Adult-Onset IgE-Mediated Food Allergy in Manitoba

Methods


Background
The term "food allergy" is colloquially used to characterize a spectrum of adverse immunologic reactions following exposure to food. When the underlying etiology is demonstrated to be immunoglobulin E (IgE)mediated, the term "IgE-mediated food allergy" provides a much more speci c and accurate description (1). IgE-mediated food allergies are characterized by their rapidity of onset upon repeat exposure to an allergen following a process of sensitization, with resultant symptoms including urticaria, angioedema (cutaneous and mucocutaneous), food-pollen syndrome (FPS), rhinitis, anaphylaxis, and food-dependent exercise-induced anaphylaxis (FDEIA) (2). Sensitization can occur following oral ingestion of a food, or through a cross-reactive aeroallergen (3)(4)(5)(6). It is commonly understood that the prevalence of IgEmediated food allergy has been increasing in recent decades, particularly as it pertains to industrialized countries (7)(8)(9).
There are 4 distinct varieties of IgE-mediated food allergy -classic anaphylactic type reactions, FPS/oral allergy syndrome (OAS), delayed anaphylaxis, and FDEIA (10). It is agreed that individual reactions to certain allergenic foods may persist into adulthood (most commonly peanuts, tree nuts, and seafood), while many reactions disappear with age (10). Further expansion of this knowledge as it pertains to an adult population is of importance, as food allergy contributes signi cantly to dietary restriction and decreased quality of life (11). Aside from these outcomes, anaphylaxis -a systemic and life-threatening disease process which can culminate in hemodynamic collapse and death (12) -is an evidently signi cant subgroup of IgE-mediated reactions for which current data in our local adult population is also lacking.
The OAS, as coined by Amlot et al. in 1987 (13) is a crucial area of discussion as it relates to symptom burden. This condition is de ned as the presence of limited perioral symptoms -throat tightness, lip swelling, and oral mucosal blebs (14) -when exposed to a food (typically a fruit or vegetable). Although rarely seen, reactions as severe as anaphylaxis have occurred from OAS (7). This phenomenon is believed to be mediated by cross-reactivity between antibodies to an aeroallergen -such as birch, mugwort, or ragweed -and proteins present in foods patients consume (3). A more descriptive term has been used in recent years to describe this pathophysiology; the food pollen allergy syndrome (FPS) (14).
In fact, in 2008 it was proposed that an even more all-encompassing term be used to represent the same processes -food contact hypersensitivity syndrome -to include latex-fruit syndrome which is believed to be on the FPS spectrum (15). All of these reactions represent an IgE-mediated process which is heavily represented in the adult-onset IgE-mediated allergy population (16).
FDEIA, another principal area of review, is de ned by a type I hypersensitivity reaction wherein symptoms are not experienced following exercise or food intake in isolation, but rather after a combination of these culprits (17). The most common perpetrator of FDEIA is wheat (17,18), however numerous other causative foods have been identi ed. Although somewhat similar in pathophysiology to cholinergic urticaria, FDEIA is distinguished by a negative passive heat challenge (19). In addition to exercise, fatigue, cold, and lack of sleep are all believed to exert some effect on the development of FDEIA symptoms (17,19).
Accurate epidemiologic tracking of allergy and atopic disease in the adult population has been notoriously di cult. This is particularly problematic with regard to adult-onset IgE-mediated food allergy, as the bulk of contemporary data focuses on the pediatric population (10,16,20,21). To outline the gaps that exist, we look to one such study that attempted to remedy this. This was a survey-based crosssectional study of food allergy at Imam Abdulrahman Bin Faisal University (IAU), with 5497 students surveyed regarding presence or absence of allergy, and age of onset of food allergy if applicable (22). This revealed that amongst those with a positive history for food allergy (174 students with clinically diagnosed food allergy of the 526 students who had a positive screening history), 51.7% developed allergy before the age of 14; with adolescent (29.1%) and adult development (19.2%) being less common (22). This outlines the relatively large proportion of patients developing food allergy at an adult age, but as with many other studies it fails to outline speci c details regarding adult-onset allergy, including reaction and culprit food.
A separate retrospective review of an adult emergency department in Qatar revealed that of 198 patients identi ed with adult-onset anaphylaxis, 19% of reactions were following food ingestion (background incidence 16.5 cases/100000 visits), with 29% of the food reactions being to seafood (23). The applicability of these gures to a Canadian population is quite debateable, further delineating the need for more local data.
Within, we describe a series of 14 patients seen in the allergy clinic in Winnipeg, Manitoba, who were referred for the question of adult-onset allergy to foods previously tolerated.

