Allergy
REVIEW ARTICLE
Factors augmenting allergic reactions B. Niggemann & K. Beyer , Berlin, Germany Division of Pediatric Pneumology and Immunology, University Children’s Hospital Charite
To cite this article: Niggemann B, Beyer K. Factors augmenting allergic reactions. Allergy 2014; 69: 1582–1587.
Keywords anaphylaxis; augmenting factors; food allergy; risk factors; sports. Correspondence Bodo Niggemann, MD, Divsion of Pediatric Pneumology and Immunology, University , Augustenburger Children’s Hospital Charite Platz 1, 13353 Berlin, Germany. Tel.: +49 30 450 666653 Fax: +49 30 450 566931 E-mail: [email protected] Accepted for publication 8 October 2014 DOI:10.1111/all.12532 Edited by: Thomas Bieber
Abstract
Elicitors of anaphylactic reactions are any sources of protein with allergenic capacity. However, not all allergic reactions end up in the most severe form of anaphylaxis. Augmenting factors may explain why certain conditions lead to anaphylaxis. Augmenting factors may exhibit three effects: lowering the threshold, increasing the severity, and reversing acquired clinical tolerance. Common augmenting factors are physical exercise, menstruation, NSAIDs, alcohol, body temperature, acute infections, and antacids. Therapeutic options may address causative, preventive, pragmatic, or symptomatic considerations: avoid the eliciting food, take an antihistamine before any situation with a possible risk of augmentation, separate food and sport (at least for 2 h), and carry an adrenaline autoinjector at all times. Individual patterns include summation effects and specific patterns. In conclusion, in the case of a suggestive history but a negative oral challenge, one should consider the possible involvement of augmenting factors; after anaphylactic reactions, always ask for possible augmentation and other risk factors during the recent past; if augmentation is suspected, oral food challenges should be performed in combination with augmenting factors; and in the future, standardized challenge protocols including augmenting factors should be established.
Elicitors of anaphylactic reactions are any sources of protein with allergenic capacity, such as foods, drugs, insect venoms, pollen, animal dander, occupational allergens, or seminal fluid. However, not all allergic reactions end up in the most severe form of anaphylaxis. Accompanying factors may explain why some conditions lead to anaphylaxis, while in other cases, the allergen is tolerated. It is becoming increasingly accepted that certain accompanying factors or conditions play an important role in the development of allergic reactions, especially for anaphylaxis (1–6). In the presence of these factors, allergic reactions may be elicited at lower doses or there may be more severe or even life-threatening clinical reactions. A consensus on the treatment of acute anaphylactic reactions has recently been reached (7). Terminology ‘Risk factor’ is a general term covering any factor, which may lead to more severe allergic reactions (Fig. 1). But for anaphylaxis, the term risk factor comprises three distinguishable entities: First are the augmenting factors, defined as factors, which lower the reaction threshold or which make allergic
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symptoms more severe by directly influencing the immunological mechanism of type I allergy (modified from (8)). Typical examples are physical exercise, acute infectious diseases, certain drugs (e.g., nonsteroidal anti-inflammatory drugs, proton pump inhibitors), alcohol, or menstruation. Unfortunately, a range of terms are currently in use, such as aggravating factors, amplifying factors, summation factors, facilitators, cofactors, risk factors, and x-factors. We propose the use of augmenting factors. Second are the concomitant diseases, which jeopardize patients or which increase mortality; typical examples are underlying diseases such as bronchial asthma, mastocytosis, or cardiovascular disease. Third are the cofactors, defined as a subgroup of risk factors not acting on an immunological basis themselves (no influence on the allergen-IgE-effector cell-mediated allergic reaction itself); typical examples are certain allergens (e.g., peanuts or tree nuts), certain stages of development (e.g., adolescence), psychological factors (e.g., emotional stress), or drugs used on a daily basis (e.g., ACE inhibitors). In our view, a three-section classification comes closest to these underlying pathophysiological mechanisms. However, the following review is limited to the consideration of augmenting factors.
Allergy 69 (2014) 1582–1587 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Factors augmenting allergic reactions
Niggemann and Beyer
Risk factors for anaphylactic reactions
Augmenting factors
Concomitant diseases
Cofactors
= Co-existing diseases,
(= a subgroup of risk factors,
= Factors, which lower the reaction threshold or which make symptoms more severe by directly influencing the immunological mechanism of type I allergy
which jeopardize
not acting on an
patients or
immunological basis
which increase
themselves)
mortality e.g. certain allergens,
e.g. physical exercise, menstruation, NSAID, alcohol,
e.g. bronchial asthma,
adolescence, beta-blocker,
cardiac diseases, mastocytosis
ACE-inhibitors, psyche
body temperature, infections, antacids
Figure 1 Proposal for a new terminology of risk factors for anaphylactic reactions.
Effects
Common augmenting factors
Augmenting factors have three main effects on allergic reactions (Fig. 2): 1. Lowering the threshold: Without augmentation, allergic reactions only occur after consuming a larger amount of food, if at all. But with augmentation, severe allergic reactions may be observed at much lower doses. 2. Increasing the severity: With augmentation, more severe reactions are elicited by the same dose of food or anaphylaxis is observed for the first time. 3. Reversing acquired clinical tolerance: After acquiring clinical tolerance over time, allergic reactions may suddenly re-occur due to the acute influence of augmenting factors (9).
Physical exercise
History The first report of an exercise-induced allergic reaction (10) was followed by the publication of a number of cases and case series (11–13). From the 1990s, the subject of exerciseinduced anaphylaxis became more common in the literature. Even familiarity of exercise-induced anaphylaxis (EIA) has been observed (14, 15).
