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3D Swabs, Saliva Sampling, Anosmia, Delirium: COVID-19 Updates

Research Updates

The first nationally representative estimate of COVID-19 seroprevalence in the U.S. suggests few people on dialysis have developed antibodies in the first wave, finds a study by researchers from Stanford University and Ascend Clinical Laboratories that published in The Lancet. The cross-sectional analysis of more than 28,000 U.S. patients receiving dialysis finds fewer than 10% of people had COVID-19 antibodies by July 2020, and fewer than 10% of those with antibodies had been diagnosed by antigen or PCR testing. The study additionally shows higher COVID-19 infection rates among ethnic minorities and people living in lower-income, high-density, urban areas—underlining the need for COVID-19 public health efforts that prioritize these populations in order to prevent general community spread. Accounting for the externally validated test sensitivity, seroprevalence ranged from 8.2% to 9.4% in the sampled population compared to approximately 9.3% in the general population, with significant regional variation ranging from less than 5% in the western U.S. to greater than 25% in the northeast. By comparing seroprevalence data from their study with case counts per 100,000 population from Johns Hopkins University, researchers estimated that 9.2% of seropositive patients were diagnosed. The authors say their representative population is ideal for studying the general spread of COVID-19 in the U.S. because these patients undergo monthly, routine blood draws and represent other similar COVID-19 risk factors such as age, non-white race, and poverty. Renal disease is also a Medicare-qualifying condition, so patients don't face many of the access-to-care barriers that limit testing among the general population. DOI: 10.1016/S0140-6736(20)32009-2

Tel Aviv University researchers have found that carriers of the genetic mutations PiZ and PiS appear to be at high risk for severe illness and even death from COVID-19. These mutations lead to deficiency in the alpha1-antitrypsin protein, which protects lung tissues from damage in case of severe infections. Previous studies have associated deficiency in this protein with inflammatory damage to lung function in other diseases. Findings were based on an analysis of data from 67 countries on all continents, and a highly significant positive correlation between the prevalence of the two mutations in the population and COVID-19 mortality rates was seen in many countries, including the U.S., U.K., Belgium, Spain and Italy. Conversely, in many countries in Africa and South East Asia as well as in Japan, Korea, Taiwan, Thailand, Vietnam and Cambodia where these mutations are relatively rare, COVID-19 mortality rates have been correspondingly low.  The authors propose that their findings be corroborated by clinical trials and, if validated, should lead to population-wide screening for detecting mutation carriers and prioritizing them for vaccination once COVID-19 vaccines have been approved. Results published in the FASEB Journal. DOI: 10.1096/fj.202002097

Healthcare workers infected with COVID-19 return to work faster using time- and symptom-based protocols rather than relying on resolution of fever without fever-reducing medications, improvement in respiratory symptoms, and two or more consecutive negative nasopharyngeal tests, according to a study by researchers in Boston that published in Infection Control and Hospital Epidemiology. Guidelines of the Centers for Disease Control and Prevention recommend that one strategy or the other be employed. But making the switch to the time-plus-symptom approach would have averted more than 4,000 days of lost worktime among more than 1,000 infected healthcare workers from across the Mass General Brigham health system, the researchers found. One additional potential benefit of moving away from test-based approaches, though not assessed in this study, was the psychological impact on employees of repeat testing. About 70% of participants had at least one negative test result during the study and, of those, about 62% had two negative test results in a row. A substantial number of healthcare workers diagnosed and treated for COVID-19 had repeatedly positive PCR tests. DOI: 10.1017/ice.2020.438

Radiologists should raise the possibility of COVID-19 when identifying thromboembolic abdominopelvic findings, given that infection by SARS-CoV-2 may present with medium to large arterial and venous abdominal and extremity macrothrombi, report physicians from NYU Langone Medical Center and NYU Winthrop in the American Journal of Roentgenology. The authors retrospectively compared 82 patients with COVID-19 who underwent abdominal ultrasound or CT with 82 patients without COVID-19 for thromboembolism and solid-organ infarction. Nine patients with COVID-19 had thromboembolic findings. DOI: 10.2214/AJR.20.23617

