Impact on laboratory medicine of transitioning from COVID-19 pandemic to “tripledemic”

AUTORI

ABSTRACT

Impact on laboratory medicine of transitioning from COVID-19 pandemic to “tripledemic”

It has now become clear that SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) will remain among us for long time, becoming a “harmingly” endemic infectious disease. Although virulence and pathogenicity have gradually decreased over time, the infectivity has instead increased after the emergence of new sublineages belonging to Omicron family, so that the volume of tests that need to be performed for diagnosing and monitoring coronavirus disease 2019 (COVID-19) remains paramount. The situation has become even more complicated after resurgence of other infectious respiratory diseases, namely Influenza and Respiratory Syncytial Virus (RSV), which are now responsible for an unprecedented “tripledemic”. In this catastrophic scenario, laboratory medicine needs to be proactive and timely adapt to the new challenge. Further development and implementation of SARS-CoV-2 antigen rapid diagnostic testing (Ag-RDT) will play a crucial role in the future, especially encompassing devices that will enable to confirm (or rule out) more infectious diseases at the same time (i.e., COVID-19, Influenza and RSV). Considering that the clinical phenotypes of the three viruses is overlapping, new diagnostic tests designed for simultaneous assessment of multiple viruses within a single Ag-RDT device represent a valuable option for achieving a rapid differential diagnosis between different respiratory infections, or even for diagnosing multiple concomitant infections. A novel strategy could hence be profiled, entailing the screening by means of combined Ag-RDT of all subjects whose infective status may jeopardize their own health as well as the health of other people.

INTRODUCTION
More than three years after the first official case of coronavirus disease 2019 (COVID-19) has been diagnosed in November 2019, the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic is still among us, with magnified infectivity but lower virulence and pathogenicity (1). The ongoing transition from a pandemic to a virtually endemic disease is being accompanied by substantial implications for society and healthcare, thus including laboratory medicine. As specifically concerns the entire healthcare, future health policies based on managing COVID-19 would need to specifically address preventive and safety measures, isolation, vaccination, therapeutic management of acute infections, coupled with rehabilitation and clinical management of subjects with long-COVID (2), as well as delivery of extra care to those who will experience an increased burden of chronic diseases caused by the lower availability of screening, primary care and diagnostics since this pandemic has begun (3).
As specifically concerns laboratory medicine, the volume of tests that need to be performed every day for diagnosing and monitoring COVID-19 is paramount. The FIND initiative estimates that the number of daily diagnoses of SARS-CoV-2 infection is still as high as 39.1 million on worldwide scale, with nearly 150 thousand of these performed in Italy (4). These figures mirror the challenges that laboratory medicine is facing to maintain timely and accurate responsiveness to the huge demand of COVID-19 diagnostic tests, leading the way to design and implement new strategies encompassing different forms of decentralized testing by means of point-of-care and, especially, rapid diagnostic tests, mostly including fast SARS-CoV-2 antigen(s) detection with lateral flow immunoassays (LFI). Diagnostic strategies, entailing the use of SARS-CoV-2 Antigen Rapid Diagnostic Testing (Ag-RDT) has recently been legitimized by both the World Health Organization (WHO) (5) and the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) (6), thus making rapid decentralized testing an essential driver of future diagnostic scenarios.

SARS-CoV-2 IMMUNOASSAYS

State-of-the-art

The massive diffusion that SARS-CoV-2 Ag-RDT has achieved at the end of 2022 is undeniable. As evidenced by the statistics of the FIND initiative (7), the largest part of SARS-CoV-2 diagnostic testing in Italy at the end of the year 2022 has been conducted with Ag-RDT (129329/156173; 82.8%), with a frequency that has increased by over 5-fold (odds ratio: 5.01; 95%CI, 4.99-5.15) over July 2021 (i.e., 93187/191298; 48.7%) when FIND monitoring has commenced. As concerns the global market (8), FIND data shows that antigen immunoassays that have been cleared for clinical use by national or international regulatory agencies have largely offset molecular tests (i.e., 795/1277; 62.3%), with the vast majority of these immunoassays now available as Ag-RDT (748/795; 94.1%), followed by cartridge-based immunoassays (12/795; 1.5%), laboratory-based immunoassays (11/795; 1.4%) and other formats (24/795; 3.0%). Notably, 18% (i.e., 143/795) of all such tests are licensed for self-usage. A large number of these tests (i.e., over 60) is also available in Italy, as reported by the Emilia-Romagna Health Agency in its regularly updated website (9). Importantly, a market analysis released by the Grand View Research reports that the market size value for COVID-19 diagnostic testing has been as high as 95.2 billion US$ in 2022, but will display a negative compound annual growth rate (CAGR) of -7.7% between 2020-2030 (10). Nonetheless, although the number of COVID-19 cases that would need testing may probably decline in the future, the global diagnostic market will still grow in the coming years due to a predictable increase in the epidemiologic burden of other infectious respiratory diseases, that would need additional efforts in a challenging process of differential diagnosis.

