Allergy

POSITION PAPER

Pathophysiological mechanisms of exercise-induced anaphylaxis: an EAACI position statement L. Ansley1, M. Bonini2, L. Delgado3, S. Del Giacco4, G. Du Toit5, M. Khaitov6, M. Kurowski7, J. H. Hull8, A. Moreira3 & P. J. Robson-Ansley1 1

Faculty of Health & Life Sciences, Northumbria University, Newcastle Upon Tyne, UK; 2Department of Public Health and Infectious Diseases, ‘Sapienza University’, Rome, Italy; 3Servicßo de Imunoalergologia, Centro Hospitalar Sã o Joã o and Immunology Laboratory, Faculty of Medicine, University of Porto, Porto, Portugal; 4Department of Medical Sciences ‘M. Aresu’, University of Cagliari, Cagliari, Italy; 5 Department of Paediatric Allergy, MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, Division of Asthma, Allergy and Lung Biology, King’s College London and Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 6National Research Center, Institute of Immunology, Federal Medicobiological Agency, Laboratory of Molecular immunology, Moscow, Russian Federation; 7Department of Immunology, Rheumatology and Allergy, Medical University of Lodz, Lodz, Poland; 8Department of Respiratory Medicine, Royal Brompton Hospital, London, UK

To cite this article: Ansley L, Bonini M, Delgado L, Del Giacco S, Du Toit G, Khaitov M, Kurowski M, Hull JH, Moreira A, Robson-Ansley PJ. Pathophysiological mechanisms of exercise-induced anaphylaxis: an EAACI position statement. Allergy 2015; 70: 1212–1221.

Keywords allergy; anaphylaxis; exercise; immunology; physiology. Correspondence Les Ansley, Faculty of Health & Life Sciences, Northumbria University, Newcastle Upon Tyne, UK. Tel.: +44 191 243 7773 Fax: +44 191 227 4515 E-mail: [email protected] Accepted for publication 16 June 2015 DOI:10.1111/all.12677

Abstract

This document is the result of a consensus on the mechanisms of exercise-induced anaphylaxis (EIAn), an unpredictable and potentially fatal syndrome. A multidisciplinary panel of experts including exercise physiologists, allergists, lung physicians, paediatricians and a biostatistician reached the given consensus. Exerciseinduced anaphylaxis (EIAn) describes a rare and potentially fatal syndrome in which anaphylaxis occurs in conjunction with exercise. The pathophysiological mechanisms underlying EIAn have not yet been elucidated although a number of hypotheses have been proposed. This review evaluates the validity of each of the popular theories in relation to exercise physiology and immunology. On the basis of this evidence, it is concluded that proposed mechanisms lack validity, and it is recommended that a global research network is developed with a common approach to the diagnosis and treatment of EIAn in order to gain sufficient power for scientific evaluation.

Edited by: Thomas Bieber

Exercise-induced anaphylaxis (EIAn) is a rare, unpredictable, potentially fatal syndrome in which anaphylaxis occurs in conjunction with exercise or physical activity. EIAn may occur independently of food allergen ingestion or may require the ingestion of a food allergen either pre- or postexercise, known as food-dependent exercise-induced anaphylaxis (FDEIAn). The symptoms of FDEIAn may vary in severity; reassuringly, fatalities are rare. EIAn occurs in all ages, in both sexes, and is more common in atopic individuals (1, 2). EIAn is generally reported following submaximal exercise of a relatively short duration; this fact alone eliminates the majority of the proposed pathophysiological mechanisms. EIAn has been described in high-performance athletes and in individuals undertaking only occasional exercise or physical activity; indeed, even nonstrenuous physical activity, for example raking garden leaves, has been reported as a trigger for EIAn. There are now more than one hundred reviews on the topic of EIAn (food dependent and nonfood dependent)

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upon which much of our current knowledge of the condition is based. A recent publication has reviewed some of the current working hypotheses for (FD)EIAn and indicated that many of these are inappropriate for the physiological changes that occur within the exercise time frame and intensity domain in which EIAn episodes have been reported (3). The aim of the Task Force was threefold: firstly, to evaluate the scientific validity of the current working hypotheses in the context of exercise physiology and immunology; secondly, to provide a position statement on pathophysiological mechanisms underlying EIAn; and finally, to identify research needs. Literature search strategy An overview of the search method is provided in Fig. 1. Briefly, the primary method to locate potentially eligible studies was a computerized literature search in the

