Inaccuracies in Total Serum IgE Measurements by Immulite Caused by Omalizumab in Specimens

To the Editor

I read the paper by Dal Negro and colleagues (1) with great interest in which the authors search for an effective predictor of atopic asthma patient responsiveness to prolonged anti-IgE (Omalizumab) treatment. Identification of a useful predictor of anti-IgE effectiveness would be a significant contribution to the management of these patients since anti-IgE therapy is expensive and one could use such a biomarker to decide to stop treatments early (e.g., by 3 months) in the regimen for those individuals in whom minimal long-term clinical benefit of 1 year or more would be expected. In their study, the authors quantified total serum IgE levels and compared early temporal changes in the total IgE levels to other measures of asthma management, including the patients’ forced expiratory volume in the first second (FEV1), the symptom complaints, and the number of emergency room visits, hospitalizations, and exacerbations. More specifically, sera from 23 severe asthmatics were collected at intervals over a 12-month course of Omalizumab. Total serum IgE was then measured using the Immulite system (Siemens Healthcare Diagnostics, Deerfield, IL, USA). The Immulite system is clearly an excellent, accurate, and reproducible automated assay platform for the quantification of total serum IgE in patients not receiving Omalizumab (2). Unfortunately, the authors must not have read the 2006 report (3) that showed the adverse impact that IgE:IgG–anti-IgE immune complex formation after omalizumab administration has on the accuracy of the total serum IgE Immulite assay.

In this 2006 study (3), plasma from atopic adults were incubated with therapeutic levels of Omalizumab (50 or 200 molar excess to IgE) or equal volumes of buffer as sham controls. These specimens were then sent masked to 159 clinical laboratories in the United States, which routinely participate in the College of American Pathologists Diagnostic Allergy Laboratory Proficiency Survey that involves three challenge cycles per year. This evaluation was performed twice (over the course of two survey cycles) from 2003 to 2005 to verify the marked trends in interference observed with some total serum IgE assays. The total serum IgE data in kU/L from both survey cycles were then sent to a statistics analysis facility in Chicago at the College where they were collated and inhibitory effects produced by Omalizumab on the accuracy and reproducibility of the total serum IgE assays were computed. Since these were data from an national proficiency survey involving over 150 laboratories, the data can be considered impartial to any particular assay method or laboratory. The results showed clearly that total serum IgE levels as measured in one of the total serum IgE assay platforms were minimally altered by the presence of therapeutic levels of Omalizumab. Unfortunately for the authors of this Journal of Asthma paper (1), marked and variable reductions in accuracy occurred with the Immulite system (up to 52% reduction in IgE levels measured) simply by the presence of therapeutic levels of Omalizumab in the specimen.

The levels of both total serum IgE and Omalizumab in the specimen affected the extent of interference. We interpret the College’s study data to indicate that Omalizumab is binding to IgE in the serum specimen and blocking IgE binding to the capture and/or detection anti-IgE reagents in the Immulite assay. Thus, the accuracy of the IgE measurements collected on the specimens in the study conducted by Dal Negro and colleagues must be seriously questioned. Given this concern for the accuracy of the measured total serum IgE levels in these patients on Omalizumab, one must seriously question the fundamental conclusions of the study and the identified threshold value of 250 IU/mL of IgE as a useful biomarker for Omalizumab therapeutic efficacy. Since the extent of interference of Omalizumab in the Immulite assay reportedly varies as a function of the total serum IgE level, one cannot expect a constant degree of inhibition as it will vary with each subject in their study. We look forward to hearing how the authors address this fundamental concern with the accuracy of their published total serum IgE data as a result of Omalizumab interference in their Immulite measurements.

Acknowledgments

The author has research projects with Phadia now ThermoFisher Scientific, Siemens Healthcare Diagnostics, and Hycor Biomedical Corporation, which produce the ImmunoCAP, Immulite, and HyTech total IgE assay autoanalyzers, respectively.

Declaration of Interest

The author reports no conflicts of interest. The author alone is responsible for the content and writing of the paper.