key: cord-0715523-dyllx17g authors: Mack, Christina D.; Wasserman, Erin B.; Hostler, Christopher J.; Solomon, Gary; Anderson, Deverick J.; Walton, Patti; Hawaldar, Kalyani; Myers, Emily; Best, Michele; Eichner, Daniel; Mayer, Thom; Sills, Allen title: Effectiveness and use of reverse transcriptase polymerase chain reaction point of care testing in a large‐scale COVID‐19 surveillance system date: 2022-03-11 journal: Pharmacoepidemiol Drug Saf DOI: 10.1002/pds.5424 sha: 330f6159ecaa071b67077e20662463b57b75ee73 doc_id: 715523 cord_uid: dyllx17g BACKGROUND: Rapid COVID‐19 testing platforms can identify infected individuals at the point of care (POC), allowing immediate isolation of infected individuals and reducing the risk of transmission. While lab‐based nucleic acid amplification testing (NAAT) is often considered the gold standard to detect SARS‐CoV‐2 in the community, results typically take 2–7 days to return, rendering POC testing a critical diagnostic tool for infection control. The National Football League (NFL) and NFL Players Association deployed a new POC testing strategy using a newly available reverse transcriptase polymerase chain reaction (RT‐PCR) rapid test during the 2020 season, and evaluated diagnostic effectiveness compared to other available devices using real‐world population surveillance data. METHODS: RT‐PCR POC test results were compared to NAAT results from same‐day samples by calculation of positive and negative concordance. Sensitivity analyses were performed for three subgroups: (1) individuals symptomatic at time of positive test; (2) individuals tested during the pilot phase of rollout; and (3) individuals tested daily. RESULTS: Among 4989 same‐day POC/NAAT pairs, 4957 (99.4%) were concordant, with 93.1% positive concordance and 99.6% negative concordance. Based on adjudicated case status, the false negative rate was 0.2% and false positive rate was 2.9%. In 43 instances, the immediate turnaround of results by POC allowed isolation of infected individuals 1 day sooner than lab‐based testing. Positive/negative concordance in sensitivity analyses were relatively stable. CONCLUSION: RT‐PCR POC testing provided timely results that were highly concordant with lab‐based NAAT in population surveillance. Expanded use of effective RT‐PCR POC can enable rapid isolation of infected individuals and reduce COVID‐19 infection in the community. • Reverse transcriptase polymerase chain reaction (RT-PCR) point of care tests became available later in the 2020 COVID-19 pandemic and demonstrated high concordance with labbased nucleic acid amplification testing (NAAT), performing significantly better than antigen point of care (POC) assay in broad surveillance settings and presymptomatic individuals. • Real-world evidence collected through routine surveillance of over 10 000 NFL players and staff in 2020 allowed key insights into the effectiveness of this new diagnostic. • Point-of-care RT-PCR provided an early signal of infection, allowing for prompt isolation ahead of pending NAAT result. • Expanded use of effective RT-PCR POC can enable rapid isolation of infected individuals and may reduce community transmission of COVID-19. • Real-world evidence from this cohort is applicable to other occupational and large-scale surveillance settings. Lab-based COVID-19 testing in the community can take 2-7 days to return, creating a challenge to prevent spread of infection. Point-of-care (POC) rapid tests allow for immediate detection and isolation of infected individuals. The National Football League (NFL) and NFL Players Association used a newly available RT-PCR rapid test during the 2020 season. Using data from realworld operations, the effectiveness of the rapid testing device was compared to the lab-based nucleic acid amplification testing (NAAT) using positive and negative concordance and comparing to an adjudicated COVID-19 case status. Among 4,989 same-day test pairs, 99.4% were concordant, with 93.1% positive concordance and 99.6% negative concordance. Based on adjudicated case status, the false negative rate was 0.2% and false positive rate was 2. 9% . In 43 instances, the immediate turnaround of results by POC allowed isolation of infected individuals one day sooner than lab-based testing. Because of high concordance between lab-based testing and RT-PCR POC, which allowed for immediate isolation, RT-PCR POC is a useful tool for community infection control. As with many industries, the COVID-19 pandemic significantly impacted professional athletics around the world. Some leagues canceled seasons, some utilized isolated "bubbles," 1 while others implemented mitigation strategies and proceeded through their seasons with some level of disruption due to canceled or postponed games. The National Football League (NFL) successfully played all 269 games of the 2020 season due to risk mitigation strategies applied throughout their facilities, educational efforts for athletes and staff, and a focus on aggressive testing for early identification of COVID-19 infection to limit the risk of large outbreaks through isolation of infected individuals and quarantine of close contacts. 2 As part of the COVID-19 strategies, the NFL and National Football League Players Association (NFLPA) conducted daily nucleic acid amplification (NAAT) tests among players and most staff throughout the 2020 season, with a point of care (POC) test used as an additional tool on a for-cause basis or when NAAT results were not available. 