NEW YORK ─ Some 10 months into the COVID-19 pandemic, testing for individuals who may be infected with the SARS-CoV-2 virus but who may not show symptoms remains a hodgepodge of methods, modalities, and technologies, many of which have not been authorized by regulators specifically to test asymptomatic patients.
Some insiders emphasize the importance of doing rapid turnaround testing of asymptomatic people at the point of care enabled by either antigen or molecular assays, while others contend that laboratory-based tests ─ whether molecular- or antigen-based ─ ought to be the modalities of choice.
But regardless of the modality, being able to identify asymptomatic patients in order to limit the number of people they may infect will be crucial to containing the pandemic, experts said, and both industry players and regulators are taking greater notice.
"Testing makes our enemy visible, so more asymptomatic testing gives us a better chance of getting infectious folks into isolation to avoid spreading the disease further," College of American Pathologists President-elect Emily Volk said in an interview. "We know a high percentage of COVID-19 cases are spread by asymptomatic carriers, so quickly identifying them provides significant public health value."
During the pandemic, testing has been focused heavily on people with coronavirus symptoms, partly because the demand has continued to exceed supply and the sickest people need to be prioritized. As tests have become more available, however, so too has testing of asymptomatic people.
In San Antonio, where Volk is co-chair for the city's testing and laboratory reporting work group for the COVID-19 community response coalition, testing of asymptomatic people has been ongoing for months. Physicians and lab directors looking to test people who don't have SARS-CoV-2 symptoms didn't wait for regulators to authorize assays for that purpose.
"Some of the Emergency Use Authorization language for specific tests address whether or not they are appropriate for asymptomatic testing, but ultimately it is up to a physician to decide which platform they want to use for their patients and it is also up to public health medical directors to make those decisions for a community," Volk said.
In the US, where authorizations for asymptomatic tests are on the rise, Hologic believes it is important that laboratorians and clinicians select high-sensitivity, nucleic acid amplification tests, Maurice Exner, its vice president of research and development and clinical affairs for the company, said in an interview.
At the end of September, the Marlborough, Massachusetts-based company received an updated FDA authorization for its high-throughput Panther Fusion SARS-CoV-2 assay to enable testing people without symptoms.
The agency subsequently amended an EUA for Hologic's Aptima SARS-CoV-2 assay to include testing of people without symptoms.
Assays with especially high sensitivity "are needed when you want to screen people to identify who may be unknowingly transmitting the virus," Exner said. "In so doing, you can minimize the number of outbreaks and better manage people in congregate living facilities such as nursing homes and prisons. The same is true for schools, where you also have a need for rapid detection of people carrying the virus before it spreads rapidly and have an exponential increase in infections."
The FDA in June provided test developers with new EUA guidance on the validation processes it expects for the screening of asymptomatic people.
It recommended that a new test be evaluated in a clinical study of the intended population. The number of patients should be enough to detect 20 positive samples, with a positive percent agreement, or PPA, with a comparator test of 95 percent, and negative percent agreement, or NPA, of 98 percent.
"Though you need to compare the sensitivity of your test with that of a high-sensitivity assay, there is room for interpretation by test developers about what constitutes high sensitivity," Exner said. "We would suggest you shouldn't really have any leeway, and that the level of sensitivity of the comparison test be specified."
Already a number of important use cases have emerged for asymptomatic testing that speak to the need for high-quality, high-sensitivity assays, Kevin Thornal, president of diagnostic solutions at Hologic, said in an interview. One example is screening by hospitals of people presenting for surgery. Additionally, hospital testing for COVID-19 is done in emergency and urgent care settings for people who may present with symptoms initially but whose symptoms subsequently subside.
These patients need to be tested to determine whether they should be isolated or allowed to return to normal activities, Thornal said.
Prior to the FDA's revisions of its EUAs for Hologic's SARS-CoV-2 assays, the FDA reissued in July an EUA for Laboratory Corporation of America's COVID-19 RT-PCR Test to include the test's use with asymptomatic individuals.
Over the past few months, the agency has become increasingly active in its support of asymptomatic testing, and in October, it updated a template for SARS-CoV-2 antigen tests on its website to include recommendations for studies that support claims for screening asymptomatic individuals.
