key: cord-0327145-8jlfencz
authors: Blanchard, A. C.; Desforges, M.; Labbe, A.-C.; Nguyen, C. T.; Petit, Y.; Besner, D.; Zinszer, K.; Seguin, O.; Laghdir, Z.; Adams, K.; Benoit, M.-E.; Leduc, G.; Longtin, J.; Ragoussis, I.; Buckeridge, D. L.; Quach, C.
title: Evaluation of real-life use of Point-Of-Care Rapid Antigen TEsting for SARS-CoV-2 in schools for outbreak control (EPOCRATES)
date: 2021-10-14
journal: nan
DOI: 10.1101/2021.10.13.21264960
sha: 21bd5baa9c90fca4c27bd8c8d9cd744d0cb4ea96
doc_id: 327145
cord_uid: 8jlfencz

We evaluated the use of rapid antigen detection tests (RADT) for the diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in school settings to determine RADT performance characteristics compared to PCR. Methods: We did a real-world, prospective observational cohort study where recruited high-school students and staff from two high-schools in Montreal (Canada) were followed from January 25th to June 10th, 2021. Twenty-five percent of asymptomatic participants were tested weekly by RADT (nasal) and PCR (gargle). Class contacts of a case were tested. Symptomatic participants were tested by RADT (nasal) and PCR (nasal and gargle). The number of cases/outbreak and number of outbreaks were compared to other high schools in the same area. Results: Overall, 2,099 students and 286 school staff members consented to participate. The overall RADT specificity varied from 99.8 to 100%, with a lower sensitivity, varying from 28.6% in asymptomatic to 83.3% in symptomatic participants. The number of outbreaks was not different in the 2 participating schools compared to other high schools in the same area, but included a greater proportion of asymptomatic cases. Returning students to school after a 7-day quarantine, with a negative PCR on D6-7 after exposure, did not lead to subsequent outbreaks, as shown by serial testing. Of cases for whom the source was known, 37 of 57 (72.5%) were secondary to household transmission, 13 (25%) to intra-school transmission and one to community contacts between students in the same school. Conclusion: RADT did not perform well as a screening tool in asymptomatic individuals. Reinforcing policies for symptom screening when entering schools and testing symptomatic individuals with RADT on the spot may avoid subsequent significant exposures in class.

Timely diagnosis of infection enables outbreak control through rapid isolation of index cases and subsequent contact tracing 1, 2 . Diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is predominantly based on polymerase chain reaction (PCR) testing, which has a turnaround time (TAT) of 24-48 hours. Rapid antigen detection tests (RADT) were used for years to diagnose other respiratory pathogens, such as influenza and respiratory syncytial virus. These tests detect the presence of a specific viral antigen and are usually performed on nasopharyngeal or nasal specimens. RADT are relatively inexpensive and can be used at the point-of-care. Their performance characteristics vary, but they usually have high specificity and moderate sensitivity compared with PCR [3] [4] [5] [6] . Given their rapid TAT, RADT allow for efficient triage, management and cohorting of exposed individuals 7 . The potential use of RADT is especially relevant in school settings, where COVID-19 outbreaks can interrupt in-person teaching, contribute to social isolation and negatively impact learning [8] [9] [10] [11] .

The performance of RADT largely depends on the circumstances in which they are used -they perform best in the early stages of infection, when viral load is generally very high [12] [13] [14] [15] and may help in situations where a person was exposed to a confirmed case of COVID-19. RADT sensitivity was reported with a range from 28.9% to 98.3%, with improved RADT sensitivity in samples with high viral loads and in symptomatic individuals, with a specificity of 99.5% 16, 17 . PCRs' usual limits of detection (LOD) is 600-1000 viral RNA copies/ml, whereas RADTs usually have LOD 2-3 logs higher (10 5 to 10 6 ) 18 . Many studies have indicated the importance of high viral load dynamics with infectiousness and transmissibility 19, 20 . There is a strong correlation between cycle threshold (Ct) values and the ability to recover infectious virus and thus transmissibility: for each unit increase in Ct value, the odds of recovering infectious virus decreased by 0.67 being under 10% when Ct-values were > 35. Ct values of 17 to 32 corresponded to 10 5 and 10 1 SARS-. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 14, 2021. ;  https://doi.org/10.1101/2021. 10.13.21264960 doi: medRxiv preprint CoV-2 RNA copies/µL, respectively 21 . The real-world sensitivity of RADT to detect an infection with high risk of transmission may be higher than the pure analytical sensitivity compared to a PCR-based method.

