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3. Adding COVID-19 and other virus testing to your laboratory

Maybe you've been running an environmental health laboratory and want to expand into clinical health testing. Perhaps you're in charge of an academic research lab but want to expand to the clinical diagnostic side. Or maybe you're running a physician office laboratory (POL) and are wondering if it's even possible to expand your waived testing efforts to COVID-19. Where the previous chapter discussed the "what" of COVID-19 and viral testing, this chapter aims to help you with the "how" of adding it to your laboratory offerings.

Naturally, many questions come with the "how":

  • Does using one method make the most sense, or will your lab turn to multiple methods for virus testing? This may be determined by current equipment, space considerations, and budget.
  • What type of lab are you running? A POL is going to have fewer options available than a CLIA moderate- or high-complexity lab.
  • How interoperable are you existing laboratory and clinical informatics solutions? Research laboratories face more challenges in integrating their systems with EHRs and other clinical systems.
  • What vendors and consultants are out there to help get equipped? Some vendors have very specific solutions, whereas others may have a broader range of offerings.

These questions and more are addressed this chapter.

3.1 What methodologies will you use?

3.1.1 PCR

SARS-CoV-2 PCR screening test by nasal swab in Strasbourg on August 21, 2020.

In the previous chapter, the most common testing methodologies for COVID-19 and other coronaviruses were discussed in detail. The prevailing method (often called the "gold standard") among them all is real-time reverse-transcription polymerase chain reaction (rRT-PCR) assays for testing. Broadly speaking, PCR is useful in pharmaceutical, biotechnology, and genetic engineering endeavors, as well as clinical diagnostics. As such, labs in those industries that already have PCR infrastructure in place have a theoretical step-up over a lab that doesn't.

PCR technology has advanced to the point where it is more efficient and user-friendly than prior, yet "the high cost of the instruments, servicing contracts, and reagents pose major challenges for the market, especially to the price-sensitive academics."[1] Writing about the thirty-fifth anniversary of PCR in 2018, science writer Alan Dove not only highlighted these cost issues but also the size and energy requirements for running the equipment. "As a result, one of the defining techniques of modern molecular biology has remained stubbornly inaccessible to educators and unusable in many remote locations."[2] Various efforts have been made over the years to bring costs down by modifying how heating and temperature control are performed[3][4][5][6], but many of those system aren't typically optimal during a pandemic when turnaround time is critical.

Amidst the pandemic, additional challenges also exist to those wanting to conduct PCR testing for COVID-19 and other viruses. As was discussed at the end of the previous chapter, supplies of reagents and consumables are not particularly robust mid-pandemic, with shortages being reported since March 2020.[7][8][9][10][11][12][13][14][15] These shortages may eventually work themselves out, but they highlight the need for other varying methods that don't necessarily depend on the same reagents and consumables that are in short supply.

For those labs wishing to adopt PCR testing of viruses—particularly COVID-19—into their workflow while providing reasonable turnaround times, all is not lost. However, careful planning is required. For example, you'll want to keep in mind that some PCR machines require vendor-specific reagents. If you're going to acquire a particular instrument, you'll want to do due diligence by verifying not only the supported reagents but also those reagents' overall availability (real and projected). You'll also want to consider factors such as anticipated workload (tests per day), what your workflow will look like, and how to balance overall investment with the need for reasonable turnaround times.

As of August 2020, an increasing body of research is being produced suggesting ways to improve turnaround times with PCR testing for COVID-19, with many research efforts focusing on cutting out RNA extraction steps entirely. Alcoba-Florez et al. propose direct heating of the sample-containing nasopharyngeal swab at 70 °C for 10 minutes in place of RNA extraction.[16] Adams et al. have proposed an "adaptive PCR" method using a non-standard reagent mix that skips RNA extraction and can act "as a contingency for resource‐limited settings around the globe."[17][18] Wee et al. skip RNA extraction and nucleic acid purification by using a single-tube homogeneous reaction method run on a lightweight, portable thermocycler.[19][20] Other innovations include tweaking reagents and enzymes to work with one step, skipping the reverse transcription step,[21] and using saliva-based molecular testing that skips RNA extraction.[22][23]

