June 26, 2020 | Clinician-scientists have identified pink eye as a possible primary symptom of COVID-19. Meanwhile, a new pilot study is exploring the development of a low-cost, rapid, COVID-19 diagnosis system using simulant fluorescently labelled RNA. Plus more from this week’s COVID-19 news and research in the diagnostics industry.
Literature Updates
University of Alberta clinician-scientists have identified pink eye as a possible primary symptom of COVID-19, according to a case study published in the Canadian Journal of Ophthalmology. The 29-year-old woman was as interesting case because the main illness presentation was not a respiratory symptom and there was no fever or cough, so COVID-19 was not initially suspected. Academic studies at the outset of the pandemic identified conjunctivitis as a secondary symptom in about 10%-15% of cases. The finding makes eye exams more complicated for ophthalmologists and staff. Patients coming into an eye clinic with conjunctivitis and keratoconjunctivitis are now treated as potential cases of COVID-19 and extra precautions are taken by staff performing eye exams, including wearing personal protective equipment to minimize potential exposure. DOI: 10.1016/j.jcjo.2020.03.003
Researchers from the University of California Berkeley reviewed recent advances in COVID-19 testing techniques and highlighted barriers facing widespread testing in RNA. In the U.S., labs have devised innovative new approaches for testing, as well as for overcoming the bottlenecks that hampered testing efforts early in the pandemic. Some labs, like at Berkeley, have set up their own rapid testing operations to serve local communities and quickly published their methods. Complicating efforts to quash the virus is that it can be spread by people who don't even know they’re infected, and testing may spot infection only when an infected person is actively producing lots of the virus. That's why three types of testing are vital for people with any COVID-19 symptoms, those who have been in contact with an infected person and healthcare providers who may have already been infected and have antibodies to the virus. In addition to PCR, viable testing approaches include repurposing the gene editing technique CRISPR (as scientists at MIT are doing), genetic sequencing and antibody testing. Accelerating the pace of testing has been the real problem. Lack of a coordinated national response effort in the U.S. left states, companies, and university labs scrambling to fill the gap amidst supply bottlenecks. Testing capacity still falls far short of what is needed. To cast a wider net without so many individual tests, one approach is to lump together many samples in a pool so that large groups of people can be monitored with only one test. Another, potentially more powerful method is to monitor sewage since the virus can appear in feces within three days of infection, far earlier than the onset of symptoms. DOI: 10.1261/rna.076232.120
Some patients who receive hospital care for COVID-19 exhibit clinical and neurochemical signs of brain injury, a University of Gothenburg (Sweden) study published in Neurology shows. Even in moderate COVID-19 cases, finding and measuring a blood-based biomarker for brain damage proved to be possible. Blood samples from 47 patients with mild, moderate and severe COVID-19 were analyzed and compared with those from a healthy control group comprising 33 people matched by age and sex. The glial fibrillary acidic protein marker was elevated in patients with moderate disease. Elevated levels of neurofilament light chain protein were seen in those who required ventilator treatment and the increase over time was greater than previously seen in studies connected with intensive care. This suggests that COVID-19 can directly bring about a brain injury. The authors say blood tests for biomarkers associated with brain injury could be used for monitoring patients with moderate to severe COVID-19. DOI: 10.1212/WNL.0000000000010111
COVID-19 patients with extremely high levels of the stress hormone cortisol in their blood are more likely to deteriorate quickly and die, according to a 535-patient observational study published by a team of London researchers in The Lancet Diabetes & Endocrinology. This suggest cortisol levels can be used to identify patients who are more likely to need intensive care. Cortisol levels for patients in the COVID-19 group ranged as high as 3241—higher than after major surgery. Those with a baseline cortisol level of 744 or less survived on average for 36 days and those with levels over 744 had an average survival of just 15 days. Over the March 9 – April 22, 2020 study period, just under 27% of the COVID-19 group died compared to just under 7% of the non-COVID-19 group. DOI: 10.1016/S2213-8587(20)30216-3
