There will be lessons learned aplenty when the COVID-19 pandemic finally breaks, including how serological and molecular testing can be used to maximum effect to corral a future pandemic. Carmen Wiley, president of the American Association of Clinical Chemistry, told BioWorld that the existing instrument types are up to the job, but that surge capacity is needed, and that it is not clear how the cost of that capacity will be handled.

Among the instrument types that are available to clinical labs are immunoassay and chemistry analyzers, the former of which is used to test for cancer biomarkers and indicators of infectious diseases. Some immunoassay analyzers are benchtop units, but some are full-sized, cabinet models with a footprint comparable to a large gas grill. A chemistry analyzer can be used for photometric and colorimetric testing, as well as ion-selective potentiometry and latex agglutination. These can be used to analyze samples such as blood serum, plasma and urine for features such as proteins, enzymes and electrolytes.

These systems are found in both small point-of-care clinical settings and high-throughput labs. Many chemistry analyzers are benchtop units, but there are more compact units for use at the bedside. In contrast to immunoassay and chemistry analyzers, polymerase chain reaction (PCR) testing requires the use of a thermocycler to provide the mass replication of the DNA or RNA of interest for molecular testing, and thus a fully equipped clinical lab must be in possession of a range of expensive equipment in addition to the supplies, such as reagents, needed to conduct tests.

Wiley, who is also the chief medical officer for Veravas Inc., of Charleston, S.C., told BioWorld that while there are compact, bench-top PCR units widely commercially available, some reference labs and large hospital labs may require a high-throughput PCR unit. A lab’s choice of equipment and analyzers “depends on the size of the lab. Every lab will have some sort of clinical chemistry and some sort of immunoassay system,” Wiley said, but the larger labs usually have a molecular testing platform as well.

Excess capacity a poor business model

One of the requirements for the next pandemic is excess capacity, but Wiley confirmed that this requirement runs counter to the business model adopted by most labs. Administrators at labs look for efficiency because “health care is a business too, and people can’t have excess capacity” without damaging the bottom line, she said. The excess capacity would not have to be entirely idle as the ordinary testing load can be shuttled back and forth between these systems, even if they are underutilized, strictly speaking.

Wiley said one approach to this might be to increase rates for the tests in these labs that bring on excess capacity, adding that the higher rates could be dropped back to normal once the operator has amortized the cost of the new equipment. Whether this is currently a policy point for legislators and the executive branch is not yet clear, but any associated considerations are likely to be neglected until the worst of the pandemic has passed.

Another consideration when it comes to excess capacity is the time needed to purchase, set up and validate the equipment. Wiley said delivery of these systems typically takes a week at the inside, and the lab operator must validate the installation and operational set-up prior to conducting actual test runs on the new system. All told, this process can take three to six months, so these more complex systems have to be in place already when the pandemic strikes, or they’ll play little or no role in the effort to normalize the impact of the virus.

Wiley also confirmed that high-speed, point-of-care (POC) tests are “inevitably more expensive” on a per-test basis, due in part to the less efficient use of supplies and reagents in addition to the greater use of disposables.

Still, Wiley noted, “what would make the biggest difference … is molecular testing nearer to the patient” when a pandemic strikes, which might call for purchase and storage of supplies along with the purchase of analytical equipment. Another question policymakers will have to answer is whether the current national stockpile system and its associated distribution mechanisms are well designed to respond to these emergencies.

Opposition to FDA regulation may spike

The most important lesson for the U.S. is that all labs and diagnostic companies must be brought into the loop regarding preparations for the onset of the next pandemic, Wiley said. There was an undue delay in deployment of tests because of federal regulation, and when asked whether the current predicament might influence the appetite on Capitol Hill to give the FDA explicit authority to regulate lab-developed tests (LDTs), she said, “I think that could change. We don’t need FDA oversight of lab-developed tests,” she said, emphasizing, “this is evidence that we don’t need FDA oversight.”