Children being the last group to be fully immunised, we thus aimed: 1) to determine the performance characteristics of RADT for SARS-CoV-2 compared to PCR in different groups of high-school students and staff and 2) to determine if serial testing of close COVID-19 contacts would allow for a safe and faster return to school.

The study was conducted in two Montréal high schools (QC, Canada), with a total of ∼3000 students. The Pensionnat du Saint-Nom-de-Marie (PSNM) is a private school in a predominantly affluent neighbourhood, with 80% of students born in Québec (> 50% of students' parents born in Quebec). École secondaire Calixa-Lavallée (ESCL) is a public school where students predominantly come from multiethnic, first-generation immigrant communities. Both schools followed the Ministry of Education recommendations during the COVID-19 pandemic, by forming closed "classroom bubbles" and providing in-person teaching, except for entire classes in secondary 3 to 5 (grades 9-11) that stayed home every other day. Masks were mandatory in common areas as of September 2020 and at all times, as of October 8, 2020. Students, on average 30 per class, were seated approximately one metre (three feet) apart from each other. Students remained in the same classroom throughout the day and teachers moved from one class to the next. Staff working at the school, including teachers and administrative personnel, were invited to participate. A first dose of COVID-19 vaccine was offered to staff members as of April 9, 2021, and to students ≥12 years as of May 25, 2021.

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This study was a "real-world", prospective observational cohort study comparing RADT to PCR. Subjects were high-school students and staff from the two participating schools followed from January 25 th to June 10 th , 2021.

The RADT used in this study was a lateral flow immunoassay [PanBio TM COVID-19 Ag test (Abbott Laboratories, Illinois, USA)], authorised by Health Canada 22 . Nasal swabs were self-collected under the supervision of a research assistant who performed the RADT on site. For symptomatic participants, once the RADT was done, the remaining buffer fluid was tested by PCR. In addition, spring water gargle specimens were collected from all participants for PCR testing 23 . Laboratory-developed PCR was performed in the CHU Sainte-Justine virology laboratory (Montréal (QC), Canada), with a LOD of 400 copies/mL (based on Corman et al. 24 ). Extraction and purification of genetic material (nasal and gargle specimens) was done with Roche's MagNA Pure 96 system. The laboratory testing protocol and the water gargle validation have been described elsewhere [25] [26] [27] [28] .

Decisions about management of cases and contacts were taken by two members of the research team (AB, CQ), in collaboration with local public health (CT, OS), based on RADT and PCR results and history of contacts. In addition, the school principals (YP, DB) were actively involved in the study design and fully engaged during the 5-month study period. 1) Testing protocol in the absence of a known exposure: a. Asymptomatic students and staff: Nasal swabs and gargle specimens on a random sample of 25% of participants were collected weekly for RADT (nasal) and PCR (gargle), stratified by class.

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The copyright holder for this preprint this version posted October 14, 2021. ; https://doi.org/10.1101/2021.10.13.21264960 doi: medRxiv preprint b. Symptomatic students and staff: Gargle specimens for PCR and a nasal swab for RADT and PCR were performed on site. Results from RADT and PCR were officially reported to public health and an individual was considered infected if the PCR result was positive. If symptoms occurred while in school, the research team proceeded with sample procurement. If symptoms developed while at home, the participant could either get tested through the usual process of care or through a walk-thru process at school (by appointment, in a specific room away from public areas).

2) Management of exposed contacts of a positive individual in a class Students and staff who were considered contacts of a confirmed COVID-19 positive individual were isolated at home. Groups were allocated to either a 7-or 14-day quarantine, staffs were allocated to a 7day quarantine, with tests (nasal RADT and gargle PCR) three days after last contact with the known positive case, and up to two days before the end of quarantine. RADT was performed in school on day (D)14, D21 and D28, if the initial PCR was negative. If symptoms developed, both the RADT and PCR were performed, as previously described. Students who did not consent to the study were quarantined for 14 days, even if their group was allocated to a 7-day quarantine. Students and staff concerned with significant off-campus exposure were provided to be tested through the project.

The primary outcome was to assess the performance characteristics of RADT in: a) asymptomatic participants randomly screened (compared to gargle PCR); b) asymptomatic close contacts of a confirmed positive case (compared to PCR on nasal swab and gargle); c) symptomatic participants (compared to PCR on nasal swab and gargle).

