Interim guidance on the use of rapid antigen detection tests for the identification of SARS-CoV-2 infection

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Overview

This document provides interim guidance on the use of rapid antigen detection tests (RADT) for SARS-CoV-2 in the context of the public health system. This is a rapidly evolving field as new tests and technologies come to market through the regulatory process and data on performance and utility increase. These guidelines were developed in collaboration with provincial and territorial public health authorities and will be updated periodically as the science evolves.

Executive summary

Current approach to SARS-CoV-2 testing in Canada

Since the emergence of SARS-CoV-2, testing has been a key pillar of Canada's response to the pandemic. As of October 7, 2020, Health Canada has authorized 38 COVID-19 tests. The broad use of testing, as part of a suite of public health measures, led to a flattening of the epidemic curve in the spring of 2020, demonstrating the value of testing as a part of the COVID-19 response. To date, testing has relied on RT-PCR testing performed on a nasopharyngeal sample (NP) or alternate respiratory sample collected by a health care professional. This testing method will remain the gold standard for detecting SARS-CoV-2 infection in Canada.

New testing technology: antigen testing

Over the past several months, a number of new testing technologies for SARS-CoV-2 have been under development. Of these, a number of antigen-based tests have been submitted to Health Canada for review. The current antigen tests under review are intended for use at the point-of-care, outside of the laboratory environment. Some technologies require the use of a portable digital reader, while others use an optical readout and format analogous to a disposable pregnancy test. The performance characteristics of these new tests are under active investigation and thus are not yet fully characterized. There are limited data published on the performance characteristic of assays to date. A recent Cochrane review based on 8 evaluations in 5 studies found the average sensitivity of RADTs compared to RT-PCR was 56.2% with a specificity of 99.5% (Dinnes et al., 2020). It is critically important to understand the timing of the collection in comparison to symptom onset, since the lower sensitivity is not uniform over the course of infection. Viral loads, which are generally high in early disease, are sufficiently above the limit of detection for some antigen tests for the first 5 days of symptoms (preliminarily >90% concordance of RT-PCR and antigen tests, internal NML data), with a rapid decrease in performance beyond that initial period as the viral load starts to decrease.

Notwithstanding the difference in the performance profile, other potential characteristics of these tests (faster turnaround time, lower per-test cost, ability to do the test in a setting by non-professionals on a more frequent basis, amongst others) suggest that they will have an important role to play in the next phase of the response. It is important for the public health, infectious diseases experts and laboratory communities to identify the scenarios where the use of RADTs may further strengthen the public health response by expanding access to testing beyond existing indications for molecular detection of SARS-CoV-2. Furthermore, establishing mechanisms to allow these new point-of-care tests to report into the public health system efficiently is critical (see Reporting Considerations section below).

Balancing test sensitivity against other considerations

The intrinsic performance characteristics of a test are not the only factors determining its utility. The final interpretation of a test must take into account the performance parameters, the prevalence of infection, predictive values as well as the intended use of the test result. Therefore, the tolerance for sensitivity and specificity thresholds for a given type of test will vary based on the reason for ordering the test and the expected action that would follow either a positive or a negative test.

Clinical situations that need high sensitivity

In scenarios where critical decisions and actions rest on a test result (e.g., a symptomatic resident in a long-term care home, a patient in the ICU who needs remdesivir), the recommended test would be the most accurate test. At the time of writing, the indicated (best) test would be RT-PCR performed on a NP sample (or appropriate alternate respiratory sample). Please refer to the national polymerase chain reaction (PCR) testing indication guidance for COVID-19 for an up-to-date list of preferred sample types for RT-PCR testing based on clinical presentation.

Clinical situations where high sensitivity is not the main consideration

While there is at present limited use for SARS-CoV-2 RADT for cases when definitive action is needed, there may be other settings where RADTs may be acceptable or even preferable. There are limited data that evaluate the utility of RADT in the current pandemic (Dinnes et al.). Since the capacity to test using RT-PCR may not meet demand, it is important to identify scenarios where RADTs can be used effectively to increase access to testing in a manner that accounts for the lower sensitivity parameters. Furthermore, testing protocols that mitigate the decrease in sensitivity, such as through the use of repeated testing, can define the scenarios where RADT offer added value. Preliminary data suggests that performance in early disease (within 5 days of symptom onset) is similar to RT-PCR and may be a viable alternative. This will need to be further corroborated through comparisons with RT-PCR as antigen tests enter clinical practice (see 2-step algorithm in Figure 1).

