Early in the coronavirus disease 2019 (COVID-19) pandemic, the Centers for Disease Control and Prevention (CDC) published return-to-work criteria for healthcare personnel who had recovered from severe acute respiratory coronavirus virus 2 (SARS-CoV-2) infection. These criteria were most recently updated on April 3, 2020.1 The CDC has endorsed 2 different approaches to allow staff to return to work: a symptom or time-based strategy and a test-based strategy. Many institutions initially adopted the test-based strategy, in part because CDC initially recommended it as the preferred option (but no longer does so) and, in part, because it seemed the more definitive or conservative of the 2 CDC options

Babcock, H.

Forde, C.A.

Guzman-Cottrill, J.

Haessler, S.

Hayden, M.K.

Henderson, D.K.

Logan, L.K.

Malani, A.

Murthy, A.R.

Rock, C.

Van Schooneveld, T.

Weber, D.J.

Wright, S.B.

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State of the Pandemic CommentaryThe perplexing problem of persistently PCR-positive personnelDavid K. Henderson MD1, David J. Weber MD, MPH2, Hilary Babcock MD, MPH3, Mary K. Hayden MD4, Anurag Malani MD5,Sharon B. Wright MD, MPH6, A. Rekha Murthy MD7, Judith Guzman-Cottrill DO8, Sarah Haessler MD9, Clare Rock MD, MS10,Trevor Van Schooneveld MD11, Latania Logan MD, MSPH4 and Corey Forde MD, DM12 for the SHEA Board of Trustees1National Institutes of Health, Bethesda, MD, 2University of North Carolina at Chapel Hill, Chapel Hill, NC, 3Washington University School of Medicine, St. Louis,MO, 4Rush University Medical Center, Chicago, IL, 5St. Joseph Mercy Health System, Ann Arbor, MI, 6Beth Israel Deaconess Medical Center, Boston, MA, 7Cedars-Sinai Health System, Los Angeles, CA, 8Oregon Health and Science University, Portland, OR, 9Baystate Health, Springfield, MA, 10Johns Hopkins University Schoolof Medicine, Baltimore, MD, 11University of Nebraska Medical Center, Omaha, NE and 12Queen Elizabeth Hospital, BarbadosEarly in the coronavirus disease 2019 (COVID-19) pandemic, theCenters for Disease Control and Prevention (CDC) publishedreturn-to-work criteria for healthcare personnel who hadrecovered from severe acute respiratory coronavirus virus 2(SARS-CoV-2) infection. These criteria were most recentlyupdated on April 3, 2020.1 The CDC has endorsed 2 differentapproaches to allow staff to return to work: a symptom ortime-based strategy and a test-based strategy. Many institutionsinitially adopted the test-based strategy, in part because CDCinitially recommended it as the preferred option (but no longerdoes so) and, in part, because it seemed the more definitive orconservative of the 2 CDC options.As a result of using the test-based strategy, many institutionsnow have significant numbers of staff whose nasopharyngeal swabsremain RT-PCR positive for COVID-19, despite the fact that theyhave recovered from their episodes of illnesses and have beenasymptomatic for weeks or, in some instances, months. These staffeffectively remain in limbo; they feel well but have persistentlypositive PCR studies, and driven by the test-based strategy, theycannot return to the workplace until they have 2 negativeCOVID-19 PCR tests.This phenomenon (persistently positive PCR tests for extendedperiods after recovery from COVID-19 infection) has now beenwell described in the literature, including a paper describing thefirst 12 COVID-19 cases in the United States,2 a detailed studyof 9 cases from Germany3 and a recent paper from Manitoba.4Similarly, Strong and Feldmann described a lack of clear linkagebetween PCR positivity and viral infectiousness during theEbola epidemic.5 The Center for Infectious Diseases of theNational Academy of Medicine of Singapore issued a positionstatement, including data demonstrating that, of 73 COVID-19patients, virus was not cultivable in any of them after day 11 of theirillnesses.6 Similarly, the Korean Centers for Disease Controlevaluated 285 patients who were found to be PCR positive forCOVID-19 8–82 days following recovery from a documentedCOVID-19 illness.7 They were able to attempt viral culture in108 of these individuals and could not isolate virus from any ofthem.7 Each of the COVID-19 studies cited here performed viralculture in addition to PCR testing for viral RNA. In each of thestudies, coronavirus RNA could be detected long after virus couldno longer be cultured from upper respiratory samples. Thesedata document that individuals who had illnesses not requiringhospitalization, who recovered from the disease and who remainpersistently positive by PCR, no longer harbor cultivable virus10 days after symptom onset. Notably, these studies have assessedrelatively healthy populations who developed