Allergy 70 (2015) 1212–1221 © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

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Mechanisms of exercise-induced anaphylaxis

Studies identified in inital search (n = 6222): Medline (n = 5291) SportsDiscus (n = 931) [13 duplicates]

Excluded (n = 5911): non-original articles and/or not pertinent to the review aims

Studies identified for full text review (n = 311) Excluded (n = 132): reviews (n = 70) no paper (n = 7) not English (n = 55)

Studies included for full text review (n = 179) Excluded (n = 147): no hypothesized mechanism

Studies included in final analysis (n = 32): gastro-intestinal permeability (n = 7) tissue transglutaminase activation (n = 6) blood flow redistribution and mast cell heterogeneity (n = 14) osmolality (n = 4) pH and mast cell activation (n = 1)

Excluded (n = 11): not relevant (n = 10) duplicate (n = 1)

Studies included review (n = 21): gastro-intestinal permeability (n = 3) tissue transglutaminase activation (n = 3) blood flow redistribution and mast cell heterogeneity (n = 11) osmolality (n = 3) pH and mast cell activation (n = 1)

Figure 1 Flow diagram depicting the process of selection of the papers for final inclusion.

MEDLINE and SportDiscus databases, without any initial restriction on language of publication. A list of search words and terms was compiled using the Boolean search terms: sport OR exercise OR (physical* AND activ*) OR run OR cycle) AND (anaphyla* OR allerg* OR hypersensitive* OR atop*). The search was completed by November 2012 and yielded a total of 6222 unique studies (MEDLINE 5291; SportDiscus: 931). These studies were then evaluated by two independent members of the Task Force to exclude those that were nonoriginal articles and/or not pertinent to the review aims. All relevant titles and abstracts, identified by the search, were selected for a full-text review. This phase yielded 311 studies with exclusion of 5911 studies. At this point, all non-English papers (55) were excluded along with reviews (70) and those for which a full-text was not available (7). The reference lists of selected studies and recent reviews were reviewed to identify additional trials not retrieved by the electronic process. Published pathophysiological mechanisms for EIAn were categorized into 5 main areas with two experts assigned to evaluate publications: 1 Exercise-induced increases in gastrointestinal permeability (n = 3) 2 Increased activity of tissue transglutaminase in the gut mucosa (n = 6) 3 Exercise-induced blood flow redistribution and mast cell heterogeneity (n = 11) 4 Exercise-induced increases in plasma osmolality inducing basophil histamine release (n = 3)

Exercise-induced acidosis and mast cell degranulation (n = 1). Categories were reviewed by all panel members who identified papers relevant to their assigned hypothetical area. Trials were assessed for inclusion by looking at the ‘methods’ section of each paper while remaining unaware of the study’s results, conclusion and authors. A formal grading of the evidence and recommendations was also performed (4, 5). 5

Published proposed pathophysiological mechanisms for EIAn All the studies and their grading are presented in Tables 1–5, but only the most pertinent studies are discussed in the text. Exercise-induced increases in gastrointestinal permeability Background to hypothesis There are two routes through which normal uptake of food proteins occurs across the epithelium, either transcellular transport or paracellular transport (Table 1). Endocytosis, diffusion and active transport use transcellular transport. The paracellular route involves the transport of larger molecules through tight junctions into the interstitial space. These molecules can then enter the systemic circulation from the interstitial fluid between the enterocytes. When tight junctions become relaxed (for example due to thermal injury, alcohol ingestion, nonsteroidal anti-inflammatory agents, prolonged

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Table 1 Evaluating the strength of evidence of studies proposing increased gastrointestinal permeability as a pathophysiological mechanism for EIAn Other considerations

Overall quality

No serious imprecision Low subject numbers

None

Low

Aspirin elevated absorption in EIAn and controls in the absence of exercise

Very low

Low subject numbers

None

Very low

Studies

Design

Limitations

Inconsistency

Indirectness

Imprecision

(58)

RCT Case–control

(59)

Nonexperimental (case reports)

No important inconsistencies Timing and dosage of food ingestion, duration of exercise trial; aspirin elevated absorption in EIAn and controls in the absence of exercise No important inconsistencies

Animals

(6)

No serious limitations Incompatible with current exercise physiology

No serious limitations

Direct

Focus on skin prick testing in EIAn, no evaluation of GI effects.