Physical exercise is the best-known augmenting factor. Exercise-augmented symptoms range from exercise-induced urticaria to full-blown exercise-induced anaphylaxis. Certainly, there is a dose–response relationship between both increasing amounts of food and increasing physical exercise with clinical symptoms. The food may be consumed from 4 h before exercise up to 1 h after exercise. Discussed mechanisms include (i) muscular activity leading to elevated body temperature and elevated blood circulation leading to increased influx of allergen from the gut, (ii) increased osmolarity and a lowered ph, ending up in basophil activation and increased histamine releasibility (20), and (iii) elevated IL-6, elevated tissue glutaminase building aggregates with higher IgE binding and cross-linking (21). Hormonal influences The influence of estrogen and progesterone on bronchial asthma has been under debate for years (22), but cases of food-dependent exercise-induced anaphylaxis have only recently been reported (23, 24). The underlying mechanism may be heterogeneous (25).
Epidemiology The prevalence of exercise-induced anaphylaxis has been addressed in two Asian studies: One study from Japan investigating 11 647 children found no cases in nursery, 0.06% in preschool, and 0.21% in school (16). A Korean study looked at 978 146 patients and found four cases of EIA in this population (17). The prevalence of accompanying factors in anaphylaxis is reported to be around 30% in adults (6) and 18% in children (18). The youngest reported child was 4 years old (19).
Antiphlogistics Nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, may enhance food-dependent exercise-induced anaphylaxis (26). NSAIDs may augment anaphylaxis even in the absence of exercise (27). It has been shown that NSAID can cause gastrointestinal hyperpermeability, which elevates serum gliadin levels in a dose-dependent manner and may therefore accelerate symptom development in gliadin-sensitized patients with wheat allergy (28). These
Allergy 69 (2014) 1582–1587 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
1583
Factors augmenting allergic reactions
A Without augmentaon
Niggemann and Beyer
With augmentaon
Food allergy Food allergy Symptom threshold Food tolerance
Symptom threshold Food tolerance
B Without augmentaon
With augmentaon
Severe symptoms
Severe symptoms Mild symptoms
Mild symptoms
Body temperature The equilibrium of the body temperature seems to have a narrow range. A cold environment (32, 33) or a warm environment (34) may augment severe allergic reactions. The pathophysiology of these conditions is unclear. Acute infections From studies with specific oral tolerance induction (SOTI), it is well known that a much lower threshold to the corresponding food is observed during phases of acute infection. Further evidence derives from case reports (35). The pathophysiology may be explained by fever, followed by elevated blood circulation and subsequent influx of allergen. For gastrointestinal infections, an inflamed and disturbed mucosal barrier may lead to larger undigested proteins passing through the mucosa, which then come into contact with sensitized lymphoid structures. Furthermore, several possible immunological mechanisms were recently discussed in more detail (6). Antacids
C Food allergy
Augmentaon
Symptom threshold
Clinical tolerance
Antacids may be involved in allergic reactions by several mechanisms, both long term and short term. Proton pump inhibitors (PPI) may alleviate allergic sensitization, the acute use of PPIs may lead to clinical symptoms of food allergy (36), or some individuals may develop direct allergy to the group of drugs (37). The possible augmenting effect of antacids on anaphylactic reactions may result from restricted digestion so that intact allergens reach lower parts of the gastrointestinal tract.
Time Mechanisms Figure 2 Different effects of augmenting factors. (A) Lowering the threshold, (B) Increasing severity, (C) Reversing acquired clinical tolerance.
augmenting effects may even be induced by low-dose aspirin therapy (29). Alcohol Although alcohol consumption and allergic reactions are related in many minds, astonishingly little is known in the literature about the effects of alcohol on anaphylaxis. There have been few case reports on this topic (30, 31). Hypothetically, alcohol may augment allergic reactions by the following mechanisms: (i) Alcoholics show higher IgE levels than nondrinkers; (ii) individuals can react to various ingredients in alcoholic beverages (e.g., to sulfite); and (iii) alcohol may act as an augmenting factor (although there is no direct evidence for this). Finally, drinking alcohol may lower the inhibition to reintroduce a food, which has been eliminated from the diet for a long period of time.
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Factors may augment anaphylactic reactions in many ways. Figure 3 presents an overview of possible interacting effects, many of which remain hypothetical at present. Therapeutic options Therapeutic options, which can be recommended to patients with augmented anaphylaxis, may address different considerations: 1. Causative: Avoid the eliciting food (if known. . .) 2. Preventive: Take an antihistamine before any situation with a possible risk of augmentation (or even on daily basis in selected cases) 3. Pragmatic: Separate food and sport (at least for 2 h) 4. Symptomatic: Carry an adrenaline autoinjector at all times Individual patterns For an individual, the following factors may play a role: 1. Summation effects: Although severe reaction may be observed at all dose levels during oral food challenges
Allergy 69 (2014) 1582–1587 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Factors augmenting allergic reactions
Niggemann and Beyer
Augmentation factors
Psyche Psycho-Neuro-Immunology
Physical exercise
Body temperature up
Acute infections
Antacids
Internal warming
Alcohol
Circulation elevated
Hormonal?
Antiphlogistics
Influx of allergen increased Intestinal permeability increased IgE-production facilitated Tissue transglutaminase
Peptide-aggregates with high binding
Hapten-allergen effects? Mastocytosis
Releasability increased
Figure 3 Possible interacting mechanisms of augmentation.
2.
