key: cord-0830271-p1ibyza5
authors: Krueger, L. J.; Gaeddert, M.; Koeppel, L.; Bruemmer, L.; Gottschalk, C.; Miranda, I. B.; Schnitzler, P.; Kraeusslich, H.-G.; Lindner, A.; Nikolai, O.; Mockenhaupt, F.; Seybold, J.; Corman, V. M.; Drosten, C.; Pollock, N.; Cubas-Atienzar, A.; Welker, A.; DeVos, M.; Knorr, B.; Wright, A. H.; Kontogianni, K.; Collins, A. M.; Adams, E. R.; Sacks, J.; Denkinger, C. M.
title: Evaluation of the accuracy, ease of use and limit of detection of novel, rapid, antigen-detecting point-of-care diagnostics for SARS-CoV-2
date: 2020-10-04
journal: nan
DOI: 10.1101/2020.10.01.20203836
sha: 93beac7531dd654929a3b17ce3e64292a469bdff
doc_id: 830271
cord_uid: p1ibyza5

Abstract Background: Reliable point-of-care (POC) diagnostics not requiring laboratory infrastructure could be a game changer in the COVID-19 pandemic, particularly in the Global South. We assessed performance, limit of detection (LOD) and ease-of-use of three antigen-detecting, rapid POC diagnostics (Ag-RDT) for SARS-CoV-2. Methods: This prospective, multi-centre diagnostic accuracy study, recruited participants suspected to have SARS-CoV2 in Germany and UK. Paired nasopharyngeal swabs (NP) or NP and/or oropharyngeal swabs (OP) were collected from participants (one for clinical real-time reverse transcription polymerase chain reaction (RT-PCR) and one for Ag-RDT testing). Performance of each of three Ag-RDTs was compared to RT-PCR overall, and according to predefined subcategories e.g. cycle threshold (CT)-value, days from symptom onset, etc. In addition, limited verification of analytical limit-of-detection (LOD) was determined. To understand the usability of each Ag-RDT a System Usability Scale (SUS) questionnaire and ease-of-use assessment were performed. Results: Between April 17th and August 25th, 2020, 2417 participants were enrolled, with 70 (3.0%) testing positive by RT-PCR. The best-performing test (SD Biosensor, Inc. STANDARD Q) was 76.6% [95% Confidence Interval (CI) 62.8-86.4] sensitive and 99.3% [CI 98.6-99.6] specific. A sub-analysis showed all samples with RT-PCR CT-values <25 were detectable by STANDARD Q. The test was considered easy-to-use (SUS 86/100) and suitable for POC. Bioeasy and Coris showed specificity of 93.1% [CI 91.0%-94.8%] and 95.8% [CI 93.4%-97.4%], respectively, not meeting the predefined target of [≥]98%. Conclusion: There is large variability in performance of Ag-RDT tests with one test showing promise. Given the usability at POC, these tests are likely to have impact despite imperfect sensitivity; however further research and modelling are needed.

The study protocol was approved by the ethical review committee at the Heidelberg University Hospital for the study sites in Heidelberg and Berlin (Registration number S-180/2020), and by the NHS review board, IRAS number 282147, for the study in Liverpool, UK. Each participant provided written informed consent.

Three novel rapid antigen-based diagnostics were assessed: Gyeonggi-do, Korea; henceforth called SD Biosensor).

All assays utilize the lateral flow assay principle for the detection of viral antigens. Both Coris and SD Biosensor use colloidal gold conjugated to antibodies to enable a colour change and read-out with the naked eye, while Bioeasy uses fluorescent readout and thus requires the use of a proprietary reader device. Coris is designed as a dipstick, whereas Bioeasy and SD Biosensor use a cassette-based assay format. For Coris and SD Biosensor the manufacturers' instructions for use (IFU) were followed; except for Bioeasy, the IFU was followed except the developer requested for pipettes to be used to transfer adequate quantities of liquid (in the IFU no pipette is needed and a nozzle is provided). 17 Bioeasy and SD Biosensor include swabs within their test kits for sample collection, while for Coris, a commercially available swab was used: the eSwab system from Copan Diagnostics (Murrieta, CA, USA), which contains 1ml of Amies solution and was approved for use by Coris. A prespecified quantity of proprietary buffer solution was applied to the lateral flow cassette for Bioeasy and SD Biosensor and into the test tube with the dipstick for Coris as per the respective IFU. The readout was done within the recommended time for each Ag-RDT (10 minutes for Bioeasy, 15 minutes for Coris and 15 to 30 minutes for SD Biosensor).