A routine test used to monitor patients' breathing—counting breaths over a 30-second period—may be unreliable and putting them at risk, suggests a study by researchers at the University of Edinburgh (U.K.) that published in ERJ Open Research. The problem with the method is that it fails to take account of people's irregular breathing patterns, they say. The practice, which is key to assessing risk in many COVID-19 cases, could be improved by increasing the time of measurement to two minutes. The team analyzed recordings of breathing in 25 hospital patients and found a large variation in the respiration rate for each patient; more than half of the measurements differed by more than three breaths per minute. In 40% of cases, the incorrect rate would have meant the warning score chart was wrong. DOI: 10.1183/23120541.00023-2020

A multisite clinical trial, led by University of South Florida (USF) Health and Tampa General Hospital (TGH), provides the first evidence that 3D-printed nasopharyngeal swabs work as well as commercial swabs for COVID-19 diagnostic testing. A multidisciplinary team from USF Health, TGH, Northwell Health and Formlabs rapidly designed, tested and produced a 3D-printed nasal swab prototype. Bench testing using respiratory syncytial virus as a proxy for SARS-CoV-2, as well as local clinical validation of the final prototype, was successfully completed in mid-March 2020. The larger-scale clinical trial began in late March at TGH, Northwell Health, and Philadelphia-based Thomas Jefferson University Hospital, with other sites joining later. Although USF Health held a provisional patent on the concept and design of the new 3D-printed swab, it has freely shared the information with hospitals, clinics, governments and international agencies experiencing supply chain shortages. Study results published in Clinical Infectious Diseases. DOI: 10.1093/cid/ciaa1366

Separately in Clinical Infectious Diseases, a research team led by a scientist at Hokkaido University (Japan) report on a quick and effective mass testing approach using saliva samples to detect individuals who have been infected with COVID-19 but are still not showing symptoms. Researchers tested and compared the nasopharyngeal swabs and saliva samples of almost 2,000 people in Japan who did not have COVID-19 symptoms. Both the PCR tests and less commonly used but faster and more portable RT-LAMP test were performed on most of the samples. The number of positive and negative results in all samples was very similar, with the nasal swabs and saliva samples able to detect those with the infection in 77%-93% and 83%-97% of subjects, respectively. Both tests were also able to identify those without the infection in greater than 99.9% of subjects. The virus loads detected in nasal swab and saliva were equivalent and highly correlated. DOI: 10.1093/cid/ciaa1388

Body position and ECG lead placement greatly affect ECG tracings and their interpretation, meaning clear annotation of unconventional lead placement should be made, according to researchers at Rush University Medical Center in a case series published in JAMA Internal Medicine. It is critically important to discern a prone ECG from a supine ECG to avoid misinterpretations that could lead to potentially costly and fruitless investigations, the authors say. Vectorcardiograms are a useful adjunctive tool that provide intuitive and visual confirmation of posterior lead placement, thereby aiding in recognition of a prone ECG., Hospitals have been implementing ECG-based monitoring protocols whenever hydroxychloroquine and chloroquine are used for treatment of patients with COVID-19, they note. DOI: 10.1001/jamainternmed.2020.3818

In a quality improvement study published in JAMA Open Network, researchers at Weill Cornell Medicine and New York-Presbyterian Hospital observed that the rate of past infection in a clinically screened asymptomatic cancer population of 537 patients was exceedingly low (approximately 4%) and the rate of SARS-CoV-2 PCR positivity was less than 1%. This contrasts with the COVID-19 prevalence of close to 20% in New York City at that time. They found that patients who tested negative for COVID-19 could receive chemotherapy without increasing the risk of contracting the disease, further bolstering the argument that clinicians may resume anticancer therapy in asymptomatic patients. DOI: 10.1001/jamanetworkopen.2020.23121

A new mobile app Genopo—developed by the Garvan Institute of Medical Research (Australia) in collaboration with the University of Peradeniya (Sri Lanka)—has made it possible to analyze the genome of the SARS-CoV-2 virus on a smartphone in less than half an hour. This makes genomics more accessible to remote or under-resourced regions, as well as the hospital bedside. Until now, genomic analysis has required the processing power of high-end server computers or cloud services. The new app could execute bioinformatics workflows on nanopore sequencing datasets that are downloaded to a smartphone and combines several “miniaturized” versions of available bioinformatics tools that work on the processing power of a consumer Android device. Researchers tested their app on different Android devices, including models from Nokia, Huawei, LG and Sony. The app is a free, open-source application available through the Google Play store and described in Communications Biology. DOI: 10.1038/s42003-020-01270-z

