Julian Zirbes,Christian M. Sterr,Christian Keller,Rita Engenhart-Cabillic,Claudia Nonnenmacher-Winter,Frank Günther
Efficiency analysis of rapid antigen test based SARS-CoV-2 in hospital contact tracing and screening regime: test characteristics and cost effectiveness
COVID-19,POCT,Cost effectivity,Rapid antigen test,SARS-CoV-2
In the context of the current SARS-CoV-2 pandemic, reliable and cost-efficient screening and testing strategies are crucial to prevent disease transmission and reduce socioeconomic losses. To assess the efficiency of a rapid antigen test (RAT)-based SARS-CoV-2 contact-tracing and screening regime, we conducted a retrospective analysis of RAT and polymerase chain reaction (PCR) test data over a 1-year period, assessed test characteristics and estimated cost-effectiveness. The RAT had a sensitivity of 70.2% overall and 89.3% for people with a high risk of infectivity. We estimated inpatient treatment and quarantined healthcare worker costs of over € 5860.83, whereas the cost of identifying one SARS-CoV-2 positive person by RAT for our patient cohort was € 1210.75. In contrast, the estimated respective PCR cost was € 5043.32. Therefore, a RAT-based contract tracing and screening regime may be an efficient and cost-effective way to contribute to the early identification and prevention of SARS-CoV-2 transmission.
Efficiency analysis of rapid antigen test based SARS-CoV-2 in hospital contact tracing and screening regime: test characteristics and cost effectiveness

In the context of the current SARS-CoV-2 pandemic, reliable and cost-efficient screening and testing strategies are crucial to prevent disease transmission and reduce socioeconomic losses. To assess the efficiency of a rapid antigen test (RAT)-based SARS-CoV-2 contact-tracing and screening regime, we conducted a retrospective analysis of RAT and polymerase chain reaction (PCR) test data over a 1-year period, assessed test characteristics and estimated cost-effectiveness. The RAT had a sensitivity of 70.2% overall and 89.3% for people with a high risk of infectivity. We estimated inpatient treatment and quarantined healthcare worker costs of over € 5860.83, whereas the cost of identifying one SARS-CoV-2 positive person by RAT for our patient cohort was € 1210.75. In contrast, the estimated respective PCR cost was € 5043.32. Therefore, a RAT-based contract tracing and screening regime may be an efficient and cost-effective way to contribute to the early identification and prevention of SARS-CoV-2 transmission.

In late 2019, Chinese authorities reported the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which was responsible for an accumulation of cases with pneumonia [1], [2], [3]. Within a few weeks, the virus spread globally and was declared a pandemic on March 11, 2020 by the World Health Organization. The worldwide spread of the virus is facilitated by its respiratory transmissibility, which can be present even before the occurrence of symptoms, which accounts for more than 50% of all transmissions [4], [5], [6], [7]. Over time, genetic mutations led to the appearance of multiple variants with altered properties such as increased infectivity or immune evasiveness [8]. Following a containment strategy, a variety of public health measures were established and regularly adjusted worldwide. Interrupting chains of infection is mainly achieved by contact tracing, isolation of infected people, quarantining close contacts as well as by intensified infection control measures [9], [10], [11]. In late 2020, also the first vaccines against SARS-CoV-2 became available [12]. Early detection and containment of outbreaks are especially important for in-patient health care, where there is a multitude of vulnerable risk groups, and physical distance cannot always be maintained [13]. Thus, it is imperative to implement an adequate and standardized testing regime, including a screening strategy and a close-meshed testing concept for contacts among patients and hospital personnel [14]. Polymerase chain reaction (PCR) is considered the gold standard for the detection of SARS-CoV-2 because of its high sensitivity, but it is often not suitable in situations where a short result duration is necessary. Reliable point-of-care tests are of utmost importance in this context. The literature suggests that when used on a regular basis, they are a potent and inexpensive tool to detect infections in time for action [15]. However, opinions about their significance differ because of their low sensitivity compared to that of PCR [16]. This study evaluated the efficiency of a screening and contact-testing regime based on rapid antigen tests (RAT) at Marburg university hospital.

