Might clinical laboratories soon be called on to conduct mass testing to find people who show little or no symptoms even though they are infected with the coronavirus?
Clinical laboratory managers understand that as demand for COVID-19 testing exceeds supplies, what testing is done is generally performed on symptomatic patients. And yet, it is the asymptomatic individuals—those who are shown to be infected with the SARS-CoV-2 coronavirus, but who experience no symptoms of the illness—who may hold the key to creating effective treatments and vaccinations.
So, as the COVID-19 pandemic persists, scientists are asking why some people who are infected remain asymptomatic, while others die. Why do some patients get severely ill and others do not? Researchers at the University of California San Francisco (UCSF) and Stanford University School of Medicine (Stanford Medicine) are attempting to answer these questions as they investigate viral transmission, masking, immunity, and more.
And pressure is increasing on researchers to find the answer. According to Monica Gandhi, MD, MPH, an infectious disease specialist and Professor of Medicine at UCSF, millions of people may be asymptomatic and unknowingly spreading the virus. Gandhi is also Associate Division Chief (Clinical Operations/Education) of the Division of HIV, Infectious Diseases, and Global Medicine at UCSF’s Zuckerberg San Francisco General Hospital and Trauma Center.
“If we did a mass testing campaign on 300 million Americans right now, I think the rate of asymptomatic infection would be somewhere between 50% and 80% of cases,” she told UCSF Magazine.
On a smaller scale, her statement was borne out. In a study conducted in San Francisco’s Mission District during the first six weeks of the city’s shelter-in-place order, UCSF researchers conducted SARS-CoV-2 reverse transcription-PCR and antibody (Abbott ARCHITECT IgG) testing on 3,000 people. Approximately 53% tested positive for COVID-19 but had no symptoms such as fever, cough, and muscle aches, according to data reported by Carina Marquez, MD, UCSF Assistant Professor of Medicine and co-author of the study, in The Mercury News.
Pandemic Control’s Biggest Challenge: Asymptomatic People
In an editorial in the New England Journal of Medicine (NEJM), Gandhi wrote that transmission of the virus by asymptomatic people is the “Achilles heel of COVID-19 pandemic control.”
In her article, Gandhi compared SARS-CoV-2, the coronavirus that causes COVID-19, to SARS-CoV-1, the coronavirus that caused the 2003 SARS epidemic. One difference lies in how the virus sheds. In the case of SARS-CoV-2, that takes place in the upper respiratory tract, but with SARS-CoV-1, it takes place in the lower tract. In the latter, symptoms are more likely to be detected, Gandhi explained. Thus, asymptomatic carriers of the coronavirus may go undetected.
“Viral loads with SARS-CoV-1, which are associated with symptom onset, peak a median of five days later than viral loads with SARS-CoV-2, which makes symptom-based detection of infection more effective in the case of SARS-CoV-1,” Gandhi wrote. “With influenza, persons with asymptomatic disease generally have lower quantitative viral loads in secretions from the upper respiratory tract than from the lower respiratory tract and a shorter duration of viral shedding than persons with symptoms, which decreases the risk of transmission from paucisymptomatic persons.”
Rick Wright (above), an insurance broker in Redwood City, Calif., was infected with the COVID-19 coronavirus while aboard a Diamond Princess Cruise. He underwent 40 days of isolation, and though he consistently tested positive for the coronavirus, he experienced no symptoms of the illness. “I never felt sick. Not a cough, wheezing, headache. Absolutely nothing,” he told Mercury News. (Photo copyright: The Mercury News.)
Stanford Studies Immune Responses in COVID-19 Patients
Meanwhile, scientists at the Stanford University School of Medicine were on their own quest to find out why COVID-19 causes severe disease in some people and mild symptoms in others.
“One of the great mysteries of COVID-19 infections has been that some people develop severe disease, while others seem to recover quickly. Now, we have some insight into why that happens,” Bali Pulendran, PhD, Stanford Professor of Pathology, Microbiology, and Immunology and Senior Author of the study in a Stanford Medicine news release.
The Stanford research suggested that three molecules—EN-RAGE, TNFSF14, and oncostatin-M—“correlated with disease and increased bacterial products in human plasma” of COVID-19 patients.
“Our multiplex analysis of plasma cytokines revealed enhanced levels of several proinflammatory cytokines and a strong association of the inflammatory mediators EN-RAGE, TNFSF14, and OSM with clinical severity of the disease,” the scientists wrote in Science.
Pulendran hypothesized that the molecules originated in patients’ lungs, which was the infection site.
“These findings reveal how the immune system goes awry during coronavirus infections, leading to severe disease and point to potential therapeutic targets,” Pulendran said in the news release, adding, “These three molecules and their receptors could represent attractive therapeutic targets in combating COVID-19.”
Clinical Laboratories May Do More Testing of Asymptomatic People
The research continues. In a televised news conference, President Trump said COVID-19 testing plays an important role in “preventing transmission of the virus.” Clearly this is true and learning why some people who are infected experience little or no symptoms may be key to defeating COVID-19.
Thus, as the nation reopens, clinical laboratories may want to find ways to offer COVID-19 testing beyond hospitalized symptomatic patients and people who show up at independent labs with doctors’ orders. As supplies permit, laboratory managers may want to partner with providers in their communities to identify people who are asymptomatic and appear to be well, but who may be transmitting the coronavirus.
