Book:COVID-19 Testing, Reporting, and Information Management in the Laboratory/Diagnostic testing of COVID-19 and other coronaviruses/Current test methods and their differences

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2.4 Current test methods and their differences

NOTE: Information shown here may rapidly become outdated given how quickly response to pandemic testing can change. A full attempt to keep the content relevant will be made.

2.4.1 Background on the laboratory testing environment

Before continuing, it should be noted that many elements of the prior-mentioned COVID-19 testing guidance have governmental public health laboratories in mind. However, as the scale of the epidemic has grown, the need for commercial laboratories and assay developers to get involved with efforts towards increasing analytical testing throughput—through a more rigorous public-private partnership—has become abundantly clear.[1][2][3][4] Even so, at least in the United States, turnaround times have been slow due to a variety of factors, from lack of in-house laboratory resources to handle high test volumes and a slower-than-expected ramping up of test kit production[1][3][4], to actually getting diagnostic assays that are more rapid (yet still accurate) in their diagnosis, simpler to use, and useable at the point of care.[5][6] The good news is examples of these rapid point-of-care molecular test kits are now becoming available around the globe, including the United States as part of the U.S. Food and Drug Administration's Emergency Use Authorization (EUA) process.

As the demand for expanded diagnostic testing grows in the face of a pandemic, it's important to compare the U.S. laboratory testing environments of public health and large commercial testing labs with those of small, in-office clinical labs. In the U.S., all but research-based laboratory testing of human specimens is regulated under CLIA, including public health laboratories. Of the more than 256,000 non-exempt CLIA-registered labs in the U.S., only 33,153 or 12.9 percent of them are certified to perform moderate- and high-complexity testing.[7] Your public health labs and commercial diagnostic labs fall into this category, with investments in the personnel, training, certifications, and equipment to conduct those sorts of tests. Contrast this with the small yet numerous physician office laboratories (POLs) and how they operate. As of March 2020, some 46.2 percent of non-exempt CLIA-certified laboratories in the United States are POLs.[7] Located in an ambulatory or outpatient care setting, these labs test specimens from human patients to assist with the diagnosis, treatment, or monitoring of a patient condition. Testing in the clinical lab generally depends on three common methodologies to meet those goals: comparing the current value of a tested substance to a reference value, examining a specimen with microscopy, and detecting the presence of infection-causing pathogens.[8]

These POL's operate in a different environment than your average public health laboratory or reference lab that receives, processes, and reports on specimens en masse. The POL is typically a smaller operation, performing simple laboratory testing that can produce useful diagnostic data cheaply and rapidly. Rather than performing advanced pathology and molecular diagnostic procedures that require specific equipment and expertise, the POL typically focuses on blood chemistry, urinalysis, and other testing domains that don't require significant resources and provide rapid results. This can be seen in Centers for Medicare and Medicaid Services statistics reported in March 2020 that show 67.1 percent of non-exempt POLs in the U.S. are certified to provide CLIA-waived tests[7], "simple tests with a low risk for an incorrect result."[9]

As of late November, with 1. all but several handfuls of the current EUAed molecular in vitro diagnostic COVID-19 test kits being limited to moderate- and high-complexity CLIA labs[10] (the FDA claims that EUAed SARS-CoV-2 tests authorized for "use at the point of care" are considered CLIA-waived tests[11]), and 2. serology testing still being considered moderate- to high-complexity in nature[10], a significant majority of clinical laboratories are left with only a handful of CLIA-waived options for assisting with the effort to test the U.S. population for SARS-CoV-2 infection. Given the rapid rate of change at multiple levels of government and society, and wildly varying levels of reliable information being given to the public[12][13], it's important to remember these fundamental differences in laboratories when trying to explain to someone why they are, as of yet, unable to go to their primary care physician and get tested for SARS-CoV-2 in the doctor's office. Should researchers develop and the FDA provide EUAs for more CLIA-waived point-of-care assays, these differences may become less noticeable, and more people will be able to be tested.