Saliva as a specimen

The saliva molecular tests in particular are intriguing. Talk of the potential utility of using saliva as a specimen for COVID-19 was occurring as early as April[24][25], and the first saliva-based COVID-19 test, produced by Spectrum Solutions in cooperation with RUCDR Infinite Biologics Laboratory[26] and Vault Health[27], was given an FDA EUA in April. On August 15, Yale School of Public Health was given an EUA for it SalivaDirect molecular test. Although still PCR-based (and a CLIA high-complexity test), SalivaDirect is being touted as a means to improve specimen collection safety, consume fewer reagents, prove compatible with high-throughput workflow, and cut overall turnaround time. Not only is saliva easier to collect and safer for healthcare staff, the test is essentially "open sourced," not requiring proprietary equipment from Yale, making the test more flexible by being validated to reliably function with a wider array of reagents and instruments.[28][29] When compared to using a nasopharyngeal swab specimen using the ThermoFisher Scientific TaqPath COVID-19 combo kit, results were comparable 94.1% of the time.[23] While sensitivity and specificity may be slightly less comparable to other PCR options[30], the overall advantages during reagent shortages and a definitive need for broader testing likely outweigh the slightly lesser sensitivity and specificity.

3.1.2 Pooled testing

Another method some labs are taking to speed up turnaround time is using pooled testing. The general concept involves placing two or more test specimens together and testing the pool as one specimen. The most obvious advantage to this is that the process saves on reagents and other supplies, particularly when supply chains are disrupted. This methodology is best used "in situations where disease prevalence is low, since each negative pool test eliminates the need to individually test those specimens and maximizes the number of individuals who can be tested over a given amount of time."[31] However, it's best left to situations where expectations are that less than 10 percent of the population being tested is affected by what's being tested for.[31][32][33]

The downside of pooled testing comes with the issues of dilution, contamination, and populations with 10 or more percent infected. A target-positive specimen that comingles with other target-free specimens is itself diluted and in some cases may cause issues with the limit of detection for the assay. Additionally, if the pool tests positive, target-free specimens may become contaminated by a target-positive specimen. This may cause issues with any individual specimen assays that get ran. And the workflows involving pooling must be precise, as a technician working with multiple specimens at the same time increases the chance of lab errors.[31][32][33] Finally, at least in the U.S., a Food and Drug Administration (FDA) emergency use authorization (EUA) for a validated pooled testing method is required.[31] (Validation of pooled methods may differ in other countries.[32]) The U.S. Centers for Disease Control and Prevention (CDC) has published interim guidance on pooled testing strategies for SARS-CoV-2.

3.1.3 Rapid antigen testing

As mentioned in the previous chapter, the benefits of antigen testing For COVID-19 and other viral infections are 1. specimen collection can typically be done with a simple nasal swab rather than a more invasive nasopharyngeal swab, 2. testing is more rapid and convenient, and 3. it takes some pressure off the PCR supply chain. However, antigen testing only tests what's there, rather than amplifying the amount, resulting in generally lower sensitivities.[34][35] As such, the real 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. If your lab is able to support this sort of testing, then this type of testing may be an option. However, as of August 2020, only three vendors have EUAs for antigen diagnostic tests: Quidel Corporation; Becton, Dickinson and Company; and LumiraDx UK Ltd.[36] With six U.S. states already contracted to purchase hundreds of thousands of two of those companies' test kits[37][14], it's not clear how well they'll manage to meet demand.

3.1.4 LAMP and CRISPR

Early on in the pandemic, while PCR was getting most of the attention, reverse transcription loop-mediated isothermal amplification (RT-LAMP), an isothermal nucleic acid amplification technique that allows for RNA amplification, was also quietly being discussed[38][39], and it has since gained more attention.[40][41][42][43][44][45] The University of Oxford, for example, is in the process of getting a rapid, affordable, clinically-validated RT-LAMP test approved for the European market. Oxford also notes that "[a]n advantage of using LAMP technology is that it uses different reagents to most laboratory-based PCR tests."[45] Thi et al. have tested a two-color RT-LAMP assay with an N gene primer set and diagnostic validation using LAMP-sequencing, concluding that the pairing of the two "could offer scalable testing that would be difficult to achieve with conventional qRT-PCR based tests."[43] And California-based Color Genomics have set up their own proprietary RT-LAMP system, capable of handling up to 10,000 tests per day.[46]

In most cases, LAMP-based testing is much simpler than PCR, lacking the requirement of specialized instruments. Despite LAMP generally being thought of as less sensitive than PCR[46][35][47], the recent explosion of research into RT-LAMP methods for testing for the presence of SARS-CoV-2 seems to gradually indicate that "under optimized conditions," RT-LAMP methods may actually be able to rival the sensitivity and specificity of many RT-PCR COVID-19 tests.[44] Esbin et al. add[44]:

These methods allow for faster amplification, less specialized equipment, and easy readout. LAMP methods also benefit from the ability to multiplex targets in a single reaction and can be combined with other isothermal methods, like [recombinase polymerase amplification] in the RAMP technique, to increase test accuracy even more. These techniques may be particularly useful for rapid, point-of-care diagnoses or for remote clinical testing without the need for laboratory equipment.