It can take up to eight days after onset of symptoms for a person’s immune system to develop antibodies, so serological tests are not designed for diagnosing recent or active infections, stated a Mayo Clinic news story. However, Reuters reported that the availability of serological tests is “a potential game changer” because they could identify people who are immune even if they had no symptoms or only mild symptoms.
“Ultimately, this might help us figure out who can get the country back to normal,” Florian Krammer, PhD, told Reuters. Krammer’s lab at the Icahn School of Medicine at Mount Sinai in New York City has developed a serological test. “People who are immune could be the first people to go back to normal life and start everything up again,” he said.
However, some experts advise that the presence of antibodies is not necessarily a “get out of jail free” card when it comes to the coronavirus. “Infectious disease experts say immunity against COVID-19 may last for several months and perhaps a year or more based on their studies of other coronaviruses, including Severe Acute Respiratory Syndrome (SARS), which emerged in 2003,” reported Reuters. “But [the experts] caution that there is no way to know precisely how long immunity would last with COVID-19, and it may vary person to person.”
Additionally, it is also “uncertain whether antibodies would be sufficient protection if a person were to be re-exposed to the virus in very large amounts,” such as in an emergency room or ICU, Reuters reported.
Serological Survey Studies Get Underway Worldwide
Aside from detecting potential immunity, the World Health Organization (WHO) says serological tests could be useful for widespread disease surveillance and epidemiological research.
In the US, the Vitalant
Research Institute is leading several large serological survey or
“serosurvey” studies in which regional blood centers save samples of donated
blood for antibody testing, Science
reported.
Science also reported on a similar WHO initiative in which six countries will pool data from their own antibody studies. And in the Netherlands, blood banks have begun screening thousands of blood donations for presence of antibodies, Wired reported.
FDA Emergency Use Authorization
On March 16, the federal Food and Drug Administration (FDA) announced that it would allow commercial development and distribution of serological tests that “identify antibodies (e.g., IgM, IgG) to SARS-CoV-2 from clinical specimens” without an Emergency Use Authorization (EUA). The agency noted that these tests are “less complex than molecular tests” used to detect active infections, and that the policy change is limited to such testing in medical laboratories or by healthcare workers at the point-of-care. “This policy does not apply to at home testing,” the FDA reiterated.
“Serological tests can play a critical role in the fight against COVID-19 by helping healthcare professionals to identify individuals who have overcome an infection in the past and have developed an immune response,” said FDA Commissioner Stephen M. Hahn, MD (above with President Trump during a Coronavirus Task Force press briefing), in an April 7 press statement. “In the future, this may potentially be used to help determine—together with other clinical data—that such individuals are no longer susceptible to infection and can return to work. In addition, these test results can aid in determining who may donate a part of their blood called convalescent plasma, which may serve as a possible treatment for those who are seriously ill from COVID-19.” (Photo copyright: CNBC.)
FDA Issues First EUA for Rapid Diagnostic Test
Cellex Inc., based in Research Triangle Park, N.C., received the first EUA for its qSARS-CoV-2 serological test on April 1. As with other rapid diagnostic tests (RDTs) under development, the qSARS-CoV-2 test detects the presence of immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies in human blood. The biotechnology company’s RDT can be used to test serum, plasma, or whole-blood specimens, stated Cellex, and can produce results in 15 to 20 minutes.
The FDA has authorized use of the antibody test only by laboratories certified under CLIA to perform moderate and high complexity tests. Cellex has set up a COVID-19 website with information about the qSARS-CoV-2 test for clinical laboratories, patients, and healthcare providers.
Other Serological Tests Under Development
Mayo
Clinic Laboratories announced on April 13 that it is ramping up
availability of an internally-developed serological test. “Initial capacity
will be 8,000 tests per day performed at laboratory locations across Mayo Clinic,” stated the announcement.
“Testing will be performed 24 hours a day, and Mayo Clinic Laboratories is working
to ensure turnaround time is as close as possible to 24 hours after receipt of
the sample.”
Emory University in Atlanta announced on April 13 that it will begin deploying its own internally developed antibody test. Initially, testing will be limited to 300 people per day, comprised of Emory Healthcare patients, providers, and staff members. Eventually, testing will be “expanded significantly,” said Emory, with a goal of 5,000 tests per day by mid-June.
RDTs are typically qualitative, meaning they produce a
positive or negative result, stated the Center for Health Security. An ELISA
test “can be qualitative or quantitative,” noted the Center, but it can take
one to five hours to produce results.
A third type of serological test—the neutralization assay—involves infecting a patient’s blood with live coronavirus to determine if antibodies exist that can inhibit growth of the virus. The test takes three to five days in a level 3 biosafety laboratory to produce results. The Straits Times reported on one laboratory in Singapore that developed a neutralization assay to trace the source of COVID-19 infections that originated in Wuhan, China.
Serological testing is another important tool clinical
laboratories and epidemiologists can use to fight and ultimately defeat the
COVID-19 pandemic and is worth watching.
Example is a big data-based study involving Optum and Mayo Clinic that indicates diabetes management can be too aggressive for some patients
Mayo Clinic has tapped Optum Labs’ huge data set to fuel research suggesting diabetes management can be too aggressive among those diabetics who don’t have problems controlling their glucose level. Optum Labs’ data is also being mined to investigate dozens of research initiatives, including a major fight against Alzheimer’s disease. These projects provide a glimpse into the growing role of big data in healthcare.
Because more than 70% of a typical patient’s permanent medical record consists of clinical laboratory test data, pathologists and medical laboratory scientists have a stake in the growth of big-data analytics, which are a core component in healthcare’s journey toward personalized medicine. (more…)
