who experienced what is normally a lower-risk heart attack rose sharply during the peak of the COVID-19 pandemic in England, according to an analysis of NHS data published in the European Heart Journal - Quality of Care and Clinical Outcomes. In comparison, the death rate for people who had a more severe heart attack fell. It also revealed a substantial drop in the number of people who were arriving at hospital with a heart attack. At its lowest point, hospitals were treating just over half the cases they would normally expect to see. The number of people seeking medical help still had not returned to pre COVID-19 levels when the study period ended on May 22. The reduction in patients seeking timely help is likely to have resulted in people dying at home or developing chronic heart problems, report the research team, led by the University of Leeds. DOI: 10.1093/ehjqcco/qcaa062

One of the immune system's oldest branches, called complement, may be influencing the severity of COVID disease, according to researchers at Columbia University Irving Medical Center. Among other findings linking complement to COVID, the researchers found that people with age-related macular degeneration—a disorder caused by overactive complement—are at greater risk of developing severe complications and dying from COVID. The connection with complement suggests that existing drugs that inhibit the complement system could help treat patients with severe disease. The study published in Nature Medicine. The authors also found evidence that clotting activity is linked to COVID severity and that mutations in certain complement and coagulation genes are associated with hospitalization of COVID patients. Findings stem from an earlier finding that coronaviruses are masters of viral mimicry, particularly with proteins involved in coagulation and proteins that make up complement. DOI: 10.1038/s41591-020-1021-2

A large proportion of U.K. healthcare workers may already have been infected with COVID-19, according to research led by the University of East Anglia in collaboration with University College London. Findings were based on a questionnaire completed by 262 healthcare workers in April, before anosmia was listed as an official symptom and diagnostic testing among NHS workers was limited to those displaying symptoms of a new continuous cough and/or a high temperature. Nevertheless, 27.9% of the participants had been tested for COVID-19, with 76.7% of these confirmed positive. Interestingly, nearly two-thirds of those surveyed reported that they had lost their sense of smell or taste at some point between mid-February and mid-April, as reported in The Lancet Microbe. Those who had lost their sense of smell were also almost five times more likely to test positive. The study also involved a follow-up survey in May, in which 47% of respondents reported that their sense of smell and taste had completely recovered. A further 42% said they had partially recovered their sense of smell and taste, but just over 7% still suffered anosmia. DOI: 10.1016/j.wjorl.2020.04.001

Researchers in Korea have determined that the viral load of asymptomatic and symptomatic patients is similar, and that the cycle threshold values of envelope genes from lower respiratory tract specimens (sputum) in asymptomatic patients tended to decrease more gradually than those of symptomatic patients. Symptom-based surveillance and screening methods may result in substantial under-reporting of infected patients, they say, noting a report of SARS-CoV-2 transmission from an asymptomatic person to four family members that offers biological plausibility to the infectiveness of asymptomatic people. The retrospective evaluation was conducted for a cohort of 303 symptomatic and asymptomatic patients with SARS-CoV-2 infection who were isolated in a community treatment center. Results appeared in JAMA Internal Medicine. DOI: 10.1001/jamainternmed.2020.3862

Patients experiencing severe COVID-19 symptoms had improved outcomes when administered an Interleukin-6 (IL6ri) inhibitor (sarilumab or tocilizumab) to mediate severe systemic inflammatory responses, researchers at Boston Medical Center have found in an observational study that included 255 COVID-19-confirmed patients. The treatment was more effective when administered earlier in the disease course and reduced mortality rates and the need for intubation. Published in the International Journal of Infectious Diseases, the results show Interleukin-6 inhibitors appear to be a more effective treatment compared to other options, including remedesvir and dexamethasone, which are recommended and currently used in the pandemic. The average length of stay in the hospital was 12.9 days, but patients treated when their fraction of inspired oxygen (FiO2) requirement was less than 45% had a shorter average length of stay (11.3 days) than those treated whose FiO2 was above that level. Of the 68 patients requiring mechanical ventilation, 44 were intubated 24 hours later after receiving IL6ri. DOI: 10.1016/j.ijid.2020.07.023

