The COVID-19 pandemic affected diagnostic testing much like it did other parts of the healthcare delivery system — it demanded completely novel approaches at some points, and merely accelerated trends underway at others.
In other words, an evolution became a revolution.
That revolution, according to Quest Diagnostics Chief Medical Officer Jay Wohlgemuth, MD, can be categorized by just a few words, most notably “convenience.”
“Anything you can do from your home, you should,” Wohlgemuth said. “Then you should come in to a Quest patient service center or Walmart for the next layer. Then, you would go to your local health system for things you absolutely needed to, like having a baby or getting a knee replaced. That is absolutely a huge trend in the industry. We are investing heavily in home-based self-collection kits which are very consumer-centric and friendly, and then telemedicine services.”
It’s not only long-established entities like Quest that have been preparing for the consumer-friendly testing future. Emeryville, Calif.-based Lucira Health, for instance, was already developing an at-home testing platform, but not for COVID-19.
“Lucira was in the final stages of developing of an at-home flu test kit when the pandemic hit,” Kelly Lewis Brezoczky, executive vice president at Lucira, said. “We quickly realized in early 2020 that the platform we had developed might work for COVID. Lucira’s assay team was up for the challenge and within two months we had a COVID assay ready for clinical testing.”
FDA granted Lucira emergency use authorization for its molecular prescription take-home test in November. FDA Commissioner Stephen M. Hahn said the test, the first self-administered test to receive approval, represented “an important diagnostic advancement to address the pandemic and reduce the public burden of disease transmission.”
The at-home testing market accelerated further in December 2020, with EUA approval of Abbott’s BinaxNOW antigen test, available by prescription in tandem with telehealth guidance.
The approvals served as exemplars of a diverse new ecosystem of diagnosis and clinical guidance and also help illustrate how testing experts view a post-pandemic world in which COVID-19 will be with us as an additional respiratory infection that will regularly join others such as flu and respiratory syncytial virus.
New approaches, new defaults
In addition to the trend of enabling widespread at-home testing, the market can also expect two other trends to emerge in the next round of respiratory virus surges — there will almost certainly be a much greater need for tests capable of testing for a variety of illness, and testing for COVID-19 itself will include a pervasive “search for nothing.”
“The future is never certain,” William Morice, MD, PhD, president of Mayo Clinic Laboratories, said. “But most people in the infectious disease expert field feel COVID will probably be something that will circulate through like other respiratory pathogens. So the testing will be with us and I think more than likely will become part of the normal armamentarium of clinical tests for respiratory illness. The vaccine will decrease the amount of testing and it might change the focus of testing, but it won’t obviate the need completely.”
In future surges of respiratory illness, Morice said, it will be highly likely that combination testing for more than one type of virus will become commonplace. Recalling the concern over the 2020-21 flu season that ultimately turned out to be almost non-existent, Morice said it will be natural and normal to have to narrow down what a symptomatic patient may be presenting with.
“In the long view, if somebody comes in with a respiratory illness next winter, there will almost certainly be some need for combination testing,” Morice said.
Numerous developers have received FDA authorization for combination testing. Abbott was the latest to get clearance on March 4, joining platforms by BioFire, GenMark, Roche, Qiagen, and others.
Brian Weinstein, partner and head of life sciences equity research at investment and financial services firm William Blair, concurs with Morice’s contention combination testing will be a necessity, and adds that additional vagaries surrounding how long the vaccines’ immunity lasts, and who has and has not received a vaccine, will mandate an entirely new rationale for testing.
“At the heart of what I think the future of testing for COVID-19 in the post-vaccination world is this — testing will no longer be used to diagnose active infection or tell you you have the disease,” he said. “Instead, the use case is changing and it will be used much more for people who show no symptoms, to clear them.”
Open-ended questions of COVID testing
The novelty of the SARS-CoV-2 virus leaves diagnostics professionals with many ambiguities that will need to be addressed: Who to test? Where to test? When to test? How to test? How much will it cost to test? How will we know who has been tested, and what is their status?
The answers to some of these questions, such as the drive to deliver at-home convenience, often paired with integrated virtual clinical guidance, are clearly emerging in the marketplace. But others, such as settling on whether or not to use antigen or PCR tests, at what price point insurers, providers, and consumers will accept testing at regular intervals, and how data on testing will be integrated into everyday life, are still works in progress.
On one hand, the ubiquity of testing that occurred throughout 2020 when people were symptomatic, or that were mandated as essential workplaces, and later, as schools and universities opened up, produced a society-wide awareness of testing, and probably an appreciation for options that did not entail driving to a central location and waiting for a prolonged period of time.
“Another really important part of this is, just because testing has been made available, there has to be a willingness by an individual to get tested,” Weinstein said. “There will be instances where there will be a gatekeeper, like getting back to work, or if you want to get on a plane or cruise ship. Those are points you may be required to be tested.
“But then there are all the other times where people just have to make the decision — do you want to be tested if you feel fine? And I’m not sure that market will really germinate. That’s still to be determined.”
Weinstein also said trying to set a definitive acceptable price point per test will depend on numerous factors, including the environment the individual being tested will inhabit. A precautionary antigen at-home test for an asymptomatic person will be much less costly than a pre-surgical molecular test, for instance. The CDC has released algorithmic interim guidance for best practices around the less-sensitive antigen tests, and Wohlgemuth said Quest instituted a testing program with Mid-American Conference football teams during the fall 2020 season that employed antigen tests that were confirmed by PCR testing when necessary.
“It worked really well, because you’d identify the individuals early on who needed PCR, but once they got going they were able to play and practice the entire season,” he said. “And it was basically a daily antigen test.”