Using a technology called VirScan to study coronavirus antibody responses in a large cohort of SARS-CoV-2-infected and control individuals, a collaborative research effort led by Harvard Medical School has identified epitopes recognized by a large fraction of COVID-19 patients, epitopes cross-reactive with antibodies developed in response to other human coronaviruses, and 10 epitopes likely recognized by neutralizing antibodies. The data was used to design a simple, rapid diagnostic tool for rapid SARS-CoV-2 antibody detection., as described in Science.  VirScan was used to explore the antibody response to SARS-CoV-2 and other human coronaviruses in more than 200 COVID-19 patients and nearly 200 pre-COVID-19 era controls. Blood serum from COVID-19 patients exhibited much more SARS-CoV-2 reactivity compared to pre-COVID-19 era controls, though (as expected) some cross-reactivity toward SARS-CoV-2 peptides was observed in the pre-COVID-19 era samples. Only COVID-19 patients’ antibodies primarily recognized peptides derived from the spike (S) and nucleoprotein (N) of the virus. Among members of the SARS-CoV-2-infected group who had been hospitalized for their infection, antibody responses to S and N peptides were stronger and broader while antibody responses to nearly all viruses, except SARS-CoV-2, were weaker. Males also exhibited greater SARS-CoV-2 antibody responses than females. A machine learning model trained on the VirScan results accurately classified patients infected with SARS-CoV-2, guiding design of the diagnostic with 90% sensitivity and 95% specificity. DOI: 10.1126/science.abd4250

In a study that published in JAMA Open Network, members of the U.S. Army Public Health COVID-19 Task Force describe results of an independent investigation of the shore-based USS TR outbreak response and 736 USS TR sailors in isolation status between March 31 and April 15, 2020. Of these, 80.2% were characterized as symptomatic, with a median symptom duration of 7 days (19.8% remained asymptomatic for the duration of the study). Prevalence of observed symptoms among the sailors was cough, (13.6%), cold-like symptoms (9.7%), anosmia (9.3%), headache (8.8%), ageusia (7.9%), and fever (1.3%). During the study period, six of the sailors were hospitalized and one died. COVID-19 is unlikely to be clinically distinguishable from other acute respiratory illness without specific laboratory testing, researchers note. DOI: 10.1001/jamanetworkopen.2020.20981

In a letter appearing in JAMA Otolaryngology - Head & Neck Surgery, physicians at the University of Iowa Hospitals and Clinics make the first known report of an iatrogenic cerebrospinal fluid (CSF) leak in a woman in her 40s after a nasal swab for COVID-19. They believe the invasive test caused trauma to the patient’s preexisting encephalocele. Although high-quality instruction on how to properly obtain an adequate nasopharyngeal specimen for testing is available, adverse events may still occur owing to complex and delicate anatomy, they say. This case of iatrogenic CSF leak from nasal swab testing illustrates that prior surgical intervention, or pathology that distorts normal nasal anatomy, may increase the risk. Alternative methods to nasal screening in patients with known prior skull base defects, history of sinus or skull base surgery, or predisposing conditions to skull base erosion, should be considered. DOI: 10.1001/jamaoto.2020.3579

Researchers in the U.K. call for loss of smell (anosmia) to be recognized globally as a symptom of COVID-19. Four out of five people experiencing a recent loss of smell and/or taste tested positive for COVID-19 antibodies—and, of those who tested positive, 40% did not have cough or fever—they report in PLOS Medicine. Results were based on a study enrolling 590 people self-reporting a loss of taste/smell in the previous month, verified via a telemedicine consultation, 567 of whom underwent a SARS-CoV-2 antibodies test. Of those, 78% had SARS-CoV-2 antibodies, and participants with loss of smell were almost three times more likely to test positive compared to those with loss of taste. DOI: 10.1371/journal.pmed.1003358

