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 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.

A recent report was delivered by the Testing and Screening Expert Panel on January 15, 2021. This report provides a comprehensive overview of RADTs and the report was reviewed, along with input from other key stakeholders such as the Canadian Public Health Laboratory Network and the Special Advisory Committee on COVID-19, in the drafting these interim guidelines.

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 February 9, 2021, Health Canada has authorized 49 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 molecular testing (e.g. RT-PCR) 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.

Integrating newer technologies such as antigen testing

As of February 18, 2021, Health Canada has authorized 3 antigen-based tests in Canada. The currently authorized antigen tests 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.

Data continues to accumulate regarding the performance characteristics of these tests in a variety of deployed settings. A recent study from Alberta focused on 145 symptomatic individuals within 7 days of symptom onset demonstrated a positive percent agreement of 86.2-87.7%. Of the 17 false negatives, 14/17 had cycle threshold (CT) values of >25. In this same study, a larger community-based cohort of 1641 symptomatic individuals underwent testing, with 268 being confirmed SARS-CoV-2 infections by RT-PCR. The Abbott Panbio test detected 231/268, revealing 37 as false negatives. Finally, specificity was quite good. Two false positives were detected by Panbio, though the authors argue that both of these were likely true positives based on case history (Stokes et al. 2021). These findings reveal somewhat better performance than other studies, which have positive percent agreement values in the 72-86% range, though these studies had somewhat different methods and confirmatory assays, potentially explaining the variation (Fenollar et al. 2020, Gremmels et al. 2021, Linares et al. 2020). The finding that CT values above 25 have a significant impact on performance mirrors internal National Microbiology Laboratory data demonstrating improved concordance in samples with higher viral loads.

The use of antigen tests in identifying individuals infected by SARS-CoV-2 that are either asymptomatic or pre-symptomatic remains an area of intense study. A preprint publication detailing screening testing in football players demonstrated that 52/2425 tests were positive by RT-PCR. Of these, sensitivity for a paired Panbio test ranged from 61.8-69.1%, while specificity ranged from 99.5-100%. The range of performance was impacted by 16 inconclusive tests, which were hard to interpret (Winkel et al. 2020). Uncertainty in band interpretation is an important consideration in implementing antigen tests, as discussed further below. By contrast, a preprint reporting a study performed on household and non-household asymptomatic contacts of known cases demonstrated a lower sensitivity (48.1%) but excellent specificity (100%) (Torres et al. 2020). In that study, the majority of cases that were not detected by RADT but were positive by PCR had CT values >25, consistent with other study findings. There is no established viral load that facilitates transmission, but higher viral load does appear to be linked to a higher chance of transmission (Kawasuji et al. 2020).

As the health care and public health systems continue to learn more about antigen tests, a balance between lower overall sensitivity and other helpful characteristics (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) point to a number of settings where RADT use can be considered.

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

As outlined above, RADTs demonstrate lower sensitivity when compared to RT-PCR testing but excellent specificity. As a result, implementation of RADTs should be done with appropriate protocols to best leverage the test technology. When used in symptomatic individuals in the context of sufficient community transmission, positive RADT tests represent an actionable result and may not need confirmatory testing. Their variable sensitivity in individuals who are symptomatic (72-88%) should prompt individuals who test negative to receive a RT-PCR test for confirmation.

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. As outlined in the evidence above, there is data that is accumulating but sensitivity is relatively low (49-69%) and is, as expected, related to the viral load.Footnote 1 RADTs used in this context appear able to identify individuals with higher viral loads, which are thought to be most likely to transmit, but will miss a significant number of cases if used as a single point in time. Repeated testing may provide a mean of mitigating this risk, as demonstrated by the higher sensitivity (61-69%) in the frequent-testing scenario used by Winkel et al., compared to single-point in time (49% Torres et al. 2020) but the optimal frequency of repeat testing has not yet been determined. It is important to note that, at this time, the market authorizations 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 must be based on clinical validation.

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 the time of writing, RADTs are authorized for use as diagnostics in early disease. There are a number of expanded potential uses that have been explored to date, serving different health goals. It should be emphasized that these expanded uses are meant to supplement the existing testing capacity in Canada and should be implemented with close linkage to local systems and public health, to ensure responsive action as needed. Broadly speaking, these fall under the following categories:

  1. Use in symptomatic individuals: as articulated above, this use is inline with the current Health Canada authorization. Many implementation approaches include positive antigen tests confirmed by PCR. Once comfort is achieved with a particular workflow, however, the confirmation could be discontinued when used in symptomatic individuals within the appropriate time window from symptom onset given the high specificity in symptomatic individuals (Stokes et al. 2021).
  2. Repeat serial testing of asymptomatic individuals as an addition to other infection prevention & control measures: these situations represent scenarios where frequent in and out events multiply the potential introduction of the virus into high risk congregated settings where spread of infection has been known to occur. It is clear that a false negative test can occur early in infection even with the most sensitive RT-PCR methods. As such, repeat serial testing is likely necessary to support this type of approach. Repeated testing protocols raise important considerations regarding the resourcing necessary to collect, process, report and act on results. Furthermore, acceptability of repeat testing protocols may be lower unless less invasive sampling, such as nasal samples, can be offered. It should be noted that Health Canada has authorized several tests that are based on nasal collection. Since performance characteristics and the impact of a repeated testing protocol is dependent on multiple factors, including local disease burden, engagement with local public health authorities to implement such a programme is recommended. Repeated testing in asymptomatic populations should not generally require confirmatory testing of negative tests, since this places significant strain on laboratory systems and have limited additional value. This should not be conflated with confirming negative tests in symptomatic individuals, where confirmatory testing is advisable (see Approaches section below). 
  3. Deployment to provide testing to specific populations: The relative ease of use of these tests and rapid turnaround time make RADTs suitable for use in situations where time-to-result is a primary concern.

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.

RADTs have also demonstrated utility in the context of "pop-up" testing events for asymptomatic individuals in community based setting (such as community centers, and entertainment or food service establishments). In this model testing can be administered in a flexible, movable manner and helps to access populations that might not otherwise engage in regular care (young, healthy adults that are likely to be asymptomatic but can still transmit).

The model has been used successfully in Nova Scotia, where it was developed as an additional layer of testing to supplement symptomatic testing delivered by traditional health care services. By using a model where volunteers and non-health care providers are trained to provide testing the Nova Scotia model has enabled people in communities across the province to get involved, take ownership and be a part of a movement to slow the spread of COVID-19 while at the same time preserving health care resources.  Importantly this model has also:

  • build capacity in communities across the province through engagement, education, and empowerment;
  • Increased the awareness of the importance of testing as a public health measure; and engages the community to reinforce the ongoing public health measures to help mitigate transmission
  • Destigmatized and increased testing for all populations in the jurisdiction.

RADTs are also potentially useful when testing individuals who are highly mobile or who are inconsistent in care-seeking, such as those that might be transient or underhoused where the rapid results can help with public health management and engagement.

Deployment in northern, remote and isolated settings

Northern, remote and isolated (NRI) settings face additional barriers to timely test results due to transportation time. Given the importance of identifying new cases in NRI 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 and well as linkage with P/T systems for public health action.

RADTs tend to be low complexity tests since they are single use and have a visual indicator. This translates to RADTs being an alternative test option where they could be a useful option as an initial test, to be followed by PCR confirmation. If positive, then presumptive action can be quickly put in place. Since remote settings are particularly vulnerable to outbreaks of COVID-19, given the limited health care resources, both positive and negative RADTs in this context should undergo confirmatory testing by PCR.  As such, dual swabbing should be considered along with the importance of linkage with an accredited laboratory for confirmatory testing activities.

Approaches to the use of rapid antigen detection tests

These recommendations are interim and represent an update from the recommendations issued October 7, 2020. These recommendations will be reviewed periodically and are subject to change further studies and pilot deployments.

Correct interpretation of the results of a RADT is critical in successful deployment. A positive test result by RADT in a symptomatic individual may or may not need further confirmation depending on the local context and experience with the test in question. A positive RADT in an asymptomatic individual that was tested under a "screening" programme should be considered to be a "presumptive positive" case until it is confirmed using a reference RT-PCR method. Despite the high specificity of RADTs, band interpretation can be difficult. As demonstrated in the preprint by Winkel et al., and consistent with internal NML data generated during the evaluation of these devices, careful attention must be paid to training tests users in band interpretation and how to manage potentially inconclusive results. This issue can be particularly pronounced when users are newly using the tests and have a limited experience in the range of band intensity. This issue, along with lower pre-test probability, may contribute to the higher rate of false positives observed in some pop-up type settings. All patients with a positive result should isolate pending confirmation. 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 and be counselled a negative test does not mean that an individual can forgo public health measures. All individuals should be counselled that although their test is negative at the time of testing, it is possible they could be incubating an infection or get exposed leading to infection in the coming days or weeks so it is critical they continue to follow public health guidance to protect themselves and others (physical distancing, wearing a mask, washing hands, and keeping their social bubble small).

As highlighted above, these tests are ideally used in a program that sees individuals get repeat tests however, the ideal frequency of testing is not yet defined. The efficacy 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 24 hour turnaround time to initiate self-isolations in positive cases would reduce transmission by 23% (Grassly et al. 2020).

The contrast in sensitivity depicted in a frequent testing framework (Winkel et al. 2020) compared to single-point in time testing (Torres et al. 2020) (61-69% versus 49%) supports the concept that frequent testing does improve performance, but optimal frequency has yet to be defined and likely will be different depending on the setting.

