Polyethylene glycols, also known as macrogols, are hydrophilic molecules that are often used in medical, pharmaceutical, and cosmetic products. They are available in a range of molecular weights from 200 to 35,000 g/mol with PEG 3350 as a common ingredient in laxatives and bowel preparations.4 PEG derivatives are structurally similar polymers and are often used as drug excipients,5 as is the case for Definity® microspheres. Many severe immediate-type hypersensitivity reactions have been reported following the use of PEG 4000, 6000, 8000 and 20,000,6 and in reports between 1989 and 2017, the US FDA identified 53 cases of anaphylactic reactions to bowel preparations or laxatives containing PEG.5 However, anaphylaxis to PEGylated products such as Definity® has been rare overall. In a retrospective analysis, more than 66,000 administered doses of Definity® over a period of 4.5 ± 2.4 years were analyzed, of which only 8 serious adverse events were reported as probably related to Definity®. Of these, 4 were described as anaphylactic, with symptoms including hypotension, dyspnea, urticaria, and swelling of the face and throat. They all occurred within 15 minutes of administration and patients recovered after 4 to 8 hours in the hospital after being treated with fluids, antihistamines, steroids, and/or epinephrine. Thus, the incidence of anaphylaxis to Definity® was recorded to be 0.006%,3 although confirmatory allergy testing was not performed; thus, the mechanism(s) of the reactions were not determined.
To our knowledge, there is only one case report of an anaphylactic reaction to Definity®, with the culprit being the PEGylated part of the microsphere. The patient was a 58-year-old male who, within minutes of being given Definity® for a stress myocardial perfusion scan, developed urticaria, shortness of breath, and hypotension. Previously, he had developed swollen hands when handling paints containing high molecular weight PEG and anaphylaxis to oral PEG 3350 during preparation for a colonoscopy. He later tested positive on SPT to PEG 3350 and methylprednisolone acetate (containing PEG), and positive on IDT to triamcinolone acetonide (containing polysorbate 80). It was concluded that his immediate reactions to the PEG products and Definity® were due to an IgE-mediated reaction to PEG.4
On the other hand, our patient had a positive IDT to perflutren (Definity®) but not to PEG-containing medications, and tolerated an oral challenge to PEG 3350. She also tested negative for PEG 8000 SPT, deeming the higher molecular weight PEG 5750 in Definity® to be an unlikely culprit. Definity® contains excipients in the buffer such as glycerin and propylene glycol which are often considered immunologically inert.2 Thus, we suspect that the patient likely experienced anaphylaxis to a non-PEGylated component of perflutren contrast agent. Of note, our patient had exercise as a cofactor, which could have contributed to the severe presentation.
In summary, immediate hypersensitivity reactions to Definity® are rare, with most reported cases attributing PEG as the likely allergen. We present the first documented case of an IgE-mediated reaction potentially triggered by a non-PEG component of Definity®. This case highlights a new response to Definity® unrelated to the PEG excipient and the importance of physicians to be aware of this rare but critical situation.