CRISPR methods are also being used in conjunction with RT-LAMP.[35][44][48] RT-LAMP creates complementary double-stranded DNA (cDNA) from specimen RNA and then copies (amplifies) it. Then CRISPR methods are used to detect a predefined coronavirus sequence (from a cleaved molecular marker) in the resulting amplified specimen. Though as of August 2020 approved assays using CRISPR-based detection of SARS-CoV-2 are limited to a handful of companies[35][49], the technology has some promise as an alternative testing method. It has the additional advantage of being readily coupled with lateral flow assay technology to be deployed in the point-of-care (POC) setting.[44][49]

3.1.5 Point-of-care and other alternative testing

Example of a microfluidic chip used in point-of-care medical devices

On August 5, 2020, the WHO published a draft blueprint for what they call Target Product Profiles (TPP), which "describe the desirable and minimally acceptable profiles" for four difference COVID-19 test categories.[50] Addressing POC testing, the WHO recommends that such assays[50][51]:

  • have a sensitivity (true positive rate) or at least 70 percent;
  • have a specificity (true negative rate) of at least 97 percent;
  • provide results in less than 40 minutes;
  • require diagnostic machines that cost less than $3,000 U.S.;
  • individually cost less than $20 for the patient;
  • be simple enough that only a few hours of training are required to run the test; and
  • operate reliably outside a clean laboratory environment.

While few of the available test systems can meet all these requirements, it's clear the push to expand COVID-19 testing to the point of care is accelerating.[51][52][52][53][54] The U.S. National Institutes of Health's Rapid Acceleration of Diagnostics (RADx) funding program has sought to speed up innovation in COVID-19 testing and promote "truly nontraditional approaches for testing that have a slightly longer horizon."[55] As of August 2020, RADx has chosen to fund seven biomedical diagnostic companies making new lab-based and POC tests that could significantly ramp up overall testing in the U.S. into September 2020. Four offerings are lab-based (from Ginkgo Bioworks, Helix OpCo, Fluidigm, and Mammoth Biosciences) and three are POC tests (from Mesa Biotech, Quidel, and Talis Biomedical), all using varying technologies and methods such as next-generation sequencing, CRISPR, microfluidic chips, nucleic acid testing, antigen testing, and saliva testing.[56] Both Mesa Biotech's rapid, cartridge-based RT-PCR Accula System and Quidel's rapid Sofia SARS Antigen FIA test are already EUAed and CLIA-waived[36], with Talis' Talis One LAMP-based lateral flow immunoassay kit still awaiting EUA and CLIA status approval. Whether or not these POC and lab-based tests make it to the average physician office laboratory remains to be seen, however.

Outside the RADx program, enterprising researchers in other parts of the world are also attempting non-traditional approaches to improving COVID-19 testing options. Examples include[44][54][57]:

  • a method of DNA nanoswitch detection of virus particles;
  • a dual biomarker-based finger-stick test for acute respiratory infections;
  • a rapid breath test to detect volatile organic chemicals from the lungs;
  • an affordable, hand-held spectral imaging device to detect virus in blood or saliva in seconds;
  • an ultrahigh frequency spectroscopic scanning device to see virus particles resonating;
  • a method that combines optical devices and magnetic particles to detect virus RNA;
  • an RNA extraction protocol that uses magnetic bead-based kits;
  • the additional use of an artificial intelligence (AI) application to better scrutinize test results; and
  • the miniaturization of PCR technology to make it more portable and user-friendly.

Of course, most of these are largely experimental technologies, and realistically getting them into the lab may be far out. But they represent out-of-the-box ideas that have some kind of chance at playing a greater role in the clinical laboratory or in point of care settings in the future.

