American Association for Clinical Chemistry
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December 2010 Clinical Laboratory News: New Food Allergy Guidelines

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December 2010: Volume 36, Number 12



New Food Allergy Guidelines
What’s the Recommended Role for Lab Tests?

By Genna Rollins

Are food allergies on the rise in the U.S.? Recent news reports and growing public awareness of the potentially dire consequences of eating problem foods would certainly suggest so. But what is the real evidence surrounding food allergies, and what are the best methods for diagnosing and monitoring food allergies? Guidelines released this month by the National Institute for Allergy and Infectious Diseases (NIAID) seek to answer these and other questions (J Allergy Clin Immunol 2010;126: 1105-18).

“Our hope is that we can standardize how we diagnose and manage food allergies so that patients get optimal care for the things we know based on evidence. We also hope to drive the research agenda and fill in the information gaps where we are lacking evidence,” explained Hugh Sampson, MD, professor of pediatrics, allergy, and immunology and dean for translational biomedical research at the Mount Sinai School of Medicine in New York City. Sampson was a member of the expert panel that developed the guidelines, and is a former president of the American Academy of Allergy, Asthma and Immunology (AAAAI), one of 34 organizations on the guidelines coordinating committee.

A key conclusion of the guidelines is that although lab tests are important in the work up of food allergies, a single test result alone is not sufficient to diagnose a food allergy. “One of the things we wanted to make abundantly clear in this document is that the laboratory method for supporting the diagnosis of food allergy, the presence or absence of food-specific IgE, is not, in and of itself, an indication that a patient has food allergy,” explained Joshua Boyce, MD, associate professor of medicine at Harvard Medical School in Boston. “An individual can have food-specific IgE and be clinically asymptomatic on consumption of that food.” Boyce chaired the guidelines expert panel.

Even though lab tests can’t provide definitive answers about food allergies, members of the guidelines panel and other experts emphasized how important lab analysis is in diagnosing food allergies, a role that is only expected to grow in the coming years. “In the case of children in particular, the lab plays a very key role in the diagnostic process,” explained Robert Hamilton, PhD, professor of medicine and pathology and director of the dermatology, allergy, and clinical immunology reference laboratory at Johns Hopkins University in Baltimore. “Children don’t tolerate skin testing as well as adults. You also have the inherent positive attribute that the IgE antibody serology is quantitative and provides some potential predictive value.” Although Hamilton did not serve on the expert panel, he has written extensively about food allergy diagnostics. He also manages the College of American Pathologists’ diagnostic allergy proficiency survey.

Reaching a Wide Spectrum of Clinicians

Developed over the course of 2 years, the guidelines are aimed at both primary care physicians and specialists, in recognition that the diagnosis and management of food allergies has expanded beyond the domain of allergists. “What we hope to accomplish with these guidelines is to have a very effective dissemination across multiple specialties. We worked very hard to make sure this was a product not just written by allergists for allergists,” said Matthew Fenton, PhD, chief of the asthma, allergy, and inflammation branch in NIAID’s Division of Allergy, Immunology, and Transplantation. “This is a product created by a broad base of the clinical community, and now we can disseminate the guidelines back to a broad community so that an allergist in New York City or a family practitioner in rural Wyoming are working off the same guidelines.” Reflecting the effort to make the guidelines widely available, the journals of several professional associations that participated in the effort also plan to print a summary of the guidelines concurrently with their release in the Journal of Allergy and Clinical Immunology.

AAAAI and the American College of Allergy, Asthma and Immunology collaborated to issue allergy diagnostic testing and food allergy practice parameters in 2006 and 2008, respectively, but these detailed documents were written specifically for the allergist members of those organizations. In addition to being directed at clinicians of all types, the NIAID guidelines are unlike those earlier efforts in another important way. NIAID commissioned a first-of-its-kind food allergy-related evidence review. That effort, carried out by investigators at the RAND Corporation under contract to NIAID, identified more than 12,000 food allergy-related studies that had been published in a 20-year period, but only 72 met the team’s inclusion criteria. As the researchers noted wryly, “there is a voluminous literature related to food allergy, but high-quality studies are few.”