2.4.2 PCR-based methods

As of mid-November 2020, the U.S. Food and Drug Administration (FDA) has issued 190 EAUs for all types of molecular in vitro diagnostic test kits. One hundred and fifty-eight of those 190 are only authorized to be used in CLIA-certified high-complexity laboratories, and 16 are rated for both moderate- and high-complexity. When looking at the makeup of the EUAs, a huge majority of those tests use some form of RT-PCR methods, with most using real-time or qualitative versions of RT-PCR (qRT-PCR). CLIA-waived RT-PCR tests are still rare, however. Four PCR-based kits—Mesa Biotech's Accula SARS-Cov-2 Test, Roche Molecular Systems' cobas SARS-CoV-2 & Influenza A/B, Cepheid's Xpert Xpress SARS-CoV-2 and SARS-CoV-2/Flu/RSV, and BioFire Diagnostics' BioFire Respiratory Panel 2.1-EZ—have an additional authorization for point-of-care (POC) use (and thus CLIA-waived use) when used with their authorized POC devices.[10]

Of course, there are many more test kits than those approved in the United States. The Foundation for Innovative New Diagnostics (FIND) is currently "collating an overview of all SARS-CoV-2 tests commercially available or in development for the diagnosis of COVID-19."[14] As of mid-November, their site shows more than 260 commercialized manual NAAT tests around the world (most being RT-PCR), with nearly 30 in development. The AdVeritasDx test and controls database is also useful.[15]

2.4.3 LFA and isothermal amplification methods

LFAs are currently rare, but due to their advantages of being quick and useable at the point of care, some healthcare professionals have suggested that as a format for antigen and antibody (serology) testing, they could positively change the testing landscape.[16][17][18] As of mid-November, 16 of 58 serology tests that have received EUAs by the FDA for moderate- and high-complexity CLIA-certified labs are explicitly labeled as being LFAs. (Also of note: one LFA serology test, the Assure COVID-19 IgG/IgM Rapid Test Device, is approved for POC/CLIA-waived use.)[10] An article by Sheridan in Nature Biotechnology highlights a handful of others developed around the world (see their Table 1).[16] FIND shows more than 300 commercialized rapid diagnostic immunoassay tests around the world, though it's not clear how many of them actually LFAs (from their list, only six are explicitly stated as being LFA).[14] At this point, it's safe to say that LFA are still being developed, and it may be a while before we start seeing more of them, at least in the United States.[17]

Also of note are isothermal amplification methods. Abbott's ID NOW and Cue Health's Cue COVID-19 tests are described by the FDA as using "isothermal nucleic acid amplification technology for the qualitative detection of SARS-CoV-2 viral nucleic acids."[19][20] Isothermal amplification tends to be an easier process to manage due to being able to keep amplification at a constant temperature.[21] In fact, Abbott has stated its EUAed ID NOW COVID-19 test can be completed within five minutes.[22] However, mid-May findings by New York University put the test's accuracy into question. On July 1, an FDA spokesperson allegedly indicated receipt of 126 reports of "adverse events" concerning the test.[23] (That number was beyond 300 as of a September 30 statement[24] and a November 18 FDA MAUDE search.[25]) The FDA has since been investigating the data and working with Abbott to have additional studies performed on the test's accuracy.[26] In October 2020, Abbott released additional study data showing overall sensitivity of 93.3% and specificity of 98.4%, emphasizing the ID NOW's best use with samples taken within seven days of symptom onset.[27]

Specific isothermal amplification techniques called loop-mediated isothermal amplification (LAMP) and reverse transcription LAMP (RT-LAMP) are beginning to emerge as options for COVID-19 testing. For example, Talis Biomedical is developing the Talis One COVID-19 system for point-of-care testing. It has received National Institutes of Health's Rapid Acceleration of Diagnostics (RADx) funding[28] and, should it receive its EUA, is expected to be among the first U.S.-approved RT-LAMP tests for COVID-19.[29] In mid-November, the first LAMP-based, prescription "collect and test" at-home kit—the Lucira COVID-19 All-In-One Test Kit—was approved by the FDA for emergency use.[30] Globally, examining FIND's list of more than 260 commercialized manual NAAT tests around the world, four of them are explicitly shown to be some form of LAMP test. Multiple preprints on medRxiv and bioRxiv, as well as published papers, suggest that RT-LAMP could provide rapid results for SARS-CoV-2 testing.[31][32][33][34][35]