Chest CT can distinguish negative from positive lab results for COVID-19 pneumonia, according to a study that published in the American Journal of Roentgenology. Researchers in China found that the less pulmonary consolidation on chest CT, the greater the possibility of negative initial RT-PCR results. Participants were 21 patients with confirmed COVID-19 pneumonia who underwent chest CT and swab RT-PCR tests within 3 days of admission. Most of the COVID-19 lesions were in multiple lobes (67%) in both lungs (72%). Most frequently observed were ground-glass opacities (95%) and consolidation (72%) with subpleural distribution (100%). Patients otherwise had lesions around the bronchovascular bundle. Additional chest CT findings included air bronchogram (57%), vascular enlargement (67%), interlobular septal thickening (62%), and pleural effusions (19%). Compared with the positive initial RT-PCR results group, CT of the group with negative initial RT-PCR results was less likely to indicate pulmonary consolidation (p < 0.05). DOI: 10.2214/AJR.20.23012
Researchers from New York City’s Renal Research Institute and Icahn School of Medicine at Mount Sinai examined the feasibility of using pool testing to identify patients with COVID-19 in a setting with limited testing availability and, using a decision analytical model, determined that its efficiency varies with prevalence, test sensitivity and patient pool size. The strategy builds on testing a pooled sample from several patients; if the results from the pool test are negative, all patients in the pooled sample are declared not to have COVID-19 and, if the results of the pool are positive, each patient sample is tested individually. Conclusion: pool testing may be considered as an alternative, especially in circumstances of limited SARS-CoV-2 test availability and a COVID-19 prevalence of less than 30%. The study published in JAMA Network Open. DOI: 10.1001/jamanetworkopen.2020.13075
In a letter published in JAMA Dermatology, researchers from Geneva University Hospitals (Switzerland) describe a male COVID-19 patient in his 60s with a papulovesicular eruption 12 hours after piperacillin-tazobactam and lopinavir-ritonavir treatment were initiated. The papules were asymptomatic and within 48 hours evolved to an extensive, but not confluent, purpuric rash. The clinical differential diagnosis was a severe acute respiratory syndrome coronavirus-2–associated eruption, Grover disease, herpes simplex virus infection, or a drug reaction. Clinicopathologic correlation suggested a viral-induced skin eruption associated with COVID-19. DOI: 10.1001/jamadermatol.2020.1966
Two papers published in the Journal of Clinical Microbiology address reverse transcriptase PCR (rt-PCR) tests for current infection and antibody tests that reveal if an infection has taken place. Researchers at Columbia University Irving Medical Center say that when patients test negative for the presence of COVID-19 RNA, despite either a "high clinical suspicion" of infection or a likelihood that the patient has been exposed, a repeat test is indicated. A total of 27,377 tests were performed on 22,338 patients and repeated for 3,432 of them. Among 2,413 who had tested negative the first time, 802 tested positive. Among the repeats in people who had tested positive, investigators found that conversion to a negative result was unlikely to occur before 15 to 20 days following initial testing, or before 20 to 30 days post-onset of symptoms. DOI: 10.1128/JCM.00995-20
In the second paper, researchers at the Mayo Clinic found that two antibody tests (from Abbott Laboratories and Ortho-Clinical Diagnostics) that excelled in sensitivity also proved 99% accurate for specificity. A third test, from Euroimmun (Germany), excelled for sensitivity but not for specificity. DOI: 10.1128/JCM.01243-20
A surge in flu-like infections in the U.S. in March of 2020 suggests that the likely number of COVID-19 cases was far larger than official estimates, according to a study of existing surveillance networks for influenza-like infections. The findings, published in Science Translational Medicine, support a scenario where more than 8.7 million new SARS-CoV-2 infections appeared in the U.S. during March, and estimate that more than 80% of these cases remained unidentified as the outbreak rapidly spread. Furthermore, the results suggest that surveillance networks for influenza-like disease offer an important tool to estimate the prevalence of COVID-19. DOI: 10.1126/scitranslmed.abc1126
Researchers at São Paulo State University (Brazil) have developed a computational tool that acts like a "COVID-19 accelerometer," plotting in real time the rate at which growth is accelerating or decelerating in more than 200 countries and territories. Available free of charge online, the application automatically loads the most recent notified case numbers from the European Center for Disease Prevention and Control, updated daily, and applies mathematical modeling techniques to diagnose the current stage of the pandemic in each country. An article published in Frontiers in Medicine shows how the mathematical modeling framework can be used to assess the effects of public health measures. Japan is one of the only countries that has managed to decelerate the growth of new cases with mitigation measures alone. DOI: 10.3389/fmed.2020.00247
