Anaphylaxis: A Rapid-Onset, Life-Threatening Allergic Reaction
Anaphylaxis is a serious, systemic allergic reaction that occurs rapidly and can be fatal if not treated promptly. It is classified as a type I hypersensitivity reaction, mediated by immunoglobulin E (IgE) antibodies that trigger the release of histamine and other inflammatory mediators from mast cells and basophils. Once the allergen is introduced into the body, the reaction may progress within minutes, sometimes even seconds. The hallmark symptoms involve multiple organ systems, including respiratory distress (e.g., wheezing, throat tightness), cardiovascular compromise (e.g., hypotension, tachycardia), cutaneous reactions (e.g., hives, flushing, angioedema), and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Common allergens that trigger anaphylaxis include certain foods (e.g., peanuts, shellfish), medications (e.g., penicillin, NSAIDs), insect stings, and latex. Prompt administration of intramuscular epinephrine is the first-line treatment, followed by supportive measures such as antihistamines, corticosteroids, oxygen, and intravenous fluids. Anaphylaxis is a medical emergency requiring immediate recognition and intervention to prevent death or long-term complications. Increasing awareness, timely diagnosis, and availability of epinephrine autoinjectors are essential to improving outcomes in individuals at risk.
PEG Anaphylaxis: An Emerging Concern in Modern Medicine
Polyethylene glycol (PEG) is a polyether compound widely regarded as pharmacologically inert and used extensively as an excipient in drugs, cosmetics, food, and medical devices. PEGylation, the process of attaching PEG molecules to therapeutic compounds, is employed to increase drug solubility, stability, and half-life. While PEG is considered safe for the vast majority of the population, mounting evidence suggests that it can elicit immunologic responses in a sensitized subset of individuals. Specifically, anti-PEG IgE antibodies have been implicated in immediate-type hypersensitivity reactions, including life-threatening anaphylaxis. PEG anaphylaxis, although rare, has gained increased recognition following reports linked to PEGylated drugs and COVID-19 mRNA vaccines.
One of the most striking examples of PEG-induced anaphylaxis occurred with Omontys® (peginesatide), a PEGylated erythropoiesis-stimulating agent approved for the treatment of anemia in patients undergoing dialysis. Each therapeutic dose of Omontys delivered approximately 2.56 mg of 40 kDa PEG. Shortly after its market introduction, the FDA Adverse Event Reporting System (FAERS) documented over 49 cases of immediate-onset anaphylaxis, some of which were fatal, occurring after the first dose. These events led to the voluntary market withdrawal of Omontys in 2013. Investigations suggested that pre-existing anti-PEG antibodies, particularly anti-PEG IgE, may have predisposed some patients to severe reactions. The Omontys case exemplifies how high-dose, high-molecular-weight PEG exposure, particularly via parenteral routes, can trigger serious hypersensitivity in susceptible individuals.
The emergence of COVID-19 mRNA vaccines brought renewed attention to PEG as a potential allergen. Both the Pfizer-BioNTech and Moderna vaccines utilize PEG-2000 as a lipid nanoparticle stabilizer. The PEG content in these vaccines is significantly lower than that in Omontys—approximately 50 µg per dose in Pfizer’s BNT162b2 and 100 µg per dose in Moderna’s mRNA-1273. Despite the smaller dose and lower molecular weight, a small number of immediate allergic reactions were reported following vaccination, prompting investigations into the potential role of PEG. However, several studies (e.g., Zhou et al., 2023; Khalid et al., 2024) found that most individuals who experienced vaccine-related reactions did not test positive for anti-PEG IgE, and reactions often lacked elevated tryptase levels or other markers of true IgE-mediated anaphylaxis. Many such events were ultimately attributed to immunization stress-related responses (ISRR) or non-IgE mechanisms such as complement activation (CARPA) or mast cell activation via alternative receptors like MRGPRX2.
Nonetheless, a small number of confirmed cases have demonstrated PEG IgE involvement, validating the need for improved screening and diagnostic strategies. Current assays such as ELISA and skin testing vary in sensitivity and specificity, often yielding inconclusive results. This diagnostic uncertainty has complicated efforts to stratify risk, especially in preclinical and post-marketing drug safety assessments. The development of more sensitive and specific assays, such as those based on the FocalTuning™ platform, offers a promising solution. With high-resolution signal deconvolution, robust background suppression, and picogram-level sensitivity, FocalTuning enables detection of anti-PEG IgE even in ambiguous or borderline cases.
Given the projected growth of the PEGylated drug market—which exceeded USD 6 billion in the U.S. in 2017 and is expected to surpass USD 8 billion by 2024—the need for proactive safety measures is more urgent than ever. Incorporating reliable PEG IgE screening into drug development and clinical practice may prevent adverse outcomes and improve patient confidence. While the overall prevalence of anti-PEG IgE remains low (estimated at ~0.1% in the general population), the clinical stakes are high in settings involving high PEG dose or parenteral administration. As seen in the Omontys and mRNA vaccine cases, accurate identification of at-risk individuals can significantly impact public health outcomes, regulatory actions, and therapeutic trust.
In conclusion, PEG-induced anaphylaxis represents a rare but serious risk that warrants heightened awareness and improved diagnostic tools. Anti-PEG IgE testing, particularly using advanced platforms like FocalTuning, may provide a path forward in identifying susceptible individuals before exposure. As PEGylated biologics and nanoparticle-based therapies continue to expand, establishing best practices for PEG hypersensitivity screening will be critical in ensuring both safety and innovation in modern medicine.