AI can detect COVID-19 in the lungs like a virtual physician, finds a study published in Nature Communications. A University of Central Florida researcher co-developed an artificial intelligence algorithm that can accurately identify COVID-19 cases, as well as distinguish them from influenza, along with collaborators from State University of New York-Upstate Medical Center (Syracuse) and NIH's National Cancer Institute Molecular Imaging Branch and Center for Interventional Oncology. The algorithm was trained to classify COVID-19 pneumonia in lung CT scans with up to 90% accuracy and to correctly identify positive cases 84% of the time and negative cases 93% of the time. Benefits include deeper insight into COVID-19 diagnosis and progression relative to RT-PCR tests and the ability to detect COVID-19 in people without symptoms and in those who have early symptoms. Researchers trained the algorithm to recognize COVID-19 in the CT scans of 1,280 multinational patients from China, Japan, and Italy. DOI: 10.1038/s41467-020-17971-2

Researchers at King's College London have analyzed data from the COVID Symptom Study app (535 users reporting a positive test result), and 322 COVID-positive patients aged 65 or over admitted to St Thomas' Hospital in London to show delirium is a key symptom of COVID-19 in frail, older people. The older hospitalized adults classified as frail (per Clinical Frailty Scale, or CFS) were more likely to have had delirium as one of their symptoms than people of the same age who were not classed as frail. Delirium, along with tiredness and breathlessness, were also more common among frailer users (per questionnaire based on the CFS) of the COVID Symptom Study app compared with fitter people of the same age. One-third of app users experiencing delirium did not report suffering classic COVID-19 symptoms, while delirium was the only symptom for around one in five of the hospitalized patients. Findings published in Age and Ageing. DOI: 10.1093/ageing/afaa223


Industry Updates

Among many research abstracts presented at the recent ESCMID (European Society of Clinical Microbiology and Infectious Diseases) Conference (ECCVID) on Coronavirus Diseases was one suggesting that the higher risk of poor COVID-19 outcomes in men could be explained by differences in circulating proteins and immune system cells compared with women, and that immune mediators that contribute to a more severe infection are already intrinsically higher in males. Press release. Another study abstract presented at ECCVID indicated that around half of roughly 3,000 frontline responders (police, fire and healthcare workers) in the U.K. with self-reported symptoms of COVID-19 did not test positive for antibodies to the disease and therefore probably did not have the disease. Press release. A third study abstract showed that the severe COVID-19 immunological profile, represented by changes in cell populations and 28 circulating inflammatory proteins, is already partly present in older healthy individuals. That study looked at two cohorts of healthy Western European individuals, 776 in all ranging in age from 18 to 75. Press release. A fourth abstract shows emergence of SARS-CoV-2 was associated with a large drop in circulation of other common respiratory viruses during the first wave. Press release. A fifth found that a shorter time from symptom onset to hospitalization is associated with more serious disease and death in patients with COVID-19. Press release.

More than five million highly sensitive COVID-19 tests developed by researchers from the Norwegian University of Science and Technology (NTNU) have been supplied to Norwegian health authorities. Now, the Technical University of Denmark (DTU) and APS LABS (India) will benefit from the technology. DTU is doing tests for several Danish hospitals and hopes to increase the lab's capacity to do as many as 10,000 tests daily. The NTNU system can be used with DTU’s open robot system using reagents from different vendors. The NTNU test was approved for use in mid-April, after validation results showed it was at least as good as conventional tests. One key aspect of the test is a specific combination of polar solvents, buffers, salts and other chemicals that do not damage the viral RNA molecule itself. The solution contains substances that crack the virus open so that its genetic material can be extracted. NTNU has also developed iron oxide magnetic nanoparticles that strongly bind RNA. Once the magnetic nanoparticles are coated with the viral RNA, they can be removed from the solution using a magnet. PCR technology can then identify the genetic code from the RNA and compare it to the coronavirus. A newly developed manufacturing process has allowed the production of up to 1.2 million test kits per week, which will now scale to 5 million test kits weekly. Press release.