In a letter to The BMJ, a group of senior clinical academics and physicians express their concern about the rapid rollout of COVID-19 antibody testing in England, questioning both how good the tests are and what they mean. They argue that there is currently no valid clinical reason for large-scale testing, test performance has not yet been adequately assessed, and testing risks inefficient use of scarce resources. UK Prime Minister Boris Johnson described antibody testing as "game-changing" and last month the government purchased 10 million test kits from Abbott and Roche after Public Health England (PHE) studies showed they worked. But the authors point to several problems with PHE's evaluation of those tests, including quality of samples, the absence of data on age and sex, and use of repeat samples. DOI: 10.1136/bmj.m2420
More than 300 scientists and clinicians from the federal government, industry and academia who convened for a workshop in May published a report of their conclusions and recommendations on COVID-19 serology studies online in Immunity. Attendees recommended additional research to determine if and to what extent a positive antibody test means a person may be protected from reinfection with SARS-CoV-2. Attendees emphasized that until such data is available, serology tests should not be used as a standalone tool to make decisions about personal safety related to SARS-CoV-2 exposure. Researchers are now pursuing studies in humans and in animal models to better understand SARS-CoV-2 immunity, which could help identify optimal donors of convalescent plasma that potentially could be used to help treat those with severe COVID-19. DOI: 10.1016/j.immuni.2020.06.012
In an editorial published in the American Journal of Perinatology, the researchers from UC Davis Health highlighted the importance of understanding the timing and the route of SARS-CoV-2 infection in maternal-fetal transmission. They describe the three potential mechanisms of vertical transmissions of coronavirus—intrauterine, intrapartum and transient viremia—and recommend as a minimum procedure a swab of the respiratory tract of the newborn in the first and second 24-hour periods in cases of the mother's confirmed infection with SARS-CoV-2. If the initial swab tests negative, it may be repeated if the baby shows symptoms. There may also be a role for antibody testing in selected patients to diagnose past infection. DOI: 10.1055/s-0040-1712457
A study of SARS-CoV-2 testing results across five Johns Hopkins Health System hospitals (emergency departments and outpatient clinics), which published in JAMA, highlights coronavirus racial disparities in the Baltimore-Washington area. Among nearly 38,000 people tested, the positivity rate among Latinx populations (42.6%) was about three times higher than for any other racial and ethnic group. About half of those Latinx who tested positive were women and half were men, and most (61.5%) were between the ages of 18 and 44. They were notably less likely to be admitted to the hospital (29.1%) compared with black (41.7%) and white (40.1%) patients. The researchers concluded that crowded living conditions and continuous working at jobs due to economic necessity and essential worker status contributed to the higher rate of positive tests in the Latinx community. The study also found the number of positive cases in each group peaked at different times. Results of diagnostic tests performed between March 11 and May 25 were analyzed. Researchers say their data are already informing practices and planning across the Johns Hopkins Health System. DOI: 10.1001/jama.2020.11374
One-third of U.K. pediatricians report seeing emergency “delayed presentations” during the COVID-19 pandemic lockdown, based on results of a snapshot survey published online in Archives of Disease in Childhood. Children with diabetes were most often involved, but with life-threatening sepsis and cancer also featured prominently. The survey, conducted by British Paediatric Surveillance Unit in late April, was completed by 2,433 senior pediatricians working in the U.K. and Ireland. DOI: 10.1136/archdischild-2020-319848
The unusual purplish red lesions seen on the feet and/or hands of some COVID-19 patients—mimicking the dermatological condition called chilblains—appear not to be directly associated with COVID-19, based on a 31-patient case series that Belgium researchers published in JAMA Dermatology. Lifestyle changes associated with community containment and lockdown measures are a possible explanation for these lesions. Participants were generally in good health; most were teenagers or young adults, and 19 were women. DOI: 10.1001/jamadermatol.2020.2368