2.4.4 Blood serum

Blood in tubes (9617266704).jpg
Blood serum or serology assays come in three common varieties: LFA, enzyme-linked immunosorbent assay (ELISA), or neutralization assay.[36] As discussed prior, LFAs are intended to be rapid point-of-care tools for qualitatively testing body fluids for patient antibodies or viral antigen. The ELISA is, in contrast, a more lab-bound method which produces results that are qualitative or quantitative. In the context of COVID-19 testing, ELISA tests for the presence of patient antibodies in a given specimen based upon whether or not an interaction is observed with the viral proteins present on the test plate. However, even if antibodies are present, ELISA isn't able to tell a clinician if those antibodies are able to protect against future infection. Neutralization assays are the lengthiest to complete, taking from three upwards to five days.[36] This is largely due to the fact that the assay depends on culturing cells that encourage growth of the target virus. Afterwards, introduced patient antibodies, if present, will fight to prevent viral infection of cells. This process is performed in decreasing concentrations, giving the clinician an opportunity to "visualize and quantify how many antibodies in the patient serum are able to block virus replication."[36] In contrast to ELISA, a neutralization assay is able to determine if a patient's antibodies are actively fighting against the target virus, even after recovering from the infection. In November 2020, the FDA granted an EUA to the first ELISA-based serology test to detect nuetralizing antibodies from recent or prior SARS-CoV-2 infection.[37]

Johns Hopkins' Center for Health Security appears to be tracking serology-based COVID-19 tests that are in development or have been approved in various parts of the globe. However, for the most up-to-date list of serology tests that have received EUAs in the United States, the FDA's EUA list appears to be the best source. As of August 23, the FDA shows 58 serology assays approved for diagnostic use in the U.S. Of those 58, eleven are explicitly listed as being ELISA-based.

A review of Johns Hopkins' tracking list showed more LFA-based tests among those approved in other parts of the world. Among their list of those still in development, an LFA stands out for integrating CRISPR detection.[38] CRISPR (clustered regularly interspaced short palindromic repeats) represents bacterial and archaeal DNA sequences derived from DNA fragments of previous infection. This genetic material can then be used as an activator of biomarkers when attached RNA "guides" find a match with target viral RNA in patient specimen.[39] This CRISPR-based LFA, called DETECTR, was further described in a paper published in October 2020, with the authors concluding it could be used "as a complementary technically independent approach to qRT-PCR, thereby increasing the testing capacity of medical microbiological laboratories and relieving the existent PCR-platforms for routine non-SARS-CoV-2 diagnostic testing."[40]

2.4.5 Antigen tests

An antigen is a substance—often a protein but may also be an environmental like a virus—that provokes the immune system to produce an antibody against it.[41] As such, another approach to testing for the presence of a virus in a specimen is to test for the antigen rather than the antibody. An antigen test is useful as a repeated surveillance test, but it has drawbacks as a one-time diagnostic test.[42][43][44] For COVID-19 and other viral infections, an antigen test has the advantage that specimen collection can typically be done with a simple nasal swab rather than a more invasive nasopharyngeal swab. Another advantage, on one hand, is that antigen testing is more rapid and convenient because the extraction and amplification steps of PCR are not used. On the other, antigen testing is less sensitive for the same reason: you test only what's there (rather than amplifying the amount for greater sensitivity).[43][45]

A theory increasingly gaining traction, however, is that "[a] higher frequency of testing makes up for poor sensitivity.”[43][44][46] Several researchers have shared pre-print and published research suggesting this outcome[43]:

Larremore and his colleagues have modeled the benefits of more frequent tests, even ones that are less accurate than today’s. Fast tests repeated every three days, with isolation of people who test positive, prevents 88% of viral transmission compared with no tests; a more sensitive test used every two weeks reduced viral transmission by about 40%, they report in a 27 June preprint on medRxiv. Paltiel and his colleagues reached much the same conclusion when they modeled a variety of testing regimes aimed at safely reopening a 5000-student university. In a 31 July paper in JAMA Network Open, they found that, with 10 students infected at the start of the semester, a test that identified only 70% of positive cases, given to every student every two days, could limit the number of infections to 28 by the end of the semester. Screening every seven days allowed greater viral spread, with the model predicting 108 infections.

