News, Analysis, Trends, Management Innovations for
Clinical Laboratories and Pathology Groups

Hosted by Robert Michel

News, Analysis, Trends, Management Innovations for
Clinical Laboratories and Pathology Groups

Hosted by Robert Michel
Sign In

Pooled Testing may Provide a Method of Increasing the Number of Coronavirus Tests Being Performed in the US

Pooled testing could become a critical tool for clinical laboratories to spot the SARS-CoV-2 coronavirus among asymptomatic and pre-symptomatic individuals

COVID-19 testing for individuals has expanded in the US, but the number of people actually tested remains a small proportion of the country’s total population and clinical laboratory testing supply shortages continue to hamper progress. A technique known as pooled testing may help. Federal experts hope it will substantially increase the number of individuals who are tested for the SARS-CoV-2 coronavirus before it makes a possible resurgence in the fall.

One-by-one, some of the nation’s largest clinical laboratory organizations are developing the capability to do pooled testing. For example, on July 18, the Food and Drug Administration (FDA) announced it had issued Quest Diagnostics (NYSE:DGX) an Emergency Use Authorization (EUA) for its SARS-CoV-2 rRT-PCR test, and that it is valid for up to four individual samples as a pooled test.

Quest’s rRT-PCR test was the first COVID-19 diagnostic test to be authorized for use with pooled samples, the FDA noted in a new release.

Stephen M. Hahn, MD, FDA Commissioner
In the FDA’s statement announcing Quest’s EUA for its rRT-PCR test, Stephen M. Hahn, MD (above), FDA Commissioner, said, “This EUA for sample pooling is an important step forward in getting more COVID-19 tests to more Americans more quickly while preserving testing supplies.” He added, “Sample pooling becomes especially important as infection rates decline and we begin testing larger portions of the population.” (Photo copyright: CBS News.)

Following the announcement of Quest’s EUA, on July 24 the FDA announced LabCorp’s (NYSE:LH) EUA for its COVID-19 real-time reverse transcription polymerase chain reaction (rRT-PCR) test. The test, the EUA states, is intended for the “qualitative detection of nucleic acid from SARS-CoV-2 in upper and lower respiratory specimens” in individuals suspected of COVID-19, using “a matrix pooling strategy (i.e., group pooling strategy), containing up to five individual upper respiratory swab specimens (nasopharyngeal, mid-turbinate, anterior nares or oropharyngeal swabs) per pool and 25 specimens per matrix.”

Exponentially Increasing Testing

In pooled testing, instead of performing a coronavirus test on every specimen received by a clinical laboratory, samples from each individual specimen are taken and then combined with samples from other specimens. A single test is then performed on the entire collection of specimen samples.

If the results of the pooled samples are negative for coronavirus, it is safe to assume that all the specimens in the batch are negative for the virus. If the pooled sample comes back positive, then it will be necessary to go back to the original specimens in that pooled sample and test each specimen individually.

In an exclusive interview with Dark Daily’s sister print publication The Dark Report, Steven H. Hinrichs, MD, Chair of the Department of Pathology and Microbiology at the University of Nebraska Medical Center (UNMC), noted that one pitfall of pooled testing is that it works best in areas of low virus prevalence.

“For pooled testing, the ideal level of low prevalence would be an infection rate below 10%,” he said, adding, “For COVID-19 test manufacturers, pooled testing has the potential to reduce the number of standard tests labs run by roughly 40% to 60%, depending on the population being tested.

“Cutting the number of COVID-19 tests would be a disadvantage for test manufacturers, because pooled tests would identify large numbers of uninfected individuals who would not require standard testing with EUA tests.

“On the other hand, this policy would be a significant advantage for US labs because pooled testing would cut the number of standard tests,” he continued. “Clinical labs would save money on tests, reagents, and other supplies. It would also ease the burden on the lab’s technical staff,” Hinrichs concluded.

 In research published in the American Journal of Clinical Pathology (AJCP) titled, “Assessment of Specimen Pooling to Conserve SARS-CoV-2 Testing Resources,” Hinrichs and fellow researchers from UNMC and the University of Nebraska-Lincoln noted that “five is the ideal number to batch in a COVID-19 testing pool.”