Table 2 Evaluating the strength of evidence of studies proposing increased tissue transglutaminase activation as a pathophysiological mechanism for EIAn Studies

Design

Limitations

Inconsistency

Indirectness

Imprecision

Other considerations

Overall quality

(12)

Case–control

WDEIAn not confirmed by challenge test

No important inconsistencies

Direct

Low subject numbers

Low

(14)

Case–control

No important inconsistencies

Direct

Low subject numbers

(13)

Case–control

WDEIAn not confirmed by challenge test WDEIAn not confirmed by challenge test

Measuring cytokines (proinflammatory, immunomodulatory) and not only mRNA after stimulation with food allergens (exercise context) would add much None

No important inconsistencies

Direct

No serious imprecision

None

Low

Low

exercise), then permeability to larger molecules is increased. Exercise-induced increased gastrointestinal permeability has been proposed as a means through which EIAn may be triggered with larger molecules (such as some allergenic peptides) having greater access to the gut-associated immune system (6).

of maximal oxygen uptake. Only when exercise was performed at much higher intensities (80% maximal oxygen uptake for 60 min), did gut permeability become increased. Furthermore, Pals et al. found no conclusive evidence of enhanced gastric permeability following exercise at any intensity.

Exercise and gut permeability Evidence indicates that exercise may alter gut permeability; this is however only described in some studies and only after exercise of long duration or high intensity. Very prolonged exercise, for example Ironman triathlons and 24-h marathon runs, can induce alterations in gut integrity and permeability, which results in endotoxin entering the circulation (7) and could potentially facilitate allergen entry. Exercise of a shorter duration does not appear to alter small intestinal permeability at low intensities. Data from Pals et al. (8) suggest that small intestinal permeability is unchanged compared to pre-exercise following 60 mins of exercise at 40% and 60%

Research testing the hypothesis To test the hypothesis, Matsuo et al. (6) had patients who consume a wheat-based food product prior to exercise. Plasma appearance of wheat proteins was measured along with signs and symptoms of allergic reaction. All patients completed the graded exercise protocol whereby exercise intensity or incline was increased every 3 min until voluntary exhaustion (9). The test is designed to typically last less than 20 min with individuals perhaps achieving 80–100% maximal oxygen uptake for a short duration of time in the latter stages of the test. Although the specific duration of exercise is not reported, it is likely that this would have been no

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Table 3 Evaluating the strength of evidence of studies proposing blood flow redistribution as a pathophysiological mechanism for EIAn Other considerations

Overall quality

Low subject numbers No serious imprecision Low subject numbers Low subject numbers

None

Low

None

Low

None

Low

Sound methodical protocol

Low

Low subject numbers. Missing data points Low subject numbers Low subject numbers

None

Low

None

Very low

Observational with no statistical evaluation Observational with no statistical evaluation None

Very low

None

Low

Observational with no statistical evaluation

Very low

Studies

Design

Limitations

Inconsistency

Indirectness

Imprecision

(60)

Case–control

No important inconsistencies

Direct

(61)

No important inconsistencies

Animals

(62)

Randomized control trials Case–control

No important inconsistencies

Direct

(63)

Case–control

No serious limitations No serious limitations No serious limitations No serious limitations

One patient did not exhibit EIU-A after intervention

(64)

Case–control

No serious limitations

No important inconsistencies

Urticaria– angioedema not anaphylaxis Direct

(65)

Case–control

No important inconsistencies

Direct

(66)

Nonexperimental (case reports)

No serious limitations No serious limitations

No important inconsistencies

Direct

(67)

Nonexperimental (case reports)

No serious limitations

No important inconsistencies

Direct

Low subject numbers

(68)

Randomized control trials Randomized control trials Nonexperimental (case reports)

No serious limitations No serious limitations No serious limitations

No important inconsistencies

Animals

No important inconsistencies

Animals

No important inconsistencies

Direct

No serious imprecision No serious imprecision Low subject numbers

(69) (70)

Very low

Low

Table 4 Evaluating the strength of evidence of studies proposing an exercise-induced increased osmolality leading to basophil histamine release as a pathophysiological mechanism for EIAn

Studies

Design

Limitations

Inconsistency

Indirectness

Imprecision

Other considerations

Overall quality

(36)

Nonexperimental (case reports)

Serious limitations

No important inconsistencies

Case–control

Serious limitations

No important inconsistencies

Low subject numbers, underpowered study Only one case subject, underpowered study

Observational with no statistical evaluation Observational with no statistical evaluation

