Understanding Food Allergen Thresholds Requires Careful Analysis of the Available Clinical Data.

The recent editorial by Luccioli and Kwegyir-Afful1Luccioli S. Kwegyir-Afful E.K. Benefits of understanding allergen thresholds.J Allergy Clin Immunol. 2014; 134: 399-400Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar appropriately highlights the potential benefits derived from understanding food allergen thresholds across the spectrum of patients with specific food allergies. That editorial highlighted the study of Blumchen et al,2Blumchen K. Beder E. Beschorner J. Ahrens F. Gruebl A. Hamelmann E. et al.Modified oral food challenge used with sensitization biomarkers provides more real-life clinical thresholds for peanut allergy.J Allergy Clin Immunol. 2014; 134: 390-398Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar which contributes to our knowledge of peanut thresholds and especially identified several biomarkers that appear useful in the identification of the most sensitive patients with peanut allergy. The editorial by Luccioli and Kwegyir-Afful1Luccioli S. Kwegyir-Afful E.K. Benefits of understanding allergen thresholds.J Allergy Clin Immunol. 2014; 134: 399-400Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar offered additional comments on the limitations in estimating population thresholds, although we would assert that they overlooked some published evidence and mischaracterized other evidence, including the study by our own consortium.3Allen K.J. Remington B.C. Baumert J.L. Crevel R.W.R. Houben G.F. Brooke-Taylor S. et al.Allergen reference doses for precautionary labeling (VITAL 2.0): clinical implications.J Allergy Clin Immunol. 2014; 133: 156-164Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar Allen et al3Allen K.J. Remington B.C. Baumert J.L. Crevel R.W.R. Houben G.F. Brooke-Taylor S. et al.Allergen reference doses for precautionary labeling (VITAL 2.0): clinical implications.J Allergy Clin Immunol. 2014; 133: 156-164Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar reviewed data on the individual oral threshold doses for patients with peanut, hazelnut, milk, and egg allergy from more than 55 studies of clinical oral threshold challenges. Luccioli and Kwegyir-Afful1Luccioli S. Kwegyir-Afful E.K. Benefits of understanding allergen thresholds.J Allergy Clin Immunol. 2014; 134: 399-400Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar indicate that our comparisons found significant eliciting dose (ED) distribution variability when population age, geographic origin, starting dose, and challenge material type were analyzed separately. We wish to point out that distribution variability is only one way to examine such comparative data. In fact, although some distribution variability did occur for peanut when comparing adults and children, the predicted ED05 doses were not different for children versus adults with peanut allergy. Furthermore, no differences were observed in distribution variability or ED05 values between adults and children for hazelnut. Of course, most allergic subjects outgrow egg and milk allergies, and therefore few adults with egg and milk allergy were available for comparative analysis. With respect to geographic origin, Allen et al3Allen K.J. Remington B.C. Baumert J.L. Crevel R.W.R. Houben G.F. Brooke-Taylor S. et al.Allergen reference doses for precautionary labeling (VITAL 2.0): clinical implications.J Allergy Clin Immunol. 2014; 133: 156-164Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar again observed some distribution variability for peanut (between populations from France, The Netherlands, the United Kingdom [UK], and the United States) and milk (between populations from The Netherlands, Italy, and Australia), but again, the predicted ED05 doses were similar, except for the group with peanut allergy from the UK and the group with milk allergy from Australia. Allen et al3Allen K.J. Remington B.C. Baumert J.L. Crevel R.W.R. Houben G.F. Brooke-Taylor S. et al.Allergen reference doses for precautionary labeling (VITAL 2.0): clinical implications.J Allergy Clin Immunol. 2014; 133: 156-164Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar pointed out that the difference observed for the group with peanut allergy from the UK was likely due to a bias in patient selection because most of the data were obtained from subjects involved in immunotherapy studies in which investigators might intentionally attempt to select patients with low individual threshold doses in comparison with those of the overall population. Allen et al3Allen K.J. Remington B.C. Baumert J.L. Crevel R.W.R. Houben G.F. Brooke-Taylor S. et al.Allergen reference doses for precautionary labeling (VITAL 2.0): clinical implications.J Allergy Clin Immunol. 2014; 133: 156-164Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar also pointed out that the higher observed ED05 value for the group with milk allergy from Australia was due to the use of a dosing scheme by the Australian investigators that started at a comparatively high dose compared with the Dutch and Italian groups. With respect to the nature of the challenge material type, Allen et al3Allen K.J. Remington B.C. Baumert J.L. Crevel R.W.R. Houben G.F. Brooke-Taylor S. et al.Allergen reference doses for precautionary labeling (VITAL 2.0): clinical implications.J Allergy Clin Immunol. 