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The laboratory tests of pandemic summer

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Karen Titus

August 2020—In March, the COVID-19 pandemic came in like a lion—and has yet to leave, like a lamb or anything else. Instead, it roared through April and May in early hot spots like New York City and New Orleans. As lockdowns took hold, the cautious hope was that by summer the virus would be tamed (if not simply go away “like a miracle” or “as the heat comes in,” per several infamous predictions), giving health care providers a chance to exhale before a likely second wave in the fall.

Instead, June and July saw other cities and states hit hard in turn, while many places that appeared to have flattened the curve were starting to see concerning upticks in cases. And rather than planning for a return of the virus later in the year, laboratories are now talking about SARS-CoV-2 as an ongoing presence.

For months the national narrative has called for the country to test its way out of the crisis. “It doesn’t appear to be working,” says Frederick Nolte, PhD, D(ABMM), professor of pathology and laboratory medicine, vice chair of laboratory medicine, and director of clinical laboratories, Medical University of South Carolina, Charleston. “We can’t get ahead.”

“It just keeps getting surprisingly worse,” says Susan Fuhrman, MD, president, CORPath, Department of Pathology and Laboratories, OhioHealth Riverside Methodist Hospital, Columbus.

As summer totters on, several laboratory experts paused to speak with CAP TODAY about their current work and their expectations for the months ahead. As it turns out, weathering the pandemic feels like one long March.

As Gregory Sossaman, MD, reviews how Ochsner Health has responded to COVID-19 in Louisiana, he calls it “engaging in an iterative conversation. The same things we were focusing on before we’re still focusing on now: testing capacities, supply chain, staff. That’s what I’m working on day to day,” says Dr. Sossaman, system chairman, pathology and laboratory medicine, as well as service line leader, pathology and laboratory medicine.

Dr. Frederick Nolte at MUSC with Julie Hirschhorn, PhD, associate director of the molecular pathology laboratory (left) and April Kegl, technical coordinator of the molecular pathology lab. “We’re not on a good glide path right now,” Dr. Nolte said of South Carolina in late June.
(Photo: Sarah Pack/MUSC)

Dr. Fuhrman’s experience has been similar. It’s not as if she and her laboratory colleagues are done cleaning up the mess that was spring. “I don’t object to using that word,” she says. “It’s ongoing.”

Not everything is the same, of course. Many of the instruments that laboratories worked hard to acquire are up and running, and the multiple, daily COVID-19 meetings have been dialed back, in many cases to just a few a week. C-suite administrators are no longer wondering what the laboratory does or asking for tours.

But testing remains parlous. Dr. Nolte is still using the word “pivot” with distressing regularity. “It’s always been a part of my vocabulary, but never in this way. On a regular basis you’re asked to switch to a different sample type, to a different test, to a different testing criteria. It’s maddening.”

As the virus lingers, so do the questions. The one Dr. Nolte says he’s asked most often is astoundingly basic: What is the diagnostic sensitivity and specificity of the SARS coronavirus PCR test that you offer, Dr. Nolte?

“My answer is, ‘I don’t know,’” he says.

He can report the analytical sensitivity and specificity “in excruciating detail,” he says. “I can tell you what looks like a strong positive reaction and a weak positive reaction. I can tell you how we performed in proficiency testing programs. I can tell you to some extent how well we compare with other platforms.” But months into the pandemic, “I honestly cannot tell you what the diagnostic sensitivity and specificity of this test is.”

He unspools more questions in need of answers. “What are the true clinical performance criteria of the test we are offering and will probably continue to offer for some time? The true diagnostic sensitivity and specificity of serology? Are there better markers of disease? Do we need qualitative tests? Do we need to be looking at host response? Do we need to be looking at subgenomic messenger RNA in clinical specimens to figure out, of all these RNA specimens, which ones are actually infectious?”

“This is our stock in trade,” he says. “It’s not rocket science, but it’s the basic stuff that none of us have been able to do.”

Laboratories also lack a standard reference material. The search for transport media and swabs, not to mention reagents, continues. Beyond that lie other issues, including capacity—how to build it, how to staff for it, how to share it.

Moreover, deciding who to test, where, and why is a pendulum kept in motion by hospital administrators and government leaders.

