Anaphylaxis to excipient mannitol: evidence for an immunoglobulin E-mediated mechanism

Summary Background Anaphylaxis to mannitol present naturally in pomegranate and cultivated mushroom in a sensitized subject has been described recently, and an IgE‐mediated mechanism to this sugar alcohol has been proposed. The same subject also experienced severe allergic reactions to a chewable pharmaceutical (cisapride drug). Objective The purpose of the study was to identify allergenic component in the pharmaceutical preparation, and also, to understand the mechanism of immediate hypersensitivity to mannitol. Methods Methodology involved skin prick tests (SPTs), high‐performance liquid chromatographic (HPLC) analysis of pharmaceutical preparations, separation of mannitol by Ca++‐ion‐moderated cation‐exchange chromatography, preparation of alditol–protein conjugates by reductive amination, SPT using the conjugates, hapten affinity purification of the allergic serum on d‐mannitol–keyhole limpet haemocyanin (KLH)–Sepharose CL‐6B, and detection of serum mannitol‐specific IgE by ELISA. Results Component testing by SPT, and HPLC analysis of various pharmaceuticals indicated that the excipient mannitol is the causative allergen. Mannitol separated from Cisapid MPS showed allergenic activity by SPT. Among the several conjugates tested by SPT, d‐mannitol–bovine serum albumin and d‐mannitol–KLH showed positive weal/flare reaction, demonstrating the presence of cell‐bound mannitol‐specific IgE in vivo. Negative results with d‐glucitol, d‐galactitol, meso‐erythritol, and l‐mannitol protein conjugates clearly showed that the mannitol‐specific human IgE is very specific to the d‐isomer of mannitol. ELISA using the hapten affinity‐purified allergic serum was positive, demonstrating the presence of mannitol‐specific serum IgE in the allergic subject. Conclusion Mannitol, which is widely used as a food and drug additive (excipient), can rarely cause IgE‐mediated anaphylaxis. This study is the first one to demonstrate the presence of mannitol‐specific human IgE in a sensitized allergic subject to validate an IgE‐mediated hypersensitivity mechanism for mannitol.