key: cord-1042008-yqpjkwhf
authors: Turcato, Gianni; Zaboli, Arian; Pfeifer, Norbert; Sibilio, Serena; Tezza, Giovanna; Bonora, Antonio; Ciccariello, Laura; Ausserhofer, Dietmar
title: Rapid antigen test to identify COVID-19 infected patients with and without symptoms admitted to the Emergency Department
date: 2021-10-22
journal: Am J Emerg Med
DOI: 10.1016/j.ajem.2021.10.022
sha: 269264f7e970233921ae660e024af6192e1103ce
doc_id: 1042008
cord_uid: yqpjkwhf

PURPOSE: Early detection of SARS-CoV-2 patients is essential to contain the pandemic and keep the hospital secure. The rapid antigen test seems to be a quick and easy diagnostic test to identify patients infected with SARS-CoV-2. To assess the possible role of the antigen test in the Emergency Department (ED) assessment of potential SARS-CoV-2 infection in both symptomatic and asymptomatic patients. METHODS: Between 1 July 2020 and 10 December 2020, all patients consecutively assessed in the ED for suspected COVID-19 symptoms or who required hospitalisation for a condition not associated with COVID-19 were subjected to a rapid antigen test and RT-PCR swab. The diagnostic accuracy of the antigen test was determined in comparison to the SARS-CoV-2 PCR test using contingency tables. The possible clinical benefit of the antigen test was globally evaluated through decision curve analysis (DCA). RESULTS: A total of 3899 patients were subjected to antigen tests and PCR swabs. The sensitivity, specificity and accuracy of the antigen test were 82.9%, 99.1% and 97.4% (Cohen's K = 0.854, 95% CI 0.826–0.882, p < 0.001), respectively. In symptomatic patients, sensitivity was found to be 89.8%, while in asymptomatic patients, sensitivity was 63.1%. DCA appears to confirm a net clinical benefit for the preliminary use of antigen tests. CONCLUSIONS: The antigen test performed in the ED, though not ideal, can improve the overall identification of infected patients. While it appears to perform well in symptomatic patients, in asymptomatic patients, although it improves their management, it seems not to be definitive.

Since the beginning of the SARS-CoV-2 pandemic, the rapid recognition and isolation of infected patients have proven to be crucial factors in limiting the spread of the virus and containing the pandemic [1, 2] . The early and accurate identification of SARS-CoV-2 patients in the emergency department (ED) remains a major challenge [2, 3] . In addition to the confirmation or exclusion of SARS-CoV-2 infection in symptomatic patients, the ED must simultaneously manage a large number of patients with pathological conditions other than COVID-19 [4] . These patients may be asymptomatic carriers of SARS-CoV-2 infection or, if not infected, they should be separated from This retrospective observational study was conducted in the ED of the General Hospital of Merano (70,000 visits per year). The study period was from 1 July 2020 to 10 December 2020. This study considers patients with data previously published in the form of a preliminary report [12] . The data reported in this study are the conclusion of the previous report [12] .

In July a new clinical protocol for the management of patients requiring an ED evaluation was introduced considering the use of rapid antigen tests for the timely identification patients with a SARS-CoV-2 infection.

According to the clinical protocol, the rapid antigen test for SARS-CoV-2 was performed at the initial triage and at the same time as the RT-PCR swab for SARS-CoV-2 (with two different swabs) in all the patients reporting: 1) symptoms suspicious for COVID-19 infection (fever, dyspnoea, cough, sore throat, diarrhoea, vomiting, asthenia, myalgias, conjunctivitis and deficits in smell and taste); 2) all patients without COVID-19-like symptoms but with an increased temperature (>37.3°C); and 3) one positive epidemiological criterion, such as i) provenance from areas with a high incidence of SARS-CoV-2 cases, ii) coming from other European countries (independently if as a tourist or worker), or iii) reporting contacts with a person who tested positive for SARS-CoV-2. In addition, in order to prevent the possible intra-hospital spread of the infection, we included 4) all patients evaluated in the ED for other problems not related to COVID-19 infection and who needed hospitalisation underwent both a rapid antigen test and the RT-PCR swab for SARS-CoV-2. Data from all patients who received a rapid antigen test and at least one RT-PCR swab consecutively in the ED were retrieved from the electronic database and retrospectively evaluated.

