Governance Organization

AMO – Academic Medical Organization of Southwestern Ontario

Project Title

AMO-21-003 – Improving diagnostic and epidemiologic detection of SARS-CoV-2; A Validation Study

Project Highlights

Over 18 months since the onset of the COVID-19 pandemic, as cases of COVID-19 continue to spread worldwide there remains a strong need for rapid, readily available diagnostic testing for SARS-CoV-2 infection. Detection of viral RNA by nucleic acid amplification testing (NAAT) remains the gold standard for diagnosis of SARS-CoV-2 infection but is limited by high cost and other factors, particularly in resource-constrained settings. Whether serology-based assays can be effectively incorporated into a diagnostic algorithm remains to be determined. In this project we aimed to develop a serology-based testing algorithm for SARS-CoV-2 infection.

The initial performance characteristics of immunoassays evaluated the agreement, sensitivity, and specificity of five commercial immunoenzymatic serology assays testing for different antibody isotypes at the cut-off points established by the manufacturers. The initial study allowed the development of the diagnostic algorithm. In the second part of the study, we included symptomatic unvaccinated patients evaluated in the Emergency Department of the London Health Sciences Centre for suspected SARS-CoV-2, and who had NAAT testing by real-time Reverse Transcription Polymerase Chain Reaction. The performance of the five immunoenzymatic assays was evaluated in a derivation cohort and in which optimal cut-off points were determined using receiver operating characteristic (ROC) curves and further tested using logistic regression. The assay with the best performance was further tested on the validation cohort using the modified cut-off points.

The initial study included samples from 366 individuals and was conducted by the working team in the Department of Pathology and Laboratory Medicine. That study allowed to establish the general characteristics under routine testing for the 5 assays. Subsequently, the derivation and validation cohorts included 72 and 319 patients, respectively. Based on its initial performance in the derivation cohort, the Elecsys Anti-SARS-CoV-2 assay (Roche Diagnostics) was further tested in the validation cohort. Using ROC curve analysis, we determined optimal cut-off points at which the negative predictive value (NPV) of the test was best. Such points were lower than those recommended by the manufacturer. The analysis showed that at any given cut-off point the NPV was over 97% assuming a prevalence of positive tests in the population of 5%.

Our findings suggest that by lowering the manufacturers’ recommended cut-off values for commercially available anti-SARS-CoV-2 antibodies serology we can accurately predict negative NAAT testing in unvaccinated symptomatic patients presenting to the ED. This serology-based diagnostic algorithm offers a novel and lower cost alternative to universal NAAT testing, in addition to rapid turnaround times to enable efficient triage, clinical management and infection control. Such an algorithm could be used to facilitate more judicious use of NAAT-based testing, contributing to more effective utilization of hospital resources, minimize healthcare worker exposure risk and nosocomial spread. The proposed approach has the additional advantage of using enzymatic methods that are standard for multiple applications in medicine and are widely available. In addition to a valuable tool for clinicians, an algorithm may find widespread application given the limited availability of NAAT-based testing especially in resource-constrained areas, in which NAAT testing may not be available, or the turn-around time for the results may be delayed by several days. Although this strategy only applies to unvaccinated individuals, as vaccination coverage increases, the performance of this method is yet to be determined but given the large disparities observed in many countries we believe that it still has a valuable place in clinical practice.

Based on our findings we believe that although lowering the threshold of the serology tests will not help to identify SARS-CoV2 positive symptomatic patients, it can help to identify negative ones. Our study suggests that an initial diagnostic strategy using the Elecsys Anti-SARS-CoV-2 serology test in symptomatic unvaccinated patients could help to rule out an acute SARS-CoV2 infection and potentially lead to appropriately tailored infection control measures or rational guidance for further testing with a potential cost reduction and increased availability.


Methods of Risk Reduction and Mitigation

Primary Project Lead for Contact

Dr. Alejandro Lazo-Langner


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