Standardized diagnostic approach for cold agglutinin disease: results from a Delphi-Based Expert Consensus

Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia characterized by clonal immunoglobulin M (IgM) autoantibodies that activate complement at low temperatures, leading to hemolysis. Diagnostic practices remain inconsistent, with considerable interlaboratory variability and no established guidelines. Objective - To develop a consensus-based diagnostic framework for CAD through a structured Delphi methodology, with the goal of harmonizing laboratory practices across medical centers.

A total of 30 experts in classic hematology and transfusion medicine were invited to participate in a two-round, web-based modified Delphi survey; 27 (90%) completed both rounds. A scientific board developed 37 diagnostic statements covering five domains: CAD definition, clinical evaluation, immunohematological testing, and pre-analytical and analytical procedures. Statements were rated on a 5-point Likert scale, with consensus defined a priori as a score of 4 or 5 by ≥80% of respondents.

All 37 statements achieved consensus, with 36 (97.3%) doing so in Round 1 and the remaining one in Round 2 after re-evaluation. The panel provided recommendations on when to suspect CAD and specified necessary diagnostic tests, including C3d positivity on direct antiglobulin test (DAT) with monospecific antisera and the detection of cold agglutinins in serum. They heavily emphasized the importance of sample handling at 37°C, alongside issuing recommendations on cold agglutinin titration, transfusion management, and immune-hematologic follow-up.

This expert consensus provides a standardized diagnostic approach for CAD, addressing current gaps in clinical and laboratory evaluation. Implementing these recommendations is expected to improve diagnostic accuracy and consistency, facilitating better patient outcomes and national harmonization of practices.