Researchers in Spain separately report in JAMA Dermatology that newly described acute acral lesions appear not to be a sign of COVID-19 in adolescents and children, as some had suspected. The clinical, histologic, and laboratory test results on the 20 enrolled patients were compatible with a diagnosis of perniosis, and no evidence was found that would implicate SARS-CoV-2 infection. DOI: 10.1001/jamadermatol.2020.2340
A team of Belgium and U.K. researchers have confirmed that persistent cough (57%) and fever (78%) are the most prevalent symptoms associated with COVID-19 in a review of the scientific literature that published in PLOS ONE. Other major symptoms include fatigue (31%), losing the ability to smell (25%) and difficulty in breathing (23%). The study ratifies the list of symptoms listed by the World Health Organization at the start of the pandemic. Researchers combined data from 148 separate studies to identify the common symptoms experienced by more than 24,000 patients from nine countries, including the U.K., China and the U.S. DOI: 10.1371/journal.pone.0234765
The pandemic could significantly increase the global burden of tuberculosis (TB) due to disruptions to health services, and delays to diagnosis and treatment, according to new estimates published in the European Respiratory Journal. The most probable scenario, based on current information and distancing measures, suggests 6,000 additional deaths could occur in China, 95,000 in India and 13,000 in South Africa, say U.K. researchers from the London School of Hygiene & Tropical Medicine and Lancaster University. However, if social distancing measures are minimal and there is substantial healthcare disruption, their model predicts an 8% to 14% increase in cumulative deaths from TB over the next five years. DOI: 10.1183/13993003.01718-2020
Updates from Industry
German diagnostics company SphingoTec GmbH announced that clinical experts from medical centers across Europe have agreed that novel biomarkers are required for triaging and monitoring of severe COVID-19 patients to optimally make use of the available medical resources and improve outcomes. The focus of discussions was the company’s organ-specific biomarkers for monitoring the endothelial function (bioactive adrenomedullin, or bio-ADM), kidney function (proenkephalin, or penKid) and hemodynamic instability and cardiac depressant factor (DPP3), which are currently being investigated on-site in COVID-19 patients in hospitals in Germany, Switzerland, United Kingdom, France and Italy, as well as in the U.S. and Asia. Previously gathered evidence confirmed the central role of bio-ADM endothelial function in sepsis patients. First feedback on the biomarker bio-ADM in severe COVID-19 describes a strong correlation with disease severity and the need for organ support, which can assist in a more accurate and objective risk stratification. An emerging body of evidence shows that endothelial function plays a central role in severe COVID-19 patients, and previous studies demonstrate that high bio-ADM levels independent of inflammation and comorbidities indicate distortions in the endothelial barrier function—a key driver in the development of hypotension and subsequent septic shock with loss of organ perfusion in sepsis patients. PenKid has demonstrated accuracy as a surrogate marker for true glomerular filtration rate in patients with renal impairment, without being biased by comorbidities. Studies have also shown that high blood levels of DPP3 strongly predict poor outcome in patients with cardiogenic shock. The novel biomarker tests complement a wide range of assays for acute care settings that are already available on sphingotec's widely used Nexus IB10 point-of-care platform. Press release.
The Department of Energy's Oak Ridge National Laboratory (ORNL) has launched a COVID-19 Rapid Access Licensing Program allowing companies to license select technologies at no cost for one year. In collaboration with researchers, ORNL's Technology Transfer Office is creating a growing portfolio of inventions available to license through the program. The licenses are nonexclusive and interested licensees must demonstrate intent to use ORNL's innovations to address COVID-19 and commit to disseminating resulting products as widely and quickly as possible. Only U.S. entities, companies and universities are eligible. Alternative licenses will be available for companies creating products that require exclusivity to support large development investments, such as for diagnostic platforms, drug delivery systems, therapies and vaccines. Press release.
The Innovative Genomics Institute (IGI) at UC Berkeley transformed into a COVID-19 testing lab in three weeks. To quickly scale up their systems to process over 1,000 patient tests daily, IGI used Salesforce to help manage inbound requests and outbound test results. This answered the need for a solution that was easy for doctors to use, could be immediately deployed, and ensured patient data was kept secure. In one day, IGI built a HIPAA-compliant Healthcare Provider Portal. Third Wave Analytics and Salesforce did most of the heavy lifting to get the platform launched. Press release.
