Cost-effectiveness analysis of different COVID-19 screening strategies based on rapid or laboratory-based SARS-CoV-2 antigen testing

To the Editor,

Now, in the fourth year of the coronavirus disease 2019 (COVID-19) pandemic, many important aspects have become clear concerning the pathogenesis, clinical management, outcome and, last but not least, regarding the diagnostic approach to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although it is undeniable that the clinical consequences of an acute SARS-CoV-2 infection in the general population are incomparably milder now compared to the period when the virus initially spread worldwide from China [1], the number of daily COVID-19 diagnoses is still very high. According to the World Health Organization (WHO), the number of daily diagnoses of new or recurrent COVID-19 cases still exceeds 200,000 worldwide in February 2023 [2]. We also must acknowledge that this number may be heavily underestimated for a variety of reasons discussed elsewhere [3]. Thus, diagnostic strategies only relying on molecular testing, although remaining the gold standard for detecting SARS-CoV-2, are imprudent given that the reference real-time reverse transcription polymerase chain reaction (RT-PCR) assays are characterized by low throughput, long turnaround time and high cost [4], thus paving the way to using alternative diagnostic solutions. Among various options, the identification and quantification of SARS-CoV-2 antigens by means of rapid diagnostic tests (RDT-Ag) or laboratory-based immunoassays (LAB-Ag) represent valuable alternatives, endorsed by both the WHO [5] and by the International Federation of Clinical Chemistry and Laboratory Medicine [6]. Although we certainly recognize that the diagnostic sensitivity of these tests is basically lower than that of molecular assays (i.e., comprised between 70 and 80%) [7, 8], their usage for initial “screening” of patients may provide a valuable alternative for saving precious human and economic resources, though no comprehensive information exists to confirm the validity of this second claim to the best of our knowledge. To this end, we carried out a cost-effective analysis of some potential diagnostic protocols inclusive of SARS-CoV-2 antigen tests.

The study population consisted in a series of 294 patients (mean age, 45 ± 20 years; 55% females) presenting to the SARS-CoV-2 diagnostic facility of the Pederzoli Hospital in Peschiera del Garda (Verona, Italy), to undergo routine COVID-19 testing. According to local standard operating procedures (SOPs), all patients underwent rapid diagnostic testing (RDT-Ag, ∼30 min turnaround time; Fujirebio Espline SARS-CoV-2; Fujirebio Inc., Tokyo, Japan) for enabling fast identification of positive subjects, followed by molecular (RT-PCR, 4–6 h turnaround time; Altona Diagnostics RealStar SARSCoV-2 RT-PCR Kit; Altona Diagnostics GmbH, Hamburg, Germany) and SARS-CoV-2 laboratory-based Ag (LAB-Ag, 45–60 min turnaround time; DiaSorin LIAISON SARS-CoV-2 Ag; DiaSorin, Saluggia, Italy) testing on the same nasopharyngeal sample. The specific characteristics of all these three assays are reported elsewhere [9, 10]. Each patient included in this study underwent all the three diagnostic tests concomitantly, which we incorporated in seven different diagnostic strategies, as summarized in Figure 1 (i.e., RDT-Ag alone; LAB-Ag¹ alone, with manufacturer’s cutoff; LAB-Ag² alone, with locally calculated cutoff; RT-PCR alone; RDT-Ag combined with RT-PCR in negative samples; LAB-Ag¹ with manufacturer’s cutoff combined with RT-PCR in negative samples; LAB-Ag² with locally calculated cutoff combined with RT-PCR in negative samples). The three last strategies, encompassing RT-PCR in samples testing negative with RDT-Ag or LAB-Ag^(1–2) were specifically selected for achieving the maximum possible accuracy in identifying patients with SARS-CoV-2 infection (i.e., “zero-tolerance for false negatives”). The costs of the three technique for assaying each individual nasopharyngeal sample (i.e., the cost per test) at the local facility were as follows: RDT-Ag: 7.50 €; LAB-Ag: 3.50 €; RT-PCR: 20.0 €; respectively.

Figure 1:

Description of five coronavirus disease 2019 (COVID-19) diagnostic strategies combining RDT-Ag (rapid diagnostic antigen test), LAB-Ag (laboratory-based antigen test) and RT-PCR (real time polymerase chain reaction) SARS-CoV-2 assays. ¹Manufacturer’s cutoff (200 TCID₅₀/mL). ²Locally calculated cutoff (103 TCID₅₀/mL). SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; RDT-Ag, rapid diagnostic antigen test; LAB-Ag, laboratory-based antigen test; RT-PCR, real time polymerase chain reaction.

The statistical analysis was conducted with Analyse-it (Analyse-it Software Ltd, Leeds, UK). The study was part of SOPs, using specimens collected for routine SARS-CoV-2 diagnostic screening and molecular testing at the local diagnostic facility, such that Ethical Committee approval was not required. All results were anonymized before conducting the statistical analysis. The study was performed in accordance with the Declaration of Helsinki, under the terms of relevant local legislation.

The main results of our analysis are summarized in Table 1. The locally calculated cutoff (by means of receiver operating characteristics [ROC] curve analysis; Supplementary File 1) of LAB-Ag was 103 TCID₅₀/mL (vs. the 200 TCID₅₀/mL manufacturer’s cutoff), yielding 0.78 area under the curve [AUC], 1.00 specificity and 0.03 sensitivity, respectively. No false positive test results were observed using any of the six strategies not encompassing RT-PCR alone. As implicitly assumed, all the three “zero tolerance for false negatives” strategies did not generate any false negative test result, while such a rate was 43.2 and 43.5% using the RDT-Ag and LAB-Ag¹ strategies alone, respectively, decreasing to 35.4% using the LAB-Ag² strategy alone. The most economic strategy was that encompassing LAB-Ag alone, followed by RDT-Ag alone. Nonetheless, the best balance between cost and diagnostic accuracy (i.e., “zero tolerance for false negatives”) was found for the strategy encompassing LAB-Ag² combined with RT-PCR in negative samples, which was cheaper than that based on RT-PCR alone (i.e., 5,509 vs. 5,880 €). Interestingly, the cost of the strategy encompassing LAB-Ag¹ combined with RT-PCR in negative samples was comparable to that entailing RT-PCR alone (i.e., 5,989 vs. 5,880 €). Higher expenditure emerged using a strategy based on RDT-Ag combined with RT-PCR in negative samples (i.e., 7,145 €).

In a previous analysis published by Dolatshahi et al. [11], the authors conducted an economic evaluation of different laboratory diagnostic options, concluding that although RT-PCR alone seems to improve quality of life and survival of patients with SARS-CoV-2 infection, these positive outcomes could be offset by high costs. Unfortunately, no comparative analysis was carried out with RDT-Ag and/or LAB-Ag in the work of Dolatshahi et al. [11], thus paving the way for our cost-effectiveness analysis that also included SARS-CoV-2 antigen testing. According to our findings, the optimal strategy combining “zero-tolerance” for false negative tests results with reasonable expenditures was that entailing LAB-Ag² (i.e., using locally calculated cutoff) combined with RT-PCR in negative samples, which was equally accurate but reasonably cheaper than strategies based on RT-PCR alone, LAB-Ag¹ (i.e., with manufacturer’s cutoff), or RDT-Ag combined with RT-PCR in negative samples. Notably, this strategy would enable faster patient triage, especially in short stay units, achieving a rapid and cheaper diagnosis compared to using RT-PCR alone of a discrete number of patients with SARS-CoV-2 infections, who may be rapidly addressed to specific care pathways.