Body mass index (BMI) is associated with the development of severe COVID-19 and admission to intensive care units (ICUs) in African Americans, according to a single center, retrospective cross-sectional study published online in Obesity. This is the first study that focuses specifically on the risk factors within an African American population and included 158 confirmed COVID-19 positive patients who presented to Tulane Medical Center between March 12 and April 9, 2020. About 85% of the severe cases admitted to the ICU had respiratory failure requiring intubation and mechanical ventilation; ICU mortality for severe cases was 37% at the study’s conclusion when nearly 22% of participants were still intubated and requiring mechanical ventilation, which would potentially increase this percentage. In unadjusted and adjusted analysis, the factors most associated with ICU admission were age, BMI and lung disease. The average BMI of participants was 33.2. Participants with severe disease requiring ICU admission were older (62 years versus 55 years) and had higher BMI (36.5 kg/m2 versus 31.9 kg/m2. DOI: 10.1002/oby.22937

The rate of COVID-19 transmission in New South Wales (NSW) educational settings was extremely limited during the first wave of COVID-19, research findings published in The Lancet Child and Adolescent Health have shown. Preliminary findings by researchers from the National Centre for Immunisation Research and Surveillance and the University of Sydney indicate that transmission rates were minimal across 25 educational settings (15 schools and 10 childcare settings) from January through April, particularly between children and from children to adults. This is the first comprehensive population-based assessment of coronavirus transmission in educational settings worldwide and suggests COVID-19 transmission in schools appears to be considerably less than that seen for other respiratory viruses, such as influenza. It is also consistent with other data that show lower rates, and generally milder disease, in children than in adults. DOI: 10.1016/S2352-4642(20)30251-0

A team of U.S.-based scientists has conducted a comprehensive analysis of worldwide COVID-19 data to identify key strategies moving forward to develop effective therapeutics. Their critical literature review of the 20 most-read articles published in the Journal of Immunology in May 2020 suggests that COVID-19 should be treated as an acute inflammatory disease and that severity of infection is associated with the dysregulation of inflammatory immune responses and subsequent inability to develop protective immunity from the virus. Drugs that target the virus or suppress inflammatory immune responses have produced inconsistent results and might not be the best treatment for patients with COVID-19, they report. Drugs that modulate inflammation without compromising the adaptive immune response could be the most effective therapeutic strategy. A dysregulated immune response, as opposed to viral load, appears to be the primary cause of death. They also suggest that antiviral therapies such as chloroquine, hydroxychloroquine and remdesevir might be effective as preventive strategies or in very early stages of infection but could prevent patients from gaining protective immunity. Efforts to develop novel treatment options for COVID-19 should be primarily focused on the transference of plasma from immune individuals to those with severe symptoms of the disease as well as a vaccine that prevents infection, they say. The combination of the blood pressure medication losartan with convalescent plasma in symptomatic patients could be a promising strategy for the prevention or treatment of severe clinical symptoms and allow patients to develop immunity against the virus. DOI: /10.4049/jimmunol.2000413

Minority and socioeconomically disadvantaged children have significantly higher rates of COVID-19 infection, paralleling the health disparities that have been found in adults, according to a study led by researchers at Children's National Hospital. Findings, reported online in Pediatrics, were based on data collected between March 21 and April 28, 2020 from a free drive-through/walk-up pediatric COVID-19 testing site affiliated with Children's National. Among the first 1,000 patients tested at the site, about 7% of non-Hispanic white children were positive for COVID-19 compared to about 30% of non-Hispanic black and 46% of Hispanic children. Using data from the American Families Survey, researchers then separated the 1,000 patients into estimated family income quartiles to find marked disparities in COVID-19 positivity rates by income levels, with those in the highest quartile having infection rates of about 9% versus about 38% for those in the lowest quartile. There were additional disparities in exposure status. DOI: 10.1542/peds.2020-009951

