Recalled peanut extract yields false-negative allergy tests
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Key takeaways:
- The FDA recalled lots of peanut allergen extracts after higher rates of false-negative tests.
- One lot had a fraction of the proteins of a nonrecalled lot, and another had no detectable proteins.
Patients experienced smaller skin test wheal responses due to reduced levels of content in recently recalled peanut allergen extract, according to a study published in The Journal of Allergy and Clinical Immunology: In Practice.
Qualitative standardization of extract concentrations would probably improve the safety and quality of allergen testing, desensitization and immunotherapy, Cosby A. Stone Jr., MD, MPH, assistant professor in the division of allergy, pulmonary and critical care medicine at Vanderbilt University, and colleagues wrote.
“The FDA’s recall of a peanut skin test extract that we had been using in a clinical research project prompted the study,” Stone told Healio.
In December 2022, the FDA recalled lots of peanut allergen skin test extracts because they did not perform as expected due to higher than normal rates of false-negative skin tests in truly allergic patients. “It made us wonder whether the recalled extracts might have thrown off our skin test results and whether we could examine if the recalled extracts had enough peanut allergens in them, compared to other extracts that weren’t recalled,” Stone said.
Jon Hemler, MD, a pediatric allergist at University of Virginia, had used one of these extracts before it was recalled as part of this project, leading to false-negative tests among two participants.
In fact, cases of life-threatening anaphylaxis followed false-negative tests, prompting new package label warnings for all food allergen extracts used in diagnostic skin testing beginning in March 2023.
The researchers hypothesized that amounts of peanut allergen content in the affected lots were below the target range for optimal skin testing, leading to the adverse performance in the clinical setting.
Study design, results
The researchers compared the size of skin wheals produced by extracts from recalled lot –634 among 16 individuals and nonrecalled lot –829 among eight individuals. All the study participants had known peanut allergies, and two of them had repeated skin tests with both extracts.
Median peanut/histamine skin prick test ratios included 0.63 (interquartile range [IQR], 0.25-1.06) for the recall group and 1.64 (IQR, 1.09-3.67) for the nonrecalled group (P = .01).
Initially, the two participants who were tested with both extracts both had negative SPTs with the recalled extract with wheal sizes of 0 mm and positive SPTs with the nonrecalled extract with wheal sizes of 36 mm and 13 mm.
“So, then we measured the amount of peanut allergens in the recalled lots that we had access to, and it turned out that they were really deficient in peanut allergens,” Stone said.
The researchers performed sandwich enzyme-linked immunosorbent assays (ELISAs) on two recalled lots and three nonrecalled lots of peanut extract specifically for Ara h 1, Ara h 2, Ara h 3 and Ara h 6, finding what they called clear differences in concentrations between the recalled and nonrecalled lots.
In recalled lot –744, Ara h 1 was 2.5 to 8.1 times less concentrated, Ara h 2 was 35 to 84 times less concentrated, Ara h 3 was 27 to 123 times less concentrated and Ara h 6 was 38 to 120 times less concentrated than the three nonrecalled extracts. Also, recalled lot –634 had undetectable concentrations of Ara h 1, Ara h 2, Ara h 3 and Ara h 6.
These differences of factors ranging from 10 to more than a hundred suggest that the nonrecalled extracts were selectively enriched for Ara h 2 and Ara h 6 or that these differences reflect the composition of the source material, the researchers wrote.
Conclusions, next steps
Noting that the two participants had been screened out of participation in an early study due to false-negative skin testing, the researchers said that such false negatives may result in adverse outcomes if physicians rely on their results before proceeding with oral challenges.
Further, the researchers cautioned that the FDA has not standardized any of the injectable food extracts that physicians use to diagnose allergy in the United States.
“Skin test extract batches are consistently tested for quality control by extract manufacturers,” Stone said.
Instead of measuring and quantifying the concentrations of specific allergen subunits that correspond with allergy pathogenesis, the researchers explained, current quality control measures the total protein concentration of the ground-up allergen, creating a hidden barrier to reliable testing, desensitization and immunotherapy.
“This means that sometimes there can be a gap where the protein concentration might seem right, but there’s actually not enough allergen or there's too much allergen in the extract,” Stone said.
For example, Stone noted that Mark A. Wurth, MD, PhD, pediatric pulmonologist at University of Kentucky, found similar results among aspergillus extracts did not include enough Asp F1.
“The reason that extract quality control has not measured allergens before up to this point is because we usually didn’t have the ability to do it. We just are sort of hoping that the allergens are in there if we grind up enough of the right proteins into an extract,” Stone said.
Study senior author Scott A. Smith, MD, PhD, assistant professor of medicine in the division of infectious diseases, department of medicine at Vanderbilt University Medical Center, has captured the B cells that generate IgE antibodies out of the blood samples of allergic patients, among other advances, Stone said.
“He can then keep those cells alive in the lab in a form known as a hybridoma. Those hybridomas will then create an essentially unlimited amount of allergy antibodies that are specific for the very allergen that the patient is allergic to,” Stone said. “It’s mind blowing! I get so excited about it.”
These antibodies make it possible to measure allergens, among other things such as figuring out exactly how these antibodies cause allergic reactions, Stone explained.
“When we used monoclonal IgE antibodies against key peanut allergens, they performed excellently in identifying the recalled extracts that were deficient in allergens,” Stone said.
Stone and his colleagues then backed up these results by using monoclonal IgG antibodies against the same peanut allergens with collaborators at InBio, whose tests similarly showed that the recalled lots did not have enough peanut allergens.
“Having done all this, our conclusion was that the recalled extracts were deficient in key peanut allergens, which is why they didn’t perform correctly, and that monoclonal antibodies against allergens are potentially a step forward in our future quality control and assurance for extracts,” Stone said.
In most clinical contexts, the researchers continued, physicians would not readily detect “cold lots” that have less allergen than needed, leading to inaccurate results unless they are used in screening tests that permit symptomatic challenges in error.
By putting allergen concentrations into a predictable “target zone,” the researchers wrote, quantitative standardization of extract concentrations based on allergenic content would probably improve the safety and quality of testing, desensitization and immunotherapy.
“Some extracts that we use have already been standardized to a greater degree of certainty than others. I think it would be amazing to bring the rest of our extracts up to a more rigorous standard where we are certain that they contain just the right amount of allergen,” Stone said.
Stone said that he is pleased with these results because the allergists and the FDA both essentially did everything right.
“False-negative tests were rapidly identified by allergists and reported to the FDA, which rapidly triggered a recall. The system worked the way it was supposed to,” he said.
Stone also said that as frontline clinicians, allergists need to pay close attention to their extracts, police their performance and report discrepancies to the FDA, which then would decide on the need for a recall.
“What we did in our report was to show that when the FDA made their recall, they nailed it. The recalled extracts didn’t have enough allergen in them,” Stone said.
Stone added that the future of using antibodies specific to key allergens that provoke reactions is actively being written.
“I predict with high confidence that they will be useful for an incredible number of clinical and scientific purposes and we already have lots of ideas about that,” Stone said. “The only major limitation to our imagination is the reality of funding and time to pursue what we can think of.”
For more information:
Cosby A. Stone Jr., MD, MPH, can be reached at cosby.a.stone@vumc.org.