Diagnostic performances and thresholds: The key to harmonization in serological SARS-CoV-2 assays?

Plebani, Mario; Padoan, Andrea; Negrini, Davide; Carpinteri, Benedetta; Sciacovelli, Laura

doi:10.1016/j.cca.2020.05.050

Cited by 103 publications

(90 citation statements)

References 14 publications

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“…Clinical performances were elevated, especially for IgG assay while IgM presents a lower diagnostic accuracy, confirming previously reported results with other immunoassays [2,4]. Clinical performances in terms of both AUROC and sensitivities were also very elevated, especially after 12 days post symptom onset.…”

Section: Time Kinetics Of Igm and Iggsupporting

confidence: 87%

“…There are several reasons to measure SARS-CoV-2 antibodies. First, to better understand the immune response to the virus as well as the kinetics and longevity of antibody response [2][3][4]. Second, COVID-19 convalescent plasma is one of the available treatment option and it is necessary to characterize the antibody response of each individual before accepting her/his for plasma donation [5].…”

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confidence: 99%

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Analytical and diagnostic performances of a high-throughput immunoassay for SARS-CoV-2 IgM and IgG

Padoan

Cosma

Zaupa

et al. 2020

Preprint

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BackgroundAbstractReliable SARS-CoV-2 serological assays are required for diagnosing infections, for the serosurveillance of past exposures and for assessing the response to future vaccines. In this study, the analytical and clinical performances of a chemiluminescent immunoassays for SARS-CoV-2 IgM and IgG detection (Mindray CL-1200i), targeting Nucleocapsid (N) and receptor binding domain (RBD) portion of the Spike protein, were evaluated.MethodsPrecision and linearity were evaluated using standardized procedures. A total of 157 leftover serum samples from 81 hospitalized confirmed COVID-19 patients (38 with moderate and 43 with severe disease) and 76 SARS-CoV-2 negative subjects (44 healthcare workers, 20 individuals with rheumatic disorders, 12 pregnant women) were included in the study. In an additional series of 44 SARS-CoV-2 positive, IgM and IgG time kinetics were also evaluated in a time-period of 38 days.ResultsPrecision was below or equal to 4% for both IgM and IgG, in all the studied levels, whilst a slightly significant deviation from linearity was observed for both assays in the range of values covering the manufacturer’s cut-off. Considering a time frame ≥ 12 days post symptom onset, sensitivity and specificity for IgM were 92.3% (95%CI:79.1%-98.4%) and 92.1% (95%CI:83.6%-97.0%). In the same time frame, sensitivity and specificity for IgG were 100% (95%CI:91.0%-100%) and 93.4% (95%CI:85.3%-97.8%). The assays agreement was 73.9% (Cohen’s kappa of 0.373). Time kinetics showed a substantial overlapping of IgM and IgG response, the latter values being elevated up to 38 days from symptoms onset.ConclusionsAnalytical imprecision is satisfactory as well as the linearity, particularly when taking into account the fact that both assays are claimed to be qualitative. Diagnostic sensitivity of IgG was excellent, especially considering specimens collected ≥12 days post symptom onset. Time kinetics suggest that IgM and IgG are detectable early in the course of infection, but the role of SARS-CoV-2 antibodies in clinical practice still requires further evaluations.

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Section: Time Kinetics Of Igm and Iggsupporting

confidence: 87%

mentioning

confidence: 99%

Analytical and diagnostic performances of a high-throughput immunoassay for SARS-CoV-2 IgM and IgG

Padoan

Cosma

Zaupa

et al. 2020

Preprint

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“…To the best of our knowledge, this is the first paper to describe this novel assay in a large validation study. We found that the diagnostic accuracy of the pan-SARS-CoV-2 S1-RBD Ig assay is comparable to other anti-spike protein assays determining specific IgG, with the latter assays also having been found to have similar diagnostic accuracies in other studies [30,31]. However, the evaluated assay was substantially better than the diagnostic accuracy found for SARS-CoV-2 S1 IgA, which is in agreement with the consensus that IgA should not be used in routine serological analyses to detect evidence of past SARS-CoV-2 infection [32].…”

Section: Discussionsupporting

confidence: 75%

Characterization of a Pan-Immunoglobulin Assay Quantifying Antibodies Directed against the Receptor Binding Domain of the SARS-CoV-2 S1-Subunit of the Spike Protein: A Population-Based Study