A second broad category for use includes situations that involve the prospective monitoring of asymptomatic individuals for introduction of SARS-CoV-2 into high risk settings.Footnote 1 At this time, the market authorizations being sought from Health Canada: Medical Devices Bureau (HC-MDB) are focused on symptomatic testing in the early phase of disease, so the use in a monitoring context will require clinical validation. The frequency of repeat testing is not yet defined (see below).

Figure 1. Proposed flow chart for evaluation of antigen-based testing
Figure 1. Proposed flow chart for evaluation of antigen-based testing
Figure 1: Long description

The image is a flow chart showing the correct process for evaluating antigen-based testing.

The process flow starts with the question "Does this situation meet the criteria for PCR + NP testing as outlined in the core guidance document?"

Below this box are 2 boxes labelled "Yes" and "No."

If "Yes" then "Refer individual for testing by PCR + NP or 2-step algorithm (Ag followed by PCR)." The process flow ends.

If "No" then "perform antigen testing."

Below the "No" box are 2 boxes labelled "Negative" and "Positive."

If test result is "Positive" then "Refer individual for testing by PCR+NP for confirmation. Public Health informed, individual isolates pending confirmatory test." The process flow ends. Note: At this time, positive RADTs will require confirmatory testing by RT-PCR. Following further evaluation, confirmatory testing during periods of high prevalence might be discontinued provided specificity was sufficient.

If test result is "Negative" then "Pre-test probability for SARS-CoV-2 infection is high (for example, known contact, very symptomatic, high background community transmission)."

Below the "Negative" box are 2 boxes labelled "Yes" and "No."

If "Yes" then "refer for PCR+NP testing." The process flow ends.

If "No" then "return to regular care." The process flow ends.

Proposed use cases

At this time it is not possible to provide an exhaustive list of all cases where RADTs might be of benefit. A number of scenarios are given as examples below, but is not meant to be proscriptive.

Except for the symptomatic individuals, the situations above represent scenarios where frequent in and out events multiply the potential introduction of the virus into high risk settings where spread of infection has been known to occur. At this time it is not yet possible to articulate the implementation approach that best supports the public health goal of testing since the performance of the technologies are still being assessed. It is clear that a false negative test can occur early in infection even with the most sensitive RT-PCR methods. As such, repeat and frequent testing is necessary to detect infection. Some of the RADTs in development/under evaluation may offer the ease of use, the ability to conduct testing outside traditional laboratory settings and rapid turn around time to enable frequent testing and offset the reduced sensitivity of the RADT. Laboratory and clinical verification will be required to understand the performance characteristics of these devices to allow for effective integration into the existing health systems.

Clinical situations where time-to-result is critical

Northern and remote settings face additional barriers to timely test results due to transportation time. Given the importance of identifying new cases in remote and isolated communities accurately to prevent spread in the face of limited health care resources, RT-PCR testing is the recommended test for these settings. While there have been extraordinary efforts to date to bring point-of-care PCR testing to these clinical settings, there remains training and ongoing quality assurance challenges in smaller health centres. Some antigen-based tests may be lower in complexity (single use, visual indicator). These may prove an attractive option, where an initial test would be offered prior to the PCR confirmation. If positive, then presumptive action can be quickly put in place. Given the uncertainty about the performance parameters of RADTs, a negative test would need to be confirmed through RT-PCR in symptomatic individuals or those with a known positive contact.

Approach to the potential use of rapid antigen detection tests

These are preliminary recommendations that are subject to change pending further studies and precision on the extent of market authorization by HC-MDB for these devices. A proposed framework for implementing these tests is depicted in Figure 1. At this time, if public health action follows a positive test, then the RT-PCR test should be used to confirm all antigen tests until there is more data and familiarity with this platform. As more data are gathered on the performance of these tests in Canada, it may be possible to move to a more diagnostic role in the context of sufficient transmission and adequate positive and negative predictive value.

If the use of an approved RADT is being considered, how the result is interpreted and how it impacts public health and clinical management needs to be anticipated. Positive results should be considered to be a "presumptive positive" case until it is confirmed using a reference RT-PCR method because while RADTs have high specificity, there will be false positives particularly if virus transmission is low in the local context, making the pre-test probability low. All patients with a positive result will require isolation. If the confirmatory RT-PCR is negative, discontinuation of isolation can be considered depending on the clinical context that generated the initial test.