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The copyright holder for this preprint this version posted October 14, 2021. ; https://doi.org/10.1101/2021.10.13.21264960 doi: medRxiv preprint Secondary outcomes included: a) number of positive students by RADT in groups exposed to a confirmed positive index case, allocated to early (on D8) versus standard (on D15) return to school (7 vs. 14 days of quarantine) and b) number of case clusters in schools. These clusters were compared to clusters in other high schools in Montréal during the same time frame, using public health data.

Descriptive statistics were used for characteristics of the cohort and test performance (sensitivity and specificity) of the RADT.

To determine the precision with which we would be able to estimate our primary outcome, we implemented an agent-based model (ABM) to estimate it through simulations, adapting a previously described school-based ABM 29 (Supplementary Appendix A). Based on this simulation, we expected that the number of infections and tests would be sufficient in one school but added an additional school to support generalizability of the findings, as well as to allow exploration of secondary objectives.

This project was approved by the CHU Ste-Justine Research Ethics Board (#MP-21-2021-3271). Written invitation letters to participate in the study were sent by schools' direction to parents and staff explaining the study objectives, methods and expected impacts. Online informed parental consent, as well as assent, was required for all students. Parents who preferred to keep their children home for 14 days in case of a class contact could do so. Tests results were communicated to parents and students (if ≥14 years) by the school (via email), as they became available.

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The copyright holder for this preprint this version posted October 14, 2021. ; https://doi.org/10.1101/2021. 10.13.21264960 doi: medRxiv preprint This study was funded by the Québec Ministry of Health and Social Services, to whom regular reports of the study progress were submitted.

During the 5-month study period, 2,099 students and 286 school staff members consented to participate.

Overall, the participation rate for students was 78.5% and 63.5% ( Figure 1 ) and 94.4% and 89.5% for staff members.

Of 5,583 asymptomatic RADT screening tests done on asymptomatic students (Table 1) , seven had an invalid PCR result on the gargle sample, seven were equivocal and three were weak positive, of which one was negative when repeated the next day (and was excluded). Two students with equivocal or weak positive PCR results had a positive PCR result in the previous 90 days. The infection prevalence in asymptomatic participants was 0.30% (95% CI 0.18-0.49). Therefore, the sensitivity of RADT in that population was 41.2% (95% CI 21.6-64.0), with a specificity of 100.0%.

Of 784 asymptomatic RADT screening tests done on asymptomatic randomly screened staff members, two gave invalid PCR results and six were lost. Only one RADT was positive, but the PCR was negative on both the gargle and nasal specimens, giving a specificity of 99.8% (95% CI 99.3-100.0) ( Table 1) .

2) Asymptomatic exposed contacts in a classroom A total of 1491 RADT tests and PCR were done on asymptomatic students exposed to a positive classmate index case at D3 and 2 days before returning to class. After excluding one equivocal PCR result, SARS-CoV-2 prevalence in this exposed group was 0.7% (95% CI 0.5-1.6). The sensitivity of RADT was 28.6% (95% CI . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 14, 2021. ; https://doi.org/10.1101/2021.10.13.21264960 doi: medRxiv preprint 8.4-58.1) with a specificity of 99.6% (95% CI 99.1-99.9) ( Table 1) . Of 627 RADTs done for asymptomatic exposed contacts on D14, D21 and D28, only one was positive (also positive by PCR when tested on D12 -see outbreak section). A total of 61 RADT and PCRs were done for staff members on D3 and D7 after a contact with a positive index case in school (Table 1 ). All tests were negative.

Overall, 235 students developed symptoms and were tested on site for SARS-CoV-2. As shown in Table 1, 10 had a positive RADT and 12 had a positive PCR [prevalence=5.1% (95% CI 2.7-8.7)]. The sensitivity of RADT in that population was 83.3% (95% CI 51.6-97.9) with a specificity of 100.0% (95% CI 98.4-100.0).

Sixty-four staff members were tested on site for symptoms compatible with COVID-19. Only one had a positive RADT and PCR. In addition, one positive case was identified by PCR after a negative RADT (sensitivity of 50% (95% CI 1,3-=98,7) and specificity of 100%.

Of all participants, 76 PCR (gargle or nasal) positive cases were identified, including three cases in staff members. Of the 35 classes included in the study, 20 returned on D8 after contact, if the gargle PCR was negative on D6 or D7.

