Ultrasound-Enhancing Agents and Associated Adverse Reactions: A Potential Connection to the COVID-19 Vaccines?

To the Editor:

On April 22, 2021, the federal Food and Drug Administration (FDA) notified health care professionals that ultrasound-enhancing agents (UEA) containing polyethylene glycol (PEG)—Definity (Lantheus Medical Imaging, N. Billerica, MA), Definity RT, and Lumason (Bracco Diagnostics, Monroe Township, NJ)—should not be administered to patients with known or suspected allergies to PEG due to concerns for presumed type I immediate hypersensitivity reactions. The FDA alert reported 11 anaphylactic reactions and two patient deaths after administration of UEA over a reported period of 10 years. These agents contain PEG as a component either in the vehicle or as an inactive ingredient alone (Lumason) or within the microbubble shell and lipid excipient (Definity, Definity RT).^{1 , 2} Polyethylene glycols are commonly used in products including toothpaste, cosmetics, and shampoo and in certain laxatives and bowel preparations as thickeners, solvents, softeners, and moisture carriers.¹ Recently, rare allergic reactions have been reported after administration of the Pfizer and Moderna COVID-19 vaccines. These mRNA vaccines have “PEGylated” lipid nanoparticles for improved stability and delivery of mRNA into human cells.^{3 , 4} We write to inform your readers of adverse reactions after administration of Lumason and Definity across three echocardiography laboratories within the University of Pennsylvania Health System (UPHS) and the Medical University of South Carolina (MUSC) from 2019 to 2021. From January 2019 to July 2021, 10,526 patients at UPHS (including the Hospital of the University of Pennsylvania and Lancaster General Hospital) received Lumason and 9,550 patients received Definity. During this time period, 10,132 patients at MUSC received Lumason. At UPHS, four adverse reactions to Definity occurred in the year 2019, while seven adverse reactions to Lumason occurred after January 2021. At MUSC, three adverse reactions after Lumason administration occurred after January 2021. Adverse reactions included shortness of breath, tongue and throat swelling, abdominal and back pain, hemodynamic instability, arrhythmias, and hypoxia. These adverse reactions were treated with antihistamines and/or steroids, along with supplemental oxygen, intravenous fluids, and/or epinephrine or other vasopressors when oxygenation and hemodynamics were impacted. One patient experienced a cardiac arrest due to pulseless electrical activity after Lumason administration and was resuscitated. The four adverse reactions to Definity were reported in 2019, prior to the initiation of the COVID-19 vaccine program, and occurred over a period of 4 months, with three reactions occurring within the same month. The COVID-19 vaccination program commenced in December of 2020 after emergency use authorization was granted for the Pfizer and Moderna vaccines.⁴ The 10 adverse reactions to Lumason at UPHS and MUSC (0.13% of the total Lumason doses administered) were reported after January 1, 2021. Of the 10 patients with adverse reactions to Lumason, six patients were vaccinated (five patients with Moderna, one patient with the Pfizer vaccine) and one patient was unvaccinated, and in three patients vaccination status could not be ascertained. The patient who was resuscitated after cardiac arrest was unvaccinated. These adverse reactions were reported to the UEA manufacturers. We have initiated efforts at UPHS to standardize documentation and reporting of these adverse reactions.

We agree with the expert American Society of Echocardiography consensus statement (April 2021) that echocardiography laboratory personnel should be trained in the recognition and treatment of UEA-related hypersensitivity reactions.¹ We write to your readers to report our institutional observations of a recent increase in adverse reactions to UEAs notably prominent after January 2021, which coincided with the onset of the COVID-19 vaccination program. It is hypothesis generating but certainly not scientifically tested and confirmed that these observed adverse reactions may be potentially related to possible PEG sensitization after vaccination with the COVID-19 vaccines. We also fully acknowledge that the mechanism of these reported adverse reactions is unclear as to whether they were due to a type I hypersensitivity reaction to PEG or due to immune-mediated complement activation-related pseudoallergy.¹ Given our institutional observations, it would be prudent for echocardiography laboratories to remain vigilant for detection of increased UEA-related adverse reactions.