Our contact tracing workflow has been published in detail in another study [11]. In summary, contacts among hospital employees filled out a web-based tool to receive a code for rapid antigen testing on days 1, 3, and 5 after their last contact with an index case. The tool generated a list of contacts for a specific index case and could be used to review the RAT results of the listed contacts. RATs have also been used for patient screening at hospital admissions. Contacts among patients underwent a PCR test at least on days 1, 3, and 5 after the last contact with the index case. Symptomatic patients or hospital employees were tested using PCR. People with positive RAT results generally underwent PCR for confirmation. The SARS-CoV-2 Rapid Antigen Test (Roche Diagnostics, Rotkreuz, Switzerland) was used for rapid antigen testing. The RAT were carried out and evaluated in our in-house test center as professional tests using a nasopharyngeal swab as described previously [11]. Both RAT results from asymptomatic patients and employees were evaluated as part of the study and used to determine the test parameters and effectiveness. For our evaluation, we conducted a retrospective analysis of test data from November 2020 to November 2021. Patient screening RAT results were retrieved from the hospital information system, and employee RAT results were retrieved from contact tracing lists. RNA extraction was performed with the EZ1 Virus Mini Kit (Qiagen, Hilden, Germany), followed by PCR detection using the RealStar® SARS-CoV-2 RT-PCR Kit 1.0 (Altona Diagnostics, Hamburg, Germany) on a LightCycler 480 II (Roche, Mannheim, Germany). PCR results were collected from the laboratory information system and included cycle threshold (Ct) values for the E gene. In the test results evaluated in this study, 1 × 106 copies of SARS-CoV-2 RNA per milliliter yielded a Ct value of 30. Based on culturability studies, Ct values below 30 were considered infectious, whereas Ct values ≥ 30 were attributed to a low risk of infectivity [17,18]. Based on the aforementioned test data, characteristic test parameters, such as sensitivity, specificity, and positive and negative predictive values were calculated both overall and for people with PCR Ct values below 30. In addition, the number of people needed to screen (NNS) to detect one positive person was estimated. Statistical analyses were performed using SPSS software (IBM, Armonk, NY, USA). To determine cost effectiveness, the literature was reviewed, and characteristic data for SARS-CoV-2 were retrieved (Supplementary 1). Literature revealed that about 10% of infected people required hospitalization in Germany, and 20% of hospitalized patients required ventilation therapy [19]. Secondary attack rates were reported as 0.7% in the hospital setting and 18% among household contacts, however, these were subject to high heterogeneity [20]. Based on the data, a general secondary attack rate of 6% was assumed in another modeling study [21]. The average number of contacts per index case (20) was obtained from previous analysis of the data [11]. To determine the cost per Covid-19 case an inquiry was sent to a large German health insurance provider and the associated research institute (AOK, Allgemeine Ortskrankenkasse, Berlin, Germany; WidO, Wissenschaftliches Institut der AOK, Berlin, Germany). Their data consisted of 152,500 patients who were either hospitalized because of Covid-19 or due to other reasons while being infected with SARS-CoV-2. The average cost per case totaled € 5,800 without the necessity for ventilation therapy and € 33,600 when ventilation therapy was administered. From these data, the average inpatient treatment costs resulting from one unidentified SARS-CoV-2 index case in the hospital setting were calculated (Fig. 1 A). To estimate the cost of quarantined hospital personnel resulting from an initially unidentified SARS-CoV-2 index case, the average number of quarantined contacts per index case, quarantine length at the time of the study, and average personnel cost for a hospital employee were assessed ( Fig. 1B). The average number of quarantined contacts per index case was calculated from in-house personnel data and equaled to 1.5. A quarantine period of 14 day was assumed. The average personnel cost for a hospital employee in Germany (€ 77,959 annually) was calculated from official statistics of German hospitals in 2019 [22,23]. The RAT test costs were divided into material and personnel costs. In-house material costs for RAT varied during the reviewed time frame, with an average cost per test of € 5.99. The personnel cost per test was defined as the average 5-minute salary of an assistant nurse in our clinic (€ 1.26). The NNS for the RAT was calculated from the evaluated data. However, estimating the cost of each PCR test is complex. While a RAT can be performed in close proximity to the tested person, PCR samples need to be transported to the laboratory and pass through a specific process. This process includes sample registration, nucleic acid extraction, and specimen preparation before the actual PCR is performed, and the resulting data are interpreted by a medical professional. As none of these factors could be considered in detail, the average cost per PCR test charged by an external laboratory in Germany (€ 42.74) [24] was used for our calculations. Because PCR was not used as a screening tool in our hospital, a valid NNS for PCR could not be calculated from our data. Therefore, the NNS for PCR was estimated from the NNS of the RAT and the difference in sensitivity between the 2 methods. To calculate the test costs to identify one SARS-CoV-2 index case in our testing regime, the RAT costs were multiplied by the NNS (Fig. 1C).