Clinical implications

The first and foremost issue that would need to be addressed is, certainly, the diagnostic accuracy achieved by the current SARS-CoV-2 diagnostic tests. As shown in Figure 1, the higher cost of molecular tests is compounded by a considerably higher diagnostic accuracy, as revealed by a recent meta-analysis which evaluated 25 different SARS-CoV-2 RNA RT-PCR assays and concluded that the cumulative diagnostic sensitivity of this technique is as high as 89.0% (95%CI,
85.4-91.8%) (11). The cost per test of laboratory-based SARS-CoV-2 Ag immunoassays is lower, but compounded by an inferior cumulative diagnostic sensitivity (73%; 95%CI, 72-74%), as also shown in Figure 1 (12).
Finally, the raw expenditure per test of Ag-RDTs is indeed the lowest, as it is their cumulative diagnostic sensitivity (i.e., 68.9%; 95%CI, 66.0-71.7%) according to the recent meta-analysis published by the Cochrane COVID-19 Diagnostic Test Accuracy Group, including over 200 individual studies (Figure 1) (13).
On this preamble, the unfoundedness of the former assumption that positivity at molecular testing will always reflect an acute (ongoing) SARS-CoV-2 infection has been now convincingly demonstrated. Several studies showed that detection of SARS-CoV-2 RNA could be longer than the real infectivity, since the last period of viral RNA shedding is almost entirely sustained by elimination of extra-viral genetic material or non-vital particles (14,15). Contrarily, several lines of evidence convincingly demonstrate that negativity of clinically validated
SARS-CoV-2 Ag-RDT closely reflects the negativity of viral cultures (16). In particular, the outcome of the recent meta-analysis of Parvu et al. has allowed to conclude that the diagnostic sensitivity of SARS-CoV-2 Ag-RDT was as high as 90% (95%CI, 84-94%) for positive viral cultures, thus not so far from the value observed for RT-PCR (i.e., 99%; 95%CI, 96-100%) (17). It can hence be inferred that the lower cumulative sensitivity of Ag-RDT may turn out to be a relative advantage in terms of identifying people with higher viral load in respiratory samples (Figure 2), who incidentally are those more likely to propagate the infection (≈80% of secondary infections are triggered by the so-called “superspreaders”) and/or experience a worse short- and long-term (i.e., long-COVID) clinical outcome (18). Likewise, designing and lifting healthcare policies according to results of Ag-RDT has been confirmed as a safe and plausible strategy for averting the many social and economic consequences caused by prolonged (and hence mostly avoidable) isolation and/or quarantine (19,20).

Economic implications

In a world with limited resources, which has not so far recovered from the direct and indirect economic consequences of the COVID-19 pandemic (21), whatever population-based strategy will be proposed for managing the infection must be sufficiently affordable and sustainable from an economic perspective. The cost of SARS-CoV-2 Ag-RDT is relatively limited compared to other diagnostic tests, as shown in Figure 1, thus paving the way to its appropriate usage within integrated care models.
The fact that diagnostic algorithms entailing SARS-CoV-2 antigen testing may be cost-effective has been demonstrated in several studies, some of which will be presented and discussed here. Diel et al. evidenced the favorable cost-benefit ratio linked to the introduction of point-of-care COVID-19 rapid antigen testing at emergency room admission, in Germany (22).
In their analysis, the authors concluded that performing SARS-CoV-2 rapid antigen testing in emergency departments could be associated with an over 220 US$ saving per patient compared to a clinical-judgement-only policy. The largest part of cost savings was attributable to the over 20-fold reduction of unnecessary bed occupation during the first days of hospitalization. In another simulation, on a larger scale, Paltiel et al. estimated the economic revenue of widespread implementation of a home-based SARS-CoV-2 Ag-RDT program (23). In their analysis, the authors concluded that availability of Ag-RDTs may save as many as 2.8 million SARS-CoV-2 infections and 15700 COVID-19-related deaths. Such benefits would be reached at the expense of over 22 billion dollars more, but will yield an incremental cost-effectiveness ratio of 7890 US$ per infection and 430000 US$ per death averted, respectively. Thus, the justifiable cost of a nationwide SARS-CoV-2 screening campaign supports its possible inclusion within widespread containment strategies, especially when the circulation of the virus is larger.
Another interesting analysis has been published at the end of 2022 by Dolatshahi et al. (24), who carried out an economic comparison of various laboratory techniques for diagnosing SARS-CoV-2, and concluded that
SARS-CoV-2 antigen screening in settings with low COVID-19 prevalence was more cost-effective than RT-PCR due to the modestly increased health gains combined with the considerably higher net cost of the latter technique. Another interesting analysis has then been published by Vilches et al. (25), who concluded that twice weekly workplace screening with SARS-CoV-2 Ag-RDT early during a surge and without a confirmatory RT-PCR test may be the best strategy for detecting asymptomatic infections within workplaces.