3.2 What kind of space, equipment, and supplies will you need?

3.2.1 Laboratory space arrangements

PCR considerations

Whether adding PCR to your existing laboratory, modifying existing PCR workflows, or starting from scratch, preventing contamination is a top priority. As PCR can effectively amplify even the tiniest of quantities of DNA and RNA, the risk of amplifying a contaminant and ruining the validity of an assay is very real.[58][59][60][61][62][63][64] Contamination typically comes from non-amplified environmental substances such as aerosols, and from carryover contamination of amplicons from earlier PCR cycles. As such, not only do best-practice processes and procedures (P&P) need to be followed (e.g., unidirectional workflow, thorough cleaning procedures, proper preparation and disposal), but also where to place PCR-related equipment must be carefully considered.[58][59][61][63]

When possible, separate rooms for sample preparation, PCR setup, and post-PCR activities, each with their own airflow control, are encouraged.[58][59][62][63][64] However, the laboratory attempting to add PCR to an already small clinical diagnostic lab may not have the luxury of having multiple rooms. In that case, a single-room setup may suffice, if the workflow areas remain demarcated or physically partitioned. Additionally, a single-room setup must also have stricter P&P and design controls to offset the space constraints. For example, the sample preparation area of the room should have a laminar flow hood with UV light that is regularly cleaned, and post-PCR analysis may need to occur later in the day after cleanup from prior steps.[58][60][64] Of course, always maintaining unidirectional workflow—regardless of number of rooms—is also critical to minimizing contamination. For example, technicians shouldn't be transporting amplified materials into the DNA extraction area.

Although dated, Roche Diagnostics' 2006 PCR Applications Manual[59] provides a detailed breakdown of setting up the laboratory for PCR. Das et al.[63] and Dr. Jennifer Redig[61] provide additional valuable insight. The World Health Organization (WHO) also provides guidance for setting up molecular testing in the lab.[64]

Isothermal amplification considerations

Similarly, because DNA and RNR amplification is involved, contamination concerns exist with isothermal amplification techniques. Multiple pipetting steps and repeated freezing and thawing of reagents can still lead to cross-contamination[65], as does opening the reaction chamber after reaction is completed.[66] However, the advent of microfluidics and lateral flow technologies in isothermal amplification processes has seen the development of "fully enclosed microstructured devices into which performing the isothermal amplification reduces the risk of sample contamination and allows integration and portable device realization."[67][68] Even more cutting-edge techniques to reduce contamination such as the CUT-LAMP technique of Bao et al.[69] or the dUTP/UDG system for COVID-19 RT-LAMP reactions of Kellner et al.[42] hold further promise in making isothermal amplification processes in the laboratory easier to manage. That said, labs running isothermal amplification processes such as LAMP requiring analysis with agarose gel electrophoresis or a method requiring the opening of reaction vessels will preferably have a secondary area set up for analysis steps so as to minimize the chances of contamination.[70][71]

3.2.2 Instruments and assays

Eppendorf Mastercycler Pro S, a thermal cycler for PCR and other applications

High- and moderate-complexity CLIA testing

Thermal cyclers are the standard instruments for PCR testing. Today, real-time or quantitative (qPCR) systems largely fill this niche. However, digital and droplet digital PCR systems are emerging, and they have the benefit of producing even more rapid, precise, sensitive, accurate, and reproducible results, and they are capable of direct quantification and multiplexing. Other instruments and accessories for PCR workflows include proper power supplies, analytical balances, electrophoresis chambers, water and/or dry baths, and mini/micro centrifuges. However, if you're considering the addition of PCR workflow to your laboratory, the thermal cycler is typically where the largest up-front cost will be. As such, it's important to ask yourself critical questions to help guide your acquisition decisions.

As part of their June 2018 survey on PCR equipment, Lab Manager poses five questions potential buyers should ask before making PCR purchases[72]:

  1. Do your current and long-term needs require basic PCR systems, qPCR systems, or digital PCR systems?
  2. What sample formats do you anticipate using?
  3. What throughput requirements do you have now and anticipate in the near future?
  4. What are you willing to sacrifice in regards to temperature ramp up and cool down times and accuracies?
  5. Do you anticipate needing to run more than one independent PCR at the same time (multiblock PCR)?

Given the considerable investment that goes into these and other life science instruments, you may want to seek vendors who have a strong track record of supporting and supplying parts for instruments they manufacture and distribute years after the instruments are introduced.[73]

As for PCR-based assays, the U.S. FDA has issued EUAs for more than 100 of them. The most up-to-date listing is of course found at the FDA website. However, sorting through the extra details can be tedious. The Center for Systems Biology at Harvard has been maintaining a contextual PDF chart of the various COVID-19 diagnostic tests, which includes information such as run time, manufacturer-supplied data, and published clinical data (when available). This may prove useful in deciding on one or more particular tests. As with many aspects of this pandemic, other factors that may influence your choice of test kit include overall availability, cost, reagents included with the assay, and reagents separately required and their availability.