Very low

(35)

(71)

Nonexperimental

No serious limitations

No important

In vitro study, using unphysiological levels of ‘exercise-induced’ osmolality Exercise challenge not performed; diagnosis of EIAn based only on clinical history; basophil test performed few months after the reported episode of EIAn Paper focused on the predicting value of the basophil test in differentiating subjects with HWP-WDEIA from those with CO-WDEIA

Low subject numbers, underpowered study

Letter to the Editor

Low

(case reports)

inconsistencies

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Very low

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Table 5 Evaluating the strength of evidence of studies proposing an exercise-induced reduction in pH as a pathophysiological mechanism for EIAn

Studies

Design

Limitations

Inconsistency

Indirectness

Imprecision

(38)

Nonexperimental (case reports)

Serious limitations

No important inconsistencies

Direct

Low subject numbers: single case report

greater than 20 min. Unfortunately, there were no statistical analyses conducted on the data and some methodological flaws were apparent. The timing between wheat ingestion and exercise varied as did both the source and the dose of wheat provided. Results suggest that serum gliadin concentration was elevated in some of the WDEIAn group postexercise as well as in some of the control, non-WDEIAn group. One participant experienced symptoms of anaphylaxis following the wheat and exercise challenge, but serum gliadin levels remained at baseline. Significantly, Matsuo et al. (6) investigated the influence of a dose of aspirin prior to a wheat challenge (without exercise) and report that aspirin intake increased serum gliadin in both healthy subjects (3 of 4 subjects) and patients with WDEIAn (3 of the 3 patients). Baskin et al. (10) observed that 10 min following a routine dose of 600 mg, 25% of surface epithelial cells obtained by gastric biopsy were damaged in healthy subjects and damage was present in all biopsies after aspirin treatment. Recovery occurred rapidly and within 1 h following ingestion, but a small degree of cell damage remained. More recently, Oshima et al. (11) demonstrated that aspirin can induce gastric epithelial barrier dysfunction by altering the modulation of tight junctions. Based upon these findings, aspirin may increase absorption of larger molecules such as gliadin in both healthy patients and patients with fooddependent, exercise-induced anaphylaxis (FDEIAn). Conclusion In the context of current exercise physiology and pharmacological studies, it is highly unlikely that the exercise load per se associated with the onset of EIAn would have been sufficient to induce any alterations in gastrointestinal permeability and enhanced absorption of specific food allergens. The combination of exercise and ingestion of substances that damage the ultrastructure of the gastric mucosa, for example aspirin or alcohol, may significantly increase the risk of food-allergic patients developing anaphylaxis. Increased activity of tissue transglutaminase in the gut mucosa Background to hypothesis Individuals who develop FDEIAn present severe generalized allergic symptoms with exercise or physical activity and after the ingestion of specific food allergens (ingested prior to and, occasionally, following exercise) (Table 2). Wheat is a common allergen implicated in FDEIAn and more specifically

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Other considerations

Overall quality

None

Very low

omega-5 gliadin (Tri a 19). Individuals with WDEIAn have specific IgE antibodies directed against ethanol-soluble storage proteins, that is gliadins. In particular, x5-gliadin (Tri a 19) has been identified as a major allergen with cross-reactive allergens present in rye (secalins) and barley (c3-hordein) (12–14). It has been hypothesized that exercise-induced alterations in tissue transglutaminase (tTG) enzyme may result in peptide aggregation which leads to increased IgE cross-linking (14). Coeliac disease research has highlighted the importance of the tTG enzyme which is localized beneath the gut epithelium; tTG modifies specific glutaminase residues in wheat, specifically x-5 gliadin, potentially resulting in the formation of large peptide aggregates facilitating greater IgE cross-linking. Exercise and tTG TG is a ubiquitous calcium-dependent enzyme – localized beneath the single-layer gut epithelium – that may be involved in wide range of biologic processes, for example cell growth and differentiation, tissue repair, endocytosis, apoptosis induction (15). TTG catalyses post-translational modification of proteins and is released from cells upon stress-like stimuli such as inflammatory process, oxidative stress and exercise (15, 16). Tissue transglutaminase modifies gliadinderived peptides through deamidation which transforms them into dominant epitopes playing a crucial role in T-cell activation associated with development of coeliac disease [reviewed by Nurminskaya and Belkin (15)]. It may also cross-link specific glutamine residues, which results in formation of gliadin–gliadin complexes and incorporate itself into highmolecular-weight complexes with gliadins. Inflammatory mediators, specifically interleukin-6, increase the expression of tTG (17). The main sources of IL-6 in vivo are monocyte/macrophages, fibroblasts and endothelial cells (18); however, many other cellular sources of IL-6 have been identified. During exercise, IL-6 is actively produced within contracting skeletal muscles and the central nervous system (CNS) as well as peritendinous tissue (19). For example, marathon distance running was shown to increasing resting IL-6 levels approximately 50- to 100-fold (20, 21). Research testing the hypothesis In patients with WDEIAn, the simultaneous action of both stimuli (i.e. exercise and specific IgE cross-linking with wheat proteins) is required for elicitation of anaphylaxis symptoms. The details of the necessity of this dual triggering are not