A limited verification of the analytical sensitivity (lower limit of detection) was performed using standardized, quantified viral cultures. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

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The SARS-CoV-2 isolate REMRQ0001/Human/2020/Liverpool was propagated in Vero E6 cells (C1008; African green monkey kidney cells). Cells were maintained in Dulbecco's minimal essential medium (DMEM) containing 10% foetal bovine serum (FBS) and 0•05 mg/mL gentamycin at 37°C with 5% CO2 and FBS concentration was reduced to 4% for viral propagation.

Ten-fold serial dilutions of virus stock starting from 1•0 x 10 6 Plaque forming units (PFU)/ml were made using culture media as a diluent (DMEM + 2% FBS % + 0•05 mg/ml gentamycin). Two-fold dilutions were made between 1•0 x 10 4 to 1•0 x 10 2 . Lateral flow tests were performed in triplicate. For SD Biosensor and Bioeasy, the swab included in each individual kit was immersed into the virus dilutions and spiked (soaked). Subsequently, the test was performed using the spiked swab following the manufacturer's instructions. For Coris, the eSwab from Copan was spiked with serial dilutions of virus and then added to the 1 ml of Amies solution contained in the swab tube. 100μl of each of the sample dilutions were added to the test tube with the dipstick and was read-out as per manufacturer's instructions.

Coris and SD Biosensor tests were read by two operators, each blinded to the result of the other. A third operator read any discrepant tests and final result was agreed (2/3). The Bioeasy result is a digital readout, and the first operator recorded the result, which was checked by the second operator, and printed out directly from the machine.

The primary objective of the clinical multicentre diagnostic accuracy study was to estimate the sensitivity and specificity of a single antigen test compared to a single PCR test as the reference method.

Participant recruitment and sample collection was conducted at three sites: (1) A drive-in testing station in Heidelberg, Germany; (2) a clinical ambulatory testing facility in Berlin, Germany and (3) secondary care facilities at Liverpool University Hospital Foundation Trust, Royal and Aintree (LUHFT), Liverpool, United Kingdom. Participants screened for the study were adults (age ≥18 years) identified as at risk for SARS CoV-2 infection according to the local department of public health based on exposure to a SARS CoV-2 positive person, suggestive symptoms, or travel to a high risk area.

Participants were excluded if they had previously been diagnosed with SARS CoV-2 or if their command of either English or German was insufficient to give informed consent for participation.

Antigen-detecting testing . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

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The copyright holder for this this version posted October 4, 2020. . https://doi.org/10.1101/2020.10.01.20203836 doi: medRxiv preprint After obtaining written consent, participants underwent a first swab for testing with RT-PCR, which was taken either as (i) a nasopharyngeal (NP) swab or (ii) oropharyngeal (OP) swab (if clinically contra-indicated to do a NP swab (e.g. because of risk of bleeding)) in Heidelberg or (iii) combined as NP/OP swab in Berlin and Liverpool as per institutional recommendations (with OP done first, followed by NP with the same swab). Subsequently, participants underwent collection of the same type of swab again for Ag-RDT.

Ag-RDTs were performed at the sample collection site in Heidelberg and Berlin. In Liverpool samples were transported on ice to a category 3 facility and then processed. For on-site testing, separate areas were maintained for clean material (without sample) and 'unclean' areas of benches (material with sample) to avoid cross-contamination.

Disinfection was performed and gloves exchanged after each sample. Negative control testing with buffer without sample was performed regularly to capture possible contamination. For the Ag-RDTs with visual read-out (Coris and SD Biosensor), the results were interpreted by two operators, each blinded to the result of the other. If a discrepant result was obtained, both operators re-read the result and agreed on a final result. Invalid results were repeated once using the remaining buffer according to the respective IFUs.