Other companies that have been greenlighted by FDA to offer their SARS-CoV-2 tests for asymptomatic testing include Helix and Gravity Diagnostics. Additionally, last month, PerkinElmer announced that its SARS-CoV-2 Real-time RT-PCR assay received the CE-IVD mark for the use of saliva as a specimen type. The assay can now be used to pool up to five specimens collected from individuals suspected of having COVID-19 or from asymptomatic patients.
Among SARS-CoV-2 tests in development to test people with or without symptoms, Cleveland-based Canary Health Technologies and Delhi, India-based Divoc Laboratories announced this week that they will collaborate on a clinical trial to develop a rapid breath test for the detection of COVID-19. The disposable breath test is being developed to detect the virus in less than three minutes
Further, diagnostic firm Veravas said recently that it is planning a pair of prospective clinical studies for an antigen test designed to diagnose infection in symptomatic patients and plans to follow that with a prospective study of the test in asymptomatic patients.
Additionally, Ortho Clinical Diagnostics recently told 360Dx that it has submitted an EUA application for a high-throughput antigen assay that it expects could issue soon for the testing of people with symptoms, and that it is pursuing authorizations in the US, Europe, and elsewhere to test people who are asymptomatic. Laboratories using high-throughput instruments capable of running thousands of antigen tests per day, are returning test results within 24 hours of getting a sample, far faster than most RT-PCR lab tests, the firm said.
Asymptomatic testing in the UK
In the UK, the government is pushing ahead with its plans for asymptomatic testing using a variety of testing platforms.
Early in November, UK Prime Minister Boris Johnson announced that Liverpool, England, would participate in a citywide COVID-19 testing pilot program to offer every resident and worker repeat SARS-CoV-2 testing, regardless of symptoms. The program offers a combination of laboratory PCR tests, rapid turnaround lateral flow assays that don't require a laboratory, and loop-mediated isothermal nucleic acid amplification testing.
Separately, the UK Department of Health and Social Care (DHSC) also said that it will provide roughly 670,000 rapid SARS-CoV-2 tests to local public health officials this week to expand testing in asymptomatic individuals.
David Wilson, commercial director at Weatherby, UK-based test developer Avacta, noted that while some progress is being made toward the adoption of asymptomatic testing, only people with symptoms are still getting tested in many regions of the world because of test capacity constraints.
"What we really need as an industry is the capability to test people who are symptomatic and asymptomatic frequently," Wilson said recently while speaking on an online IVD industry panel about diagnostic design and manufacturing organized by Marlborough, Massachusetts-based Cytiva, a Danaher company formerly known as GE Healthcare Life Sciences.
Avacta is developing a saliva-based rapid SARS-CoV-2 antigen test with Cytiva.
Frequent testing could play an important role not only to ensure that people remain infection-free but also to compensate for a lack of sensitivity in testing, Wilson added.
At the same time, getting to those numbers of tests to enable frequent testing is going to be an enormous challenge. "We are talking about needing to run billions of tests per year to get to that point," Wilson said. "Current global manufacturing capacity is significantly lower than what is needed to implement testing at that scale."
In getting to broader levels of testing, including for asymptomatic patients, molecular testing in the laboratory provides the potential to achieve the greatest accuracies, but such tests can also "be potentially difficult to scale, and we can't rely on PCR alone to give everyone access to testing," Wilson said.
As a result, there's a critical role here for decentralized testing involving point-of-care PCR and lateral flow antigen testing, he added.
David Persing, chief medical and technology officer at Danaher's Cepheid, who also spoke on the panel, said that antigen tests can be "really valuable to provide short-term results around infectivity." Antigen tests may prove to be particularly useful in testing people getting on a "four-hour flight or attending a four- to six-hour sports event," he said.
However, whether testing people with or without symptoms, "nucleic acid tests are really good at identifying the first possible signs of infection," Persing said. "Within two days after exposure, we see evidence of nucleic acid test positivity. Then there are a few days of incubation while a patient becomes infectious. So, there is an intervention window when you can act on that test result, and that window is much shorter for antigen tests."