Isothermal amplification techniques have the advantage of not requiring an expensive thermal cycler.[43] Instrument-appropriate reaction vessels, baths, heating units, turbidimeters, thermocyclers, etc. may be required, depending on what type of amplification you're doing. Companies like Meridian Bioscience offer LAMP-based molecular platforms, though they may not offer a specific COVID-19 assay to run on the platform.[74] As can be seen in Table 1, two isothermal amplification assays that run on their own proprietary instrument have received EUAs and are CLIA-waved, with a third potentially on the way. Using these systems and their COVID-19 assays at the point of care provides a somewhat more attractive option for laboratories wanting to add COVID-19 or even multiplex viral assays to their offerings.


CLIA-waived testing

If you're running a POL, or attempting to provide COVID-19 testing at the point of care, you'll be looking at the following assay and instrument options shown in Table 1:

Table 1. CLIA-waived COVID-19-related in vitro diagnostic tests receiving U.S. FDA Emergency Use Authorizations (EUAs)
Date EUA issued Manufacturer Name of test or assay Required instrument Technology (method) RADx-funded? Additional comments
20 March 2020 Cepheid Xpert Xpress SARS-CoV-2 test GeneXpert Xpress System (Tablet and Hub Configurations) Molecular (RT-PCR) No Has largely received positive review of sensitivity and specificity[75][76][77]; company is reportedly working on a multiplex assay for SARS-CoV-2, Flu A, Flu B, and RSV[78]
23 March 2020 Mesa Biotech Inc. Accula SARS-CoV-2 test Accula Dock or Silaris Dock Molecular (RT-PCR) Yes Has received only minor scrutiny[79], with no formal FDA complaints[80]
27 March 2020 Abbott Diagnostics Scarborough, Inc. ID NOW COVID-19 ID NOW Molecular (isothermal amplification) No Targets "a unique region of the RNA-dependent RNA polymerase (RdRP) gene"[81]; as of August 2020, the sensitivity of the test is still under scrutiny[82][83][84][85]
08 May 2020 Quidel Corporation Sofia SARS Antigen FIA Sofia 2 Antigen Yes With a comparatively lower specificity, best used as surveillance, repeat screening tool[34][35]
10 June 2020 Cue Health Inc. Cue COVID-19 Test Cartridge Cue Health Monitoring System Molecular (isothermal amplification) No "Test primers amplify the nucleocapsid (N) region of the gene"[86]
02 July 2020 Becton, Dickinson and Company BD Veritor System for Rapid Detection of SARS-CoV-2 BD Veritor Plus Antigen No With a comparatively lower specificity, best used as surveillance, repeat screening tool[34][35]
N/A (Anticipated) Talis Biomedical Talis One Cartridge Talis One Instrument Molecular (RT-LAMP) Yes Expectations are that it will receive an FDA EUA and be CLIA-waived[87], but yet to be determined.

3.2.3 Reagents

High- and moderate-complexity CLIA testing

Reagent shortages since April have hampered efforts to expand testing in parts of the world, including the United States. As such, your reagent choices will likely be closely tied to both the assays you choose to implement and how reliably the supplier can get them to you. This in turn is likely driven by whether you're using a lab-developed test or a test kit. In some cases, e.g., the Xiamen Zeesan Biotech SARS-CoV-2 Test Kit (Real-time PCR), all but the Virus RNA Extraction Kit is included.[88] On the other hand, Biomeme's SARS-CoV-2 Real-Time RT-PCR Test requires the separate acquisition of PCR buffer and external controls other than the exogenous RNA Process Control that comes with the kit.[89] Yale's SalivaDirect is a more flexible test, validated for use with multiple instruments and reagents that are not proprietary to Yale.[28][29] Pay close attention to what comes with the assay, typically by reviewing the instructions for use (IFU; found on the FDA's EUA page).

For PCR, the five basic reagents are template DNA, PCR primers, nucleotides, PCR buffer, and thermostable DNA polymerase. Some of these components can be acquired pre-mixed as a "master mix." For example, Thermo Fisher's PCR Master Mix contains a thermostable DNA polymerase called Taq, nucleotides called deoxynucleotide triphosphates (dNTPs), and a buffer, which "saves time and reduces contamination due to a reduced number of pipetting steps."[90]

Reagent cost and usage for isothermal amplification methods such as LAMP are similar, though buffers and primers specific to the method are required.[65][70][91][92]

CLIA-waived testing

The FDA EUA devices (Table 1) all come with the necessary reagents, with the exception of any controls or references you may require. Refer to the IFU for the waived test kit to determine what additional consumables you'll require.