“In our study, we show that it’s reasonable to pool five samples, although we realized that some people may want to pool 10 samples at once,” noted Hinrichs. “But even if one sample is positive in a pool of five, then testing five samples at once saves 80% of our costs if all of those samples are negative. But, if one sample is positive, each of those five samples needs to be retested using the standard test,” Hinrichs explained.

During an American Society for Microbiology (ASM) virtual conference, Deborah Birx, MD, White House Coronavirus Response Coordinator, said, “Pooling would give us the capacity to go from a half a million tests per day to potentially five million individuals tested per day,” STAT reported.

Advantages of using pooled testing for the coronavirus include:

  • Expanding the number of individuals tested,
  • Stretching laboratory supplies, and
  • Reducing the costs associated with testing.

Health officials believe that individuals who have COVID-19 and are asymptomatic are largely responsible for the rising number of coronavirus cases in the US, STAT reported.

“It allows you to test more frequently in a population that may have a low prevalence of disease,” Benjamin Pinsky, MD, PhD, Associate Professor, Departments of Pathology and Medicine at Stanford University School of Medicine, told STAT. “That would allow you to test a lot of negatives, but also identify individuals who are then infected, before they develop symptoms.”

Pooled testing also could be advantageous for communities where COVID-19 is not prevalent, in neighborhoods that need to be tested during an outbreak, and for schools, universities, organizations, and businesses that want to remain safely open while periodically monitoring individuals for the virus, CNN reported.

“The goal is to increase the capacity of testing in a relatively straightforward fashion,” Pinsky told STAT. “The caveat is that by pooling the sample, you’re going to reduce the sensitivity of the test.”

According to Pinsky, “pooling only makes sense in places with low rates of COVID-19, where you expect the large majority of tests to be negative. Otherwise, too many of the pools would come back positive for it to work as a useful surveillance tool,” STAT reported.

As Clinical Lab Testing Increases, Pooled Testing for COVID-19 Could Be Critical

Pooled testing has been used in other countries, including China, to test larger amounts of people for COVID-19.

“If you look around the globe, the way people are doing a million tests or 10 million tests is they’re doing pooling,” Birx said during the ASM virtual conference, CNN reported.

In a press release, the American Clinical Laboratory Association (ACLA) stated that about 300,000 tests for COVID-19 were performed per day in labs across the US in late June. That number was up from approximately 100,000 tests being performed daily in early April.

“All across the country, clinical laboratories are increasing the number of labs processing tests, purchasing additional testing platforms, and expanding the number of suppliers to provide critical testing materials,” said Julie Khani, ACLA President in the press release. “However, the reality of this ongoing global pandemic is that testing supplies are limited. Every country across the globe is in need of essential testing supplies, like pipettes and reagents, and that demand is likely to increase in the coming months.”

Clinical laboratory managers will want to keep an eye on these developments. As the need for COVID-19 testing increases, pooled testing may provide an efficient, cost-effective way to spot the coronavirus, especially among those who are asymptomatic or pre-symptomatic and who display no symptoms.

Pooled testing could become a critical tool in the diagnosis of COVID-19 and potentially decrease the overall number of deaths. 

—JP Schlingman

Related Information:

Labs Warn COVID-19 Testing Demand will Top Capacity Soon as New Hotspots Emerge

Safer Reopening will Require Millions More Covid-19 Tests Per Day. One Solution: ‘Pool Testing’

Pooling Coronavirus Tests Can Spare Scarce Supplies, But There’s a Catch

Here’s What Pooled Testing is and How It Can be Used for the Coronavirus

Coronavirus (COVID-19) Update: FDA Issues First Emergency Authorization for Sample Pooling in Diagnostic Testing

ACLA Update on COVID-19 Testing Capacity

LabCorp Receives Authorization for COVID-19 Sample Pooling

Is COVID-19 Pooled Testing Good for Labs, Bad for IVDs?

