ARTICLE SUMMARY:
Response to the urgent demands for more COVID-19 testing ultimately falls on the shoulders of laboratory medicine experts like Gerald Capraro of the Carolinas Pathology Group, who as head of clinical microbiology for a large core lab in North Carolina, must adjust political and societal expectations with real-world implementation. Part 2 of our two-part COVID Diagnostics Update.
Gerald Capraro, PhD, sits in one of the pandemic hot seats as director of clinical microbiology at the Carolinas Pathology Group, a private practice of pathologists, who oversee the core labs for Atrium Health Systems in Charlotte NC, one of the largest healthcare systems in the South.
The laboratory services 12 hospitals, and Capraro is also an as-needed consultant for microbiology testing point of care at hundreds of doctors’ offices in the Atrium system and its freestanding emergency clinics. (See “Why is it So Hard to Develop a Serology Test for COVID-19? COVID Diagnostics Update Part 1” MedTech Strategist, April 22, 2020.)
What follows is a glimpse inside the pragmatic reality of ramping testing from the perspective of a laboratory medicine expert who is on the front lines at a major healthcare system in the Southern US. (See “COVID Diagnostic Testing Ramp-Up Meets Reality,” MedTech Strategist, April 15, 2020 and “The Enormity of SARS-CoV-2 Testing: The Challenges for Laboratory Leaders, MedTech Strategist, April 1, 2020.)
Atrium’s core laboratory is running 1,000 molecular SARS-CoV-2 diagnostic tests per day, on three platforms: its own manual laboratory-developed test (LDT), which it launched March 9, and two Emergency Use Authorization-reviewed higher throughput commercial tests: the Roche Cobas 8800, and the Luminex NxTAG Extended Panel. North Carolina has not been a hot spot for the pandemic and to date, supply shortages have not been a big challenge for the system, but using a variety of vendors enables the laboratory to better manage any supply chain issues that do arise, says Capraro, adding “We are having conversations with manufacturers nearly every day to make sure that our numbers are up to date and accurate.”
MedTech Strategist: How effective do you think the EUA process has been and how comfortable you are with the quality of the tests that have been approved?
Gerald Capraro: This is a different process than what we’re used to in the laboratory. Typically, if we develop our own test, we have plenty of reagents, and plenty of samples that we can test to ensure the quality and the accuracy of the assay. And if we choose to go with a commercial vendor, there's plenty of data around to speak to its performance. Commercial vendors usually go through the 510(k) process for FDA approval or clearance of the assay. In this process, we do not have the breadth of data available for each of the assays. At this point, there has not been a parallel study, if you will, comparing assay to assay to really understand things like sensitivity, specificity. We know limits of detection [LOD] and so forth from the EUA process, and there are standards for figuring that out for each assay, whether it’s an in-house, lab developed test, or it’s a commercial assay. My concern is that there's not the typical amount of data to really understand how these assays are functioning clinically.
How concerned are you with false positive or false negative rates for the molecular tests?
We are not terribly concerned about false positives or false negatives. I think that any particular false negative is more likely due to a sample collection issue rather than the way the assays are working.
So far there's only one EUA-approved for a serology test [Note: as of early April. As of April 20, there were four EUA reviewed serology tests]. Is the FDA being too bureaucratic or understandably cautious?
I don’t know why it seems to take longer for development of the serology test. I don’t think it’s an issue with FDA oversight because FDA has said that they're not really granting EUA status for serologic tests. [Instead] the FDA has said these tests can be sold without EUA review but not used for diagnostic purposes.
What role do you see serology tests playing in management of the disease, and why it is taking so long for manufacturers to come out with serology testing, given that they use ELISA immunoassay technology, which is a mainstay of the clinical laboratory?
In molecular technology, we have a specific target that we can design our assays around. With serology, we don’t exactly know what epitope is going to be most effective at detecting the organism and looking for a specific immune response. In terms of management of the disease, folks are talking about using a person’s immune status in a couple of ways. One is to identify patients who have been exposed and/or infected with COVID-19 and have developed an immune response, and then potentially using that patient’s serum or plasma as therapy.
The other option is to use serology to try and identify people who have mounted an immune response, and some of the hospital systems are thinking about using that result as a way of putting people back into the workforce without making that particular person wait the necessary 14 days. The thing is, we don’t know what constitutes protection. We know an immune response is generated, but we don’t know whether a certain level of IgG or IgM will be protective – which is a critical issue for healthcare workers.
