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Infectious Disease Expert Weighs In On The Realities Of COVID-19 Testing

By Deborah Borfitz

September 22, 2021 | When it comes to diagnostic testing for COVID-19, “there is a place for everything,” says Norman Moore, Ph.D., global director of scientific affairs, infectious diseases, at Abbott Diagnostics. “Nothing is perfect.”

Moore was presenting on point-of-care (POC) infectious disease molecular testing at the recent Next Generation Dx Summit. Vaccine resistance has joined antibiotic overuse on the list of issues threatening public health, says Moore, adding that he fears the current pushback on vaccination against COVID will spread to other preventable diseases such as measles, mumps, and rubella.

While COVID will “eventually go away or maybe be mitigated to the oldest and youngest of us,” he says, antimicrobial resistance is an enduring problem that is only likely to worsen. Many people continue to question the harm in overprescribing antibiotics simply because they haven’t considered the consequences for individuals who have potential resistance and the downstream ramifications for everyone else when first-line drugs no longer work.

By 2050, Moore notes, antimicrobial resistance is predicted to kill more people than cancer and diabetes combined.

“That’s why we need these diagnostic tests,” he says. “We don’t want to be guessing. I don’t care how good of a microbiologist you are, you can’t look at a person’s throat and say whether it’s group A strep or a viral infection.”

Rapid testing is enormously helpful in POC settings to minimize inappropriate antibiotic prescribing by shortening the wait for results and guiding treatment decisions. The tests not only save money but provide “teachable moments” with patients who may otherwise insist on getting an antibiotic, Moore says. “I can’t even imagine the world today without HIV rapid diagnostics,” enabling larger numbers of people to benefit from knowing their status.

Unintended Consequences

By number, 90% of the cells in the human body are bacteria, says Moore, referencing the microbiome. Scientists are starting to appreciate “the relationship between us and our commensal bacteria is way more important than we thought before.” Throwing antibiotics at the imbalances, without any diagnostic testing, can have “unintended consequences.”

According to the hygiene hypothesis, for example, lack of early childhood exposure to microorganisms in the environment causes defects in the immune system that would otherwise protect against allergic diseases—and also explains the rise in peanut allergies over the past few decades, he says. Such allergies are more often seen in one-child households and less often among individuals growing up on a farm.

Emerging research on the microbiome has found that putting the gut flora of an obese mouse into a germfree mouse will, by itself, cause weight gain, Moore shares. Mice given low-dose penicillin will also become anxious, and anxious mice will take longer to get down off a pedestal—at least until they’ve been given a microbial boost from other, non-anxious mice. The effect also works in reverse to produce anxiety in more carefree mice.

“I know in this day and age we have a generation of very anxious children that we have to watch because suicide rates have gone up,” he says. Social media is the big, but likely not the only, culprit.

“We have to change opinions,” says Moore, adding that it is useless to run inexpensive diagnostics if patients are still demanding an antibiotic. “If we can’t change how people are doing things, we are just costing money… we [need to] change our messaging to make people understand that there are consequences in giving unintended antibiotics.”

The Contenders

When developing a diagnostic for COVID-19, it needs to be “very specific” to the SARS-CoV-2 virus, says Moore. “If it cross-reacts with SARS, I don’t care because the last time we had a SARS case was 2004.”

Fortunately, testing during prior coronavirus outbreaks have provided conserved sequences of RNA that could be developed into molecular tests for COVID-19, he says. Conserved sequences in the nuclear protein have also enabled the development of antigen-based tests. The antigen-based tests are less sensitive but can be done more frequently, which improves their sensitivity, making them ideal in back-to-school and back-to-work scenarios. 

Initially, serology-based diagnostics were seen as “the savior” for getting back to school and work, Moore continues, with IgM and IgG antibody tests delivering results within 24 to 36 hours of one another. But many of them, sailing through the Food and Drug Administration’s Emergency Use Authorization process, proven to be of subpar quality.

Over time, it also became clear that serology testing was fundamentally problematic. Having an antibody titer doesn’t necessarily mean people will never get COVID again, and not having an antibody titer doesn’t necessarily mean they are not protected, he points out. Titers rise “quite quickly” at the start of the virus but then fall off.  

Lab-based PCR tests offer the highest sensitivity possible—so good, in fact, that people can test positive for over 100 days, Moore says. That introduces questions about how to treat and care for those individuals and highlights the importance of understanding patient needs and where they are in the disease state.

At the beginning of the pandemic, he notes, some patients were being kept in the hospital for as long as 60 days because they didn’t get a negative PCR test result two days in a row “when they weren’t a threat to anybody.”

