SARS-CoV-2 Use Cases White Paper

The intended use: Although there are three intended uses listed in Table 1, this paper will focus upon one intended use; to determine if a non-symptomatic (asymptomatic or pre-symptomatic) individual has a current SARS-CoV-2 infection.

Populations to be tested: There are a number of subsets of the general population currently being screened or under consideration for screening tests. There is a great desire to continue to reopen local economies throughout the country. For this reason, the focus of this white paper will be upon employment-related screening of non-symptomatic employees. Many organizations are in the process of implementing testing of their employees in order to assess if they are able to once again join the workforce or remain within the workforce over time.

The testing protocols and timing are areas of active debate and trial. Currently, many healthcare professionals, such as physicians, nurses and other hospital staff, in close contact with infected individuals are tested regularly. In some locations, first line responders, such as firefighters and police, have implemented testing programs with a variable frequency of testing, from occasional (weekly or longer) to frequent (every one to three days), depending on the locale. Of particular concern is the level of risk individual employees might have of becoming infected and infecting others. The issues are complex due to variations in individual employee risk related to their living situation, social interactions, general health (e.g., pre-existing conditions), work environment and the general prevalence within the community in which the employee lives and works. See Table 2.

The living environment of an individual has a substantial impact on the risk of current infection. For instance, someone that lives in a free-standing home alone in a suburb is at a much lower risk of infection compared to a person living within a large family in a single dwelling, or a person living with family members in a condo where many non-family individuals are encountered daily, or a person living in a congregate living facility. The more an employee, while at home, is in continuous close proximity to multiple people free to move about outside the home, the higher the risk of infection. However, when not at home or work, the individual will be at additional and variable risk due to their daily behavior ranging from walks near the home with proper masking and physical distancing to attending large gatherings in large urban areas. These are circumstances an employer is unlikely to be aware of and that can't easily be controlled.

Risk to individual employees and the rest of the workforce is dependent upon the work environment. In contrast to individual risk outside the workplace, this is an area often under the direct control of the employer. Employees who can work at home maintain their additional living, social, and personal health risks. Employees that work in environments where teams work together without physical interactions with non-employees during their shift (e.g., factories, offices) and where social-distancing precautions have been implemented are at substantially lower risk than situations where there is constant interaction with people from the local community (e.g., restaurants, retail outlets, street food vendors). At the far end of the risk spectrum are healthcare providers and first responders who must encounter persons known to be infected as part of their duties. PPE can be used much more effectively in some of these jobs (nurses, doctors) than others (firemen).

In overall low risk settings, it is entirely possible that the only time testing of employees would be conducted would be if they were symptomatic and the testing would be conducted away from the workplace. Then, they can be referred to their primary healthcare provider. They would re-enter the workplace after they recover.

There are attempts to assess employee risk of current infection prior to, or instead of, RNA testing. See health checks and surveys in Table 1. Some companies are using daily health surveys, often taken while at home, to determine if their employees can safely join the workforce. A tech company in Boise, Idaho, uses a series of questions about recent personnel interactions, such as visits with persons that recently arrived in the city by airplane. Other employers ask their employees if they have recently been contacted by a contact tracer or know that they have been in the presence of infected people. The CDC has listed a set of health-related questions to help assess risk of infection.

Beyond questions about potential recent exposure, the surveys can contain questions about health status such as fatigue, body aches, sense of smell (anosmia), and taste (ageusia). A number of reports suggest that the correlation of anosmia with SARS-CoV-2 infection is substantial and is often not reported by individuals without asking. It also appears that some people don't know that they have lost their sense of smell, prompting some groups to investigate "scratch and sniff" tests for detection of anosmia. The results of the surveys can result in a recommendation to self-isolate, seek care, return to work, and/or report for testing.

Others use, or are trying to create, health checks. Health checks may be useful in lieu of RNA tests or in addition to them. Temperature assessments and pulse oximetry are very common in Asia and Europe in office buildings, elevators, restaurants, airports, and many other sites of socials interactions. Many employers in the US have embraced this approach, for instance since April, CVS has been testing the temperature of its ~300,000 employees daily; anyone with a fever of 100 or greater is sent home. However, these methods can't be used to accurately assess current SARS-CoV-2 infection, particularly in non-symptomatic persons. Recent estimates suggest that 10-70% of the SARS-CoV-2 infections remain asymptomatic. Depending upon local prevalence and other risk factors, with these health checks alone there will still be occasional infections in the workforce.

The broad spectrum of conditions and risks suggests that one universal solution is unlikely. At this point, a global experiment is under way to determine how best to open the economy in a pandemic. As will be discussed, a systematic means to capture and trade experiences is sorely needed.

Use settings: Depending upon the population to be tested, the sites of collection and testing of samples will differ substantially. Some aspects of health checks and surveys could occur at the employee's home prior to going to work. Geisinger has announced a program to provide many of their members with thermometers and pulse oximeters at their homes. Home collection of samples such as mid-turbinate swabs or cup-collected saliva for shipment to a lab for testing has become more available over the last several weeks. However, there have been concerns expressed by some employers that suggest it would be better to have the sample collection observed due to the temptation for employees to provide samples from other persons to ensure that the employee remains employed.

Testing itself is being performed in a number of settings. It is common for samples to be sent to large labs off-site that can process the number of samples that are needed for frequent employee testing; however, it can take many days to receive results. Some lab services offer testing to employers. LabCorp introduced a return to work program in mid-May. However, recent discussions with Anthem Group suggest that more than a wait of one day for receipt of results would be very difficult for many of the employers that they serve.

