BMC Infectious Diseases (Feb 2021)

Stringent thresholds in SARS-CoV-2 IgG assays lead to under-detection of mild infections

  • David W. Eyre,
  • Sheila F. Lumley,
  • Denise O’Donnell,
  • Nicole E. Stoesser,
  • Philippa C. Matthews,
  • Alison Howarth,
  • Stephanie B. Hatch,
  • Brian D. Marsden,
  • Stuart Cox,
  • Tim James,
  • Richard J. Cornall,
  • David I. Stuart,
  • Gavin Screaton,
  • Daniel Ebner,
  • Derrick W. Crook,
  • Christopher P. Conlon,
  • Katie Jeffery,
  • Timothy M. Walker,
  • Timothy E. A. Peto

DOI
https://doi.org/10.1186/s12879-021-05878-2
Journal volume & issue
Vol. 21, no. 1
pp. 1 – 10

Abstract

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Abstract Background Thresholds for SARS-CoV-2 antibody assays have typically been determined using samples from symptomatic, often hospitalised, patients. In this setting the sensitivity and specificity of the best performing assays can both exceed 98%. However, antibody assay performance following mild infection is less clear. Methods We assessed quantitative IgG responses in a cohort of healthcare workers in Oxford, UK, with a high pre-test probability of Covid-19, in particular the 991/11,475(8.6%) who reported loss of smell/taste. We use anosmia/ageusia and other risk factors as probes for Covid-19 infection potentially undiagnosed by immunoassays by investigating their relationship with antibody readings either side of assay thresholds. Results The proportion of healthcare workers reporting anosmia/ageusia increased at antibody readings below diagnostic thresholds using an in-house ELISA (n = 9324) and the Abbott Architect chemiluminescent microparticle immunoassay (CMIA; n = 11,324): 426/906 (47%) reported anosmia/ageusia with a positive ELISA, 59/449 (13.1%) with high-negative and 326/7969 (4.1%) with low-negative readings. Similarly, by CMIA, 518/1093 (47.4%) with a positive result reported anosmia/ageusia, 106/686 (15.5%) with a high-negative and 358/9563 (3.7%) with a low-negative result. Adjusting for the proportion of staff reporting anosmia/ageusia suggests the sensitivity of both assays in mild infection is lower than previously reported: Oxford ELISA 89.8% (95%CI 86.6–92.8%) and Abbott CMIA 79.3% (75.9–82.7%). Conclusion Following mild SARS-CoV-2 infection 10–30% of individuals may have negative immunoassay results. While lowered diagnostic thresholds may result in unacceptable specificity, our findings have implications for epidemiological analyses and result interpretation in individuals with a high pre-test probability. Samples from mild PCR-confirmed infections should be included in SARS-CoV-2 immunoassay evaluations.

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