(38), the amount of the food as well as the number of foods and finally the number of augmenting factors may contribute to summation effects, sometimes called ‘summation anaphylaxis’. In daily life, several risk factors may coincide. For example, a 16-year-old female, suffering from peanut allergy, with insufficiently controlled bronchial asthma, taking ibuprofen for relief during menstruation, visits a party and drinks alcohol, but has forgotten to carry an adrenaline autoinjector and has an empty bronchodilator with her. In such a case, several risk factors come together so that anaphylaxis becomes more likely. One may even hypothesize that an anaphylactic reaction may hardly be possible without any risk factor. Specific patterns: While certain augmenting factors may be clinically relevant for one person (e.g., physical exercise, alcohol), other factors may be relevant for another patient (e.g., infections, antiphlogistics). Individuality may be more important than the type of augmenting factor. However, exercise seems to be the most prevalent augmenting factor.
published proposals for a grouping of factors [Simons 2012]. This paper from the World Allergy Organization proposed a two-term classification of (a) patient factors, such as agerelated factors, concomitant diseases, and concurrent drugs/ medication, and (b) cofactors, such as exercise, infection, menstrual cycle, or stress (39). Other authors proposed four headings: lifestyle factors, drugs, pre-existing diseases, and patient-specific factors (40). A study from the German Registry investigated risk factors and addressed elicitors, age, and underlying atopic disease (41). As a basis for discussion, we suggest a classification of risk factors of anaphylaxis, which considers pathophysiological aspects with the aim of clarifying inconsistencies within the existing terminology. Conclusions 1. 2. 3.
Discussion While several authors use various terms interchangeably or at least without any classification, some authors have
4.
The phenomenon of augmentation has been well known for a long time, but is still neglected. It may be assumed that food allergy plays a role in most cases of exercise-induced anaphylaxis. Augmentation does not always lead to full-blown anaphylaxis, but may also induce moderate symptoms. In some cases, foods only induce allergic symptoms if augmenting factors lower the threshold for clinical reactions.
Allergy 69 (2014) 1582–1587 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
1585
Factors augmenting allergic reactions
5.
6. 7.
Niggemann and Beyer
In the case of a suggestive history but a negative oral challenge, one should consider the possible involvement of augmenting factors. After anaphylactic reactions, always ask for possible augmentation and other risk factors during the recent past. If augmentation is suspected, oral food challenges should be performed in combination with augmenting factors.
8.
In the future, standardized challenge protocols including augmenting factors should be established.
Conflicts of interest The authors declare that they have no conflicts of interest.
References 1. Cardona V, Luengo O, Garriga T, Labrador-Horillo M, Sala-Cunill A, Izqierdo A et al. Co-factor-enhanced food allergy. Allergy 2012;67:1316–1318. 2. Muraro A, Roberts G, Worm M, Bil o MB, Brockow K, Fernandez Rivas M et al. Anaphylaxis: guidelines from the European academy of allergy and clinical immunology. Allergy 2014;69:1008–1025. 3. Muraro A, Werfel T, Hoffmann-Sommergruber K, Roberts G, Beyer K, Bindslev-Jensen C et al. EAACI food allergy and anaphylaxis guidelines: diagnosis and management of food allergy. Allergy 2014;69:1026–1045. 4. Panesar SS, Javad S, de Silva D, Nwaru BI, Hickstein L, Muraro A et al. The epidemiology of anaphylaxis in Europe: a systematic review. Allergy 2013;68:1353–1361. 5. Romano A, Di Fonso M, Giuffreda F, Quarantino D, Papa G, Palmieri V et al. Diagnostic work-up for food-dependent, exercise-induced anaphylaxis. Allergy 1995;50:817–824. 6. W€ olbing F, Fischer J, K€ oberle M, Kaesler S, Biedermann T. About the role and underlying mechanisms of cofactors in anaphylaxis. Allergy 2013;68:1085–1092. 7. Dhami S, Panesar SS, Roberts G, Muraro A, Worm M, Bil o MB et al. Management of anaphylaxis: a systematic review. Allergy 2014;69:168–175. 8. W€ olbing F, Biedermann T. Anaphylaxis: opportunities of stratified medicine for diagnosis and risk assessment. Allergy 2013;68:1499–1508. 9. Garcıa-Ara MC, Valls Sanchez A, Boyano Martinez MT, Dıaz Pena JM. Cow’s milkdependent, exercise-induced anaphylaxis: case report of a patient with previous allergy to cow’s milk. J Allergy Clin Immunol 2003;111:647–648. 10. Maulitz RM, Pratt DS, Schocket AL. Exercise-induced anaphylactic reaction to shellfish. J Allergy Clin Immunol 1979;63: 433–434. 11. Lewis J, Lieberman P, Treadwell G, Erffmeyer J. Exercise-induced urticarial, angioedema, and anaphylactoid episodes. J Clin Allergy Immunol 1981;68:432–437. 12. Buchbinder EM, Bloch KJ, Moss J, Guiney TE. Food-dependent, exercise-induced anaphylaxis. JAMA 1983;250:2973–2974.