2014; 133: 156-164Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar noted no differences in ED05 values between roasted peanuts and peanut flour or between liquid milk and nonfat dry milk. A difference was noted between raw egg white and raw whole egg, but that difference is readily explained by the higher proportion of major egg allergens in egg white as opposed to whole egg, which also contains yolk, a fraction known to be less allergenic. Thus Allen et al3Allen K.J. Remington B.C. Baumert J.L. Crevel R.W.R. Houben G.F. Brooke-Taylor S. et al.Allergen reference doses for precautionary labeling (VITAL 2.0): clinical implications.J Allergy Clin Immunol. 2014; 133: 156-164Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar concluded that population age and geographic origins are not factors that significantly affect the determination of population thresholds by using statistical dose-distribution modeling. As noted earlier, Allen et al3Allen K.J. Remington B.C. Baumert J.L. Crevel R.W.R. Houben G.F. Brooke-Taylor S. et al.Allergen reference doses for precautionary labeling (VITAL 2.0): clinical implications.J Allergy Clin Immunol. 2014; 133: 156-164Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar acknowledge that population age is likely a factor with milk and egg allergy, with most affected children outgrowing these allergies. The starting dose used in the challenges can make a difference, as shown for the group with milk allergy from Australia, because the selection of higher initial doses will generate a larger proportion of first-dose reactors. The nature of the challenge material type does not appear to make major differences for the forms that are typically used in oral challenge trials, but we acknowledge that further clinical research is needed to fully explore the possible effects of processing and the food matrix on threshold doses. However, because less processed forms of foods, which likely have the greatest allergenic potency, tend to be used in food challenges, this limitation might not be especially significant. Blumchen et al2Blumchen K. Beder E. Beschorner J. Ahrens F. Gruebl A. Hamelmann E. et al.Modified oral food challenge used with sensitization biomarkers provides more real-life clinical thresholds for peanut allergy.J Allergy Clin Immunol. 2014; 134: 390-398Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar demonstrated that the challenge interval between doses in oral challenge studies is an important consideration because some subjects reacted after longer intervals than used in many earlier oral challenge trials (20-30 minutes). However, the predicted population ED05 estimates were very similar between Blumchen et al2Blumchen K. Beder E. Beschorner J. Ahrens F. Gruebl A. Hamelmann E. et al.Modified oral food challenge used with sensitization biomarkers provides more real-life clinical thresholds for peanut allergy.J Allergy Clin Immunol. 2014; 134: 390-398Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar and Allen et al.3Allen K.J. Remington B.C. Baumert J.L. Crevel R.W.R. Houben G.F. Brooke-Taylor S. et al.Allergen reference doses for precautionary labeling (VITAL 2.0): clinical implications.J Allergy Clin Immunol. 2014; 133: 156-164Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar We would note that the lowest dose reactors in the distribution have a major effect on ED05 estimates. The increments between doses at the lower end of the dosing scheme are always smaller, no matter what type of scheme is used, because each dose increment is a logarithmic or multiple increase from the preceding dose rather than a constant or fixed quantity added to it. Therefore if you start at 1 mg and go by 10-fold increments, the first is from 1 to 10, which is 9 mg. The next is from 10 to 100, which is 90 mg. The third is from 100 to 1000, which is 900 mg. The data of Blumchen et al2Blumchen K. Beder E. Beschorner J. Ahrens F. Gruebl A. Hamelmann E. et al.Modified oral food challenge used with sensitization biomarkers provides more real-life clinical thresholds for peanut allergy.J Allergy Clin Immunol. 2014; 134: 390-398Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar seem supportive of the previous population ED05 estimate for peanuts.3Allen K.J. Remington B.C. Baumert J.L. Crevel R.W.R. Houben G.F. Brooke-Taylor S. et al.Allergen reference doses for precautionary labeling (VITAL 2.0): clinical implications.J Allergy Clin Immunol. 2014; 133: 156-164Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar, 4Taylor S.L. Baumert J.L. Houben G.F. Crevel R.W.R. Brooke-Taylor S. Allen K.J. et al.Establishment of reference doses for residues of allergenic foods: report of the VITAL expert panel.Food Chem Toxicol. 2013; 63C: 9-17Google Scholar Luccioli and Kwegyir-Afful1Luccioli S. Kwegyir-Afful E.K. Benefits of understanding allergen thresholds.J Allergy Clin Immunol. 2014; 134: 399-400Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar express serious concerns about the population thresholds arising from Allen et al3Allen K.J. Remington B.C. Baumert J.L. Crevel R.W.R. Houben G.F. Brooke-Taylor S. et al.Allergen reference doses for precautionary labeling (VITAL 2.0): clinical implications.J Allergy Clin Immunol. 