The swab (eSwab, Copan) for RT-PCR testing was sent to the referral laboratory in the provided Amies solution. The RT-PCR assays were performed according to routine procedures at the referral laboratory. In Heidelberg, the SARS CoV-2 assay from TibMolbiol (Berlin, Germany), the Allplex SARS-CoV-2 Assay from Seegene (Seoul, South Korea) or the Abbott (Illinois, US) RealTime 2019-nCoV assay was performed. In Berlin the Roche Cobas SARS CoV-2 assay (Pleasanton, CA United States) on the Cobas® 6800 or 8800 system or the SARS CoV-2 assay from TibMolbiol (Berlin, Germany) was performed. In Liverpool, the Genesig® Real-Time Coronavirus COVID-19 PCR assay (Genesig, UK) was performed. Assays were calibrated with the E-gene assay as described before. 3, 19 Only samples that showed a signal above the threshold in the relevant RT-PCR target regions for each assay were considered to be positive. Staff performing the Ag-RDTs were blinded to results of RT-PCR tests and vice versa.

After completion of testing, the participants in Heidelberg were contacted for an interview focusing on symptoms and co-morbidities via telephone or email according to the indicated preference on site. In Berlin and Liverpool participants were interviewed directly on-site after obtaining the consent (questionnaire available in the supplement material Section (B)). is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted October 4, 2020. . https://doi.org/10.1101/2020.10.01.20203836 doi: medRxiv preprint All data were captured in a dedicated database utilizing Research Electronic Data Capture (REDCap TM , www.prorectredcap.org) hosted at the Heidelberg University Hospital or Liverpool School of Tropical Medicine (LSTM). REDCap TM is a secure, web-based application, which provides audit trails for tracking data manipulation and export procedures.

The protocol is provided in the supplement material Section (C).

To understand the usability of the three Ag-RDTs, a standardized System Usability Scale (SUS) 20 questionnaire and a ease-of-use assessment (EoU), specifically developed for the study, were performed. The questionnaire can be found in the supplement material Section (D). The laboratory personnel from each study site (at least 3 operators per test) were invited to complete the surveys separately for each assay. The complete EoU survey can be found in the supplement material Section (D). For the interpretation of the SUS, it can be said that a SUS score above 68 would be considered above average and anything below the score of 68 is below average. 20

In the analytical assessment, the limit of detection (LOD) was determined as the lowest concentration for which all three replicates scored positive.

In the clinical accuracy study, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the Ag-RDTs with 95% confidence intervals (CIs) were estimated by comparing the Ag-RDT result to the gold standard, RT-PCR, on the same day from the same participant (statistical analysis plan available upon request). A subanalysis was performed by CT-value. [21] [22] [23] Furthermore, a conversion of CT-values for RT-PCR tests into viral-load was performed by calibrating the test systems using quantified specific in vitro-transcribed RNA. 24 A sample size of 1000 participants per Ag-RDT under evaluation was targeted but given the variable prevalence throughout the pandemic this target was left flexible. Interim analyses were performed at predefined sample sizes (25%, 50%) and an evaluation of an Ag-RDT was stopped if the predefined performance criterion for specificity (≥98%, considering the upper bound of the confidence interval) was not met. 25 Invalid Ag-RDT results were reported separately, whereas participants with invalid RT-PCR results were excluded from the analysis. Inter-operator variability was assessed for tests read with the naked eye. The analysis was conducted with the statistical software R (R Foundation for Statistical Computing, Vienna, Austria). is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted October 4, 2020. . https://doi.org/10.1101/2020.10.01.20203836 doi: medRxiv preprint For the usability assessment, the SUS score was calculated taking the mean of all answers given for each test. For the EoU assessment, verbal answers were transferred into numerical values. Taking the mean across values, all answers given for each test were summarized into a heat map. Both SUS and Ease of Use assessment were analysed with Microsoft Excel.

The study was supported by FIND, Heidelberg University Hospital and Charité -University Hospital internal funds.

Pfizer funded the clinical team in Liverpool, UK. FIND provided input on the study design, and data analysis in collaboration with the rest of the study team. The other external funders of the study had no role in study design, data collection, or data analysis. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

SD Biosensor was positive in all replicates at 5•0 x 10 3 PFU/ml, and only one out of three replicates at 1•0 x 10 3 PFU/ml, which is approximately ten-fold higher than the supplier-reported LOD of 3•06 x 10 2.2 TCID50/ml as per ATCC.org. 19 The Bioeasy assay was positive on all three replicates at 5•0 x 10 3 PFU/ml (approximately 7•14 x 10 3 TCID50/ml) and only one out of three replicates at 2•5 x 10 3 PFU/ml (approximately 3•57 x 10 3 TCID50/ml). Coris was positive on all three replicates at 1•0 x 10 4 PFU/ml (approximately 1•43 x 10 4 TCID50/ml), which is two-fold higher than the supplierreported LOD of 7•14 x 10 3 TCID50/ml. 26 Coris was positive on only one of three replicates at 5•0 x 10 3 PFU/ml (approximately 7•14 x 10 3 TCID50/ml).

