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Keywords:

  • anaphylaxis;
  • augmentation factor;
  • cofactor;
  • infection;
  • mast cell

Abstract

  1. Top of page
  2. Abstract
  3. Exercise as cofactor of anaphylaxis
  4. Drugs as cofactors of anaphylaxis
  5. Alcohol as cofactor of anaphylaxis
  6. Infections as cofactors of anaphylaxis
  7. Conclusion
  8. Conflict of interest
  9. Author contributions
  10. References

Anaphylaxis is the systemic and most severe presentation of type I allergy. A number of conditions were identified that modulate the onset of anaphylaxis such as co- or augmentation factors, which significantly lower the allergen dose necessary for triggering anaphylaxis. Next to physical exercise or alcohol consumption, co-administration of nonsteroidal anti-inflammatory drugs (NSAID) or concomitant infectious diseases are well-documented cofactors of anaphylaxis. Registries for anaphylaxis document a role for cofactors in about 30% of anaphylactic reactions. Some disease entities such as ‘wheat-dependent exercise-induced anaphylaxis’ (WDEIA) are explicitly characterized by elicitation of anaphylaxis only in the presence of at least one such cofactor. Using WDEIA as a model disease, studies demonstrated that exercise increases skin prick test reactivity to and bioavailability of the allergen. Additional data indicate that alcohol consumption and NSAID administration display similar effects. Modulation of the cellular activation threshold is another mechanism underlying cofactor-induced anaphylaxis, most likely also functional when infectious diseases orchestrate elicitation of anaphylaxis. Cofactors are increasingly accepted to play a fundamental role in eliciting anaphylaxis. Consequently, to improve patient management modalities, a better understanding of the underlying mechanisms is warranted. This review aims to update clinicians and clinical scientists on recent developments.

Classically, the allergen-induced cross-linking of IgE antibodies bound to high-affinity Fcε receptors on mast cells initiates signal transduction and the release of preformed mediators like histamine, which elicit the clinical symptoms of type I allergic reactions. The most severe presentation of type I allergy is called ‘anaphylaxis’, defined as a generalized immediate-type hypersensitivity reaction. Anaphylaxis is clinically characterized by involvement of more than one organ system, in particular the skin, the gastrointestinal tract, the respiratory, and the cardiovascular system. The symptoms comprise relatively mild urticaria or diarrhea but also possibly life-threatening anaphylactic shock [1].

Available epidemiological data regarding anaphylaxis are widely varying, most likely due to incoherent definitions of anaphylaxis and a lack of reporting. Published studies estimate a lifetime prevalence between 0.05% and 2% and an incidence of 3.2–68.4 per 100 000 patient-years [2, 3]. Although anaphylaxis seems to be triggered by sole allergen contact in most cases, the role of additional factors, also referred to as co- or augmentation factors, for the elicitation of anaphylaxis is increasingly accepted. For the first time, cofactor-dependent anaphylaxis was described in 1979 by Maulitz et al. [4] who described a patient with ‘exercise-induced anaphylaxis to shellfish’. Meanwhile, physical exercise is the best studied cofactor of anaphylaxis and ‘food-dependent exercise-induced anaphylaxis’ (FDEIA) is accepted as a defined clinical entity. Other well-documented cofactors of anaphylaxis are nonsteroidal anti-inflammatory drugs (NSAID) like acetylsalicylic acid (ASA), alcohol consumption, and infectious diseases in general [5-12]. According to the anaphylaxis registries of different European countries, next to exercise, alcohol consumption is a relevant cofactor in up to 15.2% of anaphylactic events and drugs such as ASA were registered as a cofactor in 6.1–9% of severe anaphylactic reactions (Table 1). The role of infections as cofactors of anaphylaxis is reported to be relevant in 2.5–3% of anaphylactic reactions in children and in 1.3–11% in adults [8, 13-18]. Infections are particularly dangerous for patients with a risk to develop anaphylaxis, because in contrast to most other relevant cofactors of anaphylaxis, infections cannot simply be avoided or foreseen.

Table 1. Prevalence of cofactor-dependent anaphylaxis
ReferenceUguz et al. [17]CICBAAa [18]Treudler et al. [16]Worm et al. [8]Mullins [14]CICBAAa [18]CICBAAa [18]CICBAAa [18]Uguz et al. [17]De Swert et al. [15]Hompes et al. [13]Worm et al. [8]
  1. a

    CICBAA = French food allergy network.