The U.S. Naval Surface Warfare Center, a federal research facility (Crane, Indiana), has developed a temperature scanning sensor system and software to help contain the coronavirus. Its sensor-agnostic thermal imaging system was recently licensed to Greene County General Hospital, allowing screening staff to detect feverish persons up to 200 yards away and potentially lessen the need to quarantine from exposure. The software runs on any laptop with USB capability, which is paired with a capture card, a commercial infrared sensor, and a “calibrated black body” reference tool that the software compares with the temperature of a person. The Navy's software-enabled system can also detect fevers in near-real-time—every 0.016 seconds—and works on individuals and moving crowds. The temp-scanning invention is being made available to the hospital via a royalty-free license agreement and a cooperative research and development agreement, with support from Radius Indiana (an economic development agency) and TechLink (the Department of Defense's national partnership intermediary for tech transfer). Press release.

Yale University has designated three independent laboratories to perform its SalivaDirectTM COVID-19 test—Access Medical Laboratories, Hennepin County Medical Center, and Mirimus, Inc.—making it available to people in Florida, Minnesota and New York by late September. The testing method, which received FDA Emergency Use Authorization on Aug. 15, is less prone to supply chain bottlenecks, more economical, and less invasive than nasal swabbing. In an initial pilot program, the National Basketball Association (NBA) and National Basketball Players Association successfully used SalivaDirectTM to test asymptomatic people within the NBA. Press release.

Leinco Technologies and ADMA Biologics, Inc. has announced the launch of COVID-19 ImmunoRank Neutralization MICRO-ELISA, designed to test up to 90 samples per test kit with 99.8% specificity. The assay procedure takes approximately 80 minutes. An Emergency Use Authorization submission is currently being prepared for review and potential approval by the FDA. Under terms of the collaboration agreement between the two companies, ADMA has the right to use, market and commercialize ImmunoRank for the screening and selection of human plasma units or plasma pools containing SARS-CoV-2 neutralizing antibodies, and for manufacturing products such as plasma proteins for therapeutic use (including producing intravenous immunoglobulins or hyperimmune globulin products, for the screening of convalescent plasma or vaccinated plasma donors, as well as combining these products with SARS-CoV-2 neutralizing monoclonal antibodies). ADMA also has the rights for commercializing ImmunoRank test kits for use by plasma donation centers to screen donors for neutralizing antibodies to SARS-CoV-2. Leinco will be responsible for manufacturing ImmunoRank and has the right to market and sell the assay for all other potential markets outside of those reserved exclusively for ADMA. Press release.


Inflammatix reports that the Defense Advanced Research Projects Agency awarded the company up to $1.1 million for further development of a rapid diagnostic that reads the immune system to predict severe respiratory failure risk in COVID-19 patients. The diagnostic is being developed to help physicians make better hospital admission and resourcing decisions for COVID-19 patients at hospital presentation. Inflammatix specializes in host-response diagnostics whereby multiple mRNA biomarkers and a machine learning algorithm rapidly reads the immune system. The approach for predicting COVID-19 severity risk was shown to be superior to clinical biomarkers, including IL-6, in a new study presented at the recent 2020 European Society of Clinical Microbiology and Infection Diseases Conference on Coronavirus Disease. Press release.

The Washington COVID-19 biorepository (Seattle) has expanded to include convalescent plasma to accelerate the development of antibody assays. To support this effort, the global health nonprofit PATH has created a growing biorepository of qualified clinical samples. Convalescent plasma samples allow manufacturers to assess the performance of several designs and prototypes under development. By running multiple replicates of these relatively accessible specimens on each prototype, diagnostics developers can generate large amounts of performance data allowing for better assessment of the technology. Once proven, developers can then use scarce serum and plasma specimens from longitudinal cohorts drawn one, two, four, eight, and 12 weeks post-diagnosis to validate final performance. Press release.