Methods
We conducted a case series of patients assessed for concern of adult-onset IgE-mediated food allergy in both of Manitoba's two academic allergy clinics from May 2018 -July 2020. We de ned adult-onset IgEmediated food allergy as a history in keeping with IgE-mediated allergy -as de ned by Waserman et al (24) -following food exposure at the age of 16 or older; con rmed by epicutaneous testing, elevated foodspeci c serum IgE levels, or a positive oral challenge to the speci ed food.
We included the FPS and FDEIA as subgroups within our analysis. Patients under the age of 16, or with a history inconsistent with IgE-mediated food allergy (including food intolerance, toxic effects, and immunologic sensitivity without clinical symptomatology), as well as pre-existing food allergy to similar cross-reactive foods were excluded from our case series.
We extracted demographics such as the speci c food, index reaction, age at the time of reaction, and comorbid atopic disease; including any skin prick test (SPT) results to aeroallergens. We recorded any results, food-speci c serum IgE levels, and all oral food challenges.

Results
14 patients were included in our analysis. The majority of patients developed their index reactions before the age of 51 (12/14 patients; 86%), while only 2 patients developed IgE-mediated food-allergy at the age of ³51. As well, male patients were slightly more represented than female (8/14 patients; 57%) (table 1). With regard to speci c allergens, our population was most represented by adult-onset shell sh allergy (4/14 patients; 29%) followed by n sh, food pollen syndrome, and wheat allergy at 2 each. In the FDEIA group, the culprit food identi ed was wheat in 2 cases and shrimp in 1 case. The majority of reactions experienced by these patients were either anaphylaxis (6 patients; 43%), FDEIA and isolated (muco)cutaneous symptoms (3 patients; 21% each) (table 2). The 2 patients with adult-onset FPS had reactions to foods including zucchini, celery, and mango.