Between November 2020 and November 2021, a total of 43,082 RATs were conducted; 32,234 RATs were performed on patients and 10,848 on hospital employees. A total of 244 patients and 30 hospital employees tested positive by RAT, resulting in a positivity rate of 0.8% for patients and 0.3% for hospital employees. Overall, the positivity rate was 0.6%. Consequently, the NNS for RATs differed between the groups. The NNS score was 125 for patients and 333 for hospital employees. The overall NNS for RATs was 167. The overall NNS for PCR was estimated to be 118. Of the 274 people who had a positive RAT result, 134 underwent in-house testing via PCR on the same working day, or within a maximum of 8 hours respectively, and were included in the analysis. Nine PCR tests did not confirm the positive RAT, resulting in a false positive rate of 6.7% for the RAT. The Ct values for the positive RAT and positive PCR constellations are shown in Fig. 2 . The lowest Ct value retrieved was 12.1 and the highest was 34. To further investigate the RAT parameters, negative RATs on the same day as in-house PCR tests were evaluated. A total of 1553 nasopharyngeal swabs were performed for both RAT and PCR tests in parallel. (Table 1 A). Of these, 53 PCR tests were positive, resulting in a false negative rate of 3.4% for the RAT. In total, 71.1% of the negative RATs had a Ct value of 30 and above in the corresponding PCR (Fig. 3 ). A second calculation evaluated the RAT parameters for individuals with positive RAT and PCR Ct values of 30 and below (Table 1B). In this group, the positive predictive value was 92.4% and the negative predictive value was 99.1%. Sensitivity was estimated to be 89.3% and specificity, 99.4%. Based on these numbers, the characteristic test parameters were calculated (Table 2 ). Overall, the positive predictive value of the RAT was 93.3% and the negative predictive value was 96.6%. Overall sensitivity was estimated to be 70.2%, and the test had a specificity of 99.4%. In the second step, we evaluated the cost-effectiveness of the established test concept by approximation. Our testing regime aimed to identify SARS-CoV-2 index cases in the hospital setting early enough to prevent further infections. For the cost-effectiveness approximation, the average inpatient treatment cost for secondary cases as well as the cost of quarantined health care workers (HCW) resulting from one unidentified SARS-CoV-2 index case in the hospital setting were estimated. The average inpatient treatment cost for secondary cases was € 1363.20, whereas the cost for quarantined HCWs was € 4497.63. Additionally, the cost to identify one SARS-CoV-2 positive person by RAT/PCR was calculated. Cost per RAT was estimated to be € 7.25, and PCR was € 42.74. Overall, the RAT required testing of 167 people to identify one positive person. Consequently, the cost to identify one positive person was calculated to be € 1210.75 using RAT. The PCR required 118 people to be tested to identify 1 positive person, resulting in overall test costs of € 5043.32.

