Stringent thresholds in SARS-CoV-2 IgG assays lead to under-detection of mild infections
<br><strong>Background<br></strong> 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%. Howeve...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
BioMed Central
2021
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| _version_ | 1797096700199829504 |
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| author | Eyre, DW Lumley, SF O'Donnell, D Stoesser, NE Matthews, PC Howarth, A Hatch, SB Marsden, BD Cox, S James, T Cornall, RJ Stuart, DI Screaton, G Ebner, D Crook, DW Conlon, CP Jeffery, K Walker, TM Peto, TEA |
| author_facet | Eyre, DW Lumley, SF O'Donnell, D Stoesser, NE Matthews, PC Howarth, A Hatch, SB Marsden, BD Cox, S James, T Cornall, RJ Stuart, DI Screaton, G Ebner, D Crook, DW Conlon, CP Jeffery, K Walker, TM Peto, TEA |
| author_sort | Eyre, DW |
| collection | OXFORD |
| description | <br><strong>Background<br></strong>
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.
<br><strong>
Methods<br></strong>
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.
<br><strong>
Results<br></strong>
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%).
<br><strong>
Conclusion<br></strong>
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. |
| first_indexed | 2024-03-07T04:45:16Z |
| format | Journal article |
| id | oxford-uuid:d3073cd0-c3fb-450a-a764-d3d7ee484e5d |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T04:45:16Z |
| publishDate | 2021 |
| publisher | BioMed Central |
| record_format | dspace |
| spelling | oxford-uuid:d3073cd0-c3fb-450a-a764-d3d7ee484e5d2022-03-27T08:08:36ZStringent thresholds in SARS-CoV-2 IgG assays lead to under-detection of mild infectionsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:d3073cd0-c3fb-450a-a764-d3d7ee484e5dEnglishSymplectic ElementsBioMed Central2021Eyre, DWLumley, SFO'Donnell, DStoesser, NEMatthews, PCHowarth, AHatch, SBMarsden, BDCox, SJames, TCornall, RJStuart, DIScreaton, GEbner, DCrook, DWConlon, CPJeffery, KWalker, TMPeto, TEA<br><strong>Background<br></strong> 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. <br><strong> Methods<br></strong> 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. <br><strong> Results<br></strong> 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%). <br><strong> Conclusion<br></strong> 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. |
| spellingShingle | Eyre, DW Lumley, SF O'Donnell, D Stoesser, NE Matthews, PC Howarth, A Hatch, SB Marsden, BD Cox, S James, T Cornall, RJ Stuart, DI Screaton, G Ebner, D Crook, DW Conlon, CP Jeffery, K Walker, TM Peto, TEA Stringent thresholds in SARS-CoV-2 IgG assays lead to under-detection of mild infections |
| title | Stringent thresholds in SARS-CoV-2 IgG assays lead to under-detection of mild infections |
| title_full | Stringent thresholds in SARS-CoV-2 IgG assays lead to under-detection of mild infections |
| title_fullStr | Stringent thresholds in SARS-CoV-2 IgG assays lead to under-detection of mild infections |
| title_full_unstemmed | Stringent thresholds in SARS-CoV-2 IgG assays lead to under-detection of mild infections |
| title_short | Stringent thresholds in SARS-CoV-2 IgG assays lead to under-detection of mild infections |
| title_sort | stringent thresholds in sars cov 2 igg assays lead to under detection of mild infections |
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