The severe acute respiratory syndrome COVID-19, caused by coronavirus 2 (SARS-CoV-2), first appeared in December 2019 in Wuhan, China, with an accumulation of pneumonia and has since spread across the globe.1 Clinical features of the disease, known as COVID-19, include fever, headache, and cough, but more severe symptoms such as shortness of breath and respiratory failure have also been reported.2 As of April 30, 2021, around 151 million cases and more than 3.2 million deaths have been registered in 210 countries and territories worldwide.3

The rapid escalation of the situation caused the World Health Organization to declare a pandemic on March 11, 2020.4 Since then, the continued human-to-human transmission of SARS-CoV-2 has created tremendous challenges for healthcare systems and public health laboratories. Accurate and rapid identification of those infected with SARS-CoV-2 is therefore key to immediate clinical care and to containing the spread of the virus. The current reference test used to establish SARS-CoV infection worldwide is the real-time reverse transcriptase polymerase chain reaction (RT-PCR). These assays have nearly perfect sensitivity and specificity and are therefore well suited as “gold standard” for the diagnosis of clinically ill patients. However, utilization of RT-PCT tests for immediate COVID-19 in hospitals raises substantial challenges: As they require RNA extraction, are dependent on availability of PCR reagents and have a relatively long turnaround time, RT-PCR tests are often performed in batches in clinical laboratories outside the hospital, necessitating specimen transport. Therefore, they usually require a time-lag of one day before the report of the test result becomes available. In Germany currently 71.5% of all hospitals have eliminated their in-house laboratories.5 Thus, to ensure the correct diagnosis, nasopharyngeal swabs or other respiratory specimen of patients suspected of having COVID-19 must usually be sent to external labs for centralized RT-PCR testing.

In contrast, lateral flow assay (LFA) SARS-CoV-2 antigen tests can be performed at point of care, provide results within 15–30 min and are inexpensive. Numerous SARS-CoV-2 POC antigen tests are currently available, offering the potential for rapid identification of those individuals in the emergency setting who are not only infected, but infectious and are therefore at greatest risk of spreading the infection. For methodological reasons, the detection limit for SARS‐CoV‐2 RNA material out of clinical samples tested by RT‐PCR is always lower than the detection limit for SARS‐Cov‐2 antigen. Whilst RT-PCR results may still show positive signals for up to several weeks after reaching peak cycle threshold (Ct) values, the detectability of even the best performing antigen test deteriorates with decreasing viral load.6 However, if patients visit ER before the end of the first weeks of symptoms when pharyngeal virus shedding is very high and infected individuals are likely to be most infectious, sensitivity of high-quality antigen tests is only slightly reduced and can help to filter out the infectious persons.7 Consequently, POCT may help to prevent the hospital – if COVID-19 suspects have to be hospitalized due to the severity of symptoms - from isolating such patients and blocking a second bed in the patients´ rooms at the hospital ward unnecessarily.

Furthermore, rapid assessment of infectious COVID-19 is highly relevant to the management of scarce economic resources also for another reason. Since 1 January 2004, hospital costs in Germany are based on the German diagnosis-related groups (G-DRG) system, which assigns each COVID-19 case to the category E79C). This imposes a fixed “base rate” of payment for 13 days of treatment. If the hospital treatment exceeds the so-called “mean length of stay”, i.e., 6.9 days (as calculated mathematically by the DRG Institute for Hospital Reimbursement (InEK) using case-related data from its contracted hospitals8), then the G-DRG rate paid as reimbursement by the statutory health insurance (SHI) usually does not cover the costs incurred by the hospital. Accordingly, when treating COVID-19 patients covered by the SHI, hospitals should try to keep the duration of hospital stays as short as possible.9

According to the most recent guidelines of the German Robert Koch Institute (RKI) isolation of an immunocompetent patient can be stopped and discharge be started only if - although viral load on swabs decreases as symptoms resolve10 - at least 14 days have passed since the onset of the first symptoms, a lasting improvement in the acute COVID-19 symptoms has been present for > 48 h and a RT-PCR (preferable recommended) or an antigen test is negative.11 Again, as the negative result of a POCT test is usually available one day earlier than that of the RT-PCR costs may be saved from the hospital´s perspective by a respectively earlier discharge. The aim of our calculations was to examine whether routine implementation of POCT in COVID-19 suspects visiting an ER leads to directly measurable economic advantages from the hospital perspective, taking as an example the Sofia® SARS Antigen FIA test under the assumption that all nasopharyngeal swabs of COVID-19 suspects are sent to external labs for RT-PCR testing. Using its performance characteristics, we compared the economic outcomes to those that occurred when conventional clinical judgement alone was used to confirm or exclude SARS-CoV-2 in patients deemed to have a combination of symptoms so serious as to warrant hospitalization. The hypothetical savings would come about thanks to earlier patient classification, in anticipation of a RT-PCR result, available only one day later.