COVID-19 infectionbut were not severely ill. We do not yet know whether the 10-daycutoff is appropriate for immunocompromised healthcare person-nel (HCP) who develop COVID-19, but it clearly does not applyfor HCP who suffered severe disease (eg, with hospitalizationand/or prolonged intubation).8,9 Such individuals will have to bemanaged on a case-by-case basis until more data become available.In the Canadian study cited above, the authors retrospectivelyevaluated 90 previously identified positive samples by both PCRand viral culture in Vero-cells. They compared both the numberof days from onset of symptoms to the day the test was performedas well as the cycle thresholds of PCR positivity to recovery ofviable virus in tissue culture.4 In no instance were the investigatorsable to recover virus if >8 days had elapsed from the onset ofsymptoms, despite the persistence of positive PCR tests. Inaddition, if the cycle threshold for the sample was >24, they couldnot recover virus in tissue culture.4Relying on a cycle threshold limit as a return-to-work criterionhas some limitations. Cycle thresholds are not directly comparablefrom site to site or even from test to test. In addition to the numberof copies of RNA in a given sample, cycle thresholds depend on avariety of factors, including the specific gene target(s) and thenumber of gene targets chosen for the assay, the platform used,variability in reagents used from site to site, and more.Optimally, to use the cycle threshold, an institution would validatethe procedure in its own laboratory, demonstrating, as the studyfrom Manitoba did, that samples above a certain cycle thresholddid not contain cultivable virus. The challenge in doing sucha validation is that you need a Biosafety Level 3 laboratory to dothe tissue culture work, and many, if not most centers will not haveaccess to those resources. Additionally, if any aspects of the PCRassay change, revalidation is appropriate. Another challenge inAuthor for correspondence: David K. Henderson, Senior Advisor to the ChiefExecutive Officer, Building 10 Room 9D46A, 10 Center Drive, Bethesda, MD 20892.E-mail: dkh@nih.gov.Cite this article: Henderson DK, et al. (2021). The perplexing problem of persistentlyPCR-positive personnel. Infection Control & Hospital Epidemiology, 42: 203–204, https://doi.org/10.1017/ice.2020.343© 2020 by The Society for Healthcare Epidemiology of America. All rights reserved. This is anOpen Access article, distributed under the terms of the Creative Commons Attribution licence(http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.Infection Control & Hospital Epidemiology (2021), 42, 203–204doi:10.1017/ice.2020.343using cycle thresholds is that not all diagnostic nucleic acidamplification assays use RT-PCR, so cycle thresholds are notavailable, and some rapid instruments use PCR but do not yieldcycle threshold values. Finally, regarding the standardization oftesting, if the clinical laboratory community developed universalstandards for SARS-CoV-2 similar to the World HealthOrganization’s standards for hepatitis B and C, a multicenter studyof all currently manufactured SARS-CoV-2 nucleic acid amplifica-tion tests could be designed to correlate the cycle threshold valueson each platform for patients who have positive and negative viralcultures. Clinical laboratories could then calibrate their assaysusing the universal standard, thus allowing laboratories to estimatevirus viability from the cycle threshold with some certainty. Toassure proficiency and reliability, the College of AmericanPathologists could develop proficiency panels for labs for qualityassurance. This standardization scenario represents a desiredfuture state; for the time being, we will have to rely on otherstrategies.Conversely, relying on time from symptom development as areturn-to-work criterion is also fraught with a few challenges.The onset of COVID-19 may be insidious and may be difficultfor an individual provider to pin down. Recall bias may affectthe provider’s ability to be precise about the onset of symptoms.As asymptomatic provider surveillance testing expands, protocolswill have to be developed to manage asymptomatically infectedindividuals.So how do we approach these issues, balancing the safety ofpatients and staff with the need to avoid having staff unnecessarilysidelined staff who could be contributing to an importantpandemic response when we need them the most? Given the datacited here, the test-based strategy appears likely to delay HCPreturn to work longer than is necessary for the protection ofpatients and coworkers around them, especially at a time whenmost facilities are recommending universal masking of HCP.For HCP who had relatively