The study was conducted in accordance with the local ethical committee (Comitato etico per la All of the patients who received a rapid antigen test and at least one RT-PCR swab consecutively in the ED were retrospectively evaluated. The patient extraction procedure was performed as follows: all the electronic ED folders of patients who had performed the rapid antigenic test in the ED (computer registered request) were extracted from the ED computer database using the dedicated management software QlickView (QlikTech, Pennsylvania, PA, US). The files of the patients thus identified were manually re-evaluated by a group of ED physicians and nurses (GTu, AZ, SS, GTe, NP, DA) and only those files in which a rapid antigenic test and an RT-PCR test were registered were considered. If other RT-PCR swabs were performed after the one performed in the ED (up to a maximum of three swabs within 15 days) the results were recorded and considered. No other rapid antigen tests were performed in addition to the one performed in the ED as the test was only available in the ED for initial screening.

The rapid antigen test and the RT-PCR swab for SARS-CoV-2 were performed in the ED by appropriately trained nurses. For each patient, one nurse collected both of the swabs.

Based on the symptomatology presented at ED admission, the patients were divided into two groups: symptomatic for COVID-19 and asymptomatic for COVID-19.

The rapid antigen test for COVID-19 was performed with the STANDARD Q COVID-19 Ag (R-Ag) (SD BIOSENSOR, KR), which is a ready-to-use test, according to the manufacturer's instructions. A control line is included in the test to assess the migration of the sample. Visual interpretation of the result was performed between 15 and 30 min. The test result was reported for each patient in the personal triage record. In the case of an invalid test, a second test was performed. RT-PCR was performed with the laboratory machine GeneXpert DX System (Cepheid, CA, US), the laboratoryprocessed swabs were developed with XPRSARS-COV2-10 (Cepheid, CA, US). The system has been approved by the World Health Organization (WHO), and the development of RT-PCR has been conducted in accordance with the WHO guidelines. The nasopharyngeal swab is collected and placed into a transport tube containing 3 mL of saline. The specimen is briefly mixed by rapidly inverting the collection tube 5 times. Using the supplied transfer pipette, the sample is transferred to the sample chamber of the Xpert Xpress SARS-CoV-2 cartridge. The GeneXpert cartridge is loaded onto the J o u r n a l P r e -p r o o f Journal Pre-proof GeneXpert DX System platform, which performs hands-off, automated sample processing, and realtime RT-PCR for detection of viral RNA.

The continuous variables are expressed as median and interquartile range (25th-75th percentile), while the categorical variables are reported as percentage and total number of events. Comparisons were made using the Mann-Whitney test, Fisher's exact test or Chi-square test, as appropriate. The performance of the antigen test was determined by analysing sensitivity, specificity and accuracy using a 2X2 table with the result of the RT-PCR test, with 95% confidence intervals (95% CI) reported.

The concordance between the antigen test and the RT-PCR test was evaluated with Cohen's kappa coefficient. The clinical benefit that may be provided by testing ED patients with antigen tests was evaluated through decision curve analysis (DCA) [13] . DCA is a new simple statistical method that allows calculating the clinical practicality of predictive models and can lead to clinical considerations for decision-making. DCA is a plot of net clinical benefit (y-axis) against threshold probability (xaxis) [13] . The possible net clinical benefit of performing rapid antigen tests on ED arrival is compared with the two default strategies of "all patients are infected with SARS-CoV-2 " (assuming all patients are positive) and "no patient is infected with SARS-CoV-2" (assuming all patients are negative). A higher net benefit within a wide threshold range than the two standard strategies indicate the model has more potential in clinical application. 

The clinical characteristics of the patients evaluated in the ED for COVID-19-like symptoms are reported in Table 3 . 