In the base-case analysis, utilizing the Sofia® SARS Antigen FIA test in COVID-19 patients is on average €212.57 less costly per eventually hospitalized patient, compared to the conventional clinical approach (see Table 2a), although all POCT results, negatives as well as positives in the ER, will be re-checked by external PCR. Included in this amount is a cost saving of €20.36 in absolute terms per tested patient in favor of the hospital. The costs for the initial RT-PCR ordered by the ER are not considered here, since the incurred laboratory costs – in contrast to the POCT – are de facto reimbursed to the hospital at the expense of the SHI.

The amount of cost saving is, above all, dependent on the specificity of clinical judgement. Reducing the base case value of 68.3 to60.0% (worst case) results in a further cost savings of €48.90 on top of the €212.57, whilst an increase to 75.8% diminishes the saving by to €169.38. This is revealed by our univariate sensitivity analysis, in which all variables included in the decision analysis are changed between plausible extremes ranges (Table 3). Decreasing by 20% the opportunity costs of blocking a twin bed reduces the amount of cost saving by €43.19. The principal advantage of the Sofia® SARS Antigen FIA — namely of excluding a COVID-19 infection, with high specificity — is the third important component. However, even when assuming a decrease in specificity of the Sofia to the lower bound estimate of the 95% confidence interval, i.e. by 3.19% from the base case value of 98.9%, no reversion of the relative cost savings occurring by utilizing the Sofia takes place, the cost savings decrease only to €194.19.

An increasing number of COVID-19 cases in the ER, i.e. a higher level of prevalence, hardly influences the economic outcome. Even under worst-case assumptions, where 41.2% of all patients with respiratory symptoms reporting to an ER turn out to be COVID-19 cases, a cost saving of €207.15 in favor of the hospital remains. Also, when the revenue costs for one hospital day gained by early release of a COVID-19 patient thanks to a negative POCT are lowered by 20%, the cost savings are only reduced by €8.09. If the sensitivity of the Sofia decreases from 80% to 64.4%, the lower bound of its 95% confidence interval, savings are even less diminished (by €7.66). Variations of all other parameters do not or do only marginally change the absolute amount of expenditures in favor of the hospital.

A modified approach, where the positive result of POCT is not retested by RT-PCR, results only in relative, but not in absolute cost savings (€154.25, see Table 2b). Patients who tested false positive by POCT would have been isolated unnecessarily and received antithrombotic prevention on average for 10 days. During this period, no other patient could be admitted to the second bed in the two-bed room and thus opportunity costs for each single day would occur at the expense of the hospital. Although the specificity of the antigen test testing in the ER is very high, one of those falsely isolated non-COVID-19 patients would burden the hospital with additional costs of €6282. Although only 1.1% of the 84.4% hospitalized non-COVID-19 patients would be tested false positive, the approach without RT-PCR re-testing would on average lead to additional costs per falsely tested patient of €69.1 compared to the re-testing approach. Therefore, the approach with re-testing of POCT by RT-PCR is clearly favorable not only from the clinical but also economic point of view.

In probabilistic sensitivity analysis (PSA), i.e., under all reasonable assumptions, performing POCT on each patient prior to hospitalization reduces the costs that occur when COVID-19 suspects are isolated based only on the conventional clinical approach, by €209.91 (see Table 4). Of note, testing with Sofia® SARS Antigen FIA is constantly less expensive than the purely clinical approach and on average even less expensive than in base analysis, even when a RT-PCR test is used to confirm or deny the preceding POCT result one day later.

The major portion of this savings figure is due to the fact that in PSA, where the results are based on random-sampling and therefore differ from those of the univariate analysis, the proportion of initial unnecessary bed blocking was more than twenty-one-fold higher (25.9 vs 1.2%) with conventional clinical judgement than with the Sofia® SARS Antigen FIA. As this mistake can be corrected only 1 day later, when the result of the RT-PCR is available, the cost difference between the two strategies, with respect to opportunity costs - weighted by the proportion of 81.5% of patients who were not infected with SARS-CoV-2, is €159.24 in favor of the Sofia test. Although the sensitivity of the Sofia is minimally lower than that of the purely clinical approach, the earlier discharge by obtaining a negative POCT result one day earlier that the result of the RT-PCR results in a cost saving of €50.57.