FDA’s Regulatory Hurdles ‘Paralyzed’ Efforts of CLIA-Certified Clinical Laboratories to Offer Alternatives to CDC’s Flawed COVID-19 Test, Part Two of Two

Washington Post investigation outlines scientists’ frustrations in the early days of the pandemic, as they worked to deploy laboratory-developed tests for the novel coronavirus

In the wake of the failed rollout of the Centers for Disease Control and Prevention’s (CDC) COVID-19 diagnostic test last February, many CLIA-certified academic and public health laboratories were ready, and had the necessary resources, to develop their own coronavirus molecular diagnostic tests to help meet the nationwide demand for clinical laboratory testing. However, the response from the US Food and Drug Administration (FDA) was, in essence, “not so fast.”

In this second part of Dark Daily’s two-part e-briefing, we continue our coverage of the Washington Post (WP) investigation that detailed the regulatory hurdles which blocked private laboratories from deploying their own laboratory-developed tests (LDTs) for COVID-19. The report is based on previously unreported email messages and other documents reviewed by the WP, as well as the newspaper’s exclusive interviews with scientists and officials involved.

CDC ‘Health Emergency’ Declaration Stifled Laboratory-Developed Tests

The CDC’s COVID-19 test kits began arriving at public health laboratories on February 8, just 18 days after the first case of the novel coronavirus was confirmed in the US. As the WP noted in an earlier analysis, titled, “What Went Wrong with Coronavirus Testing in the US,” the CDC’s decision to develop its own test was not surprising. “The CDC will develop [its] own test that is suited to an American healthcare context and the regulations that exist here,” explained Jeremy Konyndyk, Senior Policy Fellow at the Center for Global Development. “That’s how we normally would do things.”

But state and local public health laboratories quickly discovered that the CDC test kits were flawed due to problems with one of the reagents. While numerous academic, research, and commercial labs had the capability to produce their own COVID-19 PCR tests, FDA rules initially prevented them from doing so without a federal Emergency Use Authorization (EUA).

The bureaucratic hurdles arose due to Health and Human Services Secretary Alex Azar’s January 31 declaration that COVID-19 was a “health emergency” in the US. By doing so, HHS triggered a mandate that requires CLIA-certified labs at universities, research centers, and hospitals to seek an EUA from the FDA before deploying any laboratory-developed tests.

Scientists, Clinical Laboratories Frustrated by Bureaucratic Delays and Red Tape

To make matters worse, the EUA process was neither simple nor fast, which exasperated lab scientists and clinical laboratory administrators. “In their private communications, scientists at academic, hospital, and public health labs—one layer removed from federal agency operations—expressed dismay at the failure to move more quickly, and frustration at bureaucratic demands that delayed their attempts to develop alternatives to the CDC test,” wrote the WP investigators.

In a Feb. 27 email to other microbiologists, Marc Couturier, PhD, Medical Director at ARUP Laboratories, a national reference laboratory network located in Utah, voiced his irritation with the red tape that stymied private laboratory development of COVID-19 tests. He wrote, “We have the skills and resources as a community, but we are collectively paralyzed by a bloated bureaucratic/administrative process,” reported the WP.

Keith Jerome, MD, PhD (above), Head of the Virology Division at the Fred Hutchinson Cancer Research Center in Seattle, maintains federal regulations muted one of the nation’s greatest assets in the fight against COVID-19. “The great strength the US has always had, not just in virology, is that we’ve always had a wide variety of people and groups working on any given problem,” he told MIT Technology Review. “When we decided all coronavirus testing had to be done by a single entity, even one as outstanding as CDC, we basically gave away our greatest strength.” (Photo copyright: Jonathan Hamilton/NPR.)

‘FDA Should Not Treat Labs Like They Are Creating Commercial Products’

Perhaps no scientist was more frustrated by the bureaucratic runaround than Alex Greninger, MD, PhD, a clinical pathologist and Assistant Professor at the University of Washington. Greninger is Assistant Director of the UW’s clinical virology laboratory, which had begun developing a test for the novel coronavirus as soon as the World Health Organization (WHO) China Country Office reported that it had been “informed” about the emergence in China of a “pneumonia of unknown cause.”

According to Kaiser Health News (KHN), Greninger was able to identify one of the nation’s first cases of community-acquired COVID-19 by taking “advantage of a regulatory loophole that allowed the lab to test samples obtained for research purposes from UW’s hospitals.”