Industry Updates

Mount Sinai Health System and Renalytix AI have launched a multi-center study to conduct in-depth investigations into kidney-related complications and long-term outcomes linked to COVID-19. KidneyIntelX, Renalytix AI’s artificial intelligence-enabled in vitro diagnostic platform, will be used to assess the risk of kidney disease progression and kidney failure, among other kidney complications, in patients surviving COVID-19 from multiple centers in the United States. The study, titled “Multi-center Assessment of Survivors for Kidney Disease after COVID-19 (MASKeD-COVID),” expands on the Pred-MAKER study previously announced April 20, 2020 which focuses on the impact of COVID-19 in the acute hospitalized setting. Investigative teams expected to participate in the study include the Mount Sinai Health System Icahn School of Medicine at Mount Sinai in New York, Yale New Haven Health/Yale School of Medicine, Michigan Medicine/University of Michigan Medical School, Johns Hopkins Medicine/The Johns Hopkins University Medical School, and Rutgers, The State University of New Jersey/Rutgers New Jersey Medical School. Press release.

Sermo, a physician-only social platform and healthcare data collection company, is releasing their COVID-19 Barometer Study with results around their physician members’ thoughts on all areas of the pandemic to aid physician collaboration and share medically crowdsourced knowledge on an ongoing basis (to keep pace with the rapidly changing COVID-19 landscape) with patients and pharma alike. Gathering data globally since March 25, The COVID-19 Barometer Study tracks health care provider infections, state of the outbreak, reopenings, treatments, and other impression. More information.

Researchers at ICFO-The Institute of Photonic Sciences (Spain) used algorithms to customize a commercial, near-infrared spectroscopy device that will provide an evaluation of the microvascular health. After the first device was sent to Hospital Parc Taulí in March to be tested on COVID-19 patients, the collaboration expanded into an international consortium named HEMOCOVID-19 that is using the response of the microvasculature in the peripheral muscles to prolonged arterial cuff or blockage as a biomarker of endothelial and microvascular health. The device—non-invasive, portable, wireless and battery-operated—takes measurements at different times during patients’ intensive care stay. The goal is to help clinicians in the stratification of patients and guide development of therapies targeting the endothelial function as well as personalized rescue therapies that play a critical role in the management of severely ill patients. The consortium currently has 10 partners in Spain, the U.S., Brazil and Mexico. Press release.

The German Center for Infection Research is building a platform that will gather the methodology and results of SARS-CoV-2 antibody tests and make the data available to interested researchers. The project, called the LEOSS.sero-survey, will be led by scientists at the Helmholtz Centre for Infection Research and implemented in collaboration with Helmholtz Federated IT Services. The objective is to learn who has overcome COVID-19 without noticing and how many people have already produced protective antibodies against the virus. Seroprevalence studies are the only way to know the actual level of immunity in the population. LEOSS.ser-survey offers research groups the opportunity to collect and jointly evaluate the anonymized data of the various studies to increase their statistical significance. The platform follows the example of the existing LEOSS patient register, which has been collecting and evaluating clinical data from COVID-19 patients throughout Europe since March. With the LEOSS.sero-survey, the second important step being taken focuses on the immunity of affected people. Press release.

The National Institute of Allergy and Infectious Diseases (NIAID) is sponsoring a Phase 2 clinical trial to evaluate the safety and efficacy of potential new therapeutics for COVID-19, including an investigational therapeutic based on synthetic monoclonal antibodies (mAbs) to treat the disease. Researchers are working with clinical sites to identify an initial 220 potential volunteers currently infected with SARS-CoV-2 who have mild to moderate disease not requiring hospitalization. They’ll be invited to take an experimental therapy or a placebo as part of a rigorously designed randomized clinical trial known as ACTIV-2, which may also investigate other experimental therapeutics later under the same trial protocol. If the investigational mAbs show promise, the study would expand to a Phase 3 trial by enrolling up to 1,780 additional outpatient volunteers to determine if the investigational therapeutic can prevent either hospitalization or death through study day 28 while also continuing to evaluate its safety. The trial will be led by the NIAID-funded AIDS Clinical Trials Group and will enroll participants at sites around the world. The first therapeutic to be tested will be LY-CoV555 (Eli Lilly and Company), discovered by AbCellera in collaboration with NIAID's Vaccine Research Center. Press release.