Newer real-time POC tests such as the Sofia® SARS Antigen FIA, which can claim specificity of nearly 99%, come close to laboratory RT-PCR testing in their ability to very rapidly and reliably exclude the presence in a patient of transmissible COVID-19. Therefore, they offer the potential to avoid unnecessary isolation that occurs extensively under the conventional clinical approach. The COVID-19 situation, which forces snap clinical decisions, does not work in favor of the conventional approach. There have been complex attempts to better predict the presence of COVID-19 by creating artificial intelligence (AI) programs which process clinical data as well as imaging techniques. Xia et al.20 describe that when considering 52 clinical and laboratory coefficients, e.g., disseminated intravascular coagulation, d-dimer, procalcitonin, enlarged lymph nodes or rhabdomyolysis together with CXR features, sensitivity increased to 94% and specificity to 75%. However, the complex information required is hardly available in the setting of an ER before deciding whether a possible COVID-19 patient should be hospitalized or not.

In real life studies, POCT with the Sofia to detect the COVID-19 virus in symptomatic patients shows sensitivity nearly identical to that of the empirical clinical approach. However, little information on the onset of symptoms among study participants was available to the researchers there, and an unknown percentage of the patients included may have been tested later than 7 days following the start of symptoms, when sensitivity of the antigen test is known to decrease, again due to decreasing viral load over time. This may at least partially explain the striking discrepancy of more than 15% between the values in the pivotal studies of the manufacturer and the few evaluation studies used for our economic analysis. Another cause may be inappropriate preanalytics, e.g., pipetting swab material into viral transport media rather than performing the POCT immediately as required by the manufacturer´s operation procedures.

Nevertheless, the key to achieving the calculated cost saving of €209.91 per patient by implementing a POC antigen COVID-19 test from the hospital's perspective lies in the time lag between taking the swabs in the ER, which in most cases get sent to an external laboratory, and receiving the RT-PCR report one day later. Each time a patient is wrongly assumed to be suffering from a SARS-CoV-2 infection; hospital capacity is reduced, leading to corresponding revenue loss in terms of one day of opportunity costs for the hospital. Performing the Sofia test on the spot results in significantly fewer false assumptions made regarding the presence of COVID-19 patients and the rate of unnecessary bed blocking on the first day of hospitalization is twenty-one nine-fold lower when compared to the conventional clinical approach.

Thus, in PSA of our model, the routine implementation of a POCT for COVID-19 suspects being moved from the ER for admission to a German hospital ward is consistently less expensive than the conventional symptom-based judgement for which the RT-PCR testing results is available only after a delay of 1 day. Of note, this ranking is not dependent on changes in the prevalence of COVID-19 in such patients, as long as during the ongoing COVID-19 “third wave” the COVID-19 prevalence in ER patients does not exceed and remain above 41.2%. Of note, we did not consider the number of those patients with severe COVID-19 who needed respiratory support (oxygen with or without subsequent invasive mechanical ventilation) at the beginning of hospital stay. As the 28-day mortality of those patients may be reduced by administering anti-inflammatory treatment with dexamethasone,21 a prompt and reliable diagnosis of SARS-CoV-2 in those patients is necessary. In their cost-effectiveness model, Ricks et al.22 found that a POCT-led strategy averted more deaths and entailed lower costs than did RT-PCR testing, given that RT-PCR testing was performed in fewer than 85% of cases, with the remainder managed through clinical judgement alone ($140,000 versus $150,000 per death averted).

However, in contrast to our model, where a sensitivity of clinical judgement was estimated to be nearly the same as that of the POCT (80.6% versus 80.0%), the authors stipulated a broad range of uncertainty for the sensitivity of clinical judgement, starting with low 45% (range 45–99%), whilst sensitivity of POCT was a priori set at 80%.

Our study has some limitations that must be kept in mind when interpreting its results. As always, the general limitation of a single-center economic model that cannot depict the reality of utilization of bed capacity of every hospital deserves consideration, as does the local SARS-CoV-2 infection prevalence among exposed health care workers. Therefore, to validate our estimates, prospective cost studies, preferably with a multicenter study design, are required. Furthermore, our calculations refer only to hospitals that must send samples to an external laboratory for COVID-19 testing and wait for the report. Hospitals that have a laboratory department at their disposal that already conducts high quality RT-PCR tests whilst the patients are waiting in the ER, even during weekends and at night, will probably not benefit by COVID-19 POCT. It is important, however, that, although test results must be quickly provided, the cycle threshold (Ct) values, which inversely correlate with the number of virus present in the sample, must be reported so as to reliably indicate infectiousness of a COVID-19 suspect.

The utilization of the Sofia® SARS Antigen FIA test, as representative of high quality POC antigen tests, is likely to reduce hospital-related costs in cases of suspected COVID-19 in German emergency departments. As such, POCT can reduce costs from the hospital´s perspective and allows resources to be allocated for other precautions. Prospective clinical studies should be undertaken to further evaluate its economic advantages in the immediate future.

Ethical approval was not necessary as only publicly available secondary data were used.