FDA Safety Reports Reassess Ultrasound Enhancing Agents Amid Pandemic Reporting Shifts

Ultrasound enhancing agents, the gas-filled microspheres injected to sharpen contrast on echocardiograms and other ultrasound studies, have long carried a reputation as the safest members of the contrast media family. Yet reports from individual medical centers during and after the COVID-19 pandemic suggested that serious reactions might be rising, and that one brand in particular might be to blame. A new retrospective analysis of the US Food and Drug Administration’s Adverse Event Reporting System, or FAERS, covering 2014 through 2024, now offers a critical reappraisal of that alarm, and its findings are more reassuring than the raw numbers first appeared.

The research team, led by investigators analyzing the full public FAERS database, counted 21,960,760 adverse events reported between 2014 and 2024, of which 11,450,891, or 52.1 percent, were classified as serious. Overall serious adverse event reports climbed from 678,953 in 2014 to a peak of 1,368,393 in 2021 before falling back to 1,065,845 in 2024. Death reports followed a similar arc, rising from 124,055 in 2014 to 195,207 in 2018 and then declining to 147,046 in 2024. Against this shifting backdrop, the investigators asked a deceptively simple question: how much of the apparent surge in serious events attributed to ultrasound enhancing agents simply reflects changes in how often everyone reports adverse events?

The answer, by their calculation, is 11.2 percent. Reported serious adverse events linked to ultrasound enhancing agents rose 23.9 percent in relative terms during the period when overall FAERS reporting was declining, peaking at 350 reports in 2023 before slipping to 326 in 2024. Deaths attributed to these agents increased from a single report in 2014 to 19 in 2023, then fell to 9 in 2024. But when the researchers modeled how much of the increase from 50 serious reports in 2014 to 350 in 2023 would be expected from background growth in reporting alone, only about 34 of the 300 additional reports could be explained that way. The majority of the rise, in other words, was not an artifact of the reporting system, though the absolute numbers remained strikingly small.

That smallness is the study’s central quantitative message. Across the entire eleven-year window, only 4,185 adverse events were attributed to ultrasound enhancing agents, including 1,673 serious events, 2,420 non-serious reactions, and 92 deaths. Serious event rates normalized to total FAERS reports stayed below one per 10,000 reports for every brand throughout the study, and trend tests found no statistically significant change over time in these absolute rates. By comparison, iodinated contrast and gadolinium-based contrast agents were associated with substantially greater adverse event risk across the same years, with rate ratios of 2.47 and 1.54 respectively relative to ultrasound enhancing agents.

The brand-level analysis adds nuance to a contentious debate. Of the adverse events reported, 73.5 percent involved Definity, 24.9 percent Lumason, and just 1.6 percent Optison, reflecting market share as much as safety. Serious events accounted for 32.1 percent of Definity reports, 64.0 percent of Lumason reports, and 27.3 percent of Optison reports, but when serious events were expressed as a rate against total FAERS reports, no statistically significant differences emerged between Definity and Lumason either before or after 2020. The authors caution that differences in utilization patterns, reporting bias, and temporal confounding make it difficult to draw firm conclusions about brand-related risk from spontaneous report data.

The pandemic context looms large over these findings. Concerns intensified after reports of anaphylaxis to mRNA COVID-19 vaccines drew attention to polyethylene glycol, or PEG, an ingredient shared by two of the three commercially available ultrasound enhancing agents in the United States. Definity contains PEG-5000 in its lipid shell, and Lumason uses PEG-4000 as an excipient. Speculation followed that mass vaccination might have sensitized patients to intravenously delivered PEGylated agents. The new analysis complicates that story: the observed increase in serious event reports actually began rising before the pandemic, and the researchers note that most suspected vaccine reactions later proved non-reproducible, with PEG confirmed as the culprit in fewer than one percent of tested reactors.

To sanity-check the national database against real-world practice, the team examined complete electronic health record data from 37 echocardiography laboratories across the Piedmont Health System in Atlanta from 2021 to 2024. Of 417,847 transthoracic echocardiograms performed, 181,759, or 43.5 percent, used an ultrasound enhancing agent, almost all Lumason. Across four years, 39 serious adverse events occurred, averaging 2.07 per 10,000 administrations, along with 60 non-serious events. Event rates peaked in 2023 and declined in 2024, mirroring the national FAERS pattern, though the single-system data, dominated by one brand, could reflect utilization changes rather than true safety shifts.

The investigators are careful about what spontaneous reporting data can and cannot show. FAERS relies on self-reporting from clinicians, industry, and consumers, lacks unique patient identifiers, cannot account for duplicate submissions, and provides no denominator of total doses administered, so rates indexed to total reports are approximations. The database also lacks information on imaging indications and patient comorbidities, leaving residual confounding possible. Deaths are counted within the serious event category, and the unit of analysis is the reaction rather than the person. Dynamic changes in reporting behavior and healthcare utilization during the pandemic may have influenced trends in ways that cannot be fully quantified.

Mechanistically, the authors consider but do not endorse a PEG-specific explanation. Contemporary studies report anti-PEG antibodies in 5 to 9 percent of the general population, up from roughly 0.2 percent of healthy blood donors in historical work, and newly standardized assays have detected IgE anti-PEG antibodies in patients with known PEG allergy. Yet clinically symptomatic IgE-mediated PEG allergy is estimated by experts at roughly one per million people, and complement activation related pseudoallergy, the classically described mechanism behind ultrasound enhancing agent reactions, may instead be potentiated by IgG and IgM sensitization. The researchers flag this as an open question requiring further study, particularly regarding whether prior reactions to other PEGylated products such as depot steroids are being overlooked.

The bottom line for clinical practice is measured. Absolute serious event rates for ultrasound enhancing agents remain exceedingly uncommon, are declining, and sit well below those of iodinated and gadolinium contrast during the same period, findings the authors say broadly support continued use of these agents as a class. They argue the data even raise questions about whether the boxed warning on ultrasound enhancing agents, absent from gadolinium and iodinated contrast labels, remains justified. At the same time, they call for rigorous standardized safety protocols, better preparedness in laboratories where these agents are given, and improved screening to identify the small minority of patients at risk, so that the diagnostic benefits of these microspheres can be preserved while the residual, but real, risks are minimized.

Subject of Research: Trends in reported serious adverse events from ultrasound enhancing agents in the FDA FAERS database

Article Title: Reported safety events from ultrasound enhancing agents: a critical reappraisal

Article References: Strom, J. B., Spetko, N., Angell-James, C. E. M., Cassidy, M. A., Stout, J. L., Winburn, M. L., Lee, R., Bradley, A., Moreau, K., Polsani, V., & Stone, C. A., Jr. (2026). Reported safety events from ultrasound enhancing agents: a critical reappraisal. Echo Research & Practice, 13(1), Article 25. https://doi.org/10.1186/s44156-026-00127-1

Image Credits: AI Generated

DOI: 10.1186/s44156-026-00127-1

Keywords: ultrasound enhancing agents, FAERS, FDA, serious adverse events, contrast media, pharmacovigilance, echocardiography, polyethylene glycol, microbubbles, COVID-19 reporting, Definity, Lumason