Secondary cases were identified in 10 classes. The number of secondary cases in each class were one (n=8 classes), three (n=1 class) and four (n=1 class). Overall, four secondary cases had a positive RADT, including three asymptomatic students and one symptomatic student who tested positive by RADT and PCR on D12, with symptoms starting on D9 after last contact with the positive classmate -a community exposure was also suspected. No tertiary case occurred. Outbreaks were limited to the classroom bubble and to school friends seen outside of school. When the source was known, 37/57 cases (72.5%) were . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 14, 2021. ; https://doi.org/10.1101/2021.10.13.21264960 doi: medRxiv preprint secondary to household transmission, 13 (25%) to intra-school transmission and one to community contacts between students in the same school.

Data from Montréal Public Health showed that in other Montréal high schools (n=177), a range of 1 to 16 exposures and outbreaks per school (median: 1; IQR: 2) were observed during the study period, for a total of 358 outbreaks, one affecting two different schools. Schools declared that 1 to 52 cases (median: 4; IQR 5) were linked to an outbreak, for a total of 1181 cases. A range of 1 to 25 classes (median: 2, IQR: 3) were involved in outbreaks (n=161), for a total of 447 classes. Outbreaks at ESCL and PSNM comprised, on average, 3 and 2 cases, respectively. ESCL and PSNM had three outbreaks, with nine and seven students involved, from four and two groups, respectively, during the same period.

Despite active surveillance of SARS-CoV-2 infection through this study, there was no difference in outbreaks observed between participating schools and the rest of the Montréal high schools. However, outbreaks declared in other schools had a lower proportion of asymptomatic cases (31.8%) compared to ESCL (55.6%) and PSNM (85.7%). Participating schools had a lower proportion of cases linked to an outbreak present in school while contagious (28.6% and 6.7%), compared to the average in other schools of Montréal (n=241; 36.5%). Interestingly, data showed that 66.0% of cases linked to an outbreak in other high schools tested positive or started their symptoms within seven days of their first exposure (Figure 2) . Furthermore, 51.0% of the 741 cases linked to an outbreak who went to school while contagious were only processed by the Public Health team, due to capacity, after the recommended first testing date.

Using the number of classes where an outbreak occurred, assuming on average that one student is in class while contagious, we estimated that 50,010 high school students were isolated during the study period in other high schools which, with 14 days of isolation, leads to an estimated 700,140 days or ~1,918 years of . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 14, 2021. ; https://doi.org/10.1101/2021.10.13.21264960 doi: medRxiv preprint cumulative isolation. A safe, accelerated return to school could have possibly saved an estimated 350,070 days or ~959 years of cumulative isolation (Table 2) .

RADTs were purchased in many countries as an additional tool to prevent outbreaks. However, their use was limited by the paucity of evidence regarding their performance in school-aged children and their impact on allowing in-person schooling. In this study, we prospectively compared the performance of a COVID-19 RADT to PCR for the purpose of limiting transmission of SARS-CoV-2 infection in a real-world setting in two high schools. In a context of low SARS-CoV-2 prevalence in school and higher prevalence in the community (5-7% test positivity in Montréal 30 ), we observed only seven false positive RADT during the 5-month study (all in asymptomatic individuals) and the specificity of the RADT remained excellent in all circumstances (99.8 and 100%). However, the sensitivity was much lower, varying between 28.6% in asymptomatic to 83.3% in symptomatic students.

A recent large observational study described the use of RADT in asymptomatic individuals as potentially beneficial, reporting a sensitivity of 64.4% (95% CI 58.3-70.2) 31 . However, as not all asymptomatic individuals included had a confirmatory PCR, this could be overestimated. In our study, only a few positive cases were detected by RADT (7/6358, 0.11% -students and staff combined) in asymptomatic individuals who were randomly tested. Ten additional cases were detected by PCR from gargle specimens. During the study, two full-time research assistants were in each school, in addition to local school staff who were supporting the study rollout. This level of required resources makes it difficult to justify the use of RADT for random screening of asymptomatic individuals given its low sensitivity in that setting.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. were tested with RADT and PCR on the day of symptoms onset. Our reported RADT sensitivity may have been higher had students been tested on subsequent days. However, the usefulness of RADT is precisely to control outbreaks and therefore delaying testing to enhance sensitivity would be counterproductive.

This trade-off may not apply to the delta variant, for which the kinetic of infection may differ 35,36 .

