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Review 2: "High Rates of Rapid Antigen Test Positive After 5 days of Isolation for COVID-19"

While results were clearly presented, reviewers point out that the manuscript’s conclusions are not backed up by these results, and the discussion should be better supported by literature.

Published onJun 08, 2022
Review 2: "High Rates of Rapid Antigen Test Positive After 5 days of Isolation for COVID-19"
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key-enterThis Pub is a Review of
High Rates of Rapid Antigen Test Positivity After 5 days of Isolation for COVID-19

AbstractBackgroundThe emergence of the highly transmissible COVID-19 variant, omicron, has resulted in high numbers of breakthrough infections, including among healthcare workers (HCW). Recent CDC recommendations now allow healthcare workers to return to work after day 5 if symptoms have improved, without a requirement for a negative rapid antigen test (RAT).MethodsFully vaccinated and non-immunocompromised HCW at a large, urban, academic medical center who tested positive for COVID-19 starting in late December, 2021 (when omicron was the predominant circulating strain) were allowed to return to work early if all symptoms had resolved excepting mild, intermittent cough and/or lingering loss of taste/smell, provided a rapid antigen test was negative upon return. Those with negative tests were allowed to return to work with the stipulations that they wear an N95 at all times and take breaks and eat meals apart from others. Those with positive tests on first attempt could return 24-48 hours later to test again for as many days as needed to achieve a negative result or until they completed 10 days of restriction from work.ResultsBetween January 2, 2022 and January 12, 2022 there were 309 total RAT done on 260 separate HCW on day 5-10 of illness. Overall, 43% (134 of 309) of all RAT were positive between days 5-10. The greatest percent positive RAT was noted among HCW returning for their first test on day 6 (58%). The rate of positivity was greatest (58%) among HCW returning for their first test on day 6. HCW returning on day 8 and 9 were less likely to have a positive test (26%, 19/74). In RAT positive HCW returning for their first test on days 5 or 6 (and for which line intensity was recorded) 49% (25/51) were recorded as having the darkest intensity on their RAT. HCW who test positive on their first test most often remained positive on their second test, with 56% of second tests, aggregated across all days 6-10, remaining positive. Over all first tests performed on days 5-10, boosted HCW were nearly twice as likely to test RAT positive: 53% (75 out of 141) of boosted HCW tested positive.DiscussionMore than 40% of vaccinated HCW who felt well enough to work still had positive RAT tests when presenting for a first test between days 5 and 10. Boosted individuals were nearly 3x as likely to result positive on day 5, their first day eligible for return, and ∼2x as likely to result positive on first RAT overall. New guidance provides clearance to exit isolation after 5 days from symptom onset, without the need for a negative rapid antigen test to exit, as long as symptoms are beginning to resolve. Per CDC, the guidance was driven by prior studies, mostly collected before Omicron and before most people were vaccinated or infected, that reported on symptom onset beginning one or more days after peak virus loads. In such an instance, where isolation based on symptom onset often did not begin until peak virus load was already attained, then release from isolation at 5 days would be appropriate. However, reports showing much earlier onset of symptoms, coupled with our own results here demonstrate that the relationship between symptom onset and peak virus load has changed, and 5 days from symptom onset may no longer be an appropriate window to end isolation without a negative rapid antigen test to support safe exit.ConclusionThese results indicate that a substantial proportion of individuals with COVID-19 are likely still contagious after day 5 of illness regardless of symptom status. Early liberation from isolation should be undertaken only with the understanding that inclusion of individuals on day 6-10 of illness in community or work settings may increase the risk of COVID-19 spread to others which, in turn, may undermine the intended benefits to staffing by resulting in more sick workers.

RR:C19 Evidence Scale rating by reviewer:

  • Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.



This is an important and well reported, timely study, even if the sample is relatively small. It clearly shows a problem with the CDC recommendation for healthcare workers to return to work from COVID-19 isolation after day 5 if symptoms have improved. It also indicates high utility of rapid antigen test based, rather than time based, return from isolation into high consequence settings. In addition, the study highlights the need for policy makers to consider viral dynamics, epidemic dynamics and population immunity dynamics with reasonable predictive rationale, rather than relying on crude calibration with previous variants, waves and vaccination/prior-infection patterns.

In the background on trade-off between pathogen and staff-shortage risks to patient safety the authors might emphasise a little more the dynamics and local context of those difficult decisions, and that a one-size policy cannot fit all contexts (in time, place and person) – test-based responses allow greater/empirical context-sensitivity than time-based policies.

It is not clear whether the used lateral flow devices were photographed. If so, relatively simple image analysis can be used to measure relative intensity of T/C areas giving more ordinal information for approximating antigen shedding load (albeit moderated by swabbing variation).

In discussing vaccination status regarding symptom timing and presentation for return to work, the authors might acknowledge that this status may also be an instrumental variable for behaviours. The biology is clearly more directly relevant, however, and is well described.

It may be better to wait for the culture results, pending approvals, than to speculate on cultivability. Prior studies may not port well to the studies variant-epidemic-immunity contextual union. Note a similar study in Liverpool, UK (NHS SMART Release & Return has reported interim results to the UK Health Security agency including culture results on a sample of those healthcare workers who were still testing antigen positive by day 7 – most were culture negative but a substantial proportion were not.

The word “recent” in the paper may be replaced with date references.

A meta-analysis of similar studies across heterogeneous contexts would be valuable to policy makers globally.

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