COVID-19 Testing: Its Role in Safely Reopening

The global COVID-19 pandemic touches and disrupts every aspect of life and livelihood across geographies. Despite progress with public health practices and vaccinations, our personal and professional futures face uncertainty. Inconsistent and ambiguous re-opening procedures hinder a robust return to pre-pandemic routines that can restore productivity and economic health. What is certain is a cornerstone of any reopening effort will be robust, precise and efficient proactive testing. Routine rapid, point-of-care testing permits identification of potentially infected people, enables appropriate patient management and provides essential data for contact tracing and community monitoring. Testing will restore confidence in our personal and public interactions and enable safer and healthier care delivery. 

About one in five infections with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) globally have occurred in the United States — nearly 33.3 million people, as the pandemic continues into its second year¹. Worldwide, SARS-CoV-2 and its variants have tallied nearly 171.33 million confirmed infections².

Interrupting the spread of the virus is a public health priority both globally and in the United States. But even with three vaccines authorized and recommended by the U.S. Food and Drug Administration (FDA), and two more in late-stage development^3,4, it will take time to reach herd immunity, and there will still be communities struggling to reach that level of protection. Vaccine hesitancy, ineffective vaccine delivery to underserved communities, and the emergence of viral variants, could well delay a minimal herd immunity level in the United States until late summer 2021, if at all^5,6. Herd immunity thresholds to protect large populations vary by model from 60 to 90 percent of persons immune to SARS-CoV-2 in a population, achieved via infection or vaccination, a rate range the United States is working to achieve^6,7. However, only 41 percent of the U.S. population was fully vaccinated, while about 26.95 percent of U.S. counties remained high- or substantial-transmission areas as of June 2, 2021^9,10. Experts believe current challenges likely will transform the SARS-CoV-2 pandemic to an endemic disease, which would require ongoing vigilance and monitoring¹¹.

Safely re-opening is a concern shared by individuals and caregivers, employers across sectors, educators, as well as local, state and federal governments. The U.S. Centers for Disease Control and Prevention (CDC) offers evidence-based guidance to stop the spread of infection from SARS-CoV-2 and its variants tailored to specific groups that reflect the latest validated science and tools.¹² However, individuals and communities have different vulnerabilities, available resources and adherence patterns that create variability in following such best practices. In these dynamic environments, social distancing, hygiene and mask-wearing are essential tools, but accurate and efficient point-of-care (POC) testing is critical to limit the spread of infection and provides peace-of-mind to those who are uninfected.

In the immediate future, the landscape for POC COVID-19 testing has at least three major paths:  Testing to aid in the diagnosis of symptomatic patients; monitoring of COVID-19-positive persons and their contacts in the community, including asymptomatic people; and for screening at-risk populations. Individuals in this later testing path can include those whose health status, such as having cancer or undergoing kidney dialysis, makes them especially vulnerable to a worse COVID-19 disease course. These at-risk populations also include those who are about to undergo medical procedures as outpatients or inpatients, those returning to a shared work-space or classroom environments (entails repeated, periodic testing of same individual), and those participating in one-time events, such as boarding an airplane or attending an indoor meeting, tournament or performance.

COVID-19 Testing Types

The FDA, via its Emergency Use Authorizations (EUAs), has permitted the marketing of COVID-19 tests in the United States. FDA-authorized COVID-19 tests are either molecular or antigen tests to detect SARS-CoV-2 genetic material or proteins, respectively, or antibody tests to detect a recent or prior infection. 

To receive an EUA, a medical diagnostic device must meet four FDA criteria:  the disease is serious or life-threatening; evidence that the test may be effective; known and potential benefits of using the test outweigh known and potential risks; and no adequate, approved and available alternatives exist.¹⁴ An EUA-authorized test differs from an FDA approved, cleared or licensed test because the EUA standard requires less evidence than these other regulatory actions.¹⁵ The FDA has authorized more than 376 COVID-19 tests and sample collection devices via EUAs, including 272 molecular tests and sample collection devices, 79 antibody and other immune response tests, and 25 antigen tests, as of May 21, 2021.¹⁶

Diagnostic tests detect active infection.

Diagnostic molecular tests detect SARS-CoV-2 genetic material¹⁸.

The genetic material of SARS-CoV-2 is ribonucleic acid (RNA). Testing requires three steps. First, this viral RNA must be converted into deoxyribonucleic acid (DNA) via a reverse transcription process. Second, the DNA is then amplified, a replication process that makes millions of copies, to reach a detectable level.  Therefore, such molecular tests are called nucleic acid amplification tests (NAAT). NAAT can employ two amplification methods:  reverse transcription polymerase chain reaction (RT-PCR) or loop-mediated amplification (LAMP). Third, the amplified product is detected. Because highly sensitive NAAT tests employ amplification methods, they can detect very low levels of the SARS-CoV-2 virus within a patient sample. Therefore, the FDA considers this molecular design to be the gold standard for COVID-19 testing. 