We [in the core laboratory] are in early stages of identifying commercial partners [for serological testing] and may take a similar tack as we have done with molecular testing, where we might have to find two or three different vendors to have enough capacity. The tests would run on high-throughput immunoassay analyzers, which are long-time standard platforms in clinical laboratories. Most of the commercial assays we are looking at run on open platforms and can be compatible with our instruments. The instruments are available if we can find the right test and application for it. We are looking for an assay that has some level of specificity—if I can understand the target that antibodies are directed against, then I have more comfort knowing they are more specific for SARS-CoV-2 than if another epitope is used that has more cross-reactivity with other, common, circulating human coronaviruses.
Are you getting that information?
This is a time-dependent situation. As time goes on, IgG and IgM become fairly specific to the antigen against which they are directed, i.e., over time after repeated exposure to that antigen, the level of specificity increases. As the antibodies get more specific for their epitope target, they tend to bind tighter to the antigen of interest. You can have IgG early in the immune response cycle that cross reacts with several viruses, but as time goes on, it gets more specific.
Why is it so hard to identify that time frame or the right epitopes?
This is a new virus. With influenza, for example, the antigens change yearly, and we need to be specific. That is why we get flu shots annually. With measles, the immunity is lifelong. We don’t know if antibodies to SARS-CoV-2 will change over months and if they will continue to protect us. That work is underway but there are still a lot of questions.
Another area of confusion is home testing and self- sampling, which people see as a potential answer to widespread testing and tracking but these have drawbacks.
As with any lab test the pre-analytic phase is critical to getting the right answer. If a good quality specimen is collected correctly, there is more confidence in the right answer. Having said that, there are lots of POCT [point-of-care tests] and some home-based tests that work as well as specimen collected by healthcare workers in the clinic. Some of these maybe applicable for SARS-CoV-2, but we don’t have that data yet. I would be wary of home-collected nasopharyngeal swabs, on the other hand. Even healthcare workers don’t get that right all the time. Any alternative would have to be oropharyngeal or sputum. Some data on those is out. The CDC has shown that oropharyngeal works as well as nasopharyngeal swabs when collected. My concern is that person doing the self-collection really understands how good that answer is.
Do you hear any guidance from FDA on near-patient testing?
The FDA put out guidance on near-patient testing but some of that language is confusing. Systems like the Cepheid and Abbott point-of-care tests cannot be collected and run in patient rooms due to the level of risk to the person doing that test. These tests should be done in biosafety cabinets. The Abbott platform, for example, has been used in doctors’ offices, but the COVID-19 test presents such a level of risk to the laboratorian or person doing that test that it should be done inside of a biosafety cabinet. Indeed, the FDA says it still needs to be done by laboratorian, which in my opinion is a certified lab technician who can run the test, document its control, and all the things we would do in a lab, but could do it in an emergency department with a biosafety cabinet. Sometimes emergency departments do have laboratorians available where they have POCT tests. That stipulation has been confusing for people. Also, while these tests are fast, they are done one-at-a time, depending on number of analyzers you have. The throughput cannot keep up with that of a central laboratory.
Obviously, payment is always a concern, but do you sense whether your lab will get reimbursed at a reasonable rate and how the new coding impacts your bottom line?
We are focused on getting testing done properly and making sure capacity is appropriate for our patients. I suspect someone in our system is working on coding but it’s not top priority for me.
Any research/findings coming out that is relevant to your work?
There is a lot of information coming out. The most relevant for us recently was a brief paper in the Journal of Clinical Microbiology from The Mayo Clinic comparing whether [four kinds] of viral transport media worked equivalently on their LDT and a commercial vendor’s molecular test. That study shows that if a facility runs out of a specific viral transport media, there are options that can be deployed.
How are you experiencing the shortage of swabs?
We are trying to get as many swabs as we can from as many vendors as we can. The FDA or CDC came out with a list of a variety of swabs that could be used. We started with the Flocked Swab (swabs that have the fibers perpendicular to shaft so looks like test tube cleaner). The alternative is something like a Q-tip with woven fiber swab run around a shaft. The flocked swab is preferred but due to shortages we moved to other sizes of flock swab. I have no idea if that change impacts test results. I hope someone somewhere is doing a comparison.
The testing capacity and our supply chain issues will resolve over next few months. Does that mean in May or June or August-September? I don’t have a good sense of time. The vendors say they are ramping up and in next month or so they will have better capacity to provide reagents. It depends on how flat we get the curve in different parts of the country.
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