Between April 17 th and August 25 th 2020, 3160 participants with presumed SARS-CoV-2 infections were invited to participate in the study. In total, 2417 met inclusion criteria, provided consent and were included in the analysis ( Figure   1 ). Of those, 1263 participants were tested using SD Biosensor from July 20 th to July 31 st 2020 in Heidelberg (N=334), from June 3 rd to July 31 st 2020 (N=910) in Berlin, and May 20 th to June 12 th 2020 (N=19) in Liverpool. Separately, 729 participants were tested using Bioeasy, 506 of whom were enrolled in Heidelberg between April 17 th and May 3 rd 2020, is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted October 4, 2020. . https://doi.org/10.1101/2020.10.01.20203836 doi: medRxiv preprint and 223 in Berlin between May 14 th and June 3 rd 2020. 425 enrolled participants were tested using Coris: 286 in Heidelberg from 11 th to 25 th May 2020; 105 in Berlin from 19 th to 25 th August 2020; and 34 in Liverpool from May 12 th to June 12 th 2020. The variance in sample size is explained by the fact that both the Coris and Bioeasy evaluations were aborted after interim analysis indicated that specificity did not meet predefined performance criteria, and after a work-up for reasons for the false-positive results was completed.

We present clinical and demographic characteristics overall and by Ag-RDT in Table 1 (Supplement Tables 2, 3 and 4 show study characteristics by study site). The average age of participants presenting for testing was 40•4 years (Standard Deviation [SD] 14•3) with 52•8% being female and 35•9% having comorbidities. On the day of testing, 80•7% of participants had one or more symptoms consistent with COVID-19 (questionnaire in the supplement material Section (B)), with most (1868 (79•3%)) reporting being only mildly ill and only 6 (0•3%) stating that they are completely bedridden due to illness (a more detailed list of symptoms and comorbidities is provided in the supplement Table 5 ). Table 5 . is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted October 4, 2020. . (Table 3) .

Corresponding viral load to CT values of RT-PCR positive results are provided in the supplement Table 6 . A sub-analysis of sensitivity of SD Biosensor by sampling strategy suggested that a NP swab alone might be less effective than a combined NP/OP swab, however confidence intervals were overlapping ( is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted October 4, 2020. . https://doi.org/10.1101/2020.10.01.20203836 doi: medRxiv preprint those with CT ≥25 only 2 out of 6 tested positive (33•3%; CI 9•7-70•0). Further sub-analyses were not performed for sensitivity because of the limited number of positive samples. Two invalid results occurred in 729 tests (0•3%). Overall, the usability was considered favourably with a SUS score of 73/100. The EoU identified a high number of test execution steps (including precision pipetting) which resulted in challenges when performing multiple tests at the same time possibly hindering the test's wide-spread use (Figure 2 ).

Coris showed a sensitivity of 50% (4 out of 8; CI 21•5-78•5) and specificity of 95•8% (CI 93•4-97•4). Two out of the three samples with CT <25 were detected, while for the five specimens with CT ≥25, sensitivity was 40%. Further subanalyses were not performed for sensitivity because of the limited number of positive samples. The low specificity determined the stop of the study as the upper margin of 95% CI was below 98%. Inter-operator reliability was very good with a kappa of 0•95. Invalid tests occurred on 8 occasions (1•9%) either due to the control line not being visible or due to smearing of the readout window. Four results were excluded due to handling issues (read-out after time limit). Overall, the usability was considered unfavourable with a SUS score of 48/100 and the EoU pointed towards challenges due to inconsistent test result interpretation (often only very faint lines visible) and deficiencies in both the test kit quality and design ( Figure 2 ).