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clear. It is hypothesized that the activation of tTG (a stressresponsive enzyme) is increased in response to exercise which may be considered a stress-like stimulus in this context. Ability of x5-gliadin to bind IgE is retained after the former is treated with digestive enzymes, peptin and trypsin. TTG cross-links the digested peptic fraction of x5-gliadin into high-molecular-weight complexes, and this cross-linking considerably increases binding of x5-gliadin by specific IgEs. According to the hypothesis, the activation of tTG, as a sequel to exercise, creates large allergen complexes that – in sensitized subjects – elicit anaphylactic reaction once two triggers, that is wheat ingestion and exercise, are present concomitantly (14). Robson-Ansley et al. (22) demonstrate that even 90 min of ‘time trial’ running produced only threefold increases in IL-6 (pre-exercise mean <2 pg/ml, postexercise mean 6.6 pg/ml). This study suggests that, at least, a prolonged bout of exercise is required to induce a moderate increase in interleukin-6, suggesting that the less vigorous activities more commonly associated with EIAn are unlikely to be associated with significant elevations in circulating IL-6. Conclusion EIAn is generally reported following submaximal exercise of a relatively short duration. Whether or not IL-6 concentrations achieved within this exercise domain suffice to activate tTG and subsequently contribute to EIAn remains to be evaluated. Redistribution of blood during exercise and mast cell heterogeneity Background to hypothesis Even during light exercise there is a significant sympathetically mediated redistribution of blood flow, both relative and absolute, away from the visceral organs (primarily the kidneys, liver, stomach and intestines) to supply the working skeletal muscle, heart and skin (23, 24) (Table 3). The redistribution of blood also results in the circulation of white blood cells to these areas which may be implicated in IgEmediated anaphylaxis (24). However, mast cells tend not to circulate but reside in different anatomical sites with substantial differences in mediator content, sensitivity to agents that induce activation and mediator release (25). Unlike other cells of hematopoietic lineage which do not leave the hematopoietic tissue until fully differentiated (neutrophils, basophils or eosinophils), mast cells invade the connective or the mucosal tissue as mast cell progenitors where they differentiate into phenotypically identifiable mast cells (26). Two phenotypes of mast cells with biochemical differences have been previously described in the animal model, namely mucosal mast cells (MMC) and connective tissue mast cells (CTMC) (27, 28). Heavey et al. demonstrated that rat MMC and CTMC differ in their quantitative release of histamine and their metabolism of arachidonic acid to leukotriene C4 and B4 (29). Indeed, functional heterogeneity has been demonstrated in human mast cells of different tissues (30); hence, the quantity and spectrum of mediators released may