Wiley said there is a misunderstanding about the false negative tests for the SARS-CoV-2 virus in that many of these were due to pre-analytical factors, such as poor swab samples. Another problem might be that a patient’s disease had evacuated the upper respiratory area by the time the swab sample was obtained, in which case the virus may not be present in sufficient quantities to return an accurate result. A quick transition to the lungs is to date associated with more severity, but Wiley said the data behind that association are preliminary. That idea makes sense to the extent that longer viral residence in nasal areas gives the immune system more time to respond.

Serology testing at present can be used to detect any one of three immunoglobulins (IgA, IgG and IgM), but Wiley said these antibodies emerge at different times in the disease. IgA and IgM are typically detectable fairly early in the COVID-19 disease cycle, but IgG takes longer to emerge. Consequently, while serology is useful for population screening, it is perhaps less useful than molecular testing to establish with certainty whether the individual patient is carrying the SARS-CoV-2 virus.

One caveat to all this is that there are still antecedent species of the coronavirus still at large, and a specificity of 97% and sensitivity of 90% is generally the rule of thumb for making this kind of distinction. Wiley noted that the medical community may ultimately revisit whether these thresholds are appropriate for determining whether a health care professional should return to work, but she also noted that molecular tests are more useful for establishing whether that doctor or nurse is still capable of actively discharging the virus.

Epigenetic echoes give a rapid picture of who’s been exposed

By Anette Breindl, Senior Science Editor

One challenge for diagnosing infections is that it can’t be done right away. It takes time for viral titers to build, and even longer for symptoms to appear. In fact, one challenge of the COVID-19 pandemic, and a major difference to SARS and MERS, is that infected, presymptomatic individuals are contagious.

A research program by the Defense Advanced Research Projects Agency (DARPA), the Epigenetic Characterization and Observation (ECHO) project, is working on a diagnostic test that could identify exposure to a pathogen, or any toxin, very rapidly.

In principle, looking at epigenomic signatures could detect an exposure as little as 30 minutes after it has occurred.

Epigenomic changes are the first step to changes in gene expression set off by an infection. The idea behind the project is that “you can use the epigenomics to detect infection,” Joshua LaBaer, executive director of Arizona State University’s Biodesign Institute and director of the Center for Personalized Diagnostics, told BioWorld.

Moreover, “because of the nature of epigenomics, there is also the possibility to have a sense of when the exposure occurred,” he said. “Different epigenomic signatures appear at different timepoints, and they disappear at different timepoints.”

In 2019, LaBaer, co-principal investigator Vel Murugan, and their team received a $39 million grant from DARPA for developing rapid diagnostics that use epigenomic marks to determine whether an individual has been exposed.

An epigenomic test could look at signatures from a blood sample to determine whether an individual had been exposed to a harmful agent, and determine the nature of the exposure.

In this and future pandemics, the test could also be used to determine the precise nature of the infection.

“If people get sick and you don’t know at all what’s causing it, you’d like to know immediately, ‘Is this viral, bacterial chemical, radiation?’” said LaBaer. “But then you want to pinpoint the exposure.”

Early responses to infections by the innate immune system are less specific than later adaptive immune responses, but LaBaer said that he is “optimistic that there are some distinguishing features.”

Murugan told BioWorld that “very early on symptoms seem to be like the flu, but there are a lot of differences between influenza and COVID-19,” including reports of early gastrointestinal symptoms and possibly the loss of smell and/or taste sensation with COVID-19 infections.

LaBaer estimated that getting the initial device to a point where it could be deployed will take around a year. But once a device that can differentiate different signatures is up and running, adding another signature in the event of future emerging threats would be much faster.

“The device itself is agnostic,” Murugan said. “You can look for any signature for any kind of exposure.”

Editor’s note: Pandemics come and go, but they keep coming. And so, even as the world grapples with COVID-19, researchers and public health officials are trying to apply its lessons to future outbreaks. Part 3 in tomorrow’s issue will look at drugs: From “fire breaks” to repurposing and host-directed therapies, the quickest paths to a therapeutic arsenal. In Friday’s issue, part 4 will explore vaccines. Read part 1 focusing on surveillance for the next pandemic.