Towards a better understanding of heterophile (and the like) antibody interference with modern immunoassays

Heterophile antibodies interfere with immunoassays. Understanding the nature and characteristics of these antibodies provides a format for better identifying and removing them. Growing evidence suggests many of these antibodies are natural antibodies. Very large number of tests are being performed with automated analyzers and there has been a problem with misdiagnosis due to interference. New commercial agents for blocking heterophile antibodies have been developed.Review of the immunology and methodological literature with critical interpretation of the findings.Heterophile antibodies consist of natural antibodies and autoantibodies. Both types are usually weak antibodies that interfere by noncompetitive mechanisms. Based on very strong circumstantial evidence, we propose that natural antibodies account for most interference with automated immunoassays. In terms of false positive results, the interference rate is very low, about 99.95% accuracy. Specific blocking agents have some theoretical advantage over nonspecific blocking agents, but in actual practice, the very low false positive frequency makes it difficult if not impossible to statistically compare blocking agents or other assay modifications with adequate statistical power. In the absence of a technique that lends itself to automation for removing all immunoglobulins, it appears that infrequent heterophile interference cannot be avoided.