The performance of molecular tests can be compared by three distinct metrics: The limit of detection, the lowest concentration of the microbe in a clinical sample that a test can consistently detect 95 percent or more of the time; inclusivity, the percentage of different SARS-CoV-2 strains the test can detect; and cross-reactivity (also known as exclusivity), the amount of non-SARS-CoV-2 microbes the test inappropriately detects.

Diagnostic antigen tests detect proteins of SARS-CoV-2²⁰
These highly specific tests use immunoassay technology to bind one or more proteins of the SARS-CoV-2 virus in a patient sample. These tests are less sensitive than RT-PCR/NAAT tests²¹.

Antibody tests detect past COVID-19 infection or vaccine-induced immune response.

These tests detect antibodies in the bloodstream of persons previously exposed to the SARS-CoV-2 virus. Because these antibodies are a response by the person’s immune system, they are typically detected several days or weeks after the infectious event or after administration of the COVID-19 vaccine and can persist for months, and possibly years, after infection recovery.

Defining Test Accuracy

No COVID-19 test is 100 percent accurate. Factors influencing test performance include the ability of a swab to collect a nasal or nasopharyngeal sample with virus; temperature control of stored samples; test reagent quality; and, of greatest importance, an individual patient’s viral load in a respiratory tract sample or COVID-19-specific antibody level in a blood sample during the course of their illness^23,24.

COVID-19 tests vary in sensitivity and specificity. The FDA considers a COVID-19 test’s sensitivity as the fraction of positive cases correctly identified as positive and its specificity as the fraction of negative cases correctly identified as negative. As noted by the FDA²⁶:

• Highly sensitive/low specific tests generally have low false-negative rates but run the risk of false-positive results. The false positive rate is also a function of the pre-test probability of COVID-19 infection in the population. When infection prevalence is low, the false-positive rates are higher. When prevalence is high, false-positive rates are lower²⁷.
• Low sensitivity/highly specific tests run the risk of false-negative results but generally have low false-positive rates.

An optimal COVID-19 test should be highly sensitive (low false-negative rate) and highly specific (low false-positive rate). 

Table 1 summarizes characteristics of current COVID-19 tests. 

*This product has not been FDA cleared or approved but has been authorized for emergency use by FDA under an EUA for use by authorized laboratories. This product has been authorized only for the detection of nucleic acid from SARS-CoV-2, not for any other viruses or pathogens. The emergency use of this product is only authorized for the duration of the declaration that circumstances exist justifying the authorization of emergency use of in vitro diagnostics for detection and/or diagnosis of COVID-19 under Section 564(b)(1) of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 360bbb3(b)(1), unless the declaration is terminated or authorization is revoked sooner.

Selecting the Right Test for Healthcare Delivery Settings

Institutions ranging from the CDC and local health departments to global public policy organizations and trade organizations all recommend diagnostic testing and screening testing as essential for the proper care of patients and safe re-opening of society^34,35,36. Diagnostic testing and screening testing each have a role in the testing landscape (Table 2). Detection of SARS-CoV-2 in an individual patient’s respiratory tract sample indicates an active COVID-19 infection and results in recommendation of his or her isolation, health monitoring and treatment. By contrast, screening of asymptomatic individuals in communities for COVID-19 infection quantifies its prevalence in the population as a function of time and place, and can identify clustered outbreaks that prompt public health control measures. COVID-19 screening tests can also be used to create COVID-19-safe zones in workplaces, schools, airplanes and public events.

A number of characteristics are important for test selection. Accuracy and speed of results are paramount, but cost-per-test is also a consideration. Test selection may also be influenced by other aspects of performance, scalability, run times and availability. In addition, selection criteria include usability (the ability of non-laboratory personnel to perform the test), and if the test location can be in a near-patient or POC setting or, by contrast, requires a central laboratory staffed by experienced technologists. Two additional selection factors are the impact of testing on workflow and delivery of patient and healthcare provider satisfaction. 

In an emergency department setting, for example, a testing device that provides accurate results in a near-patient setting with a sample-to-answer turnaround time of 30 minutes would significantly influence how rapidly a patient could be transferred from an isolation room to a hospital surgical suite, inpatient bed, heart catheterization lab or endoscopy room. Data on the full effect of a test to expedite workflow in a cost-effective manner will only come from well-designed health economic studies. 

