Interpreting the Influence of Using Blood Donor Residual Samples for SARS-CoV-2 Seroprevalence Studies in Japan: Cross-Sectional Survey Study

Background: Residual blood donor samples are commonly used in SARS-CoV-2 seroepidemiological studies; however their use may introduce bias due to the healthy donor effect, wherein blood donors are generally healthier than the general population. This potential bias is critical for accurately interpreting seroepidemiological data, as blood donors might not fully represent broader population-level infection rates., Objective: This study aims to assess the potential bias in SARS-CoV-2 seroprevalence estimates derived from blood donor samples in Japan by examining the association between blood donation history and COVID-19 diagnosis. By quantifying the healthy donor effect, we seek to refine the interpretation of SARS-CoV-2 seroepidemiological studies using residual blood donor samples., Methods: We conducted a web-based survey from December 14 to 28, 2023, recruiting 10,781 Japanese residents aged 16-69, stratified by demographic factors to match national representation. Participants provided information on demographics, socioeconomic status, COVID-19 vaccination history, comorbidities, and blood donation experience. A logistic regression model adjusting for confounders such as age, sex, education, occupation, comorbidities, and vaccination status, was used to estimate the odds of COVID-19 diagnosis among blood donors compared to nondonors., Results: Of the 10,781 participants, 3583 (33.2%) reported a history of COVID-19 diagnosis, and 5015 (46.5%) indicated they had donated blood at least once in their lifetime, and 1128 (10.5%) donated within the last year. Blood donors had mean of 13.5 (SD 43.6) donations and were older, with a mean age of 46.4 (SD 13.9) years, compared to 38.5 (SD 14.1) years for nondonors. Among blood donors, 39.9% had comorbidities (95% CI 38.5-41.2) compared to 27.9% (95% CI 26.7-29.0) of nondonors. Blood donors had 1.62 (95% CI: 1.48-1.78) times higher odds of COVID-19 diagnosis compared to nondonors. The higher diagnosis rate among blood donors likely reflects increased social interactions and health-seeking behaviors, a phenomenon we refer to as the inverse healthy donor effect. This suggests that blood donor samples could overestimate SARS-CoV-2 seroprevalence when generalized to the broader Japanese population., Conclusions: Higher COVID-19 diagnosis rates among blood donors may reflect increased community involvement and health-seeking behaviors, suggesting an inverse healthy donor effect. This pattern indicates that in terms of SARS-CoV-2 infection, blood donors might not represent the healthiest segment of the population. Consequently, seroprevalence studies using blood donor samples could overestimate SARS-CoV-2 infection rates in the general Japanese population. For more accurate public health surveillance, the development of statistical methods to adjust for this bias is recommended.