Co-factor-enhanced food allergy

Authors

  • V. Cardona,

    Corresponding author
    1. Allergy Research Unit, Institut de Recerca Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
    • Allergy Section, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Barcelona, Spain
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  • O. Luengo,

    1. Allergy Section, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Barcelona, Spain
    2. Allergy Research Unit, Institut de Recerca Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
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  • T. Garriga,

    1. Allergy Section, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Barcelona, Spain
    2. Allergy Research Unit, Institut de Recerca Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
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  • M. Labrador-Horrillo,

    1. Allergy Section, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Barcelona, Spain
    2. Allergy Research Unit, Institut de Recerca Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
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  • A. Sala-Cunill,

    1. Allergy Section, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Barcelona, Spain
    2. Allergy Research Unit, Institut de Recerca Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
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  • A. Izquierdo,

    1. Allergy Section, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Barcelona, Spain
    2. Allergy Research Unit, Institut de Recerca Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
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  • L. Soto,

    1. Allergy Section, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Barcelona, Spain
    2. Allergy Research Unit, Institut de Recerca Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
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  • M. Guilarte

    1. Allergy Section, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Barcelona, Spain
    2. Allergy Research Unit, Institut de Recerca Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
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  • Edited by: Hans-Uwe Simon

Correspondence

Victoria Cardona, Allergy Section, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Passeig Vall d'Hebron 119-129 CP 08035, Barcelona, Spain.

Tel.: +34932746169

Fax: +34932746169

E-mail: vcardona@vhebron.net

Abstract

Background

Alcohol, exercise or non-steroidal anti-inflamatory drugs (NSAID) are frequently mentioned as amplifiers of food allergic reactions but only individual cases or small series have been previously published.

Methods

Descriptive study including 74 cases of suspected co-factor enhanced food allergy, assessed by skin-prick tests, specific IgE and oral challenges.

Results

Anaphylaxis accounted for 85.1% of reactions. In 99% of cases culprit food allergens were plant-derived, mainly vegetables and cereals. NSAID were involved in 58%, exercise in 52.7% and alcohol in 12.2%. Lipid transfer protein was the most frequently involved allergen.

Conclusions

Co-factor enhanced food allergy should be considered when assessing food, alcohol, exercise and NSAID allergic reactions.

Although co-factors such as alcohol, exercise or nonsteroidal anti-inflammatory drugs (NSAID) are frequently mentioned as enhancers of food-allergic reactions [1], only individual cases or small series have been published [2-7]. Wheat-dependent exercise-induced anaphylaxis (WDEIA) is the best characterized of these syndromes, but little is known on the role of co-factors amplifying the allergic reaction elicited by other foods.

We present a retrospective study of 74 cases (median age 34.5 years (Q1–Q3 27.4–42.4) and equal gender distribution), identified as compatible with co-factor-enhanced food allergy (CEFA) (exercise, alcohol intake or NSAID intake occurring within the previous 2 or the 4 h following a meal containing the sensitizing food). In 82.4% of cases, patients had experienced previous food-allergic reactions, with urticaria as the most common clinical presentation and anaphylaxis in only 17.6% of cases. In CEFA, anaphylaxis was the most common clinical picture (85.1%) (Table 1), with no significant association between the clinical reaction and the type of co-factor or the offending food.

Table 1. Characteristics of the co-factor-enhanced food allergic reactions
Characteristics% (n/total)
  1. OAS, oral allergy syndrome; SPT, skin prick test; OFC, open food challenge; NSAID, non-steroidal anti-inflammatory drug.

Clinical presentation
Anaphylaxis85.1 (63/74)
Urticaria/angioedema14.9 (11/74)
Culprit food allergen
Vegetables28.4 (21/74)
Lettuce66.7 (14/21)
Tomato23.8 (5/21)
Other (onion, artichoke)9.5 (2/21)
Cereals (n/total)28.4 (21/74)
Wheat85.7 (18/21)
Other (oat, barley)14.3 (3/21)
Nuts (n/total)16.2 (12/74)
Mix25 (3/12)
Peanut25 (3/12)
Walnut16.7 (2/12)
Almond16.7 (2/12)
Other (sunflower seed/hazelnut)16.7 (2/12)
Rosaceae fruits (n/total)14.9 (11/74)
Apple72.7 (8/11)
Peach27.3 (3/11)
Food allergy diagnosis
Positive SPT84.5 (60/71)
Positive prick by prick100 (11/11)
sIgE (>0.35 kU/l)93.2 (69/74)
Component resolved diagnosis
sIgE Pru p 3 (>0.3 ISU)91.7 (55/60)
sIgE ra-5-gliadin (>0.3 ISU or >0.35 kU/l)17.6 (12/68)

In all but one case, the culprit foods were plant-derived (Table 1). More than one-third of patients (29/74) had experienced several CEFA reactions to the same or related food allergens (median 3 reactions [Q1–Q3 2–5.5]).

