Anti-Rubella Immunoglobulin G Proficiency Testing Results Suggest Consistent Manufacturer Differences and Opportunity for Harmonization

To the Editor.—Congenital rubella can cause significant morbidity and mortality but is rare in countries with vaccination and immune status verification programs. Testing for anti–rubella virus immunoglobulin G (IgG) and vaccinating potentially susceptible individuals are routine in preconception and prenatal care. Most quantitative anti-rubella IgG immunoassays have been calibrated to an international standard with a suggested cutoff for inference of protective immunity at 10 IU/mL.¹  However, variable results for specimens tested with different assays have been reported,^2,3  although the extent to which imprecision and laboratory-specific practices contribute to the suggested poor interassay agreement is unclear.

We assessed the current state of interassay and interlaboratory anti-rubella immunoassay performance by leveraging anti-rubella IgG results from proficiency testing (PT) Diagnostic Immunology S surveys conducted by the College of American Pathologists. Between 454 and 626 laboratories reported quantitative anti-rubella IgG results for each of the 26 positive samples sent from 2020 to 2022. We compared mean anti-rubella IgG values across the 13 reported platforms from 8 different manufacturers (Figure, A). Between platforms, large differences in the reported means for each sample were observed; for example, those for sample 5 ranged from 22 to 264 IU/mL. These results demonstrate lack of harmonization between assays that are nevertheless reported in standardized units.

Despite large differences in manufacturer-specific mean values for each sample, 2 Siemens and 2 Roche platforms consistently reported the highest results for all 26 samples (Figure, A, red and blue). In some cases, Siemens and Roche values differed from the other assays by almost one order of magnitude. This suggests that differences between manufacturers are consistent over time and may be a major contributor to lack of harmonization, which could potentially be addressed by manufacturer-specific recalibration.

Although the magnitude of a positive rubella IgG result above the 10 IU/mL cutoff does not affect clinical management, interassay variability could impact result interpretation for samples with values near this cutoff. The 2023 S-A PT survey included one specimen (RUB-04) with a participant mean anti-rubella IgG value near the 10 IU/mL cutoff. Individual RUB-04 values demonstrated good interlaboratory agreement for laboratories using assays from the same manufacturer (Figure, B). For most manufacturers, anti-rubella IgG values were below 10 IU/mL. However, results from Roche assays straddled the positivity threshold, whereas those from Siemens platforms ranged from 61 to 120 IU/mL. Thus, the consistently high Roche and Siemens results observed in strongly positive samples (Figure, A) were recapitulated in a PT sample with a consensus-defined value near the decision limit. An important limitation of these data is that PT samples may not be commutable with patient specimens. However, prior reports have suggested that Siemens and Roche platforms may also yield the highest values for patient specimens.^4,5 

Anti-rubella IgG values influence clinical management, and discordance between assays could significantly impact patient care, including unnecessary immunization of those with preexisting immunity or failure to immunize those at risk. Based on these findings, manufacturers should seize this opportunity for harmonization and evaluate the performance of their anti-rubella immunoassays, particularly around the clinical cutoff of 10 IU/mL.