Rapid and accurate COVID-19 testing can augment infection control efforts by detecting outbreaks among high-risk populations. Point-of-need applications include patients and essential staff of healthcare facilities such as emergency departments and urgent care centers, skilled nursing facilities, elective and ambulatory surgery centers, birthing suites, and out-patient cancer treatment centers, dialysis units, and clinics for transplant recipients.  

The Right Test When You Can’t be Wrong

RT-PCR POC testing, such as the fast, instrument-free Visby Medical^TM COVID-19 Point of Care Test, offers cost-effective value for the diagnosis of symptomatic persons and for physician-approved surveillance screening of vulnerable and at-risk populations across diverse healthcare settings.

The palm-sized Visby Medical device can detect SARS-CoV-2 in more than 95 percent of infected persons at each stage of their active infection in just 30 minutes ³⁷. By using proprietary RT-PCR technology, the Visby Medical device eliminates the need for confirmatory diagnostic testing.

In September 2020, the FDA issued an EUA for the Visby Medical COVID-19 Test as a single-use, disposable, fully-integrated, rapid, automated RT-PCR in vitro diagnostic test for the detection of SARS-CoV-2 genomic material in nasopharyngeal, anterior nasal, or mid-turbinate swabs collected by a health care provider. The Visby Medical COVID-19 Test and the Visby Medical COVID-19 Point of Care Test may be used in laboratories certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA), 42 U.S.C. §263a that meet requirements to perform high, moderate or waived complexity tests. The Visby Medical COVID-19 Point of Care Test is also authorized for use in patient care settings operating under a CLIA Certificate of Waiver, Certificate of Compliance, or Certificate of Accreditation.

The Visby Medical device’s portability offers practical deployment to the point-of-need, and its straight-forward single-use design lowers the risk for contamination. Its rapid results are presented visually without ambiguity. The unit is self-contained and requires no set-up or additional reading equipment, no capital laboratory equipment and no maintenance contracts. 

References

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2. Ibid
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11. Phillips N.
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14. Food and Drug Administration. Emergency Use Authorization of Medical Products and Related Authorities.FDA-2016-D-1025. January 2017. Accessed at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/emergency-use-authorization-medical-products-and-related-authorities#euas.
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18. Ibid.
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20. Food and Drug Administration. COVID-19 Frequently Asked Questions.
21. Centers for Disease Control and Prevention. Interim Guidance for Antigen Testing for SARS-CoV-2.
22. Food and Drug Administration. COVID-19 Frequently Asked Questions.
23. Food and Drug Administration. A Closer Look at Coronavirus Disease 2019 (COVID-19) Diagnostic Testing..
24. Food and Drug Administration. Coronavirus Disease 2019 Testing Basics. November 6, 2020. Accessed at https://www.fda.gov/consumers/consumer-updates/coronavirus-disease-2019-testing-basics.
25. Food and Drug Administration. A Closer Look at Coronavirus Disease 2019 (COVID-19) Diagnostic Testing.
26. Ibid.
27. Chan GM. Bayes’ theorem, COVID19, and screening tests [published correction appears in Am J Emerg Med. 2021 Apr 26;:]. Am J Emerg Med. 2020;38(10):2011-2013. doi:10.1016/j.ajem.2020.06.054.
28. Food and Drug Administration. Coronavirus Disease 2019 Testing Basics.
29. Food and Drug Administration. A Closer Look at Coronavirus Disease 2019 (COVID-19) Diagnostic Testing..
30. Food and Drug Administration. In Vitro Diagnostics EUAs. March 22, 2021. Accessed at https://www.fda.gov/medical-devices/coronavirus-disease-2019-covid-19-emergency-use-authorizations-medical-devices/in-vitro-diagnostics-euas.
31. Centers for Disease Control and Prevention. Interim Guidance for Antigen Testing for SARS-CoV-2..
32. Centers for Disease Control and Prevention. Overview of Testing for SARS-CoV-2 (COVID-19). March 17, 2021. Accessed at https://www.cdc.gov/coronavirus/2019-ncov/hcp/testing-overview.html#print.
33. Package Insert at https://www.fda.gov/media/145917/download
34. Centers for Disease Control and Prevention. Overview of Testing for SARS-CoV-2 (COVID-19).
35. The Rockefeller Foundation. Taking Back Control: A Resetting of America’s Response to Covid-19. December 16, 2020. Accessed at https://www.rockefellerfoundation.org/wp-content/uploads/2020/12/Taking-Back-Control-a-Resetting-of-Americas-Response-to-Covid-19.pdf.
36. U.S. Travel Association. COVID-19 Testing and The Opening of the U.S. Economy. July 16, 2020. Accessed at https://www.ustravel.org/sites/default/files/media_root/document/COVID19-Testing.pdf.
37. Package Insert at https://www.fda.gov/media/145917/download
38. Food and Drug Administration. COVID-19 Frequently Asked Questions