As such, the utility of antigen testing, despite its lower sensitivity, appears to be surveillance situations where a large group of individuals who are at risk can be screened at regularly scheduled intervals of two to four days. The end result, in theory, would be few people who are target-positive would be missed, positives could be isolated and verified with a more sensitive test, and more target-positive people would be identified and isolated before reaching peak infectivity.[43][47] To be clear, it's not a perfect solution, but as Harvard epidemiologist Michael Mina and Boston University economist Laurence Kotlikoff suggest, "[w]e need the best means of detecting and containing the virus, not a perfect test no one can use."[47] A coalition of six U.S. state governors has bought into that concept and agreed to work together with the Rockefeller Foundation, as well as the Quidel Corporation and Becton, Dickinson and Company, which have received FDA EUAs to market antigen tests for SARS-CoV-2.[46][48] However, it's not clear how those six states will best put the tests to use despite 1. their moderate sensitivity (and thus a greater chance of false negatives[46]) and 2. the question of whether or not the two companies can produce enough test kits for repeat testing in those states.[43] As of November 2020, seven total vendors have FDA EUAs for antigen tests; six of those seven include allowances for CLIA-waived testing.[10]

2.4.6 Testing alternatives and challenges

We’ve never faced this before, where clinical labs needed to very quickly be able to ramp up a test so fast.[49]
 
- Jennifer Doudna, Executive Director of the Innovative Genomics Institute, University of California, Berkeley

Though the dismantling and fund-cutting (proposed and real) of government programs designed to protect the populace from pandemics—as well as shortfalls in funding overall[50]—have likely hobbled local, national, and global response to COVID-19[51][52][53][54], it should be recognized that this pandemic may arguably represent a once-in-a-century type of event.[55][56] That said, even the most well-prepared governments would still face challenges in quickly learning about, controlling, and developing therapies for a novel disease agent. Shortages in supplies, workers, funding, and other resources are inevitably caused with a pandemic as people across all types of infrastructure fall ill.[50][57] This requires the additional human elements of adaptability, drive, and shared knowledge to find new and alternative solutions to fighting the challenges inherent to fighting against a novel disease.

See for example a non-peer-reviewed paper published on bioRxiv in early April 2020, where Schmid-Burgk et al. point out that though RT-PCR methods are the most common for currently testing for SARS-CoV-2, "global capacity for testing using these approaches, however, has been limited by a combination of access and supply issues for reagents and instruments." They propose "a novel protocol that would allow for population-scale testing using massively parallel RT-LAMP by employing sample-specific barcodes." They claim that a single heating step, pooled processing, and parallel sequencing with computational analysis would allow for the testing and tacking of "tens of millions of samples." Though the protocol has not been validated with clinical samples, and concerns about sensitivity levels of RT-LAMP (an isothermal nucleic acid amplification technique that allows for RNA amplification) have been raised, the authors' work exemplifies the immediacy and ingenuity going into finding workable solutions to a once-a-century problem.[31]

Another example of ingenuity in the face of difficult circumstances can be found at the University of California, Berkeley. Its Innovative Genomics Institute (IGI) has rapidly repurposed a 2,500-square-foot scientific lab into an automated diagnostic laboratory that can initially process more than 1,000 patient samples per day, with the ability to ramp up to 3,000 per day thanks to robotics and a streamlined workflow. Partnering with dozens of people from Thermo Fisher Scientific, Salesforce, Third Wave Analytics, and Hamilton Corp., the lab is focused on not only turnaround time but also accuracy of results through automation. Their continued success, of course, relies on a steady supply of reagents and related supplies from Thermo Fisher.[49][58]

Others have also expressed concerns about the global supply of reagents necessary to test for SARS-CoV-2. Successful testing using RT-PCR requires two different enzymes: reverse transcriptase, for converting RNA to DNA, and polymerase, for amplifying the converted DNA. These enzymes and other reagent components may be instrument-specific, and at least one component has to be sympathetic to detection of the target virus' RNA. Little of this can be prepared without a proper sequence of the virus in question. Dr. Ronald Leonard, president and medical director of Cytocheck Laboratory and medical director of the Labette Health hospital, has expressed the difficulties associated with reagent manufacturing thusly[59]:

With the instant demand for SARS-CoV-2 testing, the manufacturing process had to start from scratch for the SARS-CoV-2 specific components, and this did cause a lag time before reagents were available. The increased demand coupled with the decision to only allocate reagents to two national laboratories, some state health departments, and to "hot spots" has compounded the difficulty for laboratories like ours to obtain the necessary reagents to perform the testing.