No COVID diagnostic should be used as a “test of cure,” says Moore. Instead, symptomatic individuals can safely assume they are no longer infectious after 10 days, provided they haven’t had a fever for 24 hours. “Virtually all of those people would have been positive by PCR if you tested them.”

Antigen tests are best suited for routine (e.g., twice a week) screening since frequent PCR testing is in many instances unaffordable, Moore says. They can catch positive cases when individuals are in the early part of their illness and most infectious. If budgetary constraints limit PCR testing to once a month, “you are going to miss all the people who got the virus two weeks before that.”

Interpreting Results

“We now have many different ways to skin the same cat,” says Moore, with many more diagnostic options on the way. In addition to traditional PCR-based tests, where amplification requires cycling of temperatures, the menu includes tests that do this isothermally using a constant temperature. That makes isothermal amplification methods ideal for settings, including urgent care and pediatrics, where results are needed in under 15 minutes.

Many PCR tests are also now delivering results rather quickly—in some cases as little as 20 minutes—by improving their heat dynamics, he adds. The issue remains that a PCR positive result isn’t necessarily indicative of infectivity, and the complexity increases when looking at asymptomatic populations.

Cycle threshold (CT) is an important metrics to consider with PCR tests, Moore says, since every heat-and-cool cycle doubles the amount of DNA. A high CT number means a low amount of starting virus, whereas a low CT number implies a high amount, providing a way to “semi-quantify” the meaning of test results for individual patients.

The problem is that there is yet no consensus on the CT cutoff point at which a person is infectious, says Moore. Various publications have suggested a CT of anywhere from 20 to 33. But CTs will differ by the gene being targeted and, even when targeting the same gene, will vary by test manufacturer. South Korea doesn’t even count results where the CT is above 28.

In addition to his caution about CT, “use the right test for the right people,” he says. “Detecting the virus in the infectious phase is what matters most to stop the spread of COVID-19.”

The Centers for Disease Control and Prevention (CDC) is updating its COVID-19 guidelines as fast as humanly possible, says Moore. But it doesn’t have the political power to issue mandates and communities are variably opting to follow the agency’s recommendations.

Complying with CDC guidelines isn’t a straightforward proposition for individuals who test positive but are asymptomatic, he notes. “They don’t know when to start counting” on their 10-day quarantine period.

Antigen tests, when pitted against PCR, have shown highly mixed results on sensitivity, Moore says. Those performing poorly had no qualifier, such as viral culture, which would likely have changed results of the matchup. PCR tests might have decent sensitivity for 40-50 days while antigen tests would reliably detect the true positives only in the first seven days.

Changing Minds

Simply accessing a COVID test could be problematic at the beginning of the pandemic, says Moore, and manufacturers responded by ramping up production. But the “knife fights” could begin anew in areas with limited availability or affordability with the Delta variant raging.

When choosing between tests, Moore cites research pointing to testing frequency, speed to results, and the patients to be tested as the chief considerations. All test types are going to be needed, he says.

“Sensitivity of the lateral flow test is really only about 85%, but if you go to a molecular-based test and you are not willing to change prescribing habits, don’t run it, save the money,” he says. “The whole issue with these molecular-based tests is you have to get to the high 90s to… change the minds of people not to treat.”

The Infectious Diseases Society of America issued guidelines late last year on diagnosing COVID-19 with molecular tests, he notes.

It remains to be seen what will happen when, and if, COVID and flu are co-circulating, says Moore. The double-whammy was expected in South America, but the flu season there turned out to be weirdly mild.

Flu in general has been “one of the greatest threats to humankind” but underappreciated as such, he says in conclusion. The threat posed by respiratory syncytial virus likewise gets underplayed and, in the elderly, really requires a molecular test since rapid tests often do not work well in that demographic.

Final Thoughts

In the Q&A following his presentation, Moore clarifies that antigen testing is better for asymptomatic individuals only if it is done routinely in the early part of the illness. Done as a series of one-offs, he says, “you can have much lower sensitivity and then you don’t know what to do.”

In line with the CDC, he is not ready to recommend asymptomatic testing for the flu. Rather, his standard advice is “if you feel bad, stay the heck away [from others].” 

Similarly, he is not particularly enthusiastic about serology testing. “Is it going to be like hep B where I have no titer and suddenly it comes roaring back? I think it’s too early.”

Moore also takes a wait-and-see attitude on the question of using antibody testing as evidence of the need to be vaccinated. “We’re talking about boosters these days… and I don’t know that we are necessarily going to look at a titer before we give a booster [shot] to a transplant patient.”

The “million-dollar question,” he says, is if COVID can be more easily culturable. The SARS-CoV-2 virus is difficult to grow but, when done, provides a means to define the reliability of PCR and antigen tests for assessing infectious potential. “I wish there were a molecular way to say yes or no, but it is nothing I’ve seen yet.”

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