When integrated into a tailored infection control strategy, RATs have been shown to facilitate swift identification and isolation of individuals infected with SARS-CoV-2 [25,26]. However, their effectiveness in screening asymptomatic individuals remains uncertain [27,28]. We performed an efficiency analysis of our RAT-based SARS-CoV-2 contact-tracing and screening regime. To achieve this goal, the test parameters for the RAT were calculated over a one-year period. In addition, the cost effectiveness was estimated. To identify SARS-CoV-2 index cases in the hospital setting early enough to prevent follow-up infections, a testing regime needs to detect infected people with high sensitivity. This applies especially to people with high viral loads and, therefore, an increased risk of infectivity (PCR Ct < 30). In this group, a RAT sensitivity of 89.3% was calculated. Overall, RAT sensitivity was 70.2%, which is in accordance with recently published literature [29]. The reliability of a negative test result is of the utmost importance for screening regimes. Therefore, an adequate negative predictive value is required. For the RAT, the negative predictive value was estimated to be 96.6% overall and 99.1% for people with a corresponding PCR Ct of less than 30. Of the 3.4% false negative RATs, 71.7% had a Ct value > 30 in the corresponding PCR, and therefore did not present a high risk of infection. However, when interpreting Ct values, multiple preanalytical and analytical factors, such as the quality of the swab as well as the thermocycler and PCR materials used, need to be considered [30]. Furthermore, a comparison between RAT and PCR results could not be conducted for all RATs, as most people with negative RAT results did not undergo confirmatory PCR testing. The test parameters were calculated and averaged over a period of one year. During this period, alpha and delta were the dominant variants, and new vaccines became available. Both these factors must be considered when interpreting our results, as they can impact test sensitivity [31], [32], [33]. Consequently, test parameters may differ for other circulating virus variants, such as the omicron variant, and the increasing number of vaccinated people. To attempt a cost-effectiveness analysis, costs resulting from one unidentified SARS-CoV-2 index case were approximated and compared to the cost of tests needed to identify one SARS-CoV-2 positive person by RAT or PCR. The inpatient treatment and quarantined HCW costs for one unidentified SARS-CoV-2 index case was € 5860.83, whereas an estimate of the total test cost to identify one SARS-CoV-2 positive person was estimated to be € 1210.75 using RAT and € 5043.32 with PCR. This underlines the different cost dimensions of the RAT- and PCR-based test regimes and indicates the cost-effectiveness of the RAT regime. However, in our cost-effectiveness analysis, multiple limitations must be considered, including approximating cost dimensions rather than an exact calculation. First, the epidemiological characteristics of SARS-CoV-2, such as the percentage of people infected or hospitalized as well as secondary attack rates, can vary greatly between different populations and time periods, and are also affected by the number of people vaccinated and the characteristics of the circulating virus variant [34]. The parameters applied in our study were obtained from literature from within the analyzed period, focusing on a German population [19] but did not consider the aforementioned variations in detail. Second, the number of contacts for an infected individual is high and can vary over time. For our approximation, the average number of contacts per SARS-CoV-2 index case was obtained from previous evaluations of contact tracing data in our hospital [11]. Concerning inpatient treatment costs, it should be noted that the numbers used for the approximation here were costs per hospital stay and not per patient. Consequently, a SARS-CoV-2 patient who is transferred from one hospital to another would generate 2 separate cases with separate costs, leading to an underestimation of actual inpatient treatment costs. Furthermore, inpatient treatment and quarantined HCW costs are not the only aspects to be considered. Outpatient treatment, rehabilitation, and treatment of sequelae, as well as socio-economic losses, must be considered to perform a more accurate analysis. However, because of the high variability between the cases, these factors were not included in our calculations. Additionally, owing to their short duration required for obtaining results compared to PCR, RATs may help prevent costs and reduce hospital capacity arising from unnecessary isolation of patients [24]. Consequently, the actual overall costs with regard to SARS-CoV-2 follow-up cases will possibly exceed the costs estimated in our study. Of note, if there are significantly milder courses of infection through vaccination or new variants of SARS-CoV-2 the saved hospitalization costs will consequentially vary downwards, and with it the cost effectiveness. Conversely, higher cost effectiveness of screening measures could be expected in the case of more severe disease courses. Even though our cost approximation is in line with other assessments from the literature, its single-center characteristic needs to be considered when interpreting its results. Controlled prospective multicenter cost studies are required to reach a well-founded conclusion [24,35]. Finally, cost prevention is not the main goal of infection prevention strategies such as screening measures. SARS-CoV-2 infections have tremendous implications for both patients and their environments; therefore, transmission needs to be prevented by any means necessary. However, our analysis strictly focused on the cost prevention aspect of the early identification of SARS-CoV-2 infections.

Our data provide evidence that the RAT-based contract tracing and screening regime at Marburg university hospital provided an efficient and cost-effective way to contribute to the early identification and prevention of SARS-CoV-2 transmission during November 2020 to November 2021. Therefore, an RAT-based approach could provide a template for future infection outbreaks and pandemic situations.

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.