The AIDS Clinical Trials Group (ACTG) has separately announced that the ACTIV-2 trial has launched at 25 of its U.S.-based sites and will expand to include approximately 100 total sites (ACTG and non-ACTG) worldwide. To qualify for the study, participants must have tested positive for SARS-CoV-2 infection in the outpatient setting within seven days and started experiencing symptoms within 10 days of enrolling into the study. At least half of participants will have factors that put them at high risk of progressing to severe COVID-19, including being age 55 or older and having one of the following: chronic lung, kidney, or liver disease; obesity; hypertension; cardiovascular disease; diabetes; or moderate to severe asthma. The trial is being led by researchers at the University of California, San Diego; the University of California, Los Angeles; and the University of North Carolina. Press release.

Patients admitted with COVID-19 at select hospitals may also now volunteer to enroll in a clinical trial to test the safety and efficacy of a potential new treatment for the disease, the NIAID announces. The Phase 3 randomized, controlled trial, known as ACTIV-3, is a "master protocol" designed to expand to test multiple different kinds of monoclonal antibody treatments. It also can enroll additional volunteers in the middle of the trial if a specific investigational treatment shows promise. Participating hospitals are part of existing clinical trial networks and include the International Network of Strategic Initiatives in Global HIV Trials, operated by NIAID); the Prevention and Early Treatment of Acute Lung Injury network and Cardiothoracic Surgical Trials Network, supported by the NIH's National Heart, Lung and Blood Institute; and the U.S. Department of Veterans Affairs Medical Centers. As with ACTIV-2, this study will begin by studying the investigational monoclonal antibody LY-CoV555. The initial stage of the trial aims to enroll approximately 300 volunteers who have been hospitalized with mild to moderate COVID-19 with fewer than 13 days of symptoms. Participants in both the active and placebo arm of the study will also receive standard care for COVID-19, including the antiviral remdesivir. Volunteers will be followed for 90 days to analyze their response to the investigational therapeutic. If LY-CoV555 appears to be safe as well as effective, the trial will enroll an additional 700 participants, including those who are more severely ill. The primary endpoint is the participants' sustained recovery for 14 days after release from the hospital. The principal investigator is at the University of Copenhagen. Press release.

With $1.2 million in new funding from the National Science Foundation, the University of Virginia (UVA) will put a secure, high-performance computing system into nationwide use for COVID-19 research. The Virginia Assuring Controls Compliance of Research Data (Virginia ACCORD) has been offering researchers at Virginia universities access to data storage and computational capability that are compliant with the Health Insurance Portability and Accountability Act. The new effort, dubbed ACCORD-COVID, will now expand access to researchers across the U.S. It’s a team effort involving UVA as well as researchers from Georgia Tech, Indiana University, Stanford University and University of Utah. Press release.

A new Medical Imaging and Data Resource Center (MIDRC) at the University of Chicago will create a massive, open-source database with medical images from thousands of COVID-19 patients to help better understand and treat the disease. The effort is being co-led by the American College of Radiology (ACR), the Radiological Society of North America (RSNA), and the American Association of Physicists in Medicine (AAPN), with funding coming from the National Institute of Biomedical Imaging and Bioengineering of the NIH. MIDRC will enable technological advancements, guide researchers' validation and use of artificial intelligence, and translate clinical systems for the best patient management decisions. Investigators will be able to access images and data to expedite their research through the MIDRC Data Commons Portal. The project will involve five infrastructure development projects under the oversight of an MIDRC executive advisory committee that will also oversee 12 research projects in support of solutions to the COVID-19 pandemic and the provision of funding and other resources to investigators at the ACR, RSNA, AAPM, 20 universities and the FDA. Within three months, the MIDRC plans to upload more than 10,000 COVID-19 thoracic radiographs and CT scan images via the existing input portals of the RSNA repository and the ACR registry. Press release.