free bootstrap themes

healthxwiki COVID-19 applied evidence review

The COVID-19 test mess: Why RT-PCR testing is not the gold standard when it comes to COVID-19 test screenings

10 Dec 2020


COVID-19 has upended many long standing conventions related to respiratory viruses. Before COVID-19, droplets were thought to be primarily responsible for transmission, most transmission was assumed to occur at or after symptom onset and children were the most feared vulnerable group for respiratory virus fatalities. Instead, it is now widely accepted that aerosols drive COVID-19 transmission, symptoms are not a marker of liklihood of transmission and children are, empirically, least affected by severe clinical COVID-19 outcomes. More recently, COVID-19 challenges yet another assumption: RT PCR tests as the gold standard diagnostic, superior to rapid (antigen) testing, which have less test accuracy than RT PCR tests. 

While the Dec 3rd US CDC testing guidance continues to hedge on the issue of COVID-19 testing, compelling evidence indicates the 'best' test when it comes to COVID-19, is not the most accurate test. Instead, it's the test that provides a constant COVID-19 test feedback loop for an individual to navigate daily COVID-19 risk transmission to others. Such a feedback loop requires testing on a regular basis (1-3x/weekly), and where results are delivered back ideally less than a few hours, and no more than 24 hours. It enables testing information to be more actionable in a real world context- allowing for more accurate COVID-19 risk navigation in daily life in communities where the infection spread is uncontrolled. 

To date, much of the attention has gone to proving the value of rapid testing. But, an equally important factor is reassessing the role of RT PCR testing in COVID-19 asymptomatic/ presymptomatic screenings such as those described in the CDC's recent test guidance for high risk populations. We map out two weaknesses of RT PCR testing in the context of COVID-19 infection control, suggesting conventional thinking is, once again, leading us down a problematic road in fighting COVID-19.

Problem 1. PCR testing in the US optimizes the individual, not communities 

Why? Specifically, COVID-19 PCR testing in the US is primarily available if you have been exposed or are experiencing symptoms. With very limited contact tracing ongoing, most people are unaware of their exposure incidents. This leaves symptom onset as the major precipitating factor to seeking out COVID-19 PCR testing.

Why does this actually matter? While transmission can occur throughout the incubation period (from time of exposure to symptom onset), the likelihood of it occurring within 3 days prior to symptom onset is high. In other words, by the time an individual gets tested, a critical infectious window, when the likelihood of transmission is high, has already passed.

In settings where RT PCR testing is being used as a regular screening tool (e.g., well resourced businesses and schools), the timing of RT PCR tests often fail to adequately reduce risk in the pre-symptomatic infectious window. Even where RT PCR testing timelines are adequate, the timing is designed to usually optimize protection to a one set of contacts (e.g., school-based, co-workers). This may or may not optimize protection to other contacts in one's COVID-19 bubble, such as family and friends. In this sense, RT PCR tests for screening purposes come with multiple caveats. By in large, most of these caveats are not being communicated to those who are being screened. 

In contrast, high frequency antigen (rapid) testing applied as asymptomatic screening has repeatedly proven effective in breaking transmission chains among high risk communities such as nursing homes and college campuses (See here for evidence). The major takeaway from the growing body of evidence on high frequency rapid testing is that frequency- even with less accuracy- is the valuable commodity to break COVID-19 transmission chains. This contradicts conventional thinking, which largely associates accuracy with a gold standard for a diagnostic test strategy. 

Problem 2. There is a "false positive" problem with RT PCR tests, where positive is associated with infectiousness

  Positive PCR Test = You have the infection (& may or may not be infectious)
                          Positive Rapid Test = You are infectious now

Why? The higher test sensitivity/ specificity means that RT PCR tests will remain positive well past time of a COVID-19 infectious window. And while more information can be obtained via the cycle threshold (Ct level) from RT PCR tests, how much these metrics are disclosed to those tested, much less explained, is questionable.

Why does this actually matter? An artificially long positivity period vs infectiousness period means economically vulnerable communities are penalized for altruistic behavior towards the community. In practice, it creates a disincentive to get tested.

Moving Forward with More Transparency in COVID-19 Test Screening

To their credit, the recent update of US CDC guidelines related to shortened quarentine timeline. However, the same translation of the evidence has not been applied to advice to employers, schools and the public at large. There are likely many moving parts to explain this disparity in how existing high quality evidence is currently applied to COVID-19 guidance. But, a notable influence for shortened quarentine timelines is the travel industry. And while multiple industries have championed the use of rapid testing as a strategy for reopening, there is little incentive to ensure rapid testing is set up with the explicit purpose of breaking transmission chains as opposed to COVID-19 theater to reassure customers.

High frequency rapid testing has demonstrated the ability to efficiently idenify COVID-19 positive individuals – while they are infectious—and in turn, disrupt community transmission chains. But, it only works when testing protocols are frequent enough (e.g., aligned with COVID-19 infectious timeline) for a consistent COVID-19 test feedback loop, enabling more accurate risk navigation. At the same time, the public health and medical communities continue to suffer from delayed reactions when real time evidence conflicts with conventional thinking and messaging to the public heavily reflects resources available.

More transparent guidance on the strengths & limitations of different testing approaches means that when better resources are available, the public can move quickly towards more optimal strategies. More importantly, it translates into more informed risk reduction for high risk communities communities. 