mildly symptomatic cases (ie, man-aged as an outpatient), a symptom-based strategy as recommendedby the CDC appears appropriate based on the same data. Forasymptomatic cases, questions remain about relative transmissionrisk and possibly about timing of infection related to testing. TheCDC strategy of returning those HCP to work 10 days after theirpositive test seems reasonable. Staff who developed more severeCOVID-19 infections (eg, those requiring hospitalization and/orcritical care support) may represent a special case; as such, severelyill patients may shed virus for longer periods from symptomonset.8,9 In addition to the requirement that at least 10 days havepassed since symptoms first appeared, the CDC guidelines alsorequires that at least 72 hours have passed since recovery, definedin their guidance as resolution of fever and improvement inrespiratory symptoms.1 Adding the qualifier that “respiratorysymptoms must have improved” to the “10 days from symptomonset” requirement may help address this issue. Additional,unanswered questions remain about how to manage immunocom-promised HCP. Fewer data are available on viral viability durationin this latter population, and the need for further research on thistopic is urgent.Thus, based on these data, one approach to managing recoveredHCP who work primarily with patient populations at high risk ofcomplications would be to use the “time from symptomdevelopment” strategy plus “sustained improvement in respiratorysymptoms” and add a safety factor (eg, adding an additional weekor 2) to the time from symptom onset, or perhaps adding 2 weeksfrom test positivity for asymptomatic staff detected as positive.Institutions can decide howmuch of a cushion is appropriate, basedon local factors, patient populations, etc. In addition, the use ofsource-control masking should be required for such individuals.The dynamic nature of the pandemic necessitates that thehealthcare epidemiology community continue to closely monitorthe data as it emerges and to adjust policies and procedures, bothto maximize patient and staff safety, while preserving the laborforce that is essential to our ultimate success.Acknowledgments.Financial support. No financial support was provided relevant to this article.Conflicts of interest. All authors report no conflicts of interest relevant to thisarticle.*After this manuscript was submitted and accepted, the Centers for DiseaseControl and Prevention modified their recommended “return to work” criteriato state that a test-based strategy is no longer recommended and to advocatestrategies basically consistent with the suggestions outlined in this paper (Seehttps://www.cdc.gov/coronavirus/2019-ncov/hcp/return-to-work.html).References1. Criteria for return to work for healthcare personnel with suspected orconfirmed COVID-19 (interim guidance). Centers for Disease Controland Prevention website. https://www.cdc.gov/coronavirus/2019-ncov/hcp/return-to-work.html. Published May 5, 2020. Accessed July 17, 2020.2. COVID-19 Investigation Team. Clinical and virologic characteristics of thefirst 12 patients with coronavirus disease 2019 (COVID-19) in the UnitedStates. Nat Med 2020;26:861–868.3. Wolfel R, Corman VM, Guggemos W, et al. Virological assessment ofhospitalized patients with COVID-2019. Nature 2020;581:465–469.4. Bullard J, Dust K, Funk D, et al. Predicting infectious SARS-CoV-2 fromdiagnostic samples. Clin Infect Dis 2020 May 22 [Epub ahead of print].doi: 10.1093/cid/ciaa638.5. Strong JE, Feldmann H. The crux of Ebola diagnostics. J Infect Dis2017;216:1340–1342.6. Period of infectivity to inform strategies for de-isolation for COVID-19patients. Center for Infectious Diseases, National Academy of Medicine,Singapore. https://www.ams.edu.sg/view-pdf.aspx?file=media%5c5556_fi_331.pdf&ofile=PeriodþofþInfectivityþPositionþStatementþ(final)þ23-5-20þ(logos).pdf. Accessed June 19, 2020.7. Findings from investigation and analysis of re-positive cases. Korean Centersfor Disease Control and Prevention website. https://www.cdc.go.kr/board/board.es?mid=a30402000000&bid=0030. Accessed June 19, 2020.8. Liu W-D, Chang S-Y, Wang J-T, et al. Prolonged virus shedding even afterseroconversion in a patient with COVID-19. J Infection 2020 April 18 [Epubahead of print]. doi: 10.1016/j.jinf.2020.03.063.9. Van Kampen JJA, van de Vijver D, Fraaij PLA, et al. Shedding of infectiousvirus in hospitalized patients with coronavirus disease-2019 (COVID-19):duration and key determinants. medRxiv 2020 June 9 [Not yet peerreviewed]. doi: 10.1101/2020.06.08.20125310.204 David K. Henderson et al

The Perplexing Problem of Persistently PCR-Positive Personnel

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