The “Grey Zone” in Blood Donor Screening: A Retrospective Study and Proposal for Donor Re-Entry

Background/Objectives: Grey zone serologic results in blood donor screening pose challenges for transfusion safety, donor management, and blood supply sustainability. In Saudi Arabia, standardized national protocols for managing grey zone outcomes remain lacking. This study aimed to evaluate the prevalence and follow-up outcomes of grey zone serologic results among blood donors at a Saudi hospital over a five-year period. Methods: Serological screening results of six transfusion-transmissible infections (TTIs) markers were extracted alongside nucleic acid testing (NAT) results for HBV, HCV, and HIV. The grey zone was defined as a signal-to-cutoff (S/CO) of 0.90–0.99. Repeat and follow-up results, including subsequent donations, were assessed for seroconversion. Results: A total of 48,241 donations from 38,524 donors were analyzed. Anti-HBc showed the highest reactivity (n = 2312; 4.8%), followed by HbsAg (n = 2292; 0.31%) and syphilis (n = 218; 0.5%). Grey zone results were rare, and most frequent in anti-HBc (n = 76; 0.16%), HCV (n = 39; 0.08%), and HBsAg (n = 28; 0.06%). Grey zone-to-reactive conversion upon subsequent donation was rare. Three donors who initially tested in the grey zone for anti-HBc later tested reactive in subsequent donations, but their HBV NAT remained negative. Conclusions: While grey zone outcomes were infrequent, a subset involving HBV markers showed low-level reactivity on repeat testing. For other TTIs markers, grey zone results likely reflected assay variability rather than true infection. We propose a six-month temporary deferral with follow-up serologic and NAT testing, allowing conditional re-entry for donors with consistently non-reactive results, supporting both transfusion safety and a more sustainable donor pool.