Discussion
Our study represents the rst local analysis of a signi cant number of adult-onset IgE-mediated food allergic patients in Manitoba. Findings of this case-series agreed with the retrospective review by Kamdar et al at Northwestern University in 2015 regarding the most common culprit food being seafood (21). As was the case with this study, we did not attempt to analyze shell sh subtypes (mollusks vs. crustaceans).
With respect to diagnoses, all patients aside from one had positive SPT to the allergens in question. The patient without positive epicutaneous testing underwent food-speci c serum IgE levels, which demonstrated signi cant elevation. No patients included in this case-series underwent oral-food challenge, likely due to the selection bias for inclusion.
In a 2012 Canadian review, the overall prevalence of food "allergy" was 8.07%, with the most common self-reported allergens being shell sh (1.91% of those surveyed), cow's milk (1.89%), fruits (1.61%), vegetables (1.29%), tree nuts (1.07%), wheat (0.86%), peanuts (0.78%), and hen's egg (0.67%) (25). As with the majority of compendia on this pathophysiology, there were no quali ers given for an adult-age of onset, and the self-reported nature of this data limits its usefulness. A more objective 2004 crosssectional study on German patients of all age groups found a 2.6% prevalence of adverse food reactions among a 4093 patient sample population, with con rmatory clinical testing to support this prevalence. Within this study, the most common allergens with con rmatory IgE testing were nuts, apples/pears, stone fruit, vegetables, other fruit, our, milk, and egg (26).
Again, the issue of which allergens present with adult-onset symptoms fails to be outlined by either of the aforementioned studies. A more recent study in JAMA by Gupta et al. in the US population did include an adult-onset identi er in their patient subgroupings (8). Of the 40443 adult who completed their survey, 5.2% (4.9-5.4; 95% con dence interval) of respondents ful lled criteria for adult-onset food allergy. The study then outlines the most common foods to which patients had allergy -shell sh (2.9%), milk (1.9%), peanut (1.8%), tree nut (1.2%), and n sh (0.9%) -however, once again the reporting of these allergens does not distinguish between adult-onset and pediatric-onset persistent food allergy (8). Further to this, no Canadian patients were included, limiting the clinical applicability.
Interestingly, of our patients found to be shell sh allergic, only 1/4 had documented epicutaneous testing to house dust mite (HDM) in their medical records, while 2 other patients were not tested for any aeroallergens as they did not have clinical AR, and 1 patient had the documented diagnosis of allergic rhinitis, but results of inhalant allergen testing were not documented in either electronic or physical medical records. HDM-shell sh cross-reactivity is a well-documented phenomenon, believed to be secondary to the high sequence homology between tropomyosin proteins of these organisms (4,5). This hypothesis stands analogous to the FPS/OAS, wherein an aeroallergen results in sensitization and subsequent food allergic reactivity, without ingestion of the food necessary to cause this sensitization. The cockroach also possesses a highly homologous tropomyosin protein to HDM, however given the low prevalence of this aeroallergen in Manitoba, it is not commonly tested on our standard aeroallergen panel.
In vitro subcutaneous dust mite therapy studies have shown worsening of mollusk allergy following initiation (27), lending credence to the thought that they possess shared allergenic proteins with the house dust mite. Further to this, Wong et al demonstrated signi cant homology between the allergenic epitopes on snail tropomyosin and HDM (4). Our study did not divide these patients by type of shell sh allergy due to the relatively low prevalence of documented HDM allergic rhinitis. With regard to our 2 non-AR shell sh allergic patients, we hypothesize that they became sensitized to these allergenic compounds via ingestion rather than aeroallergen cross-reactivity. This is of clinical importance as both patients presented with life-threatening anaphylaxis as their index reaction, accounting for half of the shell sh allergic patients reviewed.
When examining our FDEIA population, 1 of the wheat allergic patients had negative skin testing to wheat extract but positive testing to fresh our. This phenomenon has been demonstrated previously in a small case series of wheat-dependent exercise-induced anaphylaxis (18). The pathophysiology behind this unique occurrence has yet to be elucidated.
It cannot be emphasized enough how signi cant the high proportion of anaphylaxis was in this review. The serious nature of this reaction notwithstanding, 39% of food allergic US adults report at least 1 visit to an emergency department for anaphylaxis in their lives, and 9% report at least 1 visit in the last year based on a JAMA review (8). These staggering statistics are a clear re ection of the cost -both monetary and otherwise -of severe allergic food reactions.
Unfortunately, data regarding whether our adult-onset FPS patients immigrated to Canada from a country with differing aeroallergens was not recorded. This is of interest, as it has been demonstrated that inmovers to a new environment demonstrate lower rates of atopic disease, with gradual increases as they become sensitized (28). This could theoretically provide an explanation as to adult development of crossreactive allergic disease, as accounted for by the time to sensitization. The prevalence of FPS overall (1 pre-existing, 2 adult-onset) was fairly consistent with results published by Ma et al, who reported an estimated prevalence of FPS of 8% in the general population based upon a sample of 250 US allergists (29). Confounding this nding would be our small sample size and perhaps low referral rates for patients with FPS; although this has not been studied in the Canadian population. Both aforementioned adultonset FPS patients had a history consistent with allergic rhinitis, in keeping with the cross-reactivity hypothesis of FPS (3).
The proportion of concomitant allergic rhinitis was expectedly high given the number of patients with FPS and adult-onset shrimp allergy. This was expected based upon the stated pathophysiology of shrimp allergy and FPS. One almond allergic patient also demonstrated AR with positive SPT to trees (a common cross-reactor with almonds), however their index reaction was anaphylaxis, and thus it was concluded that this was not in keeping with FPS, given the relative rarity of anaphylaxis with pure FPS, and the lack of (peri)oral tingling accompanying their reaction (7). We also felt it was important to distinguish this reaction from classically described FPS given its life-threatening nature.
Although most adult-onset allergy studies to date use the accepted legal de nition of "adult" as aged 18 and older (10,16,21,23,30), we de ned this with an age of 16 years or older as our cut-off. Although this resulted in only 1 additional case in our series, we believe this is a valid exclusion point, as the age 16 and older has been used in oral immunotherapy (OIT) Canadian guidelines (31). This is re ective of the loss of immune plasticity following childhood, which has been as a reduction in OIT response by 17% for each year after the age of 5 (32). It is also local practice that patients aged 16 or older are often referred for assessment by an adult allergist rather than a pediatric allergist in an academic setting.
Our conclusions are limited by the retrospective nature of this review and the fact that not all patients underwent the same diagnostic tests (i.e., not all patients were skin tested for aeroallergens). Further to this, the small number of cases included in this review may have skewed our data, and further study and extension of this data would be essential to expand our understanding of the true prevalence of this pathology.

Conclusion
Our case series demonstrates that a signi cant number of patients referred to our local allergy clinic for adult-onset food allergy presented with anaphylaxis and FDEIA as their index reaction. Shell sh was the most common culprit, with all patients having tolerated the food prior to their index reaction. This is signi cant, as it represents a commonly ingested food item in North America, and a signi cant reaction with outcomes including morbidity and mortality.

Consent for Publication
Not applicable.

Availability of Data and Materials
The datasets generated and/or analysed during the current study are not publicly available due to individual health data privacy, but are available from the corresponding author upon reasonable request.

Figure 1
Concomitant allergic disease in patients with adult-onset IgE-mediated food allergy