2014; 133: 156-164Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar and the potential effects of these doses on patients at risk of severe allergic reactions to peanut. Luccioli and Kwegyir-Afful1Luccioli S. Kwegyir-Afful E.K. Benefits of understanding allergen thresholds.J Allergy Clin Immunol. 2014; 134: 399-400Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar indicate that most of the data analyzed by Allen et al3Allen K.J. Remington B.C. Baumert J.L. Crevel R.W.R. Houben G.F. Brooke-Taylor S. et al.Allergen reference doses for precautionary labeling (VITAL 2.0): clinical implications.J Allergy Clin Immunol. 2014; 133: 156-164Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar excluded patients at risk of severe reactions. This is simply not true. Three of the largest sources of patients involved in the peanut dose-distribution analysis came from clinics in Nancy, France, and Utrecht and Groningen, The Netherlands, where patients with histories of severe reactions to peanuts were not excluded from challenge.5Taylor S.L. Moneret-Vautrin D.A. Crevel R.W.R. Sheffield D. Morisset M. Dumont P. et al.Threshold dose for peanut: risk characterization based upon diagnostic oral challenge of a series of 286 peanut-allergic individuals.Food Chem Toxicol. 2010; 48: 814-819Crossref PubMed Scopus (132) Google Scholar, 6Vlieg-Boerstra B.J. Duiverman E.J. van der Heide S. Bijleveld C.M.A. Kukler J. Dubois A.E.J. Should children with a history of anaphylaxis to foods undergo challenge testing?.Clin Exp Allergy. 2008; 38: 1935-1942Crossref PubMed Scopus (14) Google Scholar A direct comparison of the ED05 estimates between patients with peanut allergy with histories of severe reactions and those without such histories within the Nancy group revealed no difference.5Taylor S.L. Moneret-Vautrin D.A. Crevel R.W.R. Sheffield D. Morisset M. Dumont P. et al.Threshold dose for peanut: risk characterization based upon diagnostic oral challenge of a series of 286 peanut-allergic individuals.Food Chem Toxicol. 2010; 48: 814-819Crossref PubMed Scopus (132) Google Scholar Luccioli and Kwegyir-Afful1Luccioli S. Kwegyir-Afful E.K. Benefits of understanding allergen thresholds.J Allergy Clin Immunol. 2014; 134: 399-400Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar further question the assertion made by Allen et al3Allen K.J. Remington B.C. Baumert J.L. Crevel R.W.R. Houben G.F. Brooke-Taylor S. et al.Allergen reference doses for precautionary labeling (VITAL 2.0): clinical implications.J Allergy Clin Immunol. 2014; 133: 156-164Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar that low-dose reactions to peanuts are expected to be associated with milder reactions. We would indicate that the reactions to low doses experienced by the 750 patients with peanut allergy included in the dose-distribution analysis were indeed mild reactions. We would further note that Rolinck-Werninghaus et al7Rolinck-Werninghaus C. Niggemann B. Grabenhenrich L. Wahn U. Beyer K. Outcome of oral food challenges in children in relation to symptom-eliciting allergen dose and allergen-specific IgE.Allergy. 2012; 67: 951-957Crossref PubMed Scopus (79) Google Scholar provide evidence that patients receiving lower doses of egg, milk, wheat, and soy experience less serious reactions. We acknowledge that more sensitive patients with peanut allergy might exist and might react more severely to these same low doses, but we would contend that a data set involving 750 patients with peanut allergy that mostly does not exclude patients with histories of severe reactions is quite robust and should serve adequately for public health authorities. The benefits of the establishment of population thresholds cannot begin to accrue to populations with food allergy unless or until public health authorities accept that the existing data are sufficiently robust and without severe limitations. Benefits of understanding allergen thresholdsJournal of Allergy and Clinical ImmunologyVol. 134Issue 2PreviewRecent studies published in the Journal1,2 have shed important light on the understanding of thresholds for patients with food allergy. In most clinical contexts, a threshold can be viewed as “the level that must be reached for an effect to be produced.”3 Because the effect in question for a subject with food allergy might be a potentially life-threatening reaction for which no preventative treatments are available, understanding threshold responses to allergen exposure undoubtedly benefits the management of patients. Full-Text PDF ReplyJournal of Allergy and Clinical ImmunologyVol. 135Issue 2PreviewWe read with interest the comments from Taylor et al1 about our editorial2 and thank the authors for clarifying some of the analysis found by their consortium in Allen et al.3 We also appreciate the opportunity to elucidate some points made in our editorial2 regarding uncertainties in population threshold data from Allen et al,3 the applicability of current population thresholds to patient populations at risk for severe consequences from food challenges, and assessment of the relative severity of responses to low-dose challenges. Full-Text PDF