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

The federal Food and Drug Administration (FDA) notified health care professionals on April 22, 2021, that ultrasound-enhancing agents (UEA) containing polyethylene glycol (PEG) should not be administered to patients with known or suspected allergies to PEG.

This recommendation is due to concerns for presumed type I immediate hypersensitivity reactions. Eleven 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).

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.

The authors report 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.

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.

10,526 patients at UPHS received Lumason and 9,550 patients received Definity and 10,132 patients at MUSC received Lumason. Of these, 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.

The COVID-19 vaccination program commenced in December of 2020 after emergency use authorization was granted for the Pfizer and Moderna vaccines.

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 the vaccination status could not be ascertained.

The authors write this report to share their 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.

The authors commented that this report is hypothesis generating but 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.