A Striking Lack of Evidence

This lack of conclusive evidence permeates most issues related to food allergy, including even the definition of the term, according to the RAND researchers. “Those of us who practice in this field clinically have in mind that we’re all speaking the same language, but in fact, the vast amount published indicates that people aren’t even talking in the same language as to what constitutes a food allergy,” said Marc Riedl, MD, MS, assistant professor of medicine and section head of clinical immunology and allergy at the UCLA-David Geffen School of Medicine in Los Angeles. “Unfortunately, that leads to weak data to make decisions on.” Riedl was a member of the evidence review team.

The RAND researchers also could not find hard evidence about the prevalence of food allergies, and finally concluded that the condition affects at least 1–2% but no more than 10% of the population. “A really high percentage of people—about 30 percent of the population—think they or someone in their family has a food allergy. But if you look at good scientific studies, it appears that food allergies affect about six-to-eight percent of children younger than school age and about three-to-four percent of adults and school-age children,” explained expert panel member Wesley Burks, MD, professor and chief of pediatric allergy and immunology at Duke University Medical Center in Durham, NC. “What the evidence review group did was reinforce that public perception of food allergies is greater than the scientific reality. However, it certainly pointed out that the scientific reality is not an insignificant number.”

Finally, the evidence review panel concluded that food challenges, skin prick and food-specific serum IgE (sIgE) tests “all have a role to play in making the diagnosis but no one test has sufficient ease of use or sensitivity or specificity to be recommended over other tests.”

With these findings as a backdrop, the guidelines expert panel agreed on a common definition for food allergy as “an adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food.” The group also defined numerous food-specific allergic conditions and reviewed the natural history of food allergy generally, of specific foods, and of conditions that often co-exist with food allergy such as asthma and atopic dermatitis. The document differentiates immune-mediated and non-immune mediated allergic food reactions (See Figure, below). The expert panel did not seek to address celiac disease even though it is immune-mediated because well-developed practice parameters already exist for the condition, according to Boyce.

Breaking Down Adverse Food Reactions

Click for Figure

New guidelines for diagnosing and managing food allergies categorize adverse food reactions as either immune mediated or non-immune mediated.

Source: NIAID

Test Panels Not the Solution

The heart of the guidelines is a lengthy section on the diagnosis of food allergy. Here, the document walks readers through food allergy symptoms, as well as the differential diagnosis of food allergy. The guidelines emphasize that diagnostic tests have to be considered in the context of a thorough physical examination and medical history. “One of the things we point out is that in the evaluation of food allergies, you can’t simply send out a panel of lab tests, and in fact, we need to discourage people from doing that,” explained Sampson. “The guidelines go through the kinds of things you should be looking for to see whether it confirms or refutes your impression.”

That recommendation in particular has important implications, because the current approach of many physicians in working up a suspected food allergy is to do exactly what the guidelines advise against. “I can tell you from my clinical practice that I see all kinds of lab tests being done to diagnose food allergies. Doctors end up ordering a battery of tests that honestly, in my opinion, cause confusion and more harm than good,” observed Riedl.

Physicians who previously haven’t dealt much with food allergy diagnostics also seem to be at a loss in terms of what to make of food-specific IgE results and other tests. “We get a lot of questions about what the levels mean, and what to do with the results we’re providing,” said Hamilton. “We spend a good bit of time directing them to information to guide them in interpreting results.”

Based on lack of evidence of their utility, the expert panel advised against using numerous non-standardized tests, including basophil histamine release, lymphocyte stimulation, allergen-specific IgG and IgG4, cytotoxic assays, and mediator release assays. However, these tests already have crept into use, to the dismay of experts. “The guidelines provide a whole list of lab tests that are non-standardized and non-proven. That’s probably as important as what they do recommend, because the truth is, based on this report and our literature review, there’s very little to no evidence that these tests have anything to do with the diagnosis of food allergy as we understand it,” said Riedl. “For better or worse, they’re being ordered by physicians. That’s not to say they may not be useful in the future as more evidence surfaces.”

NIAID Boosts Funding for Food Allergies

Given the public’s mounting anxiety about food allergies, guidelines issued this month by the National Institute for Allergy and Infectious Diseases (NIAID) should be received warmly by clinicians and consumers alike. However, an evidence review commissioned as part of the guidelines development process cast somewhat of a shadow on this otherwise positive step in that it found a striking lack of evidence surrounding food allergies. The good news is that NIAID already had been leading the charge to uncover more hard evidence about food allergies. The institution’s support of food allergy research increased 12-fold over 6 years, from $1.2 million in FY2003 to 14.2 million in FY2009.

