Although polyethylene glycol (PEG) is well tolerated by most individuals, accumulating evidence indicates that it can elicit clinically significant immune responses in a sensitized subset of patients. PEG-mediated anaphylaxis remains uncommon; however, it has gained increasing clinical and regulatory attention following severe hypersensitivity reactions associated with PEG-containing products and PEGylated therapeutics. Importantly, idiopathic anaphylaxis is reported to account for up to 10% of all anaphylaxis cases, and unrecognized PEG allergy may explain a subset of these previously unexplained reactions. This possibility underscores the need for greater awareness of PEG as a potential hidden trigger in patients with recurrent or unexplained anaphylaxis.

Omontys®, also known as peginesatide, provides a compelling example of clinically significant PEG-associated risk. Omontys was a PEGylated erythropoiesis-stimulating agent approved for the treatment of anemia in patients undergoing dialysis, with each therapeutic dose delivering approximately 2.56 mg of 40 kDa PEG. Shortly after its market introduction, the FDA Adverse Event Reporting System documented more than 49 cases of immediate-onset anaphylaxis, including fatal reactions, many of which occurred after the first dose. These serious safety events ultimately led to the voluntary withdrawal of Omontys from the market in 2013. This case demonstrates that PEG-containing products may pose clinically important risks in susceptible patients, even when PEG exposure appears acceptable during preclinical and clinical development.

Ultrasound-enhancing agents represent another important example. Historically, many clinicians and echocardiography laboratories did not routinely assess patients for potential cross-reactive hypersensitivity to product constituents such as PEG, and awareness of PEG-related reactions associated with these agents was limited. In 2007, after several deaths and multiple serious adverse events were reported shortly after ultrasound-enhancing agent administration, the U.S. Food and Drug Administration issued a boxed warning contraindicating their use in patients with severe or unstable cardiopulmonary disease and requiring a 30-minute monitoring period after administration. In 2021, following an FDA MedWatch alert describing hypersensitivity reactions in patients with preexisting PEG allergy—including 11 cases of anaphylaxis and 2 deaths after exposure to ultrasound-enhancing agents—the package inserts for PEG-containing lipid-based agents, including Definity® and Lumason®, were updated to identify PEG hypersensitivity as a contraindication.

The global use of lipid nanoparticle mRNA COVID-19 vaccines has further intensified interest in PEG exposure because these vaccines contain PEGylated lipid components and have been administered in billions of doses worldwide. Although these vaccines have demonstrated a favorable overall safety profile, the long-term implications of widespread PEG exposure and potential PEG sensitization for future use of PEG-containing drugs, biologics, and medical products remain incompletely understood.

These examples highlight an important unmet need in both drug development and clinical practice: the ability to identify patients at elevated risk for PEG-mediated hypersensitivity before exposure. This need is especially relevant for patients with a history of recurrent or idiopathic anaphylaxis, in whom PEG sensitivity may otherwise go unrecognized.