New Blood Tests Fall Short of Replacing Food Challenge

Blood tests for food allergy have become more specific over time, but none can yet replace the oral food challenge, which remains the gold standard for both diagnosis and threshold analysis, according to leading experts. Although component testing, which increases blood test specificity compared with older tests, is now a staple of routine practice, other attempts to deliver a better blood test have so far fallen short. Most prominently, the basophil activation test (BAT), which entered the 2023 European Academy of Allergy and Clinical Immunology guideline for equivocal peanut and sesame cases, depends on rapid sample analysis. Few laboratories are capable of performing the test, making it impractical at scale. The mast cell activation test (MAT), which uses serum instead of fresh blood, could overcome this limitation; early data have been encouraging, but the technology remains under development. So what can a blood test tell an allergist today that it could not 10 years ago? "The answer is very little," said Robert A. Wood, MD, the Julie and Neil Reinhard professor of pediatric allergy and immunology at Johns Hopkins University School of Medicine, Baltimore. "Component testing has expanded, but the most important components, for peanut and hazelnut, were already in our hands 10 years ago." Paul J. Turner, PhD, professor of anaphylaxis at Imperial College London, answered the same question almost identically: "I would say not a lot, to be honest." The Murky Middle of Food Allergy Blood Tests Current blood tests are reliable at the extremes, Edwin H. Kim, MD, MS, chief of pediatric allergy and immunology and director of the UNC Food Allergy Initiative at the University of North Carolina at Chapel Hill, told Medscape Medical News. "There is a pretty big gray area in the middle where the tests are positive, but it is unclear if this means [patients] are actually allergic." Many actually aren't, according to a meta-analysis of 110 studies, which found that 16.6% of the European population was sensitized to a food by specific immunoglobulin E (IgE), while only 0.8% reacted in a supervised food challenge. Pretest probability of allergy determines confidence in a positive result, said Marcus S. Shaker, MD, MSc, professor of pediatrics and of medicine at the Geisel School of Medicine at Dartmouth, New Hampshire. "Just because you have a food-specific IgE doesn't mean it causes disease, just as owning a motor vehicle doesn't mean you are driving it, or that it will be involved in a motor vehicle collision," Shaker told Medscape Medical News. Resolving this gray zone currently requires an oral food challenge, which is resource intensive and carries a risk for severe reactions. Food challenges are therefore uncommon, with only 17% of allergists performing more than 10 a month, according to a 2024 position statement from the Canadian Society of Allergy and Clinical Immunology. A Food Challenge in the Test Tube For years, investigators have been trying to develop "a food challenge in the test tube," said Turner, who himself has been involved in BAT and MAT development. Studies support the newer tests as more reliable predictors of true clinical reactivity, according to Wayne G. Shreffler, MD, PhD, chief of pediatric allergy and immunology and co-director of the Food Allergy Center at Mass General Brigham, Boston. He told Medscape Medical News that they "should help to reduce the number of unnecessary food challenges, which are burdensome for patients and providers." And as the field moves away from a pure avoidance strategy to active therapies, correctly identifying food allergy is more important than ever, Kim said. But four of the five sources interviewed pointed out the same issue with BAT: It requires fresh blood. The test "has to be done within a day of drawing the blood," Kim said. "When only a few centers in the US have the expertise for the test, it becomes really hard logistically to do." According to Wood, this constraint may be eased by a new Beckman Coulter method "that would allow for 4-5 days to run the assay." However, the company's launch announcement positions the platform for research use only, and no independent validation has been published. MAT sidesteps the fresh-blood problem entirely. "Serum can be stored for many days and even weeks to months if needed," Kim said. "Even if the [MAT] is only run at specialized labs, by being able to store it and ship it when convenient, this may be a super practical option." Because the cells come from a laboratory line rather than the patient, MAT has virtually no nonresponders, according to a 2026 review. In a study analyzing blinded serum samples from 112 children, MAT identified peanut allergy with 93% sensitivity and 96% specificity, while correctly classifying every BAT nonresponder. "The limitation of the MAT is that it is very new and still needs lots of validation," Wood said. Why Challenge the Food Challenge? Even if MAT or BAT eventually prove suitable for routine use, Turner argued that they will still not answer an even more important question. "It's not, 'Am I allergic or not?' We can do that, that's easy," he said. "The question is actually, 'How allergic am I?' That's what people want to know, and there's no test out there that will tell you that information." Whether BAT can predict severity is disputed in print. Alexandra Santos, MD, PhD, of King's College London, and colleagues reported that BAT identified severe reactions during peanut challenges with high sensitivity and specificity. Turner and Adnan Custovic, MD, PhD, also of Imperial College London, reanalyzed the same data and found that once nonreactors were excluded, BAT separated severe from mild reactions too poorly to be clinically useful. Santos and colleagues responded to the reanalysis by noting that BAT still caught every severe reactor, and that missing one is the costlier error. That debate aside, Turner highlighted another aspect of food challenge that is less often discussed: the positive psychological impact. In a 2021 study, of which Turner was senior author, quality of life improved after a reactive double-blind challenge whether or not the child had anaphylaxis. "Food challenges done well can actually be life-transforming," Turner said, likening the effect to exposure therapy. "Even if [blood tests] did work as well, they don't give you that experience of a food challenge, and therefore they're not as valuable." Fear is a large part of what keeps the procedure rare, Turner argued. "Most people don't get trained how to do them properly," he said, and "they're scared to do them," leading to a wariness that is then passed on to families. A reaction in a restaurant or at school, unexpected and managed by nonexperts, is "very different from having a well-done food challenge in a very controlled setting with people who know how to do them and are there supporting you," Turner said, adding that few areas of medicine have such detailed international guidance on managing risk. Challenges take time and cost money, Turner acknowledged, "but on the other hand, they can so transform a patient and their family's well-being that, to my mind, they're absolutely worthwhile doing." A Trial Built to Answer, With Open Questions Efforts are ongoing to develop better biomarkers for food allergy, including SAFER, a trial that will enroll approximately 500 children with suspected peanut allergy at 10 US sites. The study, co-chaired by Wood and funded by the National Institute of Allergy and Infectious Diseases, will test whether a biomarker panel — including BAT, MAT, peanut components, peanut epitopes, and endpoint skin testing — can predict oral food challenge outcomes, according to Wood. "If successful, the biomarkers would not just determine food allergy or not, but also how allergic," Wood said. Turner doubted it. "These are all small increments," he said, "as opposed to some life-changing test that's going to radically change allergy." Wood reported no relevant financial relationships. Kim disclosed consultancy relationships with ALK, DBV Technologies, Regeneron and others, and grant support from Food Allergy Research & Education and the National Institutes of Health, and said none are specific to diagnostic testing. Shaker reported membership on the Joint Task Force on Practice Parameters, editorial roles at The Journal of Allergy and Clinical Immunology: In Practice and Annals of Allergy, Asthma, and Immunology, and service on the board of directors of the American Academy of Allergy, Asthma & Immunology, adding that views expressed are his own; he also serves as a strategic medical partner for allergy immunology at Social Theory. Shreffler disclosed consultant fees from Novartis, Stallergenes, Third Rock Ventures and others; clinical trial agreements with DBV Technologies, Moderna, Regeneron and others; and research funding from Genentech and the National Institute of Allergy and Infectious Diseases, and said he has no conflicts relevant to diagnostics. Turner disclosed speaker expenses from Thermo Fisher, which manufactures IgE blood tests. He has also reported serving as principal investigator for commercial food immunotherapy studies sponsored by Aimmune Therapeutics and DBV Technologies. Will Pass, DVM, is a freelance medical writer.