David W Eyre1,2,3,4,5, Sheila F Lumley6,7, Denise O'Donnell7, Nicole E Stoesser6,8,9,7, Philippa C Matthews6,8,7, Alison Howarth7, Stephanie B Hatch7, Brian D Marsden7,10, Stuart Cox6, Tim James6, Richard J Cornall7, David I Stuart7, Gavin Screaton7, Daniel Ebner7,11, Derrick W Crook6,8,7, Christopher P Conlon6,7, Katie Jeffery6, Timothy M Walker6,7,12, Timothy E A Peto6,8,7. 1. Big Data Institute, Nuffield Department of Population Health, University of Oxford, Oxford, UK. david.eyre@bdi.ox.ac.uk. 2. Oxford University Hospitals NHS Foundation Trust, Oxford, UK. david.eyre@bdi.ox.ac.uk. 3. NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK. david.eyre@bdi.ox.ac.uk. 4. NIHR Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance at University of Oxford in partnership with Public Health England, Oxford, UK. david.eyre@bdi.ox.ac.uk. 5. Microbiology Department, John Radcliffe Hospital, Headley Way, Oxford, OX3 9DU, UK. david.eyre@bdi.ox.ac.uk. 6. Oxford University Hospitals NHS Foundation Trust, Oxford, UK. 7. Nuffield Department of Medicine, University of Oxford, Oxford, UK. 8. NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK. 9. NIHR Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance at University of Oxford in partnership with Public Health England, Oxford, UK. 10. Kennedy Institute of Rheumatology Research, University of Oxford, Oxford, UK. 11. Target Discovery Institute, University of Oxford, Oxford, UK. 12. Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
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.
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-19infection 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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