1586
13. Kidd JM III, Cohen SH, Sosman AJ, Fink JN. Food-dependent exercise-induced anaphylaxis. J Allergy Clin Immunol 1983;71:407–411. 14. Grant JA, Farnam J, Lord RA, Thueson DO, Lett-Brown MA, Wallfisch H et al. Familial exercise-induced anaphylaxis. Ann Allergy 1985;54:35–38. 15. Longley S, Panush RS. Familial exerciseinduced anaphylaxis. Ann Allergy 1987;58:257–259. 16. Tanaka S. An epidemiological survey on food-dependent exercise-induced anaphylaxis in kindergartners, schoolchildren and junior high school students. Asia Pac J Public Health 1994;7:26–30. 17. Yang MS, Lee SH, Kim TW, Kwon JW, Lee SM, Kim SH et al. Epidemiologic and clinical features of anaphylaxis in Korea. Ann Allergy Asthma Immunol 2008;100:31– 36. 18. Hompes S, K€ ohli A, Nemat K, Scherer K, Lange L, Rueff F et al. Provoking allergens and treatment of anaphylaxis in children and adolescents - data from the anaphylaxis registry of German-speaking countries. Pediatr Allergy Immunol 2011;22:569–574. 19. Lashley M, Klein N. Case report: exerciseinduced anaphylaxis in a 4-year-old boy. Ann Asthma Immunol 1990;64:381–382. 20. Barg W, Wolanczyk-Medrala A, Obojski A, Wytrychowski K, Panaszek P, Medrala W. Food-dependent exercise-induced anaphylaxis: possible impact of increased basophil histamine releasability in hyperosmolar conditions. J Investig Allergol Clin Immunol 2008;18:312–315. 21. Palosuo K, Varjonen E, Nurkkala J, Kalkkinen N, Harvima R, Reunala T et al. Transglutaminase-mediated cross-linking of a peptide fraction of x-5 gliadin enhances IgE reactivity in wheat-dependent, exerciseinduced anaphylaxis. J Allergy Clin Immunol 2003;111:1386–1392. 22. Haggerty CL, Ness RB, Kelsey S, Waterer GW. The impact of estrogen and progesterone on asthma. Ann Allergy Asthma Immunol 2003;90:284–291. 23. Bito T, Kanda E, Tanaka M, Fukunaga A, Horikawa T, Nishigori C. Cows milk-dependent exercise-induced anaphylaxis under the condition of a premenstrual or ovulatory
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
phase following skin sensitization. Allergol Int 2008;57:437–439. Fischer J, Schuck E, Biedermann T. Wheatdependent exercise-induced anaphylaxis exclusively during menstruation. Allergy 2010;65:1347–1348. Bauer CS, Kampitak T, Messieh ML, Kelly KJ, Vadas P. Heterogeneity in presentation and treatment of catamenial anaphylaxis. Ann Allergy Asthma Immunol 2013;111:107– 111. Aihara M, Miyazawa M, Osuna H, Tsubaki K, Ikebe T, Aihara Y et al. Food-dependent exercise-induced anaphylaxis: influence of concurrent aspirin administration on skin testing and provocation. Br J Dermatol 2002;146:466–472. Matsukara S, Aihara M, Sugawara M, Kunimi Y, Matsuki M, Inoue Y et al. Two cases of wheat-dependent anaphylaxis induced by aspirin administration but not by exercise. Clin Exp Dermatol 2009;35:233–237. Matsuo H, Kaneko S, Tsujino Y, Honda S, Kohno K, Takahashi H et al. Effects of non-steroidal anti-inflammatory drugs (NSAIDs) on serum allergen levels after wheat ingestion. J Dermatol Sci 2009;53:241–243. Fujii H, Kambe N, Fujisawa A, Kohno K, Morita E, Miyachi Y. Food-dependent exercise-induced anaphylaxis induced by low dose aspirin therapy. Allergol Int 2008;57:97–98. Borras EA, Faraudo EB, Jane PG, Zavala BB. Alcohol-induced anaphylaxis to grape. Allergol Immunopathol 2007;35:159–161. Garcıa-Robaina JC, de la Torre-Morın F, Sanchez-Machın I, Sanchez-Monge R, Barber D, Lombardero M. Anaphylaxis induced by exercise and wine. Allergy 2001;56:357– 358. Li M, Sayama K, Tohyama M, Hashimoto K. A case of cold-dependent exerciseinduced anaphylaxis. Br J Dermatol 2002;147:368–370. Shimizu T, Furumoto H, Kinoshita E, Ogasawara Y, Nakamura C, Hashimoto Y et al. Food-dependent exercise-induced anaphylaxis occurring only in winter. Dermatology 2000;200:279. Jo EJ, Yang MS, Kim YJ, Kim HS, Kim MY, Kim SH et al. Food-dependent
Allergy 69 (2014) 1582–1587 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Factors augmenting allergic reactions
Niggemann and Beyer
exercise-induced anaphylaxis occurred only in a warm but not in a cold environment. Asia Pac Allergy 2012;2:161–164. 35. Mazur N, Patterson R, Perlman D. A case of idiopathic anaphylaxis associated with respiratory infections. Ann Allergy Asthma Immunol 1997;79:546– 548. 36. Pali-Sch€ oll I, Jensen-Jarolim E. Anti-acid medication as a risk factor for food allergy. Allergy 2011;66:469–477.
37. Lauerma AI, Petman L, M€akinen-Kiljunen S. IgE-mediated anaphylaxis to antacid. Allergy 2001;56:580. 38. Rolinck-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;67:951–957. 39. Simons FER, Ardusso LRF, Bil o MB, ElGamal YM, Ledford DK, Ring J et al.
Allergy 69 (2014) 1582–1587 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
World Allergy Organization anaphylaxis guidelines: summary. J Allergy Clin Immunol 2012;127:587–593. 40. Worm M, Babina M, Hompes S. Causes and risk factors for anaphylaxis. J Dtsch Dermatol Ges 2013;11:44–50. 41. Worm W, Edenharter G, Rueff F, Scherer K, Pf€ ohler C, Mahler V et al. Symptom profile and risk factors of anaphylaxis in Central Europe. Allergy 2012;67:691– 698.