Schaffner

Risch

Aeschbacher

et al. 2020

JCM

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Pan-immunoglobulin assays can simultaneously detect IgG, IgM and IgA directed against the receptor binding domain (RBD) of the S1 subunit of the spike protein (S) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 S1-RBD Ig). In this work, we aim to evaluate a quantitative SARS-CoV-2 S1-RBD Ig electrochemiluminescence immunoassay (ECLIA) regarding analytical, diagnostic, operational and clinical characteristics. Our work takes the form of a population-based study in the principality of Liechtenstein, including 125 cases with clinically well-described and laboratory confirmed SARS-CoV-2 infection and 1159 individuals without evidence of coronavirus disease 2019 (COVID-19). SARS-CoV-2 cases were tested for antibodies in sera taken with a median of 48 days (interquartile range, IQR, 43–52) and 139 days (IQR, 129–144) after symptom onset. Sera were also tested with other assays targeting antibodies against non-RBD-S1 and -S1/S2 epitopes. Sensitivity was 97.6% (95% confidence interval, CI, 93.2–99.1), whereas specificity was 99.8% (95% CI, 99.4–99.9). Antibody levels linearly decreased from hospitalized patients to symptomatic outpatients and SARS-CoV-2 infection without symptoms (p < 0.001). Among cases with SARS-CoV-2 infection, smokers had lower antibody levels than non-smokers (p = 0.04), and patients with fever had higher antibody levels than patients without fever (p = 0.001). Pan-SARS-CoV-2 S1-RBD Ig in SARS-CoV-2 infection cases significantly increased from first to second follow-up (p < 0.001). A substantial proportion of individuals without evidence of past SARS-CoV-2 infection displayed non-S1-RBD antibody reactivities (248/1159, i.e., 21.4%, 95% CI, 19.1–23.4). In conclusion, a quantitative SARS-CoV-2 S1-RBD Ig assay offers favorable and sustained assay characteristics allowing the determination of quantitative associations between clinical characteristics (e.g., disease severity, smoking or fever) and antibody levels. The assay could also help to identify individuals with antibodies of non-S1-RBD specificity with potential clinical cross-reactivity to SARS-CoV-2.

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“…In this context, more and more independent validations of serological tests are published by analyzing the same sample of sera against different techniques but also very often with different antibody targets. [6][7][8][9][10][11][12] The main objective of our study is to assess and compare the analytical and clinical performance of two ELISA tests detecting anti-…”

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confidence: 99%

Analytical and clinical validation of an ELISA for specific SARS‐CoV‐2 IgG, IgA, and IgM antibodies

Tré-Hardy

Wilmet

Beukinga

et al. 2020

Journal of Medical Virology

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The development of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) serological tests is massive. The external validation of their performance is needed before use in clinical routine practice. Our study aims at assessing the analytical and clinical performance of two enzyme‐linked immunosorbent assay tests detecting antibodies directed against the virus nucleocapsid protein: The NovaLisa SARS‐CoV‐2 immunoglobulin G (IgG), immunoglobulin A (IgA), and immunoglobulin M (IgM) test (NovaTec) allowing a separate detection of each antibody and the Platelia SARS‐CoV‐2 Total Ab test (Bio‐Rad) detecting total antibodies (IgM, IgA, and IgG). Two‐hundred and eight coronavirus disease 2019 samples from 48 quantitative reverse transcription‐polymerase chain reaction (RT‐qPCR) confirmed patients were used to perform the sensitivity analysis. Non‐SARS‐CoV‐2 sera (n = 79) with a potential cross‐reaction to SARS‐CoV‐2 immunoassays were included in the specificity analysis. In addition, using receiver operator characteristic curves, adapted cut‐off for improvement of the performances were proposed. The kinetics of these antibodies was also assessed over 8 weeks. Two weeks after the RT‐qPCR positive detection, the NovaLisa test shows a sensitivity and specificity of 94.9% (95% confidence interval [CI]: 83.1%‐98.6%) and 96.2% (95% CI: 89.4%‐98.7%) for IgG, of 89.7% (95% CI: 76.4%‐95.9%) and 98.7% (95% CI: 93.2%‐98.8%) for IgA, and of 48.7% (95% CI: 33.9%‐63.8%) and 98.7% (95% CI: 93.2%‐99.8%) for IgM. With the Platelia system, the specificity and sensitivity were 97.4% (95% CI: 92.1%‐99.7%) and 94.9% (95% CI: 87.7%‐98.0%) for total antibodies using the adapted cut‐offs. The NovaLisa and the Platelia tests have satisfactory analytical performances. The clinical performances are excellent for IgG, IgA, and total antibodies especially if the cut‐off is optimized.

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Diagnostic performances and thresholds: The key to harmonization in serological SARS-CoV-2 assays?

Cited by 103 publications

References 14 publications

Analytical and diagnostic performances of a high-throughput immunoassay for SARS-CoV-2 IgM and IgG

Analytical and diagnostic performances of a high-throughput immunoassay for SARS-CoV-2 IgM and IgG

Characterization of a Pan-Immunoglobulin Assay Quantifying Antibodies Directed against the Receptor Binding Domain of the SARS-CoV-2 S1-Subunit of the Spike Protein: A Population-Based Study

Analytical and clinical validation of an ELISA for specific SARS‐CoV‐2 IgG, IgA, and IgM antibodies

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