A study conducted in the Netherlands and presented at the 12th European Breast Cancer Conference suggests that the pandemic’s disruption to screening could result in an increase in the proportion of women who die of breast cancer. But the risk could be lowered by ensuring all women who would normally have been screened do not miss out, even if they are now older than the upper age limit for screening. The researchers used the modeling tool MISCAN-Breast to simulate four different strategies for re-starting breast screening following six months of disruption: delay re-start where one in four women end up getting one less screen over their lifetime; delay re-start except for women due to have their first screening; delay screening but temporarily raise the upper age limit to make sure women don't miss their final screen; and full catch-up on delayed screens over a six-month period following the disruption. The first scenario had the most damaging effect, with an estimated increase of 2.35 deaths from breast cancer for every 100,000 women in the next 10 years. Increasing capacity to achieve a full catch-up was the best-case scenario with an increase of only 0.13 deaths from breast cancer out of every 100,000 women, although this is probably not feasible for most countries' health services. Abstract.

Avacta Group (U.K.) has announced that its bead-assisted mass spectrometry (BAMS) assay to detect the SARS-CoV-2 virus has been launched as a research kit by partner Adeptrix (Beverly, Massachusetts) and presented in a new application note by mass spectrometer manufacturer Bruker Scientific (Billerica, Massachusetts). The assay uses the Affimer reagents proprietary to the Avacta Group and specific to SARS-CoV-2 to capture the virus spike protein from the sample for rapid detection by mass spectrometry, using the installed base of these instruments in hospitals. Up to 1,000 samples per day can be analyzed by a single technician using BAMS. Press release.

The National Institutes of Health has awarded nearly $234 million to improve COVID-19 testing for underserved and vulnerable populations. A part of the Rapid Acceleration of Diagnostics (RADx) initiative, the RADx Underserved Populations (RADx-UP) program will support 32 institutions across the U.S. and will focus on populations disproportionately affected by the pandemic—African Americans, American Indians/Alaskan Natives, Latinos/Latinas, Native Hawaiians, older adults, pregnant women and those who are homeless or incarcerated. The RADx-UP program has three primary components: a collaborative clinical research network of existing large-scale programs that have adequate capacity, infrastructure and relationships with underserved communities; research on the social, ethical and behavioral implications of these health disparities to inform the development and evaluation of testing programs; and a coordination and data collection center at Duke University to provide overarching support and guidance on administrative operations and logistics, facilitating effective use of COVID-19 testing technologies, supporting community and health system engagement and providing overall infrastructure for data collection, integration and sharing. Press release.

Purdue University researchers have begun a study to determine if continuously collected biometric smartwatch data could be used to reliably and accurately detect changes in a person's heart and breathing rates early, prompting a potentially asymptomatic user to get tested for COVID-19. Data from the study will inform new algorithms to be developed by physIQ (Chicago), a Purdue-affiliated digital health technology company. Initially, up to 100 Purdue students, staff and faculty will be recruited as participants to determine whether wearing a smartwatch to collect these indicators is practical, unobtrusive and user-friendly. Each participant will be sent a Samsung Galaxy smartwatch with a physIQ app loaded to collect data, FDA-cleared adhesive chest-based biosensors that collect a single-lead electrocardiogram signal, and a Samsung Galaxy smartphone to use for five days of continuous monitoring with physIQ's cloud-based accelerateIQ platform being used to analyze data from the app remotely. Data from the chest patches will be processed by PhysIQ's FDA-cleared artificial intelligence-based algorithms for deriving heart rate, respiration rate and heart rate variability. These data will serve as "gold standard" references to compare with data from the smartwatches. Press release.

A multi-institutional team of researchers led by The University of Texas Health Science Center at Houston (UTHealth) will identify COVID-19 hotspots and testing deserts in three racially diverse areas (South Texas, Houston/Harris County, and Northeast Texas), and then develop and evaluate intervention strategies to increase disease testing. Study partners include The University of Texas Rio Grande Valley and The University of Texas Health Science Center at Tyler. The study is being funded by a $5 million grant from the NIH; UTHealth is one of the 32 institutions receiving an award through the agency’s RADx-UP program. In Texas, Hispanics make up 29.4% of the population, but 40.1% of COVID-19 cases, and 47.9% of confirmed fatalities, according to the Texas Department of State Health Services. To identify priority areas, researchers will use data from regional health departments and hospital records to estimate real-time testing availability and use by residents as well as examine the incidence and test-positive rate. They hope to maximize system-level performance to increase testing by looking at the relationships among organizations providing services. Press release.

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