Lucira’s Brezoczky, however, recalled several college students who participated in a company study on asymptomatic people. The students tested positive on antigen tests and had been isolated in a COVID-positive dorm, but on both Lucira and a comparator molecular test, they were negative.
“That means they were antigen false positives in a COVID quarantine dorm,” Brezoczky said. “In a senior living environment that would have tough consequences. I think once there is better understanding that antigen tests are best at confirming a suspected positive when someone is truly sick and not so good at surveillance, especially among individuals who are carrying lower but still infectious or contagious viral loads, we’ll hopefully see a policy shift.”
Emerging benchmarks and next steps
Several testing benchmark practices are emerging as society adjusts to the presumed tail end of the pre-vaccine pandemic. One is the evolution of pooling methodology.
“There was a lot of interest in pooling,” Morice said, recalling conversations he had with other members of the American Clinical Laboratory Association’s board of directors early in the pandemic’s course. “Whenever testing was in short supply, there was interest in it. The question is, how feasible is pooling in managing a pandemic? What we found was the sweet spot for pooling is when there is less than 10% prevalence. It might be useful again if you are screening for an emerging infection or emerging hot spot.”
An emerging pooling practice is what Wohlgemuth called “pod pooling,” or sample pooling, as explained by Arvind Kothandaraman, general manager of specialty diagnostics at PerkinElmer.
“Sample pooling allows labs to combine up to five individual samples in a single test,” he said. “In practice, this means that if a pooled test is positive, each of the individual samples in that pool should be tested again separately to determine which of the samples are positive. If a pooled test is negative, then all samples can be presumed negative. An assay used to test pooled samples must have a superior level of sensitivity to effectively detect a lower amount of viral genetic material than might be in a sample from a single individual.”
Wohlgemuth said Quest had just validated the approach for use in pre-collegiate educational testing: “If there is a low infection rate it’s very efficient because I can test large populations. If I get a positive result in any given pod, then I have to go back to the kids in that pod – but it’s a very efficient approach we have just validated and will be a big part of K-8 and K-12 testing.”
Morice also mentioned there might be increased emphasis on sequencing samples of the virus.
“Right now there is an interest in getting more sequencing done in the U.S. just to understand the epidemiology of the disease and the emergence of variants of concern,” he said. “Now that we see some of the spike variants are resistant to some of the monoclonal therapies and potentially convalescent plasma from earlier in the pandemic, if these sequencing results actually start driving therapeutic decisions, they will need to push their way into the clinical labs. And, going back to the vaccines, we’ll need to watch how the virus itself reacts to the vaccinations, so through the course of this year, there will definitely be sequencing of variants that will continue to be a focus of the healthcare community.”
The experts who spoke with MD+DI offered a few common observations for the future. One is that the global nature of the pandemic and the emergence of the novel virus left the diagnostics community resolving not to let the “next one” get a head start — to that end, more global partnerships and more multi-platform capabilities will be ready to go at a moment’s notice.
“Quest, and many others, are moving way upstream now, and saying we won’t be caught again without appropriate testing,” Wohlgemuth said. “We already know what the top six to top dozen threats are for respiratory viral pandemics. So we will be in a situation where we will develop multiplex panels of all of them and be in a position to create individual assays when we need to.”
Wohlgemuth also mentioned the resources of the Global Diagnostics Network. By working with Korean partner Green Cross Labs early in the pandemic, Quest was able to validate its COVID PCR test on March 9: “The reason we were able to move so fast was because Green Cross was able to provide us samples for validation. That sort of global network has been very significantly strengthened and we are all doubling down.”
That doubling down will be facilitated by the significantly increased revenues and cash flows the pandemic brought to diagnostics labs and vendors.
“There’s no doubt all the companies selling COVID testing, or testing components, have seen a significant increase in revenue as well as cash flow over the last 12 months,” Weinstein said. “There are a lot of hot areas in diagnostics outside of COVID-19, things like precision oncology, which is getting a lot of attention and is not a cheap table to be playing at. So that may be an area for them to get involved in a deeper way.”
On the other side of the spectrum, Weinstein said, the democratization and decentralization of testing procedures that enabled the at-home testing paradigm to bloom will present an opportunity for startups and a dilemma for legacy diagnostics players.
“There is a growing awareness of testing in general as a result of COVID-19,” he said, “and I think that will enable a lot of companies, especially smaller companies, to develop products that test for other conditions. Every day it seems like I see another one, and the large companies in that space will have to make a decision as to whether they want to be part of that evolution to point-of-care testing, and move out of where most of them have traditionally played.”
The growing general awareness and acceptance of testing, and material advances in point-of-care testing the pandemic brought about might also improve the practice of medicine in ways hitherto not connected, such as helping to reduce the unnecessary prescribing of antibiotics.
In a small proof-of-concept study at the University of Bristol in the United Kingdom, researchers found a point-of-care test intended to discover if such testing could help curb overprescribing. Of the 93 patients tested (median age 29), 58% had at least one virus, 37% tested negative for any virus or bacteria, 3% had an inconclusive result and two per cent had an atypical bacteria. Before the test, clinicians prescribed antibiotics to 35% of patients who, after the test, were found to have no pathogen, and to 25% of patients who, after the test, were found to have a virus, demonstrating the potential of the tests to reduce unnecessary antibiotic prescribing.
Wohlgemuth said such seemingly discrete areas of practice might indeed benefit from a more comprehensive knowledge and infrastructure for testing.
“If we can broadly adopt appropriate testing around that issue, you can make a big difference and the pump is primed,” he said. “Every hospital lab in the country stood up COVID testing so they are deeper into it. There’s no question viral testing will move toward much more aggressive, up-front multi-plexed testing. On bacterial resistance, I think it’s a bigger problem that isn’t as far along, but maybe that will be one of the silver linings of the pandemic, and get that moving in the right direction.”