In interpretation of a negative RADT, the user must consider the clinical context of the test (asymptomatic vs symptomatic) and the pre-test probability of infection in the person tested. In patients where the pre-test probability of COVID-19 remains high (e.g., known contact, high community transmission), then the individual should undergo further testing using RT-PCR with the appropriate specimen dictated by the clinical presentation to direct further management. If the pre-test probability was low, then the individual can be monitored and remain out of isolation. As highlighted above, these tests are ideally used in a program that sees individuals get repeat tests.

If antigen tests are used in a monitoring approach, the ideal frequency of testing is not yet defined. The effectiveness depends on the proportion of infections that are asymptomatic, the sensitivity of the assay and the turnaround time (assuming that self-isolation would occur once a positive test is identified). There are modeling data based on ongoing community based transmission that suggest testing twice weekly with a PCR-based assay in high risk settings (such as in testing LTC workers) will reduce transmission of SARS-CoV-2. The reduction to once weekly may be reasonable in periods of low community transmission (Chin et al., 2020). Other modeling data have suggested that weekly testing of asymptomatic /presymptomatic health care workers with a 24hour turnaround time to initiate self-isolations in positive cases would reduce transmission by 23% (Grassly et al. 2020). There have been no studies looking at the frequency of testing using RADTs in these scenarios; however, not surprisingly, these models do suggest that a reduction in sensitivity (which would be expected with RADTs) reduces the effectiveness of the intervention. How frequently testing would be needed to overcome this limitation has yet to be modeled.

Reporting of results

The use of RADTs will most likely be occurring outside of the laboratory environment, although some RADTs require an analyzer, which would limit potential implementation locations. The current anticipated market authorizations are expected to require oversight of the testing procedure by a trained health care provider, at least in the short term. It will be essential that a mechanism for reporting of results into the public health system and/or laboratory system be developed to ensure appropriate data capture and quality control, and to support public health action.

Critical scientific questions

The state of the science continues to evolve daily as unprecedented global investment in research and development continues. Despite this, there remains a number of critical questions to inform the use of these new tests and sample types.

  1. What is the analytical sensitivity of RADTs compared to the various PCR-based methods?
  2. How do these tests perform in "real life"?
    1. Most submissions for approval have used simulated samples to evaluate the tests. This creates uncertainty about the true performance when applied to actual patients. There must be a verification of performance by comparing the real life performance of intended use in the field compared to the traditional nucleic acid amplification methodology.
  3. How frequently is testing required to make up the sensitivity gap?
    1. This requires understanding of the dynamics of the test over time. Serial sampling studies have to date been very limited and it will be important to determine the frequency of testing to best mitigate the risk of cases being missed due to the lower sensitivity of the RADTs.
  4. How do lower sensitivity tests and lower sensitivity sample types interact?
    1. If an antigen test is used with saliva, there are 2 sensitivity costs being paid and this impact must be evaluated together to inform potential for use
  5. At what threshold of community transmission is serial testing in specific environments helpful?
    1. The resource utilization to support various testing systems are considerable. There is little value in testing if the transmission rate is low but may increase if the rate of disease is high. Determining this threshold requires further investigations
    2. Public and clinician confidence in testing is very important. When there is little virus circulating (low prevalence), the positive predictive value (PPV) of an assay drops significantly even if it has excellent sensitivity and specificity. Conversely, the PPV increases as prevalence rises. It will be important to consider at what level of transmission different testing technologies can be effectively implemented.

Moving the field forward: next steps

As described above, there is a great degree of uncertainty about the technologies themselves, the sample collection methods and their place in applied "real world" settings. These real life scenarios span the gamut of use in LTC facilities, correctional facilities, specific high risk communities, specific businesses and industry, schools and daycares, to name but a few. It is not possible, at this time, to issue evidence-based recommendations for use scenarios. It is, however, necessary to generate the evidence in order to achieve this. This evidence will come from domestic deployment as well as through international engagement to learn from other countries' use of the various devices.

Once these technologies enter use in Canada, deployment strategies that enable structured data gathering will be essential to help inform future updates to these guidelines. Important dimensions to dimensions of data to gather include:

References

Endnotes

Endnote 1

Note that such a proposed monitoring role for non-PCR or antigen testing technologies is referred to as "screening" in some other documents on COVID-19 testing strategies.

Return to endnote 1 referrer

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