Testing criteria have continued to change. Early on, testing was restricted to those with a connection to travel to China or who’d had contact with a confirmed case. When that overwhelmed the public health system, the testing criteria was ratcheted down to include only the sickest patients.

“Now it’s wide open,” Dr. Nolte says. The CDC’s testing priority criteria “basically says, ‘Anybody you want to.’ Anybody you decide, as an institution, needs to be tested.”

While acknowledging the concerns about asymptomatic carriers possibly spreading the disease, he says, “That’s a difficult question to answer, because what we’ve got is a disease that has a nonspecific presentation. If you look at that data, people who were called asymptomatic really weren’t asymptomatic at all.”

‘We’ve got to have some people with the bandwidth to take a breath and start reviewing charts and determining who really has COVID.’ — Susan Fuhrman, MD

Dr. Fuhrman agrees: “It’s been a huge challenge, testing thousands and thousands of asymptomatic patients.”

With a nod to Michael T. Osterholm, PhD, MPH, director of the Center for Infectious Disease Research and Policy, University of Minnesota, Dr. Nolte calls for smart testing. (Dr. Osterholm and colleagues discuss this approach in their “COVID-19: The CIDRAP Viewpoint” report from May 20.) More targeted deployment, Dr. Nolte says, would have helped labs get ahead of the testing avalanche. Dr. Osterholm’s paper, he says, makes a strong case for not testing asymptomatic individuals, and Dr. Nolte circulated the paper within his institution and suggested it be required reading for hospital administrators and others who make decisions about testing criteria.

Nevertheless, MUSC has begun screening all inpatients. How did they arrive at that strategy? The idea had been percolating for some time, Dr. Nolte says, though the lab had initially pushed back. Two events “tipped us over the edge,” he continues: Several symptomatic patients were apparently admitted to the hospital without being tested, and there was a handful of likely nosocomially acquired COVID-19 cases. Senior leadership then acted.

MUSC is second to LabCorp in providing testing for the state, Dr. Nolte says, and the state legislature gave the university a grant to set up mobile testing sites for screening at-risk patients throughout the state and to have samples sent to the MUSC lab. To handle the “incredible volume,” MUSC has partnered with commercial reference laboratories. Obtaining sufficient swabs and transport media remains challenging, and the best specimen type—saliva, nasopharyngeal, nasal—is anyone’s guess and will likely vary for symptomatic versus asymptomatic individuals.

Using the diagnostic tests for screening “is not how they were approved,” says Dr. Sossaman. “But that’s the need, and that’s how everybody’s using them right now. We’re definitely using it that way.”

There could be good clinical reasons for that, since COVID-19 positivity is associated with higher morbidity and mortality in patients undergoing procedures. And even with serious infection control protocols in place, it seems reasonable to limit the exposure of medical personnel. But the corresponding lack of data on asymptomatic patients is almost crippling, Dr. Fuhrman says. “We have no idea how the tests perform in those patients. We have no idea whether a positive patient is infectious. We have no idea if a negative patient is infectious. We’re in the dark—that’s my biggest challenge.”

Even the analytic sensitivity of the tests—the one thing labs can talk about with reasonable confidence—might be suspect. “We know the analytical sensitivity as far as the minimum viral genomic RNA that the specific probes for each assay can detect. This minimally detected RNA is then mathematically converted to a minimum number of detected viral particles,” Dr. Fuhrman says. “We don’t know if we are detecting viable virus or just random fragments of viral RNA.”

The emergency use authorization process allowed vendors to obtain their sensitivity figures using contrived specimens from viral particles, she says, including from RNA produced in the lab “that happens to contain the sequences. That’s not very clinical, if you think about it.”

The all-comers approach has become inflated by demands for testing to help guide businesses, sports, and schools as they shuffle between reopening and shutting down.

Dr. Fuhrman, whose hospital has performed some 12 percent of the COVID testing in Ohio, has been racing to build capacity to handle testing for other institutions, meet requests from companies riding the reopening merry-go-round, and keep ahead of whatever happens this fall. “I’ve got all three going on,” she says. Major sports teams in town, along with other big businesses, are hitting her up for testing, and the governor has assigned hospitals to test symptomatic nursing home residents and asked her hospital to take on more community outreach testing. Her lab is also testing symptomatic prison employees. And when flu season hits, “we’re going to have to do way more testing than we’re doing now, even if there isn’t a resurgence in COVID.”