Mechanisms of exercise-induced anaphylaxis

differ in different locations as well as under different situations (reviewed elsewhere (25, 31, 32)). Research testing to hypothesis Robson-Ansley and du Toit (3) hypothesized that the redistribution of blood flow during exercise to skeletal muscle and skin away from the visceral organs is the trigger factor in FDEIAn. They posited that at rest, the absorbed food allergenic peptides are tolerated gut-specific mast cells. However, when physical activity is undertaken, the sudden redistribution of blood transports the allergen away from the gut to the skin and/or skeletal muscle, where phenotypically different mast cells reside (33). The interaction of the allergen with these different mast cells results in an altered mediator release and the potential for exercise-induced anaphylaxis. Conclusion The underlying physiological principles of exercise physiology upon which this theory is based are ecologically valid. However, currently there is no experimental evidence to either support or refute this theory. Exercise-induced increases in plasma osmolality inducing basophil histamine release Background to hypothesis Plasma osmolality may increase marginally during prolonged physical activity depending on environmental temperature and fluid intake (Table 4). For example, data from our laboratory indicate that mean resting values of 290 mOsm can increase to 293 mOsm following a 21-km run (n = 35) (L Ansley and PJ Robson-Ansley – unpublished data) and acute ~5% loss in body weight due to dehydration can result in osmolalities of 305 mOsm (34). In vitro studies indicate that alterations in plasma osmolarity can increase basophil activation and histamine release (35, 36); hence, EIAn may occur as a result of increased histamine releasability triggered by an exercise-induced, transient serum hyperosmolarity. Research testing to hypothesis Barg et al. (35) performed in vitro histamine release assays using a range of buffers with increasing osmolarity (280, 340 and 450 mOsm) on basophils from a patient with FDEIAn, food-allergic controls and healthy controls. Histamine release and basophil activation increased in the patient with FDEIAn at 340 mOsm and not in the food-allergic or control subjects. However, as not all food-allergic patients are hypersensitive to exercise, it is a matter of debate whether FDEIAn serum osmolarity increases during exercise or whether basophils are more sensitive to the effects of hyperosmolarity. These findings lead to hypothesize that increased basophil reactivity might play an important role in the pathogenesis of EIAn causing increased histamine release triggered by physical effort and resulting in transient serum hyperosmolarity after exposure to sensitizing food allergen. In a later case–control study, the same group of authors supported their previous results by showing an increased basophil

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activation in hyperosmolarity (340 and 450 mOsm) in two subjects with EIAn but no change in the controls (36). Conclusions Despite the above interesting results, the overall quality of evidence is rated as very low. Findings are based only on three trials performed with weak study designs which used small population sample sizes. Further reliable data are therefore needed to clearly assess the role of this mechanism in the pathogenesis of EIAn. Enhanced basophil activation and histamine release in hyperosmotic states may provide a useful diagnostic in vitro tool for EIAn, but it is unlikely to be a pathophysiological mechanism for the onset of EIAn. The plasma osmolality levels achieved in the aforementioned studies are pathological in vivo and would not be easily achieved even through intense physical exercise. It is highly unlikely that plasma osmolality values reported following acute, moderate-intensity exercise would trigger changes in basophil activation and histamine release. Exercise-induced acidosis and mast cell degranulation Background to hypothesis Moderate-to-intense exercise is associated with local and systemic changes in acid–base balance (37) (Table 5). This process naturally arises as the consequence of the release and buffering of the by-products of exercise metabolism. Indeed, the homeostatic ventilatory response to exercise is tightly coupled with acid–base status to maintain optimum cellular pH (37). The potential role of acid–base disturbance in the development of exercise-associated immune phenomena, including urticaria and anaphylaxis, arises from isolated case reports (38–40). It has been postulated that a cellular-reduced pH (i.e. in the context of acute intense exercise) promotes mast cell degranulation and therefore could heighten any propensity to anaphylaxis. This supposition may be supported by the finding that pre-exercise ingestion of sodium bicarbonate protects against FDEIAn. Research testing to hypothesis One study is included in the review. In this case study (38), a 44-year-old individual with a past history of urticaria and FDEIAn was evaluated under a series of food exposure +/ exercise challenges with and without pre-ingestion of sodium bicarbonate. Firstly, two control challenges were performed: a standard exercise challenge in the fasted state (at 8 km/h for 12 min; achieving a pulse rate between 150 and 180 beats/min) and a 70 g wheat load taken at rest. No symptoms were precipitated and plasma histamine levels remained within the normal range. Following this, further challenges employed the same exercise protocol, however with an antecedent 70 g wheat bread load, administered 40 min prior to exercise. This was followed by the development of typical FDEIAn symptoms and a commensurate rise in plasma histamine. When this identical protocol was repeated with a 3 g sodium bicarbonate load

