key: cord-0882447-hpaw8mm0
authors: Long, D. R.; Gombar, S.; Hogan, C. A.; Greninger, A. L.; OReilly Shah, V.; Bryson-Cahn, C.; Stevens, B.; Rustagi, A.; Jerome, K. R.; Kong, C. S.; Zehnder, J.; Shah, N. H.; Weiss, N. S.; Pinsky, B. A.; Sunshine, J.
title: Occurrence and Timing of Subsequent SARS-CoV-2 RT-PCR Positivity Among Initially Negative Patients
date: 2020-05-08
journal: medRxiv : the preprint server for health sciences
DOI: 10.1101/2020.05.03.20089151
sha: 2a471ca1806d22e3b9cfb7121eb24ef90ff9d7bc
doc_id: 882447
cord_uid: hpaw8mm0

Background: SARS-CoV-2 reverse transcriptase polymerase chain reaction (RT-PCR) testing remains the cornerstone of laboratory-based identification of patients with COVID-19. As the availability and speed of SARS-CoV-2 testing platforms improve, results are increasingly relied upon to inform critical decisions related to therapy, use of personal protective equipment, and workforce readiness. However, early reports of RT-PCR test performance have left clinicians and the public with concerns regarding the reliability of this predominant testing modality and the interpretation of negative results. In this work, two independent research teams report the frequency of discordant SARS-CoV-2 test results among initially negative, repeatedly tested patients in regions of the United States with early community transmission and access to testing. Methods: All patients at the University of Washington (UW) and Stanford Health Care undergoing initial testing by nasopharyngeal (NP) swab between March 2nd and April 7th, 2020 were included. SARS-CoV-2 RT-PCR was performed targeting the N, RdRp, S, and E genes and ORF1ab, using a combination of Emergency Use Authorization laboratory-developed tests and commercial assays. Results through April 14th were extracted to allow for a complete 7-day observation period and an additional day for reporting. Results: A total of 23,126 SARS-CoV-2 RT-PCR tests (10,583 UW, 12,543 Stanford) were performed in 20,912 eligible patients (8,977 UW, 11,935 Stanford) undergoing initial testing by NP swab; 626 initially test-negative patients were re-tested within 7 days. Among this group, repeat testing within 7 days yielded a positive result in 3.5% (4.3% UW, 2.8% Stanford) of cases, suggesting an initial false negative RT-PCR result; the majority (96.5%) of patients with an initial negative result who warranted reevaluation for any reason remained negative on all subsequent tests performed within this window. Conclusions: Two independent research teams report the similar finding that, among initially negative patients subjected to repeat SARS-CoV-2 RT-PCR testing, the occurrence of a newly positive result within 7 days is uncommon. These observations suggest that false negative results at the time of initial presentation do occur, but potentially at a lower frequency than is currently believed. Although it is not possible to infer the clinical sensitivity of NP SARS-CoV-2 RT-PCR testing using these data, they may be used in combination with other reports to guide the use and interpretation of this common testing modality.

subsequent tests performed within this window. 23 All rights reserved. No reuse allowed without permission.

was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint (which this version posted May 8, 2020. . https://doi.org/10.1101/2020.05.03.20089151 doi: medRxiv preprint Conclusions: Two independent research teams report the similar finding that, among initially negative 24 patients subjected to repeat SARS-CoV-2 RT-PCR testing, the occurrence of a newly positive result 25 within 7 days is uncommon. These observations suggest that false negative results at the time of initial 26 presentation do occur, but potentially at a lower frequency than is currently believed. Although it is not 27 possible to infer the clinical sensitivity of NP SARS-CoV-2 RT-PCR testing using these data, they may 28 be used in combination with other reports to guide the use and interpretation of this common testing was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Table 1 ). Results of other viral respiratory tests were available for UW 98 All rights reserved. No reuse allowed without permission.

was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint (which this version posted May 8, 2020. . https://doi.org/10.1101/2020.05.03.20089151 doi: medRxiv preprint patients and several negatively retested patients were ultimately diagnosed with other viral respiratory 99 illnesses, most commonly influenza A, rhinovirus, and RSV (Supplemental Table 1 ). However, a small 100 proportion (4.1% UW, 2.6% Stanford) underwent repeat testing within this window despite an initial 101 negative result (Figure 1A) . In this report, two independent research teams describe that, among patients initially testing negative by 120 SARS-CoV-2 RT-PCR of a NP swab, repeat testing within 7 days yielded a positive result in 3.5% of 121 All rights reserved. No reuse allowed without permission.

was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. prior to an initial negative result who were retested for persistent or worsening symptoms, a similar 124 proportion (4.3%) were subsequently found to be positive within 7 days. These observations suggest that 125 false negative NP SARS-CoV-2 RT-PCR results do occur, but potentially at a lower frequency than is 126 currently believed.

Results from each research group have limitations. Neither team is able to calculate a true clinical 129 sensitivity or false negative proportion due to the absence of retesting in all initially negative patients and 130 the lack of a gold standard confirmatory mechanism. Additionally, it cannot be ruled out that some 131 discordant test results in this cohort may be due to newly acquired infection. By limiting the scope of 132 retesting considered to a 7-day period, the likelihood of this scenario is minimized, but not eliminated.

Finally, we were unable to ascertain the disease status of the individuals who initially tested negative for 134 COVID-19 but did not undergo repeat testing; in most cases this likely reflects the absence of an 135 indication for retesting (e.g. alternative diagnosis or resolution of symptoms), but could also be the result 136 of limited access to care.

The intention of this report is not to definitively quantify the clinical performance of NP SARS-CoV-2 138 RT-PCR testing, which will likely require orthogonal approaches such as serology. Rather, by 139 characterizing the experience of two large US health systems on the short-term occurrence of newly 140 positive SARS-CoV-2 results among initially test-negative patients, we provide data on a topic of 141 practical significance that should be used in combination with other reports to guide the use and 142 interpretation of this common testing modality. 143 All rights reserved. No reuse allowed without permission.

was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint (which this version posted May 8, 2020. . https://doi.org/10.1101/2020.05.03.20089151 doi: medRxiv preprint

COVID-19) EUA Information

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was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 170 All rights reserved. No reuse allowed without permission.was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which this version posted May 8, 2020. was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.