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REVIEW ARTICLE
Factors augmenting allergic reactions B. Niggemann & K. Beyer , Berlin, Germany Division of Pediatric Pneumology and Immunology, University Children’s Hospital Charite
To cite this article: Niggemann B, Beyer K. Factors augmenting allergic reactions. Allergy 2014; 69: 1582–1587.
Keywords anaphylaxis; augmenting factors; food allergy; risk factors; sports. Correspondence Bodo Niggemann, MD, Divsion of Pediatric Pneumology and Immunology, University , Augustenburger Children’s Hospital Charite Platz 1, 13353 Berlin, Germany. Tel.: +49 30 450 666653 Fax: +49 30 450 566931 E-mail: [email protected] Accepted for publication 8 October 2014 DOI:10.1111/all.12532 Edited by: Thomas Bieber
Abstract
Elicitors of anaphylactic reactions are any sources of protein with allergenic capacity. However, not all allergic reactions end up in the most severe form of anaphylaxis. Augmenting factors may explain why certain conditions lead to anaphylaxis. Augmenting factors may exhibit three effects: lowering the threshold, increasing the severity, and reversing acquired clinical tolerance. Common augmenting factors are physical exercise, menstruation, NSAIDs, alcohol, body temperature, acute infections, and antacids. Therapeutic options may address causative, preventive, pragmatic, or symptomatic considerations: avoid the eliciting food, take an antihistamine before any situation with a possible risk of augmentation, separate food and sport (at least for 2 h), and carry an adrenaline autoinjector at all times. Individual patterns include summation effects and specific patterns. In conclusion, in the case of a suggestive history but a negative oral challenge, one should consider the possible involvement of augmenting factors; after anaphylactic reactions, always ask for possible augmentation and other risk factors during the recent past; if augmentation is suspected, oral food challenges should be performed in combination with augmenting factors; and in the future, standardized challenge protocols including augmenting factors should be established.
Elicitors of anaphylactic reactions are any sources of protein with allergenic capacity, such as foods, drugs, insect venoms, pollen, animal dander, occupational allergens, or seminal fluid. However, not all allergic reactions end up in the most severe form of anaphylaxis. Accompanying factors may explain why some conditions lead to anaphylaxis, while in other cases, the allergen is tolerated. It is becoming increasingly accepted that certain accompanying factors or conditions play an important role in the development of allergic reactions, especially for anaphylaxis (1–6). In the presence of these factors, allergic reactions may be elicited at lower doses or there may be more severe or even life-threatening clinical reactions. A consensus on the treatment of acute anaphylactic reactions has recently been reached (7). Terminology ‘Risk factor’ is a general term covering any factor, which may lead to more severe allergic reactions (Fig. 1). But for anaphylaxis, the term risk factor comprises three distinguishable entities: First are the augmenting factors, defined as factors, which lower the reaction threshold or which make allergic
1582
symptoms more severe by directly influencing the immunological mechanism of type I allergy (modified from (8)). Typical examples are physical exercise, acute infectious diseases, certain drugs (e.g., nonsteroidal anti-inflammatory drugs, proton pump inhibitors), alcohol, or menstruation. Unfortunately, a range of terms are currently in use, such as aggravating factors, amplifying factors, summation factors, facilitators, cofactors, risk factors, and x-factors. We propose the use of augmenting factors. Second are the concomitant diseases, which jeopardize patients or which increase mortality; typical examples are underlying diseases such as bronchial asthma, mastocytosis, or cardiovascular disease. Third are the cofactors, defined as a subgroup of risk factors not acting on an immunological basis themselves (no influence on the allergen-IgE-effector cell-mediated allergic reaction itself); typical examples are certain allergens (e.g., peanuts or tree nuts), certain stages of development (e.g., adolescence), psychological factors (e.g., emotional stress), or drugs used on a daily basis (e.g., ACE inhibitors). In our view, a three-section classification comes closest to these underlying pathophysiological mechanisms. However, the following review is limited to the consideration of augmenting factors.
Allergy 69 (2014) 1582–1587 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Factors augmenting allergic reactions
Niggemann and Beyer
Risk factors for anaphylactic reactions
Augmenting factors
Concomitant diseases
Cofactors
= Co-existing diseases,
(= a subgroup of risk factors,
= Factors, which lower the reaction threshold or which make symptoms more severe by directly influencing the immunological mechanism of type I allergy
which jeopardize
not acting on an
patients or
immunological basis
which increase
themselves)
mortality e.g. certain allergens,
e.g. physical exercise, menstruation, NSAID, alcohol,
e.g. bronchial asthma,
adolescence, beta-blocker,
cardiac diseases, mastocytosis
ACE-inhibitors, psyche
body temperature, infections, antacids
Figure 1 Proposal for a new terminology of risk factors for anaphylactic reactions.
Effects
Common augmenting factors
Augmenting factors have three main effects on allergic reactions (Fig. 2): 1. Lowering the threshold: Without augmentation, allergic reactions only occur after consuming a larger amount of food, if at all. But with augmentation, severe allergic reactions may be observed at much lower doses. 2. Increasing the severity: With augmentation, more severe reactions are elicited by the same dose of food or anaphylaxis is observed for the first time. 3. Reversing acquired clinical tolerance: After acquiring clinical tolerance over time, allergic reactions may suddenly re-occur due to the acute influence of augmenting factors (9).