RADTs and variants of concern

At the end of 2020, numerous variants of concern (VoC) have arisen across the globe. Variants of concern have two significant impacts in the potential for deployment of RADTs. First, mutations might arise that have a negative impact on the performance of the tests themselves. At the time of writing this particular impact had not been observed but this remains an important consideration. Health Canada provides up-to-date risk assessments regarding the impact of VoC on diagnostic assays.

The second impact of VoC on RADTs is the need for users to remember that sequencing characterization cannot be done from a RADT device. As a result, it is important to ensure that individuals with a positive RADT result that may require further characterization (such as a recent traveller, a positive case of COVID-19 following vaccination, etc.) should still have a sample collected for PCR testing. An updated list of patient populations that might require priority sequencing can be found here.

Reporting of results

The use of RADTs will most likely be occurring outside of the laboratory environment. Although, the current Health Canada authorizations require oversight of the testing procedure by a trained health care provider, the pop up model used in Nova Scotia has shown that individuals with no health care background can be trained to effectively administer the test, including the collection of the NPS, although it is important to note that the programme required oversight by health care providers. In the deployment of RADTs, it is essential that a mechanism for reporting of positive results into the public health system. For some indications, the integration of the results into a laboratory system and patient record will need to be developed to ensure appropriate data capture and quality control, while in other situations such as community pop ups, the reporting of positive results along with denominator of overall testing volumes may be sufficient to support public health action.

Knowledge sharing, best practices and external advice

There has been a great deal of information generated in the use of RADTs in the past several weeks across Canada, with a number of approaches supporting different but complementary public health goals. A federal expert committee, comprised of a broad range of expertise, has recently released a report on the use of RADTs, including a number of considerations pertaining to ethics, accessibility and behavioural considerations. In drafting the present iteration of the recommendations herein, consultation has leveraged the expert report as well as knowledge exchange at the level of the Canadian Public Health Laboratory Network and a number of federal, provincial and territorial committees. The sharing of knowledge, implementation science results and best practices was an essential process to drive the recommendations herein. These processes will continue as the pandemic response moves forward and will enable further updates to these guidelines as the science evolves and new technologies come to market. It is critical to continue to gather information about deployment strategies and their impact.

References

Footnotes

Footnote 1

Chin ET et al. 2020. Frequency of routine testing for Coronavirus Disease 2019 (COVID-19) in high-risk healthcare environments to reduce workplace outbreaks. Clinical Infectious Diseases. https://doi.org/10.1093/cid/ciaa1383.

Return to footnote 1 referrer

Footnote 2

Fenollar F et al. 2020. Evaluation of the Panbio COVID-19 Rapid Antigen Detection Test Device for the Screening of Patients with COVID-19. Journal of Clinical Microbiology. DOI: 10.1128/JCM.02589-20.

Return to footnote 2 referrer

Footnote 3

Grassly NC et al. 2020. Comparison of molecular testing strategies for COVID-19 control: a mathematical modelling study. The Lancet Infectious Diseases. doi: 10.1016/S1473-3099(20)30630-7.

Return to footnote 3 referrer

Footnote 4

Gremmels H et al. 2021. Real-life validation of the Panbio™ COVID-19 antigen rapid test (Abbott) in community-dwelling subjects with symptoms of potential SARS-CoV-2 infection. The Lancet. https://doi.org/10.1016/j.eclinm.2020.100677.

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Footnote 5

Kawasuji H et al. 2020. Viral load dynamics in transmissible symptomatic patients with COVID-19.medRxiv. doi: https://doi.org/10.1101/2020.06.02.20120014

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Footnote 6

Linares M et al. 2020. Panbio antigen rapid test is reliable to diagnose SARS-CoV-2 infection in the first 7 days after the onset of symptoms. Journal of Virology. https://doi.org/10.1016/j.jcv.2020.104659.

Return to footnote 6 referrer

Footnote 7

Stokes W et al. 2021. Real-World Clinical Performance of the Abbott Panbio with Nasopharyngeal, Throat and Saliva Swabs Among Symptomatic Individuals with COVID-19. medRxiv. doi: https://doi.org/10.1101/2021.01.02.21249138.

Return to footnote 7 referrer

Footnote 8

Torres I et al. 2020. Real-life evaluation of a rapid antigen test (Panbio™ COVID-19 Ag Rapid Test Device) for SARS-CoV-2 detection in asymptomatic close contacts of COVID-19 patients. medRxiv. doi: https://doi.org/10.1101/2020.12.01.20241562.

Return to footnote 8 referrer

Footnote 9

Winkel BMF et al. 2020. Screening for SARS-CoV-2 infection in asymptomatic individuals using the Panbio™ COVID-19 Antigen Rapid Test (Abbott) compared to RT-qPCR. medRxiv. doi: https://doi.org/10.1101/2020.12.03.20243311

Return to footnote 9 referrer

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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