PopulationAdultsAdultsAdultsAdultsAdults and childrenAdults and childrenAdults and childrenAdults and childrenChildrenChildrenChildren and adolescentsChildren
SubpopulationFood allergyFood allergyFood allergyFood allergyFood allergyFood allergy
Population size51107105156432851391147564197115
Year2000–2001200220062006–20091995–20002003200720082000–20012004–20062005–20082006–2009
CountryUKFranceGermanyGermanyAustraliaFranceFranceFranceUKBelgiumGermanyGermany
Cofactor25.6%39%18.3%14%
Exercise0%15.9%3%9.6%20.4%5.9%12.9%12.3%2.5%7.8%10%
Alcohol15.2%3.7%1%9.6%5.9%10.1%8.9%0%
Infection6.1%11%1.3%2.5%3%2.6%
NSAID4.7%1.2%4.3%3.5%3%
(Other) drugs3.7%7.1%4.3%2.6%6%2.6%
Others (menstruation, psychological stress)12.1%Mental stress: 8%10.3%12%

Extrapolation from different studies and registries suggests that cofactors play a role in about 30% of all anaphylactic reactions in adults (Table 1). These data highlight the importance of recognizing cofactors in patients with anaphylaxis and of including them into diagnostic measures. Detailed questions about a possible involvement of cofactors must be part of each allergologist's patient routine assessment. Identifying both the eliciting allergen and the dependence on cofactors is pivotal for patients' diagnostic measures, risk assessment, and doctors' advice for the patients, which should help to avoid possibly life-threatening anaphylactic events in the future.

Thus, following the increasing awareness of the role of cofactors for anaphylaxis, there is a need for a better understanding. This should also help to develop more specific treatment strategies. The research in this field is just emerging, but initial data indicate two major levels of cofactor-induced modulation eliciting anaphylaxis: increased bioavailability of the allergen and decreased activation threshold on the cellular level (Table 2). Thus, allergen doses not sufficient to induce anaphylaxis in the absence of cofactors become dangerous triggers of anaphylaxis (as schematically shown in Fig. 1) in susceptible patients [19].

Table 2. Proposed mode of action of the most important cofactors of anaphylaxis
 Increased intestinal allergen absorptionIncreased cellular activation
ExerciseTight junction dysregulation [25, 30, 31]Hypothetically due to increased plasma osmolality [25, 34, 35], activation of intestinal transglutaminase [36], or endorphin release [37, 38]
ASATight junction dysregulation [30, 40, 41]Idiosyncrasy due to cyclooxygenase blockade [42, 43]
AlcoholTight junction dysregulation [25, 54] 
Infectious diseases Cellular activation by innate immune receptors [68-71], anaphylatoxins [74, 75], or via FcγR [63]
image

Figure 1. ‘Threshold dose’ model of cofactor-dependent anaphylaxis. High allergen doses induce strong anaphylaxis, while low allergen doses induce subclinical allergic reaction but no anaphylaxis. In contrast, low ‘subthreshold’ allergen doses in combination with cofactors trigger strong anaphylaxis.

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Exercise as cofactor of anaphylaxis

  1. Top of page
  2. Abstract
  3. Exercise as cofactor of anaphylaxis
  4. Drugs as cofactors of anaphylaxis
  5. Alcohol as cofactor of anaphylaxis
  6. Infections as cofactors of anaphylaxis
  7. Conclusion
  8. Conflict of interest
  9. Author contributions
  10. References

Exercise as a cofactor of anaphylaxis was first reported by Maulitz et al. They reported on a patient who developed anaphylactic symptoms two times following jogging after shellfish ingestion, whereas physical exercise as well as shellfish alone was tolerated [4]. This constellation emerged to be no singular event and later on was defined as the separate disease entity of ‘food-dependent exercise-induced anaphylaxis’ (FDEIA). Although exercise does not exclusively trigger anaphylaxis in food allergic patients, FDEIA patients are the most relevant group of patients with exercise-triggered anaphylaxis (EIA). Meanwhile, numerous case reports describe FDEIA to pistachio, spinach, meat, shrimps, wheat, and many more [20, 21] and also for the more recently described entity of delayed type I allergy to red meat in patients sensitized to galactose-α-1,3-galactose [22]. FDEIA events are most often associated with jogging. However, symptoms can also be triggered by physical exercise of only moderate intensity [23]. For some patients, even marginal physical stress is a sufficient cofactor such as ironing in an elderly lady that was sufficient to trigger anaphylaxis to a meat loaf [24].