Physical exercise
History The first report of an exercise-induced allergic reaction (10) was followed by the publication of a number of cases and case series (11–13). From the 1990s, the subject of exerciseinduced anaphylaxis became more common in the literature. Even familiarity of exercise-induced anaphylaxis (EIA) has been observed (14, 15).
Physical exercise is the best-known augmenting factor. Exercise-augmented symptoms range from exercise-induced urticaria to full-blown exercise-induced anaphylaxis. Certainly, there is a dose–response relationship between both increasing amounts of food and increasing physical exercise with clinical symptoms. The food may be consumed from 4 h before exercise up to 1 h after exercise. Discussed mechanisms include (i) muscular activity leading to elevated body temperature and elevated blood circulation leading to increased influx of allergen from the gut, (ii) increased osmolarity and a lowered ph, ending up in basophil activation and increased histamine releasibility (20), and (iii) elevated IL-6, elevated tissue glutaminase building aggregates with higher IgE binding and cross-linking (21). Hormonal influences The influence of estrogen and progesterone on bronchial asthma has been under debate for years (22), but cases of food-dependent exercise-induced anaphylaxis have only recently been reported (23, 24). The underlying mechanism may be heterogeneous (25).
Epidemiology The prevalence of exercise-induced anaphylaxis has been addressed in two Asian studies: One study from Japan investigating 11 647 children found no cases in nursery, 0.06% in preschool, and 0.21% in school (16). A Korean study looked at 978 146 patients and found four cases of EIA in this population (17). The prevalence of accompanying factors in anaphylaxis is reported to be around 30% in adults (6) and 18% in children (18). The youngest reported child was 4 years old (19).
Antiphlogistics Nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, may enhance food-dependent exercise-induced anaphylaxis (26). NSAIDs may augment anaphylaxis even in the absence of exercise (27). It has been shown that NSAID can cause gastrointestinal hyperpermeability, which elevates serum gliadin levels in a dose-dependent manner and may therefore accelerate symptom development in gliadin-sensitized patients with wheat allergy (28). These
Allergy 69 (2014) 1582–1587 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
1583
Factors augmenting allergic reactions
A Without augmentaon
Niggemann and Beyer
With augmentaon
Food allergy Food allergy Symptom threshold Food tolerance
Symptom threshold Food tolerance
B Without augmentaon
With augmentaon
Severe symptoms
Severe symptoms Mild symptoms
Mild symptoms
Body temperature The equilibrium of the body temperature seems to have a narrow range. A cold environment (32, 33) or a warm environment (34) may augment severe allergic reactions. The pathophysiology of these conditions is unclear. Acute infections From studies with specific oral tolerance induction (SOTI), it is well known that a much lower threshold to the corresponding food is observed during phases of acute infection. Further evidence derives from case reports (35). The pathophysiology may be explained by fever, followed by elevated blood circulation and subsequent influx of allergen. For gastrointestinal infections, an inflamed and disturbed mucosal barrier may lead to larger undigested proteins passing through the mucosa, which then come into contact with sensitized lymphoid structures. Furthermore, several possible immunological mechanisms were recently discussed in more detail (6). Antacids
C Food allergy
Augmentaon
Symptom threshold
Clinical tolerance
Antacids may be involved in allergic reactions by several mechanisms, both long term and short term. Proton pump inhibitors (PPI) may alleviate allergic sensitization, the acute use of PPIs may lead to clinical symptoms of food allergy (36), or some individuals may develop direct allergy to the group of drugs (37). The possible augmenting effect of antacids on anaphylactic reactions may result from restricted digestion so that intact allergens reach lower parts of the gastrointestinal tract.
Time Mechanisms Figure 2 Different effects of augmenting factors. (A) Lowering the threshold, (B) Increasing severity, (C) Reversing acquired clinical tolerance.
augmenting effects may even be induced by low-dose aspirin therapy (29). Alcohol Although alcohol consumption and allergic reactions are related in many minds, astonishingly little is known in the literature about the effects of alcohol on anaphylaxis. There have been few case reports on this topic (30, 31). Hypothetically, alcohol may augment allergic reactions by the following mechanisms: (i) Alcoholics show higher IgE levels than nondrinkers; (ii) individuals can react to various ingredients in alcoholic beverages (e.g., to sulfite); and (iii) alcohol may act as an augmenting factor (although there is no direct evidence for this). Finally, drinking alcohol may lower the inhibition to reintroduce a food, which has been eliminated from the diet for a long period of time.
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Factors may augment anaphylactic reactions in many ways. Figure 3 presents an overview of possible interacting effects, many of which remain hypothetical at present. Therapeutic options Therapeutic options, which can be recommended to patients with augmented anaphylaxis, may address different considerations: 1. Causative: Avoid the eliciting food (if known. . .) 2. Preventive: Take an antihistamine before any situation with a possible risk of augmentation (or even on daily basis in selected cases) 3. Pragmatic: Separate food and sport (at least for 2 h) 4. Symptomatic: Carry an adrenaline autoinjector at all times Individual patterns For an individual, the following factors may play a role: 1. Summation effects: Although severe reaction may be observed at all dose levels during oral food challenges
Allergy 69 (2014) 1582–1587 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
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Augmentation factors
Psyche Psycho-Neuro-Immunology
Physical exercise
Body temperature up
Acute infections
Antacids
Internal warming
Alcohol
Circulation elevated
Hormonal?
Antiphlogistics
Influx of allergen increased Intestinal permeability increased IgE-production facilitated Tissue transglutaminase
Peptide-aggregates with high binding
Hapten-allergen effects? Mastocytosis
Releasability increased
Figure 3 Possible interacting mechanisms of augmentation.
2.