Depending upon the size of the workforce, on-site employer testing can be conducted with dedicated staff and equipment. Most tests available are either moderate- or high-complexity, necessitating appropriate build out or availability of laboratory services. Some employers, such as Amazon, have decided to build dedicated labs to test their own workforce. Small systems that can process one test at a time are available, but with a test time of ~15 minutes for each sample run in series, it would take too long to process enough samples to justify such a system, except perhaps in a small workplace. Other point of care systems can process small groups of four to 10 samples in parallel. Workflows, costs, time to results, and frequency of testing will dictate whether or not on-site testing can be justified.

Another option includes mobile van testing. Point of care devices can be set up in a van and moved from site to site, which was done for Ebola testing in West Africa in 2014. Discussions with the company Amica in Canada that runs a series of assisted living facilities in a variety of locations indicated that they see mobile testing as a potentially cost-effective approach. This could be a reasonable alternative to the cost of developing an on-site testing option. However, there are associated regulatory issues as well as issues concerning sample collection, accessioning and tracking that must be considered for effective deployment.

At this time, antigen testing is under assessment as a reasonable alternative to RNA testing. If lateral flow devices or other simple formats can be introduced with adequate performance, it could be possible to test employees with finger prick blood or oral fluid samples without a laboratory. Many such tests have been introduced, but the evaluations are still under way by the Foundation for Innovative New Diagnostics (FIND) and others. Recently, there have appeared new FDA EUA claims for commercial antigen tests that limit the tested populations to the first five days after the appearance of symptoms when the viral load is usually quite high, and the antigen is usually detected.

General requirements of testing: The requirements for an RNA or antigen screening test are nearly identical to a diagnostic test with the following exceptions. As has been indicated, turnaround time is very important for many employers. If on-site testing is performed, and employees must wait for a result to begin work, longer than a 30 minute wait could be problematic. Some testing frequency models suggest that one- to three-day time to result could be effective in limiting most transmissions. In most situations, batch testing would be the preferred format to process enough samples. As a result, it is highly desirable to use collection methods that require less training and are less invasive than NP swabs, such as other nasal swabs or saliva cups or tubes. At this time, most of the testing will be in low prevalence settings.

False positive results will be an inconvenience to the employer (workplace productivity, need to locate temporary help, project delays, insurance costs) and to the employee (need to isolate, potential loss of wages, need to arrange for care for other family members during isolation, transportation costs, medical visit costs). Fortunately, the current RNA tests available rarely deliver false positive results. False negative results are far more concerning since a non-symptomatic but infected person could continue work in an environment where they could infect others. As a result, very high sensitivity is required. However, lower analytical sensitivity leading to false negative results could be offset by frequency of testing; that is, a person with a low viral load could test negative on test day one and is not infectious at that time, but when tested again one to three days later is at a higher viral load, is infectious, and is asked to self-isolate.

Status of testing, unmet needs: Some existing RNA tests do suffer from false negative results for at least three reasons. Some tests were developed early in the pandemic and design of the primers/probes does not permit adequate binding to the viral RNA. Due to the testing technology employed, some tests' lower limits of detection are probably too high to pick up early or late infections. Sample collection is not always performed properly. Next generation versions of tests are in development to deal with some of the shortcomings. It is important that purchasers carefully consider the features of the options available. The frequency of testing required will increase the cost consciousness of employers. The typical diagnostic tests often cost over $100. This price could increase further with deployment of differential diagnostics, for example during the upcoming flu season. As the burden of cost moves further toward the employers themselves, lower cost tests will help drive adoption.

Near-term improvements: Home or simple on-site collection of samples will help increase testing substantially. The trend to switch away from NP swabs is essential. The FDA has changed the wording in their guidance document to manufacturers to include other sample types. Point of care RNA systems should become broadly accepted in moderate complexity on-site labs or in mobile labs. On-line algorithms using health surveys and checks for selecting who should be tested will help select who should be screened with RNA tests. Those that test positive will be connected to contact tracers and asked to self-isolate. More and improved antigen tests will appear in lateral flow and other formats, but the minimum level of acceptable performance, particularly false negative results, needs to be refined. Pooling algorithms are likely to be implemented.

A number of organizations have developed next generation sequencing methods (NGS) for SARS-CoV-2 RNA. Recent reports from the University of California San Francisco (UCSF) indicate that there can be detectable changes in the viral sequence in as few as two transmissions. As a result, it is possible to track the viral variants across time, populations, and locations. Epidemiological NGS studies within hospitals have been conducted that show the probable sources of initial infection and the likely mechanism of spread. It is likely that some employers will embrace this technology to monitor their workforce.

One of the use cases identified in Table 1 involves environmental testing. It is possible for employers to obtain testing of their facilities and validation of cleaning practices with RNA testing using surface swipes and other forms of sample collection. This type of testing is common in the food manufacturing industry. Environmental testing could potentially help to identify sources of transmission. It could also increase the confidence of the management and staff if practices to decontaminate the work environment are demonstrated to be effective. There are potential complications in environmental testing due to the possible detection of non-infectious RNA contaminants that will not lead to transmission. These challenges will need to be resolved.

Mid-term improvements: It is probable that health survey questionnaires can be formally tested for sensitivity and specificity as a form of triage testing for use in conjunction with an RNA or antigen confirmation test. This could dramatically improve the cost effectiveness of the overall testing process. Better, simple health checks such as anosmia tests could supplement surveys for better risk assessment. The use of questionnaires and simple measures of health status should become integrated with RNA/antigen screening testing. If efficacious and affordable antiviral drug therapy is developed and successfully deployed, the entire process to screen employees could change. Perhaps there will be no continued need to track non-symptomatic employees since once symptoms appear, they will be referred to their respective healthcare systems to obtain medication.