NIAID also established the Consortium of Food Allergy Research (CoFAR) in 2005 to conduct multi-center clinical trials, observational studies, mechanistic studies, and basic research towards further understanding the best possible treatment approaches for food allergies. The food allergy-related evidence review found numerous one-center studies with relatively small numbers of participants that did not provide enough statistical power to drive definitive conclusions. CoFAR seeks to address those shortcomings and is enrolling participants in two multi-center clinical trials examining egg and peanut allergies, respectively.

Finally, in recognition that research needs researchers, NIAID launched an initiative in 2008, Exploratory Investigations in Food Allergy, to encourage both new investigators and established investigators new to the field of food allergy to begin working in this area. The effort brought more than 25 investigators into the field for the first time, according to Matthew Fenton, PhD, chief of the asthma, allergy, and inflammation branch in NIAID’s Division of Allergy, Immunology, and Transplantation.

Linking sIgE with Food Allergies

While the guidelines explain that total sIgE lacks sensitivity and specificity in comparison to the gold standard—seeing how well patients tolerate particular foods during an oral food challenge—they suggest that food allergen-specific sIgE tests “are very useful for detecting the presence of specific IgE antibodies, which indicate the presence of allergic sensitization.” The guidelines also note that studies have associated greater levels of sIgE with increased probabilities of having an allergic reaction to a specific food, but nonetheless emphasize that these tests alone can’t be used to diagnose food allergy.

Sampson’s lab has been on the forefront of investigating the utility of sIgE in food allergy diagnostics and has performed two seminal studies that examined the predictive value of allergen-specific sIgE in the likelihood of a positive oral food challenge. The first of these efforts, which involved retrospective measurement of food-specific sIgE from stored serum samples, enabled the researchers to establish positive predictive values for food allergies to milk, egg, peanuts, and fish. The investigators confirmed these cutpoints in a subsequent prospective study. However, similar studies involving slightly different populations arrived at different cutpoints, so for now—and possibly for some time to come—it will not be possible to establish widely accepted cutpoints. “For the population we studied, our findings are very useful in correlating food-specific IgE levels with the probability of reacting to that food during a food challenge. But other work done by other investigators shows that age is an important factor,” explained Sampson. “We still believe the concept is good, but the values we generated are not necessarily universally applicable.”

Hamilton is skeptical that there ever will be standardized food-specific sIgE cutpoints. “It doesn’t surprise me that these studies came up with different levels of IgE antibodies as predictive values. Even though we’re using the same IgE antibody serology assay throughout the world, we’re dealing with a biological phenomenon that has a lot of variability,” he observed. “More data points probably won’t answer the questions because we’ll continue to see variations based on biology, the study populations, and the way the studies are performed.”

The practical fall-out of this is that as robust as they are, food-specific serum IgE levels don’t fit into a precise diagnostic formula. “The serologic measurement of food-specific IgE antibodies has evolved to a quantitative measure that’s probably close to total serum IgE in terms of analytical performance,” said Hamilton. “But the bottom line is, there’s not an absolute number you can use and you have to be very careful in translating a specific IgE level into a clinical decision.”

Lab Communications Key

As clinicians assimilate the guidelines, there are several things laboratorians can do to improve the diagnostic process, according to experts. Some labs apparently can do a better job of being aware of and communicating to clinicians when they switch assays or when there are changes in the assays themselves. For instance, a lab Boyce works with recently changed its IgE immunoassay without informing clinicians. Most allergists know—and the guidelines point out—that results from different labs and assay systems may not be comparable. But in Boyce’s case, “all of a sudden we started getting these ridiculously high food-specific IgE numbers on kids we were following to determine when a food could be reintroduced into their diet. The numbers were so high they weren’t even physiologically possible,” he said. “This is a very important issue, especially if you’re using these tests longitudinally as a means of assessing the change in risk of a reaction. You need to use the same assay all the way along.”