Acceptability

Poor compliance is one of the more (perhaps the most) important drawbacks in implementing widespread policies of SARS-CoV-2 screening. The acceptability of travelling to healthcare facilities, medical laboratories or testing centers (e.g, drive-in) is a primary reason of under-testing, together with the fear and anxiety for being subjected to a discomforting procedure during collection of nasopharyngeal samples (26). Thus, implementation of self-testing by means of rapid and less invasive SARS-CoV-2 Ag-RDT (e.g., needing only anterior nasal swabs) represent an attractive option for adults and (especially) children. The use of saliva with Ag-RDTs has been discouraged so far because of their low sensitivity (always below 50%) on this biological material. These tests have not been developed, neither certified, for this use, so that the development of novel SARS-CoV-2 Ag immunoassays especially suited for being used in saliva represents a valuable perspective.
To this end, Dallera et al. recently reported the outcome of a study aimed at establishing feasibility, acceptability and impact on decision making of a protocol encompassing professionally witnessed videoed
SARS-CoV-2 Ag-RDT self-screening before attending live mass gatherings held at full capacity (3). This survey revealed that over 80% of participants found the home-based screening convenient, nearly 74% found it economically affordable, 85% declared to have been more confident to attend the event knowing that all participants underwent pre-event testing and, finally, the vast majority of participants (up to 98% and 76%, respectively) concluded that they were sufficiently aware of the clinical implications of the rapid test and that they would recommend this strategy to others.

FUTURE STRATEGIES

It is now becoming straightforwardly clear that

SARS-CoV-2 will remain among us for quite a long time, thus becoming a “harmingly” endemic disease. Neither the recent development and administration of a new generation of COVID-19 vaccines (i.e., the so-called “bivalent” vaccines, developed for more specifically targeting the new Omicron sublineages) seems sufficient to slow the almost unstoppable emergence and surge of new recombinant variants such BQ.1.5 and XBB.1, against which the efficacy of former strains and bivalent vaccination appear already limited (27).
Thus, despite a predictable decline in the overall CAGR, the demand for SARS-CoV-2 diagnostics is expected to propel further in the foreseeable future, prevalently sustained by the segment of cheaper and faster immunoassays, which is forecast to grow at a very fast rate (i.e., CAGR of 6.1%) due low cost, widespread availability and major convenience. Importantly, Grand View Research proffers that the development of portable and/or on-site diagnostic tests is the factor that will play the most prominent role in propelling COVID-19 diagnostics, encompassing especially devices that will enable to confirm (or rule out) more infectious diseases at the same time (10). To this end, is seems reasonable to assume that the market forecast of the Grand View Research have already become real at the end of 2022. Along with COVID-19, the sinister development of a triple epidemic (provocatively called “tripledemic”) in the northern hemisphere, sustained by three concomitant “waves” of SARS-CoV-2, Influenza virus and RSV, sharing molecular and biological characteristics (Table 1), is now jeopardizing the responsiveness of many healthcare (especially pediatric) facilities (28,29). Thus, considering that the clinical phenotypes of the three viruses is frequently overlapping (Table 1), new diagnostic options are already compellingly needed, designed for simultaneous assessment of multiple viruses within a single Ag-RDT device, according to a test format reproducing that of other commercial tests which already enable triple molecular detection of the three viruses (i.e., multiplex for combined Influenza A/B, RSV and SARS-CoV-2 assessment), and which have so far displayed optimal diagnostic performance in real life scenarios (30,31). Provided that pre-analytical issues will not impair the diagnostic performance (32), and that the clinical performance of these innovative “combined” Ag-RDTs will be aligned to that of other “single” Ag-RDT (the role of laboratory validation and monitoring of variant-specific diagnostic performance will be crucial here), their adoption may thus enable to achieve a rapid differential diagnosis between respiratory infections caused by different pathogens or even for diagnosing double (or even triple) concomitant infections, which are associated with a more severe clinical phenotype, as recently underpinned by the meta-analysis published by Cong et al. (33).
A novel strategy could hence be established and implemented, entailing the screening by means of combined (e.g., “triple”) Ag-RDT of all subjects whose infective status may jeopardize their own health as well as the health of other people (Figure 3).
This type of testing could be addressed as home-testing to all symptomatic patients (especially those manifesting respiratory symptoms which have now become the hallmarks of SARS-CoV-2 Omicron infection) (34) (Table 1), those who are likely to be in near contact with vulnerable persons (older, immunocompromised, frail, bearing chronic medical conditions), before hospital admission or participation to mass gatherings, and in whatever other situation characterized by enhanced risk of contagion (e.g., prolonged permanence in close and crowded environments without using physical protective measures). In all these circumstances, the diagnosis of whatever (even multiple) infection between
SARS-CoV-2, Influenza or RSV would be important, since the virulence and the potential unfavorable clinical impact of all these viruses in specific fragile populations is similarly high (35), and may hence allow to optimize healthcare resource needs and care pathways accordingly (36). To this end, further studies are compellingly needed to define the cost-effectiveness of this intriguing strategy.

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