(38), the amount of the food as well as the number of foods and finally the number of augmenting factors may contribute to summation effects, sometimes called ‘summation anaphylaxis’. In daily life, several risk factors may coincide. For example, a 16-year-old female, suffering from peanut allergy, with insufficiently controlled bronchial asthma, taking ibuprofen for relief during menstruation, visits a party and drinks alcohol, but has forgotten to carry an adrenaline autoinjector and has an empty bronchodilator with her. In such a case, several risk factors come together so that anaphylaxis becomes more likely. One may even hypothesize that an anaphylactic reaction may hardly be possible without any risk factor. Specific patterns: While certain augmenting factors may be clinically relevant for one person (e.g., physical exercise, alcohol), other factors may be relevant for another patient (e.g., infections, antiphlogistics). Individuality may be more important than the type of augmenting factor. However, exercise seems to be the most prevalent augmenting factor.
published proposals for a grouping of factors [Simons 2012]. This paper from the World Allergy Organization proposed a two-term classification of (a) patient factors, such as agerelated factors, concomitant diseases, and concurrent drugs/ medication, and (b) cofactors, such as exercise, infection, menstrual cycle, or stress (39). Other authors proposed four headings: lifestyle factors, drugs, pre-existing diseases, and patient-specific factors (40). A study from the German Registry investigated risk factors and addressed elicitors, age, and underlying atopic disease (41). As a basis for discussion, we suggest a classification of risk factors of anaphylaxis, which considers pathophysiological aspects with the aim of clarifying inconsistencies within the existing terminology. Conclusions 1. 2. 3.
Discussion While several authors use various terms interchangeably or at least without any classification, some authors have
4.
The phenomenon of augmentation has been well known for a long time, but is still neglected. It may be assumed that food allergy plays a role in most cases of exercise-induced anaphylaxis. Augmentation does not always lead to full-blown anaphylaxis, but may also induce moderate symptoms. In some cases, foods only induce allergic symptoms if augmenting factors lower the threshold for clinical reactions.
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6. 7.
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In the case of a suggestive history but a negative oral challenge, one should consider the possible involvement of augmenting factors. After anaphylactic reactions, always ask for possible augmentation and other risk factors during the recent past. If augmentation is suspected, oral food challenges should be performed in combination with augmenting factors.
8.
In the future, standardized challenge protocols including augmenting factors should be established.
Conflicts of interest The authors declare that they have no conflicts of interest.
References 1. Cardona V, Luengo O, Garriga T, Labrador-Horillo M, Sala-Cunill A, Izqierdo A et al. Co-factor-enhanced food allergy. Allergy 2012;67:1316–1318. 2. Muraro A, Roberts G, Worm M, Bil o MB, Brockow K, Fernandez Rivas M et al. Anaphylaxis: guidelines from the European academy of allergy and clinical immunology. Allergy 2014;69:1008–1025. 3. Muraro A, Werfel T, Hoffmann-Sommergruber K, Roberts G, Beyer K, Bindslev-Jensen C et al. EAACI food allergy and anaphylaxis guidelines: diagnosis and management of food allergy. Allergy 2014;69:1026–1045. 4. Panesar SS, Javad S, de Silva D, Nwaru BI, Hickstein L, Muraro A et al. The epidemiology of anaphylaxis in Europe: a systematic review. Allergy 2013;68:1353–1361. 5. Romano A, Di Fonso M, Giuffreda F, Quarantino D, Papa G, Palmieri V et al. Diagnostic work-up for food-dependent, exercise-induced anaphylaxis. Allergy 1995;50:817–824. 6. W€ olbing F, Fischer J, K€ oberle M, Kaesler S, Biedermann T. About the role and underlying mechanisms of cofactors in anaphylaxis. Allergy 2013;68:1085–1092. 7. Dhami S, Panesar SS, Roberts G, Muraro A, Worm M, Bil o MB et al. Management of anaphylaxis: a systematic review. Allergy 2014;69:168–175. 8. W€ olbing F, Biedermann T. Anaphylaxis: opportunities of stratified medicine for diagnosis and risk assessment. Allergy 2013;68:1499–1508. 9. Garcıa-Ara MC, Valls Sanchez A, Boyano Martinez MT, Dıaz Pena JM. Cow’s milkdependent, exercise-induced anaphylaxis: case report of a patient with previous allergy to cow’s milk. J Allergy Clin Immunol 2003;111:647–648. 10. Maulitz RM, Pratt DS, Schocket AL. Exercise-induced anaphylactic reaction to shellfish. J Allergy Clin Immunol 1979;63: 433–434. 11. Lewis J, Lieberman P, Treadwell G, Erffmeyer J. Exercise-induced urticarial, angioedema, and anaphylactoid episodes. J Clin Allergy Immunol 1981;68:432–437. 12. Buchbinder EM, Bloch KJ, Moss J, Guiney TE. Food-dependent, exercise-induced anaphylaxis. JAMA 1983;250:2973–2974.
