Expert Consensus Statement from the American Society of Echocardiography on Hypersensitivity Reactions to Ultrasound Enhancing Agents in Patients with Allergy to Polyethylene Glycol

The American Society of Echocardiography is composed of health care providers and scientists committed to the well-being of patients through excellence in cardiovascular imaging. In alignment with the society's mission to provide education that improves clinical outcomes, this consensus statement has been generated to provide our members and all practitioners of echocardiography with information and recommendations that will benefit the safety of patients receiving ultrasound enhancing agents (UEAs). Specifically, this document provides expert opinion on the clinical impact of the recent alert from MedWatch, the US Food and Drug Administration (FDA) product safety reporting system, on presumed type I immediate hypersensitivity reactions to the polyethylene glycol (PEG) component of UEAs. The UEAs that are approved for use by the FDA include perfluorocarbon or sulfur hexafluoride microbubbles stabilized with 'shells"composed of albumin or lipid.1 These agents can interact with immune cells of the monocytic/phagocytic system via opsonization involving the complement (C0) system or interaction with specific immune cell surface receptors.2 These interactions contribute to the normal and uneventful mechanism for clearance of UEAs from the circulation by the reticuloendothelial (mononuclear phagocyte) system. Serious immune-related reactions to UEAs are rare and have been attributed largely to C0 activation-related pseudoallergy reactions, which are known to also occur with liposomal drug preparations.1,3-6 The lipid-based UEAs approved for human use by the FDA contain PEG either in the excipient (vehicle or inactive ingredient) alone (Lumason and SonoVue; Bracco Diagnostics, Milan, Italy) or in the microbubble shell and the lipid excipient (Definity, Definity RT, and Luminity; Lantheus Medical Imaging, North Billerica, MA). The PEG components not only stabilize the agents but when incorporated in the shell can also reduce microbubble opsonization and interaction with cells.7 The potential for rare immunoglobulin E-mediated type I hypersensitivity reactions to PEG components has been recently recognized after publication of case reports implicating PEG allergy.8,9 The MedWatch alert is based on post marketing pharmacovigilance from more than two decades that identified 11 cases of anaphylaxis, including two deaths, related to the administration of UEAs in patients with preexisting PEG hypersensitivity. The comments below provide expert opinion on the impact of newly recognized PEG hypersensitivity. We believe that it is important to recognize the potential for reactions to the PEG component of lipid UEAs. Our recommendations also take into account that these reactions remain extremely rare and that UEAs provide vital information that improves patient outcomes arising from the ability of UEAs to detect or exclude life-threatening conditions or to stratify patients to lifesaving therapies.1