Trust is perhaps the most lacking commodity in this pandemic. Basic steps to empower high risk communities on how existing testing strategies align (and misalign) with high quality COVID-19 evidence is a small but mighty first step towards rebuilding some of this trust. It speaks directly to what most are highly motivated to do in this pandemic: protect family and friends. 

1. Larremore, D. B., Wilder, B., Lester, E., Shehata, S., Burke, J. M., Hay, J. A., ... & Parker, R. (2020). Test sensitivity is secondary to frequency and turnaround time for COVID-19 surveillance. MedRxiv.

2. Hatfield, K. M., Reddy, S. C., Forsberg, K., Korhonen, L., Garner, K., Gulley, T., ... & Sievers, M. (2020). Facility-wide testing for SARS-CoV-2 in nursing homes—seven US jurisdictions, March–June 2020. Morbidity and Mortality Weekly Report, 69(32), 1095.

3. Sanchez, G. V., Biedron, C., Fink, L. R., Hatfield, K. M., Polistico, J. M. F., Meyer, M. P., ... & Kiama, K. (2020). Initial and repeated point prevalence surveys to inform SARS-CoV-2 infection prevention in 26 skilled nursing facilities—Detroit, Michigan, March–May 2020.

4. K. Ketchum. Modern Health Care. Would Abott's Antigen Test Solve COVID-19 Testing Problems? Stakeholders Emphasize Caution. 1 Sept 2020. 

5. Garg, J., Singh, V., Pandey, P., Verma, A., Sen, M., Das, A., & Agarwal, J. Evaluation of sample pooling for diagnosis of COVID‐19 by Real time PCR‐A resource saving combat strategy. Journal of Medical Virology.

6. He, X., Lau, E. H., Wu, P., Deng, X., Wang, J., Hao, X., ... & Mo, X. (2020). Temporal dynamics in viral shedding and transmissibility of COVID-19. Nature medicine, 26(5), 672-675.

7. Expert Taskforce for the COVID-19 Cruise Ship Outbreak, Epidemiology of COVID-19 Outbreak on Cruise Ship Quarantined at Yokohama, Japan, February 2020. Emerging infectious diseases, 26(11).

8. Lau, E. H., & Leung, G. M. (2020). Reply to: Is presymptomatic spread a major contributor to COVID-19 transmission?. Nature Medicine, 1-2.

9. Paltiel, A. D., Zheng, A., & Walensky, R. P. (2020). Assessment of SARS-CoV-2 screening strategies to permit the safe reopening of college campuses in the United States. JAMA network open, 3(7), e2016818-e2016818.

10. Sax, P. Relieving the COVID19 Testing Logjam. New England Journal of Medicine Journal Watch.

11. Zhang, E., LeQuesne, E., Fichtel, K., Ginsberg, D., & Frankle, W. G. (2020). In-patient psychiatry management of COVID-19: Rates of asymptomatic infection and on-unit transmission. BJPsych Open, 6(5).

12. Nishiura, H., Kobayashi, T., Miyama, T., Suzuki, A., Jung, S. M., Hayashi, K., ... & Linton, N. M. (2020). Estimation of the asymptomatic ratio of novel coronavirus infections (COVID-19). International journal of infectious diseases, 94, 154.

13. Mizumoto, K., Kagaya, K., Zarebski, A., & Chowell, G. (2020). Estimating the asymptomatic proportion of coronavirus disease 2019 (COVID-19) cases on board the Diamond Princess cruise ship, Yokohama, Japan, 2020. Eurosurveillance, 25(10), 2000180.

14. Kronbichler, A., Kresse, D., Yoon, S., Lee, K. H., Effenberger, M., & Shin, J. I. (2020). Asymptomatic patients as a source of COVID-19 infections: A systematic review and meta-analysis. International Journal of Infectious Diseases, 98, 180-186.

15. Lucey, M., Macori, G., Mullane, N., Sutton-Fitzpatrick, U., Gonzalez, G., Coughlan, S., ... & Schaffer, K. Whole-Genome Sequencing Confirms SARS-CoV-2 Transmission between Healthcare Workers and Patients.

16. Meyerowitz, E., Richterman, A., Bogoch, I., Low, N., & Cevik, M. (2020). Towards an Accurate and Systematic Characterization of Persistently Asymptomatic Infection with SARS-CoV-2. Available at SSRN 3670755.

17. Emery, J. C., Russell, T. W., Liu, Y., Hellewell, J., Pearson, C. A., Knight, G. M., ... & Houben, R. M. (2020). The contribution of asymptomatic SARS-CoV-2 infections to transmission on the Diamond Princess cruise ship. eLife, 9, e58699.

18. Yu, Y., Liu, Y. R., Luo, F. M., Tu, W. W., Zhan, D. C., Yu, G., & Zhou, Z. H. (2020). COVID-19 Asymptomatic Infection Estimation. medRxiv. [23 April 2020].

19. Furuse, Y. et al. Clusters of coronavirus disease in communities, Japan, January–April 2020. Emerg. Infect. Dis. (2020).

20. Hellewell, J., Abbott, S., Gimma, A., Bosse, N. I., Jarvis, C. I., Russell, T. W., ... & Flasche, S. (2020). Feasibility of controlling COVID-19 outbreaks by isolation of cases and contacts. The Lancet Global Health.