3.2.4 Consumables

High- and moderate-complexity CLIA testing

Non-reagent consumables for high- and moderate-complexity CLIA testing include PCR tubes and plates; pipettes and tips; films, foils, and sealing mats; swabs; and viral transport media, among others. Some like Kellner et al. have experimented with methods to make isothermal amplifications methods more approachable in resource-poor environments by, for example, developing a pipette-free version of LAMP.[42]

CLIA-waived testing

The FDA EUA devices (Table 1) may require a few extra consumables. For example, the Accula SARS-CoV-2 test kit comes with swabs[93] and the Xpert Xpress SARS-CoV-2 kit comes with disposable transfer pipettes.[93] Refer to the IFU for the waived test kit to determine what additional consumables you'll require.

3.2.5 Software and services

A June 2020 report by Weemaes et al. in the Journal of the American Medical Informatics Association describes the bottlenecks they encountered in their test workflows at the Belgian National Reference Center, and how they updated their laboratory information system (LIS) with functionality to resolve those bottlenecks.[94] In addition to adding a COVID-19–specific order set into the computerized physician order entry (CPOE) module integrated with both their LIS and electronic health record (EHR), they included an up-to-date triage criteria component, a tool for optimizing sampling and packaging, a COVID-19 status button, and improved reporting modules for automating reference testing and epidemiological reporting. They also added extra database and data mining functionality to facilitate research and insights into epidemiologies and treatments. Their conclusion: "Rapidly developed, agile extendable LIS functionality and its meaningful use alleviates the administrative burden on laboratory personnel and improves turnaround time of SARS-CoV-2 testing."[94] The Association of Public Health Laboratories comes to a similar conclusion in regard to laboratory informatics solutions and public health laboratories' COVID-19 testing.[95]

As such, adding COVID-19 and other respiratory illness testing to your workflow may necessitate an information management system, or an upgrade of your existing software systems. You may experience many of the same bottlenecks the Belgian National Reference Center experienced, especially if you're still working primarily with paper-based test ordering. Those researchers found that paper-based COVID-19 test requests often[94]:

  • omitted critical clinical status and contact information;
  • slowed down epidemiological and research studies;
  • hindered proper preanalytical biosafety procedures; and
  • impeded rapid response to evolving test criteria and clinical insights through test ordering protocols.

How interoperable your laboratory software solution is with other systems such as EHRs is also worth consideration. The next chapter addresses system interoperability in greater detail, but it's worth mentioning it here in the context of adding software to improve testing workflows for SARS-CoV-2 and other respiratory viruses. Broadly speaking, improving interoperability among clinical informatics systems—whether at the point of care or within a specific laboratory—is recognized as an important step towards improving health outcomes.[96][97] However, while developers of EHRs and other clinical informatics systems have intended to improve their software's interoperability, the COVID-19 pandemic has unfortunately shown the inadequacies still inherent in that software's overall design.[98][99][100] As such, any research into acquiring a laboratory information management system (LIMS), LIS, or other clinical information management solution should take into account how well that solution is able to integrate with your other clinical systems, as well as any other third-party systems like physician or hospital EHRs. And it's not just the software solutions you'll want to consider. Will the new instruments you add to get you rolling with clinical respiratory illness testing integrate with your software?

Finally, although rare, you may find you don't have the in-house expertise to fully implement a COVID-19 testing line to your laboratory. In such a case, you may need to turn to a laboratory services consultancy with experience in SARS-CoV-2 test method validation, instrument procurement and implementation, and legal matters. (See the next section for a representative example of consultants advertising COVID-19 testing knowledge and services for labs.)

3.2.6 Major vendors and consultants

Table 2 lists the major vendors developing and selling PCR, isothermal amplification, and NGS supplies, instruments, and software for both clinical diagnostics and life science research. "Research use only" equipment like Siemens Healthcare's Fast Track Cycler was ignored for completing the table. The vendor list was largely compiled from vendors identified in a handful of online market reports on PCR, with an added sprinkling of a few additional reagent vendors (e.g., Jena Bioscience, LGC, and New England BioLabs) who address isothermal amplification supplies in addition to PCR. Note that this is not an endorsement for any particular vendor.

