Serological testing to manage COVID-19

ABSTRACT

The natural history of serological assays for SARS-CoV2 antibodies is comparable to that of other biomarkers After an initial and excessive emphasis on the diagnostic role of serological assays, a series of papers raised serious concerns on their clinical usefulness, finally leading to a more rational and evidence-based identification of the main areas of clinical use, linked to a better methodological validation. The multifaced rationale for serological testing in COVID-19 management should be summarized as follows A) to improve knowledge on immunoresponse to SARS-CoV-2;b) to define and monitor the extent of virus spread;c) to screen particular populations and sub-populations at higher risk (e.g. healthcare workers) and define disease prevalence;d) to characterize efficacy of containment measures at local and global level;e) to screen convalescent sera for both therapeutic and prophylactic use;f) to combine the results of molecular tests (rRT-PCR) for a more accurate diagnosis (in "difficult patients") ;g) to allow the diagnosis for later stages of infection (when the virus has been eliminated);and finally h) to identify individuals who have been infected but suffered only minor suymptoms (or asymptomatics) and did not seek medical attention. From a methodological view point, the main issues are represented by the type of test (laboratory-based, pointof-care and/or neutralizing activity);the target (spike protein and/or S1/S2 subunits, nucleocapside, receptor binding protein, native antigen etc), and the immunoglobulin class or classes (IgA, IgG, IgM) recognized by the assay. Testing strategies aim to maximize specificity and thus positive predictive value (PPV), particularly as the overall prevalence is likely low;they should be summarized as 1) Choosing a test with a very high specificity (95% or greater);2) Focus testing with a high pre-test probability (e.g. history of COVID-19 illness) and 3) Employ an orthogonal testing algorithm (positive persons tested with a second test). The standardization/harmonization initiatives to improve the clinical comparability of results obtained by different assays are currently based on the optimization of the diagnostic thresholds (cut-offs), and the definition of the predictive positive and negative values (PPV/NPV) in relation to a different disease prevalence. In fact, epidemiological surveys have highlighted significant variations in seroprevalence ranging from 2-3% to 40-50% in different regional or national areas. The knowledge of antibody kinetics represents an essential issue to define the right timing for identifying the immune response and to better understand the duration of protection. This, in turn, plays a relevant role in evaluating the answer to therapies and vaccines, even if current research on the immunoresponse due to B and T lymphocytes may provide useful information for better understanding the host response to the "misterious" SARS-CoV-2 virus.