A pilot study being led by academics at the University of Bristol (UK) will explore the development of a low-cost, rapid, COVID-19 diagnosis system using simulant fluorescently labelled RNA. Research here has previously shown that very small antennas (nanoantennas) can enhance the amount of light given out by fluorophores, which can dramatically improve the sensitivity of biosensors. The research project involves collaboration with the University of Cardiff, which is developing DNA and RNA extraction techniques for pathogen detection. Press release.
Integrated Genetics Lab Services (iGLS) has been selected by Spanish health authorities to expand SARS-CoV-2 screening in the Spanish population. iGLS is utilizing Fluidigm microfluidics technology and reagents in its COVID-19 testing workflow designed to be run on the Fluidigm Biomark HD system. A grant from the local Valencian government is supporting the testing program, which began in early June. The announcement was made by the Fluidigm Corporation, whose Biomark HD system can support up to 6,000 tests per day and more than two million annual tests. Press release.
ARCpoint Labs has announced it is partnering with Ethos Laboratories to bring a new test to market that measures protective immunity to COVID-19. Tru-Immune is the first surrogate viral neutralization test to evaluate COVID-19 protective immunity in the United States and, unlike other tests, detects the presence and magnitude of neutralizing antibodies against the SARS-CoV-2 virus that could prevent future infection. ARCpoint Labs is the first national network of collection sites for the rollout. According to an article recently published by Johns Hopkins University, neutralization assays are the gold standard for determining if a patient has effective antibodies and protective immunity against SARS-CoV-2. Tru-Immune does not require the use of live virus, cell culture or even pseudovirus, and samples can be processed in less than three hours versus three to five days for viral neutralization tests. It has been approved by the FDA for Emergency Use Authorization. Press release.
Cognizant and Verily Life Sciences are teaming up to facilitate COVID-19 testing across the United States. Verily’s Baseline COVID-19 Testing Program, which launched earlier this year, is a connected solution that supports individuals through screening, testing, and receiving results safely and quickly. It is in operation at more than 140 testing sites across 13 states and has supported the administration of more than 284,000 COVID-19 tests. Plans are also in place to continue to expand testing locations nationally. Cognizant is providing a team of its life sciences experts to help scale those efforts. Press release.
Scientists from the Vienna BioCenter (Austria) have led development of a cheap, simple and quick COVID-19 test by improving a 20-year-old nucleic acid detection assay called loop-mediated isothermal amplification (RT-LAMP). Starting with a five-minute lysis step that "breaks open" cells and virus particles, RT-LAMP employs a simple reaction in which the viral RNA is converted into DNA and amplified billionfold within less than 30 minutes and directly observable by the naked eye. This method, when combined with a simple RNA enrichment step, constitutes the newly developed method that boosts sensitivity by orders of magnitude. The most challenging step is to keep the sample at a stable temperature of approximately 63°C during the 30 minutes of the reaction, a task that (if necessary) could be fulfilled by repurposed kitchen devices. The study underlying this news item will be uploaded to the preprint service bioRxiv, where it is expected to become available soon. Press release.
PPD, Inc. has expanded its laboratory test portfolio by adding five new molecular, serology and functional assays designed expressly for COVID-19 vaccine and therapy development programs. The new additions include two molecular assays (qualitative and quantitative) that utilize reverse transcriptase, polymerase chain reaction and target spike proteins that are specific to SARS-CoV-2 and nucleocapsid proteins that are more general to the coronavirus family, for disease detection. Two enzyme-linked immunosorbent assays have also been developed specifically for vaccine trials that detect immunoglobulin G to full-length recombinant protein, one for spike and the other for nucleocapsid. The fifth test is a plate-based functional assay to detect anti-spike antibodies in human serum that can prevent infection by disrupting the binding of angiotensin converting enzyme 2 to SARS-CoV-2 spike protein. The PPD Laboratories central lab also is validating molecular and serology in vitro diagnostic assays that are released for commercial use by regulatory agencies to support clinical trials. Press release.