Table 2. Major players operating in the global diagnostic PCR, isothermal amplification, and NGS market
Vendor Shop all products PCR machines Nucleic acid extraction
and purification machines 		Immunoassay analyzers
and assays 		PCR and qPCR assays PCR and qPCR enzymes
and master mixes 		DNA/RNA purification,
quantitation, and
amplification supplies 		LAMP assays Isothermal amplification
enzymes and
master mixes 		NGS supplies Supporting labware
and supplies 		Software
Abbott Abbott products ✓ - - ✓ ✓ - - - - ✓ ✓
Agilent Technologies Agilent products ✓ - - ✓ ✓ ✓ - - ✓ ✓ ✓
Becton, Dickinson and Company BD products ✓ - - ✓ - - - - - ✓ -
Bio-Rad Laboratories, Inc. Bio-Rad products ✓ - ✓ ✓ ✓ ✓ - - ✓ ✓ -
bioMérieux SA bioMérieux products - ✓ ✓ ✓ - - - - - ✓ ✓
Danaher Corporation and its companies Cepheid products,
Beckman Coulter products, and
Beckman Life Sciences products 		✓ - ✓ ✓ - ✓ - - - ✓ -
F. Hoffmann-La Roche AG Roche Diagnostics products ✓ ✓ - ✓ ✓ ✓ - - ✓ - ✓
Jena Bioscience GmbH Jena Bioscience products - - - ✓ ✓ ✓ ✓ ✓ ✓ - -
LGC Limited and its companies Lucigen products - - - ✓ ✓ ✓ - ✓ ✓ - -
Merck KGaA Sigma-Aldrich products and
Millipore Sigma products 		- - - ✓ ✓ ✓ - - ✓ ✓ -
New England BioLabs, Inc. NEB products - - - ✓ ✓ ✓ ✓ ✓ ✓ - -
Promega Promega products and catalog - ✓ - ✓ ✓ ✓ - - ✓ - -
QIAGEN N.V. QIAGEN products ✓ ✓ - ✓ ✓ ✓ - - ✓ - ✓
Siemens Healthcare GmbH Siemens Healthcare products - ✓ - ✓ - ✓ - - - - ✓
Thermo Fisher Scientific, Inc. Thermo Fisher products and
Fisher Scientific products 		✓ ✓ - ✓ ✓ ✓ - ✓ ✓ ✓ ✓

Table 2's "Software" column represents whether or not the vendor offers laboratory informatics software such as a LIMS or LIS. Those vendors' solutions may or may not be tailored to handle the specific requirements of a clinical diagnostic or virology lab handling COVID-19 and other viruses. (See the next chapter for more in-depth information about working an informatics solution into COVID-19 and other viral testing workflow.) A non-endorsed, representative example of vendors who do include:

Additionally, when in-house knowledge is lacking, a consultant may be required. These consultants are meant to be representative examples of those laboratory consulting firms indicating they have the knowledge to help a laboratory with COVID-19-related testing and other issues. This list is not an endorsement for any particular consultant:

3.3 What other considerations should be made?

3.3.1 U.S. regulatory compliance

In the previous chapter, the regulatory hurdles of the Health Insurance Portability and Accountability Act (HIPAA) and the Clinical Laboratory Improvement Amendments (CLIA) were addressed. For those laboratories that are already operating in the clinical laboratory sphere, it should be relatively simple to address the additional considerations and pandemic-specific changes to those two regulations as described previously. In addition to that information, you can always periodically check the U.S. Department of Health & Human Services' (HHS') Office for Civil Rights and their COVID-19 announcements and guidance, as well as the Centers for Medicare & Medicaid Services (CMS) emergencies page.

If for some reason you're not a clinical lab—or want to start a new lab—and want to take on COVID-19 and other clinical testing, you're going to need to get fast tracked into the CLIA program, for starters. Fortunately, CMS has already displayed a willingness to help labs wanting to perform COVID-19 testing receive their CLIA certificate rapidly. Form CMS-116 will need to be completed and submitted to your state survey agency contact. Of course, while you're waiting, you'll also want to become familiar with the trappings of CLIA by tapping into resources like the CMS page for CLIA, CDC page for CLIA, and resources available from professional organizations like the American Academy of Family Physicians. If all goes as plan, and directions are followed, you should have your CLIA certificate in no time. CMS adds[101]:

We want to ensure that laboratories located in the United States applying for a CLIA certificate are able to begin testing for COVID-19 as quickly as possible. Once the laboratory has identified a qualified laboratory director and has provided all required information on the CMS-116 application, a CLIA number will be assigned. Once the CLIA number has been assigned, the laboratory can begin testing as long as applicable CLIA requirements have been met (e.g., establishing performance specifications).

On the HIPAA side of things, you'll want to tap into resources such as the HHS' HIPAA training materials and resources, as well as their previously mentioned COVID-19 announcements and guidance.