In a related vein, Hamilton’s lab experienced unexpected variable results when one IVD company didn’t notify customers in advance that it had started supplementing its hazelnut extract with a recombinant form of Cor a 1, a hazelnut allergen, which is labile. Supplementing extract with recombinant Cor a 1 “was a great idea, but it’s structurally similar to Bet v 1, which is birch pollen allergen. So all of sudden our assays for hazelnut were measuring IgE to birch pollen and we had children who really didn’t have hazelnut sensitivity coming up as having strong sensitivity,” he explained.

After that incident, the three major IgE immunoassay manufacturers are “very sensitive” to any changes that might affect the performance of their assays, according to Hamilton. However, he emphasized that despite the manufacturers’ best efforts, labs can expect some intra-assay variability. “We bought a milk extract from the same source we had been using, but it turned out to have a totally different profile. Yet it had the same immunologic profile and was from the same source materials,” he recalled.

Because of these experiences, he strongly urged labs to stay in close contact with manufacturers and continue to educate physicians about the various immunoassays and analytical issues that surface. He also urged labs to specify on lab results which food-specific immunoassay they use as well as a brief comment that positive IgE antibody results indicate the patient has sensitivity to that allergen, which may or may not be clinically relevant.

On the Cusp of New Diagnostic Methods

Experts also recommended that labs keep abreast of diagnostic advances. “It’s quite likely that there’ll be superior assays going forward that will tell us not only how much IgE is in the serum but what epitopes it’s recognizing,” said Boyce. “That turns out to have prognostic significance.” Knowing whether an individual’s food-specific IgEs are directed primarily against conformational or linear epitopes will give insight into how likely that patient is to be desensitized in the future, he explained. This information also may indicate whether the individual will be able to tolerate a food after the relevant proteins have been denatured, by, for example, cooking them.

Sampson’s lab is actively pursuing this line of investigation. “We’re looking at where on the molecule the IgE binds. By looking at specific epitope binding we believe we can come closer to knowing whether someone will be reactive and how reactive they’ll be,” he indicated.

Hamilton’s lab is one of only a few in the U.S. using for research purposes an assay with European CE marks that measures IgE antibodies to individual allergenic proteins. “As we dissect the immune response, moving from an extract-based assay that has multiple allergens, but in which we don’t know exact-ly what we’re measuring, to an assay where we measure IgE to individual allergen components, we’ll be better able to characterize the immune response,” he noted.

Another technology approved for use in Europe is the Phadia ImmunoCAP Rapid Device and Reader II. This point-of-care test measures aero- or food allergies, but only the version that measures allergic triggers common in respiratory diseases has been cleared by the Food and Drug Administration for use in U.S. physicians’ offices. However, Hamilton advised labs to stay abreast of developments related to the technology.

As allergy diagnostics continue to advance, members of the guidelines panel look forward to further research that will unite lab technology with gaps in evidence. “The robustness of assays came before there was a broad appreciation of their meaning, and that’s where we are right now,” said Boyce. “Our hope is that within 10 to 20 years we’ll have assays with stronger predictive values and a lot more information about the most appropriate strategies for diagnosing, for primary prevention, and for managing allergies, a lot of which is really cloudy right now.”

For Further Information:

Bernstein IL, Li JT, Bernstein DI, Hamilton, R, et al. Allergy Diagnostic Testing: An Updated Practice Parameter. Ann Allergy Asthma Immunol 2008;100: S1–S148

Chapman, JA, Bernstein LI, Lee, RE, Oppenheimer, J, et al. Food Allergy: A Practice Parameter. Ann Allergy Asthma Immunol 2006;96: S1–S68

Eckman, J, Saini, SS, Hamilton, RG. Diagnostic Evaluation of Food-Related Allergic Diseases. Allergy Asthma Clin Immunol. 2009; 5: doi:10.1186/1710-1492-5-2

Hamilton, RG. Proficiency Survey-Based Evaluation of Clinical Total and Allergen-Specific IgE Assay Performance. Arch Pathol Lab Med 2010;134:975–82.

Hamilton, RG, Williams, PG. Human IgE antibody serology: A primer for the practicing North American allergist/immunologist. J Allergy Clin Immunol 2010;126:33–8.

Scheider Chafen JJ, Newberry, SJ, Riedl, MA, Bravata DM, et al. Diagnosing and Managing Common Food Allergies. JAMA 2010;303:1848–56.