3 POC testing is an attractive surveillance strategy due to the speed with which results are returned, allowing for interventions to be more rapidly deployed to mitigate the spread of COVID-19. The most prevalent platform for POC testing is antigen testing; however, multiple studies across different populations have demonstrated that antigen testing is not as sensitive as NAAT methods, particularly in early stages of infection and asymptomatic populations. [4] [5] [6] At the beginning of the NFL/NFLPA COVID-192020 monitoring program, an antigen-based platform was used primarily for POC testing for the first 4 months (mid-July through late November) of the NFL season. After observing a low positive predictive value and high rate of false negatives in asymptomatic individuals with a specific antigen-based POC test during this time, the NFL sought to replace antigen POC testing with a rapid reverse transcriptase polymerase chain reaction (RT-PCR) diagnostic device. 3, 7, 8 Accordingly, the NFL/NFL Players Association transitioned the rapid test method from antigen-based to an RT-PCR POC, utilizing the Mesa Accula platform. 9 This diagnostic was made available under FDA Emergency Use Authorization (EUA), with large-population effectiveness unknown. The clinical performance of the Accula has been validated and published both in EUA documentation 9 as well as a clinical study with primarily symptomatic patients 10 ; however, performance in a realworld setting of a low-prevalence, largely pre/asymptomatic population has not been well established, nor has the impact of having a 1 h turnaround time compared to 24 h. The objective of this study was to measure concordance between an RT-PCR POC platform and same-day NAAT tests, as well as clinically adjudicated outcomes, evaluating the POC platform's use an effective diagnostic tool for broad population surveillance and case finding. The NFL/NFLPA COVID-19 testing and monitoring program, conducted within a closed cohort of more than 10 000 individuals, produced curated real-world evidence (RWE) that enables evaluation of newly approved COVID diagnostics. 11 Briefly, NFL players and Club staff lived at home and underwent frequent, and in most cases, daily, 24-h turnaround NAAT testing for the entirety of the season (mid-July 2020 through playoffs elimination, between January and February 7, 2021). RT-PCR point-of-care testing using the Accula device was available to Clubs starting on November 5, 2020. The NFL conducted a pilot phase across five Clubs from November 9 to November 18, 2020, at which time RT-PCR POC was used directly alongside NAAT (same-day dual tests). After the pilot phase completed, RT-PCR POC served as the primary POC test for the NFL COVID-19 program starting December 1, 2020, used for-cause in conjunction with the frequent NAAT testing. This study covers November 5, 2020 through the end of the regular season (January 2, 2021). In an effort to limit infection spread in the event of a COVID-19 case, players and staff were placed into three predefined tiers based on anticipated time of interaction with players and each other; facility access and interaction among individuals was limited by tier. Tier 1 included players and essential personnel whose job function required direct access to players, such as coaches and athletic trainers. Other essential personnel who may be in occasional proximity to players and other tier 1 persons, such as some kitchen staff and video personnel, were categorized as tier 2. Persons who administered facility or event services but did not require regular access and/or close contact with essential personnel were categorized as tier 3. 3 Players and all staff were required to adhere to infection mitigation protocols, including restrictions both inside and outside the Club facility. Test results were collected directly through a central test provider (BioReference Laboratories) and sent to a curated database linking results to demographic, contact tracing and clinical information (described in detail elsewhere 2,3,12 ). Symptom information was collected at the time of a positive test result; symptomology was not systematically collected over the course of infection. Data were reviewed for quality and completeness and adjudicated with the lab provider when missingness or errors were detected. 13 During this study's timeframe, players and Tier 1 and 2 staff were tested daily with NAAT. Tier 3 staff tested at least weekly or more frequently if circumstances required (e.g., symptomatic, COVID-19 exposure, schedule/responsibility change). Consistent with CDC guidelines in 2020, individuals with documented NAAT confirmation of prior COVID-19 were not required to test in the 90 days following infection. 3 NAAT tests (Roche cobas, Hologic Panther, or Thermo Fisher QuantStudio) served as primary testing platforms, with availability within 24 h and similar PPVs in this real-world setting. 3 Throughout the season, either antigen or RT-PCR POC rapid tests were available and used for-cause, as dictated by circumstances for an individual of any Tier such as (1) recent potential exposure based on self-report or contact tracing (e.g., high-risk close contact 2 ), (2) receipt of a positive test result (confirmatory as part of adjudication process 3 ), (3) prior to facility entry in the event of delayed, invalid or unavailable NAAT results from the prior day's sample or (4) moderate pre-test probability of infection based on cases detected in the team environment or clinical concern for infection from the team's infection control officer or another medical professional. Results were available within 1 h for the POC, with all positive lab samples confirmed with subsequent testing and clinical adjudication. 