Other considerations include[102][103][104][105]:

  • taking the time to get accredited to ISO 15189:2012 Medical laboratories — Requirements for quality and competence, "used by medical laboratories in developing their quality management systems and assessing their own competence"[106];
  • understanding and training on packaging (e.g., UN3373 Biological Substance, Category B) and shipping COVID-19 specimens (e.g., International Air Transport Association (IATA) Dangerous Goods Regulations), if you will be conducting such activities;
  • understanding the significance of and validating workflow procedures to at least Biosafety Level 2 (note there is no single U.S. government entity which has total responsibility for enforcing biosafety levels[107]); and
  • understanding and training on Occupational Safety and Health Administration (OSHA) requirements for laboratory workers and employers for COVID-19.

3.3.2 Reporting

The topic of reporting COVID-19 results to local and regional health departments—as well as any internal medical reporting—is covered in detail in the next chapter. You'll want to be sure you and your team understand your state's health department reporting requirements, as well as what code sets (LOINC, SNOMED, ICD, and CPT) to use. The success of epidemiologists' response to outbreaks and pandemics depends on quality data reporting, and using the correct code sets helps labs meet reporting requirements, as well as ensure proper payment. The U.S. Centers for Disease Control and Prevention provides guidance on how to report COVID-19 laboratory data, which also makes for necessary reading.

3.3.3 Billing, Medicare, and Medicaid

The COVID-19 pandemic has unquestionably put the U.S. health care system in a tough spot. That health care system, with all its warts[108][109][110], has arguably not done well to handle so many unanticipated health issues from a broad portion of the population.[110][111][112][113] From a provider side, proper reimbursement for COVID-19 testing is among the many issues that must be addressed. One key aspect of ensuring proper reimbursement in a reasonable time frame is first making sure a clear preregistration process that captures critical patient and facility information is conducted. (This can be facilitated and made easier as a first-step process in a clinical informatics solution, for example.) Critical patient and facility information includes (but is not limited to):

  • name, date of birth, and gender
  • race and ethnicity
  • demographic information such as full address and phone number
  • ordering physician or attending health care provider for test (if applicable)
  • facility's National Provider Identifier (NPI)
  • patient insurance company name, policy ID, group ID, insured's name, and insured relationship to patient (if insured)
  • whether or not it's the patient's first test (federal reporting requirement)
  • whether or not the patient is a resident of a congregate care setting (federal reporting requirement; also, e.g., additional Medicaid reimbursement may be available in some states[114])
  • whether or not the patient is a healthcare worker (federal reporting requirement; also, e.g., may affect the patient's worker's compensation claim[115][116])
  • whether or not the patient is pregnant (federal reporting requirement; also, e.g., Medicare will only accept a COVID-19 code as secondary if the primary diagnosis code is viral disease complicating pregnancy, childbirth, or puerperium[117][118])

Secondarily, it's also important to have a plan in place for testing the uninsured. While the Families First and Coronavirus Relief Act (FFCRA) and the National Disaster Management System (NDMS) provide legal mechanisms for reimbursement for what should otherwise be free patient testing for SARS-CoV-2 and the associated visit, ambiguities of these mechanisms and how they are enforced are still creating problems.[119] For example, while providers can turn to the NDMS (until funds run out) to pay uninsured claims at 110% of Medicare rates—with states' opting to cover those costs through their Medicaid program—providers are not obligated by the law to seek reimbursement from those entities and can optionally bill the uninsured patient directly, which is against the spirit of the FFCRA.[119][120][121] As such, it's important to know what your lab's policy will be on managing uninsured patient claims. How will you get reimbursed if you're accepting uninsured patients? Resources that may help with these decisions include the NDMS Definitive Care Reimbursement Program portal and the Health Resources & Services Administration's information page and associated FAQ.

For Medicare, Medicaid, and otherwise insured patients, the lab will likely have (or presumably acquire) someone on hand with billing experience. The preregistration information previously mentioned will still be important to implement. For further guidance on billing issues, you may wish to consult with CMS' extensive document titled COVID-19 Frequently Asked Questions (FAQs) on Medicare Fee-for-Service (FFS) Billing. Also, the next chapter addresses code sets for reporting and billing, which may prove useful.

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  121. ↑ Congressional Research Service (17 April 2020). "Health Care Provisions in the Families First Coronavirus Response Act, P.L. 116-127". https://crsreports.congress.gov/product/pdf/R/R46316. Retrieved 21 August 2020. 
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