But navigating the EUA process was a different story, Greninger told the WP. He spent more than 100 hours filling out forms and collecting information needed for the EUA application. After emailing the application to the FDA, Greninger received a reply containing eCopy Guidance telling him he needed to resubmit the information to the Document Control Center (DCC) at the Center for Devices and Radiological Health (CDRH), a federal agency Greninger knew nothing about. Another FDA rule required that the submission be copied to a hard disk and mailed to the DCC.

In an interview with ProPublica, Greninger stated that after he submitted his COVID-19 test—which copies the CDC protocol—an FDA reviewer told him he would need to prove the test would not show a positive result for someone infected with either a SARS or MERS coronavirus. The first SARS coronavirus disappeared in mid-2003 and the only two cases of MERS in the US were diagnosed in 2014. Greninger told ProPublica it took him two days to locate a clinical laboratory that could provide the materials he needed.

Greninger maintains the FDA should not treat all clinical laboratories as though they are making a commercial product. “I think it makes sense to have this regulation when you’re going to sell 100,000 widgets across the US. That’s not who we are,” he told ProPublica.

FDA Changes Course

Under pressure from clinical laboratory scientists and medical doctors, by the end of February the FDA had issued new policy that enabled CLIA-certified laboratories to immediately use their validated COVID-19 diagnostics while awaiting an EUA. “This policy change was an unprecedented action to expand access to testing,” said the FDA in a statement.

Since then, the FDA has continued to respond—albeit slowly—to scientists’ complaints about regulations that hampered the nation’s COVID-19 testing capacity.

Clinical laboratory leaders and pathologists involved in testing for the SARS-CoV-2 coronavirus should monitor the FDA’s actions and be aware of when and if certain temporary changes the agency implemented during the early days of the COVID-19 pandemic become permanent.

To read part one of our two-part coverage of the Washington Post’s investigation, click here.

—Andrea Downing Peck

Related Information:

Inside the Coronavirus Testing Failure: Alarm and Dismay among the Scientists who Sought to Help

Contamination at CDC Lab Delayed Rollout of Coronavirus Tests

Pneumonia of Unknown Cause–China

How Intrepid Lab Sleuths Ramped Up Tests as Coronavirus Closed In

Key Missteps at the CDC Have Set Back Its Ability to Detect the Potential Spread of Coronavirus

Why the CDC Botched Its Coronavirus Testing

Coronavirus (COVID-19) Update: FDA Issues New Policy to Help Expedite Availability of Diagnostics

Coronavirus (COVID-19) Update: FDA Expedites Review of Diagnostic Tests to Combat COVID-19

 

Serological Antibody Tests a ‘Potential Game Changer’ and Next Phase in Efforts to Combat the Spread of COVID-19 That Give Clinical Laboratories an Essential Role

IVD Companies and medical laboratories are developing serological survey testing that will enable them to determine how widespread COVID-19 has become

While medical laboratories gear up for testing to detect SARS-CoV-2—the novel coronavirus that causes the COVID-19 illness—efforts also are underway for expanded use of serological tests that can detect whether an individual’s immune systems has developed antibodies against the SARS-CoV-2 virus, as well as serological surveys that epidemiologists will use to determine the extent of the infection in whole populations.

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.

The Center for Health Security at the Johns Hopkins Bloomberg School of Public Health lists dozens of other serologic tests that are under development, approved for use in other countries, or approved for research or surveillance purposes. Most are rapid diagnostic tests, but some developers are working on enzyme-linked immunosorbent assays (ELISA).

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.

—Stephen Beale

Related Information:

Coronavirus (COVID-19) Update: Serological Tests

Policy for Diagnostic Tests for Coronavirus Disease-2019 during the Public Health Emergency

Advice on the Use of Point-of-Care Immunodiagnostic Tests for COVID-19

Serology-based Tests for COVID-19

FDA Officially Authorizes Its First Serological Antibody Blood Test for COVID-19

Cellex Cleared to Market Antibody Test for COVID-19

What Are Antibody Tests and What Do They Mean for the Coronavirus Pandemic?

Cellex qSARS-CoV-2 IgG/IgM Rapid Test

IgG/IgM Rapid Test Approved by FDA for EUA Use

EDI Novel Coronavirus COVID-19 ELISA Kits

Mayo Clinic Laboratories Launches Serology Testing In Support of COVID-19 Response

;