3 Players and staff who were tested for cause but had a negative RT-PCR POC test were allowed to continue with their duties, when practical and as advised by team medical staff, pending their NAAT results. (3) symptoms, noting that any positive test with accompanying symptoms was considered a case of COVID-19. 3, 13 This medically adjudicated case status using multiple test results was deemed the gold standard in the analysis, rather than a single NAAT test result, due to known imperfect sensitivity and specificity of both the NAAT and RT-PCR POC platforms, 9, [14] [15] [16] indicating possibility for false negatives and false positives for a single test, and the desire to minimize the isolation of healthy personnel. Any ambiguous combination of positive and negative test results in an individual without symptoms was reviewed by a panel of medical experts and epidemiologists to determine a final case status. The adjudicated case status was used to determine whether the RT-PCR POC or NAAT result aligned with the true result. 3 (1) symptomatic vs. asymptomatic at the time of positive NAAT result; (2) pilot testing phase (described above); and (3) This number of "early catches" may have even higher impact when RT-PCR POC replaces NAAT in routine monitoring settings (vs. forcause based on exposure or symptom reports). Sensitivity analyses restricted to individuals tested daily, and likely early infection at first positive, suggest that RT-PCR POC is a useful and accurate diagnostic tool for individuals with low-tomoderate pre-test probability of infection. RT Our analysis demonstrates that RT-PCR POC performed significantly better than antigen POC assay in this population with moderate pre-test probability. Taken in conjunction with our previously published study on our testing protocols, 3 There are limitations to this study. Many individuals were tested "for-cause," and therefore had a moderate pre-test probability; PPV and NPV may not generalize to asymptomatic surveillance populations. Additionally, symptoms were not collected throughout course of illness; individuals labeled as pre/asymptomatic in this analysis may have developed symptoms. Due to differential missingness in symptom information for cases compared to non-cases (30%/60% missingness, respectively), the false positive rate for the asymptomatic subgroup may be biased. This 2020 study was prior to the prevalence of COVID-19 variants and availability of vaccinations; therefore, we cannot comment on RT-PCR POC performance specific to 2021 variants or among vaccinated individuals. RT-PCR POC testing was an effective POC test and performed well in this daily surveillance setting, allowing fast turnaround of accurate results very early in infection. RT-PCR rapid testing was an improvement from antigen point-of-care, as it was able to detect COVID-19 in both symptomatic and asymptomatic individuals, and in many cases, likely prevented transmission by providing a test result within an hour, 1 day earlier than a NAAT test was able to be reported. We observed a low rate of false positives in this infection-naive population with a moderate pre-test probability of infection. The availability of this device and its observed high performance in 2020 are be extendable to other occupational and large-scale surveillance settings. Additional supporting information may be found in the online version of the article at the publisher's website. COVID-19 lessons from the National Basketball Association Bubble-can persistently SARS-CoV-2-positive individuals transmit infection to others? Implementation and evolution of mitigation measures, testing, and contact tracing in the National Football League Optimizing SARS-CoV-2 surveillance in the United States: insights from the National Football League Occupational Health Program Diagnostic performance of an antigen test with RT-PCR for the detection of SARS-CoV-2 in a hospital setting Rapid, point-of-care antigen and molecular-based tests for diagnosis of SARS-CoV-2 infection The need for more and better testing for COVID-19 Evaluation of Abbott BinaxNOW rapid antigen test for SARS-CoV-2 infection at two community-based testing sites-Pima County Low performance of rapid antigen detection test as frontline testing for COVID-19 diagnosis CoV-2 Instructions for Use Comparison of the Accula SARS-CoV-2 test with a laboratory-developed assay for detection of SARS-CoV-2 RNA in clinical nasopharyngeal specimens Real-world evidence to support regulatory decision making: new or expanded medical product indications Lessons on data collection and curation from the NFL injury surveillance program Considerations when evaluating real-world data quality in the context of fitness for purpose SARS-CoV-2 Assay (Panther ® System) SARS-CoV-2. Qualitative Assay for Use on the cobas ® 6800/8800 Systems TaqPath™ COVID-19 Combo Kit and TaqPath™ COVID-19 Combo Kit Advanced: Instructions for Use A narrative systematic review of the clinical utility of cycle threshold values in the context of COVID-19 Distribution of SARS-CoV-2 PCR cycle threshold values provide practical insight into overall and target-specific sensitivity among symptomatic patients Authors did not receive direct funding for this manuscript. Scientific and medical advisors had independent right to publish as established by the MRAP process.