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taken orally immediately prior to exercise, his symptoms were markedly attenuated; only developed transient mild erythema. Moreover, there was no rise in histamine level. Synchronous measurement of venous pH demonstrated a reduction in the fall in pH: postexercise pH 7.39 vs 7.32 in the nonbicarbonate challenge. Sodium bicarbonate ingestion did not impact on pre-exercise pH. In discussion, the authors comment that the pre-exercise ingestion of sodium bicarbonate may have acted to control pH regulation and thus propensity to mast cell degranulation. There has been no additional study of sodium bicarbonate in FDEIAn since this time. Conclusion The evidence base implicating a role for exercise acidaemia in the development of FDEIAn is currently weak to nonexistent and is based on a single case report. Accordingly, it is not possible to comment on the bias within the study performed and no conclusion can be made with regard to cause and effect. The logic that development of an acidic state may promote mast cell degranulation is based on one study in which mast cell instability was observed at a pH below 7.0 (41). The development of acid–base irregularities in the context of physical exertion typically develops at very high work levels. Cellular pH changes are recognized to fall in response to heavy muscular work; for example, forearm muscle cell pH, estimated by nuclear magnetic resonance (NMR), can fall to approximately 6, after very short periods of rhythmic handgrip exercise (42). Whether or not an exercise-induced fall in pH would be sufficient to promote mast cell degranulation and trigger EIAn remains to be evaluated. Recent advances As is expected in an area with such little research, the advances made in EIAn are often stepwise; therefore, it is not wholly unexpected that since the end of our search strategy, some important papers on EIAn have been published. Although the majority of new publications are represented by case reports or case series in limited population samples, several studies, mainly focusing on wheat-dependent EIAn (WDEIAn), are of higher quality and deserve to be discussed individually. Cai and Yin (43) firstly explored the genetic background of WDEIAn performing a case–control study, with the aim to investigate the association between single nucleotide polymorphisms (SNPs) in three cytokine-related genes and the onset of diseases. Statistically significant differences in genotype frequencies of IL-4-C590T were found between cases and controls. Brockow et al.(44) sought to confirm a diagnosis of WDEIAn using oral gluten flour plus cofactor challenges, with the aim to determine the amount of gluten required to elicit symptoms, as well as to correlate these results with plasma gliadin levels, gastrointestinal permeability and allergologic parameters. Results obtained showed that clinical history, IgE gliadin level and baseline gastrointestinal level were not

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predictive of the outcomes of the challenge. Furthermore, exercise was not an essential trigger for the onset of symptoms in the 16 patients tested. On the contrary, sensitivity and specificity of gluten skin prick tests were particularly high (100% and 96%, respectively). Thirty-six patients with suspected WDEIAn were enrolled in the study of Kohno et al. (45) and divided into three different groups according to the results of wheat and exercise and/or aspirin challenge testing and serum gliadin levels. Data provided evidence that serum gliadin monitoring may represent a useful parameter to identify the patients with false-negative challenges. More recently, it has been reported that g-gliadin is a key allergenic component in WDEIAn supporting the importance of a component-resolved diagnosis for anticipating likely symptoms and clinically classifying specific disease phenotypes (46). With this regard, our group reported how the ImmunoCAP ISAC might provide additional information to those obtained by conventional IgE tests in identifying different sensitization profiles in polysensitized allergic athletes, representing a useful tool to detect athletes at risk for severe allergic reactions and to adopt appropriate preventive measures (47). Among narrative manuscripts on EIAn, those published in the last year may provide more updated information (48–50). Finally, for papers more broadly focused on anaphylaxis and related cofactors, rather than on its specific relationship with exercise, we strongly recommend the reading of some recently published guidelines, consensus reports and systematic reviews (51–57).

potential treatments. We propose the development of a global research network approach to gain sufficient power for scientific evaluation. The initial remit of this network would be to determine whether differences in response to exercise exist for individuals with EIAn compared with both food-allergic and nonfood-allergic controls. We suggest that by adopting a standardized approach to evaluating patients who present with suspected EIAn – which comprises food ingestion timing, exercise bout and outcome measures – significant inroads can be made into identifying the pathology of FDEIAn.

Future research needs

Author contributions

EIAn is a rare condition and, as such, it is problematic for single research groups to obtain sufficient patients to comprehensively evaluate the pathophysiological mechanisms and

All authors contributed extensively to the work presented in this study as defined by the International Committee of Medical Editor Journals (BMJ 1991;302:338-341).

Overall conclusions In order for a theory explaining the pathological mechanisms of EIAn to be supported, it is essential that the proposed mechanisms are valid and that the proposed underlying physiological changes occur within the exercise intensity domain and duration of the physical task which triggers the anaphylaxis. To progress our understanding of EIAn, studies must be well controlled, adequately powered and designed to reflect the realities of exercise physiology. Development of a global research network could facilitate progress in understanding the pathophysiological mechanisms of EIAn and inform treatment and management of the rare yet sometimes fatal condition. Conflict of interest None of the authors have a conflict of interest to declare.

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