Reports of COVID-19 test reagent shortages from various sources have appeared nearly every month since March 2020[60][61][62][63][64][65][66][48][47][67][68], though whether the shortages are a real supply issue or "a consequence of restrictive policies on where and how testing could be completed" has been previously argued by some.[59][62] As of November 2020, these shortages have even extended to supplies for non-COVID-19 tests such as those for strep throat, bronchitis, mycobacterial infections, urinary-tract infections, fungal infections, and sexually transmitted infections [67][68] In the face of these supply challenges, some have taken matters into their own hands. Noting Irish laboratories' difficulties sourcing lysis buffer (for isolating molecules of interest and keeping them stable), Cork Institute of Technology's Dr. Brigid Lucey worked with several other virologists and microbiologists, as well as pharmaceutical company Eli Lilly, to produce a custom-formulated yet high-quality lysis buffer for not only Irish laboratories but also other countries can take advantage of. "We are happy to share what we found with other countries and it’s important our scientists retain their skills to make this kind of formulation because we may need to do this again in the future if we get other pandemics," she said.[63]

Another challenge lies in the accuracy of serology-based antibody tests, let alone how much they actually tell us about immunity. FierceBiotech's Conor Hale touches upon this in late April[69]:

Compared to molecular tests—which sequence and match the RNA of the novel coronavirus to produce a result—the FDA has described antibody tests that gauge the body’s immune system response as a less-complicated endeavor that could proceed without review, dubbed “regulatory flexibility” by Commissioner Stephen Hahn. This policy shift has led to confusion, with some antibody test developers falsely claiming their tests are FDA-approved or could diagnose COVID-19 at home. Still others have sold outrightly fraudulent tests online.

At least in the U.S., these problems are compounded by company participation in test validation of EUAs being voluntary.[69] As a late April memorandum from Congress puts it: "FDA is unable to validate the accuracy of antibody tests that are already on the market, and companies are ignoring requests from the Department of Health and Human Services (HHS) to voluntarily submit their tests for validation ... FDA has failed to police the coronavirus serological antibody test market, has taken no public enforcement action against any company, and has not conveyed any clear policy on serological tests..."[70] The entire memorandum is revealing in the challenges of attempting to relax social distancing measures under the pretense of the effectiveness of antibody testing. Entities such as the University of California - San Francisco[71] and the University of California - Berkeley[72] have been emphasizing the importance of elements such as sensitivity, specificity, proper training, and the unknowns of the predictive ability of the test. Even assays running under trusted platforms such as PCR can reveal issues. For example, Thermo Fisher Scientific's TaqPath COVID019 Combo Kit, approved for EUA in March 2020, is now receiving scrutiny and updates to address issues with false-positive and -negative results[73][74], highlighting the difficulty of balancing the need for rapidly approving test kits for emergency use while also maintaining some semblance of oversight regarding their effectiveness and proper use.

Finally, the dearth of point-of-care testing, including at-home testing, remains problematic. Dozens of at-home tests remain in development (many of them antigen tests), though a major barrier is found in making them both accurate and easy for untrained people to understand and use.[75][76] These at-home tests would not be without concern, however, particularly with ensuring that test results get reported properly and rapidly.[75][77] Lucira Health's LAMP-based Lucira COVID-19 All-In-One Test Kit was approved as a prescription-based at-home test, with the stipulation that the prescribing healthcare provider would be responsible for reporting results.[30] Such a requirement could be put in place for at-home antigen-based testing as well.[75]

With public confusion growing and expectations increasingly out of line with the science[78], it's more important than ever for leaders across government, healthcare, and the media to continue to not spread misinformation and not make decisions based on poor scientific evidence. It will take organized efforts from multiple stakeholders—such as that found with a June NIH workshop on expanding and improving COVID-19 antibody tests[79]—to find responsible solutions to the challenges we still face with this pandemic.

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Citation information for this chapter

Chapter: 2. Diagnostic testing of COVID-19 and other coronaviruses

Edition: Edition 2.0

Title: COVID-19 Testing, Reporting, and Information Management in the Laboratory

Author for citation: Shawn E. Douglas

License for content: Creative Commons Attribution-ShareAlike 4.0 International

Publication date: August 2020