“We’ve already started thinking about fall,” Dr. Nolte says. “Layer a bad influenza on top of COVID—which is not going away, or will ramp up in the fall—and we’re going to have a real mess on our hands.”

He and his colleagues are considering the use of combination tests that will detect and distinguish COVID-19 from flu A and B in a single test. “Adding SARS-CoV-2 to the routine respiratory panels that are available is going to be the new normal,” he predicts.

Waiting until fall might be a luxury, Dr. Sossaman says. “It’s not going to be all that long before we see things getting worse.”

If things weren’t already complicated, “Now we’re throwing serology into the mix,” says Dr. Nolte. Not surprisingly, serology is also unencumbered by answers.

MUSC had tested more than 6,000 individuals as June was drawing to a close, with a positivity rate of about two percent. “We don’t know what to make of that yet,” he says.

The laboratory uses the Abbott assay to test for antibodies against the nucleocapsid protein. Positive samples are reflexively tested using an LDT spike protein assay. Concordant results are called positive. When results of the N-protein antibody screening test are negative, the results go out as negative. And a disagreement between the two tests is called discordant. “We think our orthogonal testing algorithm developed by Dr. Nikolina Babic [director of clinical chemistry and POC testing] is a useful tool that can identify potentially false-positive SARS-CoV-2 IgG serology results, particularly in populations with low disease prevalence.”

So far, so good. But as Dr. Nolte reviews the data, he’s left holding the existential bag: What does it mean?

The spike proteins rise later than the N proteins; if clinically indicated, the lab suggests recollecting the specimen if results are discordant. The patient population for this testing includes health care workers who want to know their antibody status, communities (“Mayors are calling us,” Dr. Nolte says), and businesses (“They want all their employees tested”). These selected populations may or may not be representative of the state at large. “That’s what we’re struggling with—how to understand that.”

Physicians are also struggling to answer another frequent question: what to make of a negative SARS-CoV-2 RNA test in the midst of a series of positive results on a patient who’s been hospitalized for weeks. What should be done with such information, when physicians are looking to use RNA testing as an indication of cure?

It might simply be a preanalytical problem, Dr. Nolte says. “We’re testing at volumes we’ve never tested before, and it’s a little scary when you’re generating a thousand results a day.” Glancing at his colleagues in clinical chemistry labs, he says, “For them that’s a piece of cake. But they’ve been doing it for years. Generating results at this scale is new for most academic molecular labs.”

Dr. Nolte also has to figure out discordant results from outside labs. “I can’t tell you how many times I’ve been dragged into, We have a patient who tested positive at another lab who was sent here and tested negative. What’s wrong with your test?” The answer, of course, might be “Nothing.” Not every referral lab has earned his confidence, particularly those that have sprung up seemingly overnight.

Even as Dr. Nolte was building up testing capacity, another problem was weighing on him—what he calls the staffing supply chain shortage. “I have the instrument capacity that exceeds the technical capacity to run those instruments like they should be run, 24/7,” he says.

It’s not from a lack of support from hospital administration. “If we put ‘COVID’ on anything, it gets approved,” says Dr. Nolte. While there have been staffing ups and downs over the years in the lab, they pale in comparison to what’s happening now. “I’ve never run into a problem like this in the 35 years I’ve been doing this.”

He mentioned his plight in an Association for Molecular Pathology COVID-19 virtual town hall in June. “After that I got a lot of emails from temporary staffing agencies: Dr. Nolte, we understand you can’t staff your lab. We’d love to help,” he says, laughing. He’s tried leveraging capacity from the research community, though that’s not a sustainable solution, he says, because those employees eventually will be returning to their own labs.

He currently has 12 staff who perform COVID-19 testing exclusively. But as other lab employees return from furloughs, “They want to go back to their day jobs,” Dr. Nolte says, which is where they’re needed. COVID-19 volumes are increasing, just as the need for other testing is returning to normal. Moreover, the molecular lab has a larger function as well. “It’s been a struggle to preserve our testing menu,” he says, “because many of those tests are run on the same instruments that are working 21/7”—with that 24/7 goal in mind—“generating COVID results. So now we have to figure out how to squeeze in our routine tests.”