RADT identified 28.6% of positive asymptomatic exposed school contacts, which was similar to that recently described by Torres et al. for non-household significant contacts (sensitivity: 35.7%) 37 . Although this percentage is relatively low, the rapid diagnosis of SARS-CoV-2 infection in exposed individuals allowed local public health to quickly manage these students' household contacts who, at the time, had to isolate until the result of the D3 testing. With changes in quarantine recommendations for vaccinated family members, the benefit of RADT in this specific population may be less. Of note, most positive cases in students, for which the source was known were due to intrafamilial and household SARS-CoV-2 transmission. In many of these instances, students were sent to school despite having a household known positive contact. Active screening of symptoms and history of significant contact with known positive . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 14, 2021. ; https://doi.org/10.1101/2021.10.13.21264960 doi: medRxiv preprint cases should be reinforced to prevent school outbreaks. Thirteen of 51 cases were acquired from school, with 15 cases belonging to the same class bubble (in five classes overall). Therefore, the asymptomatic nature of this infection makes screening for school contacts particularly important. Our results demonstrate that using a more sensitive method, such as PCR, may be more reliable for that purpose.

This study had several limitations. First, we did not collect socio-demographic and behavioral data, including risk perception, adherence to public health measures, nor did we systematically document individual contacts with positive cases occurring outside of school. However, for the most part, we were able to identify when significant household transmission occurred and relied on both the transparency of participants as well as local public health, with whom we communicated daily. We cannot infer whether PCR positive individuals were contagious. The study was performed before the advent of the delta variant in our region. Because RADT detects the N protein, we expect that its sensitivity and specificity would not be affected negatively, as viral loads of delta variant infections are reported to be higher 35 . Finally, the sensitivity of RADT in symptomatic individuals was based on a relatively small number (12 students and 2 staff members) of people with PCR-confirmed SARS-CoV-2 infections. This is the largest study to date assessing the use of RADT in school settings. The strengths of this study included its prospective data collection, as well as the real-world use of RADT in direct comparison to PCR.

We also assigned participants to earlier versus standard return to school with serial RADT testing, showing that there were no adverse outcomes or secondary outbreaks when allowing students to return to school after a shorter quarantine. Although the current study was not powered to rule this out, this aligns with other recently published data 38 and may allow policymakers to consider reducing the duration of quarantine for exposed contacts, provided a PCR is negative on D6 or D7 following contact.

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The copyright holder for this preprint this version posted October 14, 2021. ; https://doi.org/10.1101/2021. 10.13.21264960 doi: medRxiv preprint In conclusion, our findings contribute to the growing evidence that the use of RADT leads to rapid diagnosis of SARS-CoV-2 infection in symptomatic individuals in schools 39 . However, RADT does not perform well as a screening tool in asymptomatic individuals. In our study, teenagers were able to adequately proceed to self-collection of gargle specimens and nasal swabs, while supervised by a trained research assistant. It may be helpful to reinforce policies for symptom screening when entering schools, where symptomatic individuals, including students or staff could be tested with RADT on the spot. This would avoid subsequent significant exposures in class but would also allow students to attend school if symptoms were due to other viruses. A negative RADT could still mean that symptoms are due to SARS-CoV-2, but with a viral load too low to be detected and therefore less likely to transmit at that moment.

In such instance, a subsequent non-invasive sample tested by PCR would be useful.

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This study was funded by the Québec Ministry of Health and Social Services, to whom regular reports of the study progress were submitted. The study sponsor did not have a role in study design, in interpretation of data, writing of the report or decision to submit the paper for publication.

Individual-level, deidentified data, with a data dictionary will be made available to others once all manuscripts for this study will have been published. Research protocol will also be available upon these manuscripts publication. These can be requested by emailing the corresponding author and will be shared for individual-level meta-analysis, with an institutionnally and research ethics board approved protocol.

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The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Supplemental Appendix A : Sample size calculation As the school populations were fixed in size, we determined the precision with which we would be able to estimate our primary outcome. Given the non-linear nature of the epidemic process and the complexity of the quarantine and testing policies proposed, it was not possible to estimate precision through a direct calculation. We therefore implemented an agent-based model (ABM) to estimate through simulations the number of tests that would be performed, the likely results of the tests, and other outcomes of interest in planning the study (e.g. number of days in school, number of secondary infections). We implemented a variation of a previously described school-based ABM to adapt the characteristics of the school 29 . For simplicity, we did not model household transmission explicitly, although we did allow for infection outside of the school. We also extended the model to include testing and quarantine, and we simulated random testing of students, routine testing of teachers, testing of symptomatic students and teachers and the first quarantine policy where a full 14-day quarantine was imposed for a class in which any student or teacher . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)