In addition to the assessment of the diagnostic accuracy of the rapid antigen test, a wider evaluation on the possible global clinical benefit from the use of rapid antigen test to identify COVID-19-infected patients in ED was performed through DCA. The DCA plot seems to suggest that the use of rapid antigen tests as an initial screening tool in EDs can provide an important clinical benefit, especially when considering a population that includes asymptomatic individuals and in which the prevalence of infection appears close to its true prevalence in the general population. The inclusion of rapid antigen tests in ED had a net clinical benefit superior to clinical evaluation alone over a wide range of threshold probabilities, demonstrating the usefulness of this strategy in ED. Between a threshold probability (disease prevalence) of 20% and 30%, the use of rapid antigen tests resulted in a net clinical benefit of between 3% and 5%, suggesting the possibility of detecting up to 5 additional true positives per 100 patients admitted in the ED who were not correctly identified by the clinical evaluation alone (Figure 2A ). In fact, compared to testing all ED patients immediately with RT-PCR, at low disease prevalence rates (<20%) of SARS-CoV-2, the preliminary use of the rapid antigen test leads to a net clinical benefit of approximately 8%. The net clinical benefit is gradually reducing as the disease prevalence increases and at prevalence over 60%, indicating severe levels of infection circulating in the general population, the use of a preliminary screening test may not be a useful strategy, becoming useless for disease prevalence above 90%. However, it must be considered that at high disease prevalence's, above 90%, it would not be useful to apply the screening test at ED admission to identify COVID-19 positive patients. Moreover, clinical suspicion of SARS-CoV-2 infection based on the patients' history and signs and symptoms (clinical evaluation) does not seem to be a useful strategy for discriminating patients infected with SARS-CoV-2 admitted in ED, especially due to asymptomatic patients (Figure 2A ). For disease prevalence values around 10%, the J o u r n a l P r e -p r o o f Journal Pre-proof implementation of the antigen test strategy leads to the detection of 8 true positives per 100 RT-PCR tests performed, with a stable performance from a threshold probability above 22%. In addition, a hypothetical strategy involving adding the rapid antigen test to the clinical study of the symptomatology presented prior to subjecting all ED patients to the RT-PCR swab could improve by 65 out of 100 RT-PCR tests when the prevalence of SARS-CoV-2 is lower than 10% ( Figure 2B ).

Using a large cohort of patients consecutively managed in the ED, the study presents the diagnostic performance of the rapid antigen test compared to the RT-PCR swab when used in a clinical setting to identify SARS-CoV-2-infected patients in both symptomatic and asymptomatic patients managed daily in the ED. The antigen test achieved good specificity and accuracy values, as reported in previous laboratory studies, with a fair sensitivity. The results of the present study confirm the previously published data on a partial cohort of this study, confirming the usefulness of the strategy of performing the antigen test on all patients presenting in the ED, as demonstrated by DCA [12] . Even when considering 489 more patients than in the previously published preliminary report, the performance of the rapid antigen test did not change, demonstrating a clearly superior performance in symptomatic patients compared to asymptomatic patients [12] .

To the best of our knowledge, this is the study with the largest cohort that has evaluated antigen tests in daily ED clinical practice con una that has considered patients who are symptomatic as well as patients who came to the ED for other reasons and who may be asymptomatic carriers of the virus.

The first laboratory studies for the validation of the methodology have provided good initial indications for different types of antigen tests. The laboratory comparison with RT-PCR performed on the same microbiological sample revealed a sensitivity of 68%, a specificity of 100% and an accuracy of 72% for the antigen test [16] . Only 31 out of 239 patients were negative in the detection of the viral RNA, indicating a high prevalence of the disease in the limited study cohort [16] . In addition to the high prevalence of infection, the absence of clinical information may limit the application of these results in clinical practice. Similarly, Porte et al., who tested 127 samples and found 82 to be positive by RT-PCR, confirmed a 100% specificity of the antigen test and indicated a sensitivity and accuracy of 93.9% and 96.1%, respectively [10] . Despite the high prevalence of SARS-CoV-2 in the present study, the sensitivity of the antigen test seems to improve as the viral load presented in the samples increases. In the case of reduced prevalence and reduced viral load, the antigen test seems to have a decreased ability to identify patients infected with SARS-CoV-2 [10, 17] . More recently, Cerutti et al.

reported the first indications of the antigen test in a group of asymptomatic patients (travellers returning from risk areas) [18] . The sensitivity and specificity of the antigen test in this group of asymptomatic patients were 40% and 100%, respectively, with a RT-PCR swab agreement close to 98%, higher than in the symptomatic group [18] .

An initial systematic review of the performance of the antigen test was conducted in an attempt to provide precise indications that can be applied in clinical practice [11] . By grouping 943 tests from five studies, the sensitivity of the antigen tests was found to be relatively low (56.2%, 95% CI 29.5%-79.8%), but a consistently high level of specificity was observed (mean 99.5%, 95% CI 98.1%-99.9%) [11] . However, the absence of information on patient symptomatology limits the evaluation of the usefulness of the antigen test in clinical practice.

The findings of the current study are the first to translate the evidence from previous laboratory studies into clinical practice. Due to the fact that the consequences of a single error in the detection of a SARS-CoV-2-infected patient accessing the hospital can have catastrophic consequences, in daily ED practice, the confirmed high levels of specificity do not seem to be sufficient to compensate for the sub-optimal levels of sensitivity and to provide perfect flow management based only on antigen tests [14, 15, 19] . However, at the indicated levels of prevalence, a positive antigen test in symptomatic 

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