He does have a nuclear option, he says. “We could send out our routine tests to make room for more COVID testing.” He pauses to let that paradigm shift sink in. “To think that we would do that. . . .You’d think we’d take the reverse approach. But everything is so different.” It is, he says, like walking on Mars.

Dr. Fuhrman hasn’t had to resort to layoffs or furloughs, but as her institution prepares to return to more normal routines, she says she, too, will need to figure out how to staff for the already large and ever-increasing volume of COVID-19 testing.

She also counts herself among the fortunate few who haven’t had to struggle with supply chain issues as far as swabs and transport media. “We never had a shortage, which was a big win for us,” she says, crediting the hard work of her “phenomenal” supply management team as well as the vice president of labs, who oversees supply chain.

An unexpected gift came from a large academic research institution, which has been producing batch volumes of viral transport media (“It’s a complicated recipe, so you might as well make a lot of it,” she says) and, as a public service, distributing it free of charge to labs, including hers. “We do the aliquoting into individual specimen collection tubes in our pharmacy under their biological sterile conditions, and make up our own collection kits in-house. It was wonderful to be given this viral transport media, which has been impossible to get. So we’ve got plenty of collection kits. That was one thing we did really well, and we did it early, so we didn’t have that problem.

“Kudos to everyone for making that happen,” she continues. “It’s completely unprecedented. It’s a huge deal. Everybody’s working together and helping one another all across the country.”

Dr. Nolte was watching his state start to wrestle with testing in a way it hadn’t early on. “We were doing pretty well,” he says. When large-scale testing began in the state, primarily anchored in Charleston, the focus was on symptomatic individuals, who moved through the process via telehealth visits and appointments at mobile collection sites. The positivity rate early on was about six percent and steadily dropped, Dr. Nolte recalls. “Until we reopened.” Positivity rates were in the double digits in parts of the state, and had surpassed the initial rate in Charleston. Weeks later, in mid-July, infections and hospitalizations were still rising.

“Things aren’t really going the way we want them to go in South Carolina,” says Dr. Nolte, “so we’re all a little worried.” He notes that the state was one of the last to shut down as the pandemic began and one of the first to reopen. “We’re not on a good glide path right now.”

In Louisiana, Dr. Sossaman was also watching numbers rise. Unlike South Carolina, however, the graphs depicting numbers of cases looked more like a set of camel’s humps than a trip up a single mountain. When the pandemic first landed, New Orleans was hit especially hard. “That’s when my life as a system chair stopped,” Dr. Sossaman says, and he, along with several colleagues, switched to full-time COVID testing strategies. “It was nothing else for a couple of months.”

They quickly scaled up, bringing on PCR testing, followed by rapid testing. Months later, the scenery still looks the same.

“We’re using every single test every day,” Dr. Sossaman says. “I don’t think we can build out capacity fast enough. We’re still seeing the need for additional capacity throughout the state. We had to build out a whole new lab because we ran out of space.”

How fast are things moving? Says Dr. Sossaman: “We’re still constructing the lab while they’re putting the instrument together.”

‘We’re using every single test every day. I don’t think we can build out capacity fast enough.’ — Gregory Sossaman, MD

Dr. Fuhrman’s biggest challenge, still, is obtaining reagents, a situation that “has gone off the rails.”

The lab runs five different testing platforms. “That’s the only way I can get enough tests to do what I need to do,” she says. Capacity in June was 1,400 to 1,500 tests per day, but she hopes to boost that to 2,500 as fall approaches.

The normal limitations are no longer in play. “If I want money, if I want space, the system will give me whatever I need,” she says. “If it has to do with COVID testing, it will be approved at the highest level as soon as I present a cogent plan.” The importance of COVID-19 is one obvious reason for this loosening of purse strings, but she cites another factor as well. Throughout the pandemic, “The lab has garnered unbelievable respect from the health system. And we haven’t steered anybody wrong, so they trust us.”

Trust can’t unsnarl supply chains, however. “I just can’t get what I need for love or money,” she says. Vendors can’t deliver, nor do they want to overpromise, she says. That has put laboratorians in another new situation: Purchasing instruments now entails negotiating for reagents. “That is never how it worked before,” she says. “Usually they try to push more reagents than you need.”

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