1586
13. Kidd JM III, Cohen SH, Sosman AJ, Fink JN. Food-dependent exercise-induced anaphylaxis. J Allergy Clin Immunol 1983;71:407–411. 14. Grant JA, Farnam J, Lord RA, Thueson DO, Lett-Brown MA, Wallfisch H et al. Familial exercise-induced anaphylaxis. Ann Allergy 1985;54:35–38. 15. Longley S, Panush RS. Familial exerciseinduced anaphylaxis. Ann Allergy 1987;58:257–259. 16. Tanaka S. An epidemiological survey on food-dependent exercise-induced anaphylaxis in kindergartners, schoolchildren and junior high school students. Asia Pac J Public Health 1994;7:26–30. 17. Yang MS, Lee SH, Kim TW, Kwon JW, Lee SM, Kim SH et al. Epidemiologic and clinical features of anaphylaxis in Korea. Ann Allergy Asthma Immunol 2008;100:31– 36. 18. Hompes S, K€ ohli A, Nemat K, Scherer K, Lange L, Rueff F et al. Provoking allergens and treatment of anaphylaxis in children and adolescents - data from the anaphylaxis registry of German-speaking countries. Pediatr Allergy Immunol 2011;22:569–574. 19. Lashley M, Klein N. Case report: exerciseinduced anaphylaxis in a 4-year-old boy. Ann Asthma Immunol 1990;64:381–382. 20. Barg W, Wolanczyk-Medrala A, Obojski A, Wytrychowski K, Panaszek P, Medrala W. Food-dependent exercise-induced anaphylaxis: possible impact of increased basophil histamine releasability in hyperosmolar conditions. J Investig Allergol Clin Immunol 2008;18:312–315. 21. Palosuo K, Varjonen E, Nurkkala J, Kalkkinen N, Harvima R, Reunala T et al. Transglutaminase-mediated cross-linking of a peptide fraction of x-5 gliadin enhances IgE reactivity in wheat-dependent, exerciseinduced anaphylaxis. J Allergy Clin Immunol 2003;111:1386–1392. 22. Haggerty CL, Ness RB, Kelsey S, Waterer GW. The impact of estrogen and progesterone on asthma. Ann Allergy Asthma Immunol 2003;90:284–291. 23. Bito T, Kanda E, Tanaka M, Fukunaga A, Horikawa T, Nishigori C. Cows milk-dependent exercise-induced anaphylaxis under the condition of a premenstrual or ovulatory
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
phase following skin sensitization. Allergol Int 2008;57:437–439. Fischer J, Schuck E, Biedermann T. Wheatdependent exercise-induced anaphylaxis exclusively during menstruation. Allergy 2010;65:1347–1348. Bauer CS, Kampitak T, Messieh ML, Kelly KJ, Vadas P. Heterogeneity in presentation and treatment of catamenial anaphylaxis. Ann Allergy Asthma Immunol 2013;111:107– 111. Aihara M, Miyazawa M, Osuna H, Tsubaki K, Ikebe T, Aihara Y et al. Food-dependent exercise-induced anaphylaxis: influence of concurrent aspirin administration on skin testing and provocation. Br J Dermatol 2002;146:466–472. Matsukara S, Aihara M, Sugawara M, Kunimi Y, Matsuki M, Inoue Y et al. Two cases of wheat-dependent anaphylaxis induced by aspirin administration but not by exercise. Clin Exp Dermatol 2009;35:233–237. Matsuo H, Kaneko S, Tsujino Y, Honda S, Kohno K, Takahashi H et al. Effects of non-steroidal anti-inflammatory drugs (NSAIDs) on serum allergen levels after wheat ingestion. J Dermatol Sci 2009;53:241–243. Fujii H, Kambe N, Fujisawa A, Kohno K, Morita E, Miyachi Y. Food-dependent exercise-induced anaphylaxis induced by low dose aspirin therapy. Allergol Int 2008;57:97–98. Borras EA, Faraudo EB, Jane PG, Zavala BB. Alcohol-induced anaphylaxis to grape. Allergol Immunopathol 2007;35:159–161. Garcıa-Robaina JC, de la Torre-Morın F, Sanchez-Machın I, Sanchez-Monge R, Barber D, Lombardero M. Anaphylaxis induced by exercise and wine. Allergy 2001;56:357– 358. Li M, Sayama K, Tohyama M, Hashimoto K. A case of cold-dependent exerciseinduced anaphylaxis. Br J Dermatol 2002;147:368–370. Shimizu T, Furumoto H, Kinoshita E, Ogasawara Y, Nakamura C, Hashimoto Y et al. Food-dependent exercise-induced anaphylaxis occurring only in winter. Dermatology 2000;200:279. Jo EJ, Yang MS, Kim YJ, Kim HS, Kim MY, Kim SH et al. Food-dependent
Allergy 69 (2014) 1582–1587 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Factors augmenting allergic reactions
Niggemann and Beyer
exercise-induced anaphylaxis occurred only in a warm but not in a cold environment. Asia Pac Allergy 2012;2:161–164. 35. Mazur N, Patterson R, Perlman D. A case of idiopathic anaphylaxis associated with respiratory infections. Ann Allergy Asthma Immunol 1997;79:546– 548. 36. Pali-Sch€ oll I, Jensen-Jarolim E. Anti-acid medication as a risk factor for food allergy. Allergy 2011;66:469–477.
37. Lauerma AI, Petman L, M€akinen-Kiljunen S. IgE-mediated anaphylaxis to antacid. Allergy 2001;56:580. 38. Rolinck-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;67:951–957. 39. Simons FER, Ardusso LRF, Bil o MB, ElGamal YM, Ledford DK, Ring J et al.
Allergy 69 (2014) 1582–1587 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
World Allergy Organization anaphylaxis guidelines: summary. J Allergy Clin Immunol 2012;127:587–593. 40. Worm M, Babina M, Hompes S. Causes and risk factors for anaphylaxis. J Dtsch Dermatol Ges 2013;11:44–50. 41. Worm W, Edenharter G, Rueff F, Scherer K, Pf€ ohler C, Mahler V et al. Symptom profile and risk factors of anaphylaxis in Central Europe. Allergy 2012;67:691– 698.
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