When tolerance to the culprit food after the reaction was unknown, an open oral food challenge was performed, showing good tolerance in 10 of 12 cases. Two patients experienced mild oral allergy syndrome (OAS), confirmed by a double-blind placebo-controlled food challenge. Seven patients refused a controlled food challenge. Of the remaining 55 patients, 49 (66.2%) referred current good tolerance to the food and 6 reported mild OAS but regularly consumed the culprit allergen.

Sensitization to Pru p 3 was demonstrated in 91.7% cases (55/60). Sensitization to other food allergens was anecdotal, except for ω-5-gliadin and kiwi thaumatin (Act d 2) positive in 12 and five patients, respectively (ImmunoISAC, Phadia, Sweden, now Thermofisher Scientific). In cereal-allergic patients, 12 of 21 (57.1%) were sensitized to ω-5-gliadin and nine of 21 (42.8%) to Pru p 3 (one patient was sensitized to both).

Nonsteroidal anti-inflammatory drugs were involved in 43 reactions (58%), exercise in 39 (52.7%) and alcohol in nine cases (12.2%), in combination in 15 reactions. When the culprit co-factor of the reaction was suspected to be an NSAID and the patient had not received it again after the reaction, a placebo-controlled challenge with the NSAID was performed, showing good tolerance in all 24 challenges.

The median time from the food consumption to symptoms was 67.5 min (Q1–Q3 42.5–120). Time to the clinical allergic reaction after the co-factor was 60 min (Q1–Q3 10–90) and was significantly higher when NSAIDs were implicated (median 75 min [Q1–Q3 60–120] vs 10 min [Q1–Q3 10–20] for exercise [P < 0.01]).

Our findings are in accordance with Asero [8], who recently described the possible eliciting role of aspirin or NSAID in lipid-transfer protein (LTP)-allergic reactions. In a related editorial [9], Romano suggests that the diagnostic workup in patients with hypersensitivity reactions to NSAID after a meal containing LTPs (plant foods) should include testing for LTP sensitization, and if this is confirmed, a challenge with the involved NSAID should be considered. This would reduce the number of subjects falsely labelled as sensitive to NSAID. This is illustrated by the fact that in our study, all controlled NSAID challenges were negative if the sensitizing food was avoided. We propose to go even further in the diagnostic algorithm (Fig. 1), considering to perform food challenges to assess tolerance in the absence of co-factors.

Figure 1.

Proposed diagnostic algorithm in suspected nonsteroidal anti-inflammatory drugs-enhanced food-allergic reactions. 1NSAID may precede food intake. 2If only mild symptoms (OAS), consider NSAID challenge.

Allergenic foods in CEFA reactions seem to be coincident with the most prevalent foods inducing allergy in that specific population. LTPs are the most common food allergen causing reactions in adults in the Mediterranean region [10] and account for almost 92% of our reported CEFA cases. But unlike in our general food-allergic patients, in which nuts, fruits and legumes are the most frequently involved foods [11], other vegetables and cereals are the main culprit foods in CEFA. This suggests that patients may be avoiding some of the primary sensitizers, which could be fruits such as peach or nuts. In cereal-allergic patients, ω-5-gliadin was the most recognized allergen followed by Pru p 3, probably a marker of reactivity to wheat LTP (Tri a 14), which was not present in the microarray used [12].

Regarding the possible underlying mechanisms explaining the increased reactivity against foods conferred by the combination with co-factors, little is known. In WDEIA, the underlying mechanisms have been partially identified, and ω-5 gliadin is the involved allergen [13]. Dysregulation of the epithelial barrier as a primary defect in the pathogenesis of allergic reactions is currently an emerging hypothesis [14] and could be one of the possible effects of these co-factors [15-18].

There are several limitations to our study. This is a retrospective study to describe an emerging clinical condition according to our observations. One could argue that the diagnosis is not fully confirmed as patients were not challenged in a combined test including the food challenge and the co-factor. Nevertheless, the recommendations to avoid these co-factors when consuming the culprit foodstuffs often resulted in a resolution of the allergic reactions, pointing to a true relevance of co-factors as triggering agents. New clinical syndromes, especially those which combine more than one eliciting factor to induce an allergic reaction, require a high clinical suspicion of clinicians to identify them. Therefore, a careful description of such conditions is a necessary first step to increase awareness of such cases. Now, there is a need for research in prospective studies in which CEFA is confirmed by positive double challenges with tolerance of the food or the co-factor alone, and on the pathogenic mechanisms. Other potential co-factors, such as illness, stress, tiredness or menstruation, described in breakthrough reactions during oral tolerance induction, should also be studied.

The clinical observation that CEFA is not an uncommon condition has changed our way of assessing these patients. We believe that this entity has to be considered when managing food-, alcohol-, exercise- and NSAID-suspected allergic reactions.

Author contributions

VC had the initial idea for the study. OL performed the statistical analysis. All authors collaborated in the retrieval of data and in the discussion of results.

Conflicts of interest

All authors declare that they have no conflicts of interest in relation to this study.

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