An investigation of the false-positives was performed for all assays by (1) testing negative buffer (without swab) interspersed with patient samples; (2) repeating RT-PCR from Ag-RDT buffer/swab sample for a subset of false-positive Ag-RDT samples (where feasible from available quantity of buffer); (3) having the sampling performed by the same person for Ag-RDT and PCR test (to limit variability in sampling); and (4) contacting participants again and retesting with Ag-RDT and RT-PCR if they had persistent symptoms or COVID-19 cases in their surroundings. None of this workup yielded any evidence of cross-contamination, limited RT-PCR sensitivity or sampling error, which makes crossreactivity most likely as the reason for the false-positives (target of cross-reactivity unknown). is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted October 4, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

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The copyright holder for this this version posted October 4, 2020. . is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted October 4, 2020. . https://doi.org/10.1101/2020.10.01.20203836 doi: medRxiv preprint Caption: More explanation on the detailed EoU assessment is available in supplement material section (E). is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted October 4, 2020. . Furthermore, stability only up to 30° Celsius and required storage conditions are a limitation for the use in the Global South, and should be considered carefully in such settings.

Our study also shows wide variability in performance between Ag-RDTs with respect to performance and ease-of-use, indicating the importance of manufacturer-independent validations. While our findings largely corroborate the performance reported in the IFU of SD Biosensor, for Coris and Bioeasy, they differed substantially in respect to specificity. For SD Biosensor, the lower overall performance compared to the results in the IFU could relate to the fact that for some patients in our study OP swabs were used. While this is not recommended by the manufacturer, the use of OP swabs when NP is contraindicated, reflects a more clinically realistic scenario. NP/OP swabs were used based on institutional recommendations in Berlin and Liverpool. While more proteases are expected in the saliva that can degrade antigen, there should not be an impact on the sensitivity of Ag-RDTs in our study, as swabs were processed immediately. Another aspect that could explain a lower senstivtiy is the population tested in the study. The population tested was likely representative of the spectrum of COVID-19, with less ill patients likely to have lower viral load at diagnosis and more likely Ag-RDT negative. A higher clinical sensitivity would be expected when only hospitalized patients were tested. 30 For Bioeasy, our point estimate of specificity falls within the confidence interval of specificity of the only other independently published study, which had few RT-PCR negative cases. 14 Overall, our study had several strengths. The study confirmed the accuracy of the tests by two measures: analytical and clinical accuracy. The population enrolled for testing was representative of the pandemic observed in Europe with a broad spectrum of age group (initially older age group and with ongoing duration of the pandemic an increasingly younger age group presenting for testing) and a spread of clinical presentations (from asymptomatic with high-risk contacts to severely ill). We enrolled in two countries and although enrolment numbers in Liverpool were low, the results confirmed findings in Germany. Due to the wide-spread testing available particularly in Germany, the . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

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The copyright holder for this this version posted October 4, 2020. . https://doi.org/10.1101/2020.10.01.20203836 doi: medRxiv preprint population tested is expected to be a representative spectrum of disease. The tests were performed at POC at two sites (Berlin and Heidelberg) thus mimicking the real-world challenges of POC testing.

The comprehensive ease-of-use assessment with a standardized SUS-tool and a questionnaire, developed specifically for the study, captured the differences between the tests and highlighted important points for operationalization of the tests.

However, the study also has several limitations. First, the prevalence of positive cases decreased substantially over the course of the study from 10% among tested individuals in early April as documented by the local health department in Heidelberg, Germany, to 3% over the course of the study. In addition, our study assessed a preselected population based on the regulations and criteria from the local health department. Due to the nature of the pandemic, the selection criteria and patient population changed throughout the study as visible from the percentage of patients with symptoms and co-morbidities evaluated with the three Ag-RDTs, although differences between the study populations were not significant. In addition, our study did use OP swabs for a subset of patients as discussed above. Furthermore, the sub-analysis by CT-values has its limitations, as RT-PCR methods varied across sites with different genome targets, PCR instruments and reagents. This might cause misleading comparisons of CT-values between sites. 23 Therefore, we only performed an analysis of dichotomized CT-values and considered <25 as high viral load and ≥25 as low viral load. In addition, we translated CT-values into viral load, and determined the variability of the applied SARS-CoV-2 assays in testing of standardized dilutions of virus to be limited, as shown before. 21, 22 

Our results suggest that, though there is substantial variability between tests, at least one antigendetection POC test meets WHO targets and is now recommended by the WHO. 16 Given the fast turnaround-time and ease-of-use at POC, as well as the high sensitivity in patients with significant viral load, the test is likely to have impact despite imperfect overall sensitivity; however, further . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

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The copyright holder for this this version posted October 4, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted October 4, 2020. . https://doi.org/10.1101/2020.10.01.20203836 doi: medRxiv preprint

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