To date, the best characterized EIA syndrome which therefore can serve as a model disease is FDEIA following consumption of products containing wheat [25]. This most prevalent subform of FDEIA, termed ‘wheat-dependent exercise-induced anaphylaxis’ (WDEIA), was characterized in detail by Palosuo et al. [26]. Later, it was demonstrated that in most WDEIA patients, conventional tests to verify sensitization to wheat remain without reaction [27], but IgE directed against ω-5-gliadin (Tri a 19), an ethanol-soluble wheat protein, is most valuable to diagnose WDEIA [28, 29].

The current understanding of the pathophysiology of exercise-induced anaphylaxis to allergens focuses on two levels of cofactor modulation:

  1. Exercise increases the bioavailability and influences the distribution of certain allergens,
  2. Exercise decreases the threshold for activation of mast cells and basophils.

Investigations on WDEIA showed that both, exercise and ASA, increased intestinal absorption of allergens possibly by establishing a leakage of the intestinal barrier (see also Fig. 2). Matsuo et al. [30] could show significantly increased uptake of gliadin in humans after consumption of wheat followed by adequate physical exertion. One possible underlying mechanism is intestinal barrier dysfunction; however, a high intensity and a long duration of more than 8 h were shown to be necessary to obtain a relevant barrier dysfunction [25]. This indicates at least additional other mechanisms of action, because clinical observation shows that the intensity of exercise necessary to trigger FDEIA in humans varies quite tremendously from exercise near exhaustion to very mild. Interestingly, a mouse study on gastrointestinal lysozyme uptake showed that not only exercise but also lysozyme-specific sensitization significantly upregulated intestinal absorption and that sensitization and exercise together synergistically increased this uptake demonstrating the interdependence of IgE reactivity and exercise [31]. In conclusion, available data indicate the following scenario: the intensity of exercise and the degree of sensitization coregulate the intestinal absorption of allergens with the consequence of orchestrating anaphylaxis each on an individual level.

image

Figure 2. Modulation of the intestinal allergen absorption. In the presence of cofactors like alcohol or exercise, the intestinal allergen absorption is increased. The more rapid allergen uptake results in higher peak concentrations allowing even low amounts of allergen to touch or exceed the threshold for inducing anaphylaxis.

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Next to allergen bioavailability, exercise seems to influence the threshold for activation of mast cells and basophils. Regarding mast cells, this assumption is mainly based on data from immediate-type skin test reactions. These were more marked if patients underwent a defined form of exercise prior to testing [32, 33]. One explanation for this decreased cellular activation threshold that is discussed is increased plasma osmolality, because intense exercise leads to an increased serum osmolality and changes in pH [25, 34, 35]. However, in vitro studies confirming this hypothesis applied osmolality levels of at least 340 mOsm normally not reached under exercise or even under pathologic conditions, which only slightly exceed physiological values of 280–290 mOsm [25, 34, 35]. Alternative concepts postulate that activation of tissue transglutaminase (tTG) in the intestinal mucosa is able to enhance degranulation on a cellular level and that exercise-induced release of endorphins may enhance MC or basophil activation. The first hypothesis is based on observations that the cytokine interleukin (IL)-6, whose expression is 50- to 100-fold increased in marathon runners, upregulates tTG which by modifying especially ω-5-gliadin proteins allows the formation of large peptide aggregates more effectively cross-linking the high-affinity IgE receptor FcεRI [36].

The latter hypothesis is based on in vitro experiments showing that beta-endorphin induces human mast cell degranulation and histamine release [37]. Investigations in chronic allergic rhinitis patients confirmed that nasal pretreatment of sensitized patients with beta-endorphin significantly enhances histamine levels in the nasal fluid after allergen challenge, while nasal beta-endorphin treatment alone did not [38]. However, such effects were not yet analyzed in anaphylaxis.

Consequences for the clinician

Even though scientific analyses are ongoing, at present the following can be concluded: (i) exercise increases the intestinal allergen absorption and (ii) the clinical relevance of this effect and the intensity of exercise necessary to trigger anaphylaxis in a patient depend on various individual factors such as the sensitization pattern. Therefore, a complete diagnostic assessment in patients with suspected FDEIA must always include provocation tests to identify the eliciting allergen/food and to assess the individual risk of anaphylaxis. The most important differential diagnoses of FDEIA are cholinergic urticaria, exercise-induced asthma, and physical urticaria. It should also be considered that in some patients, more than one cofactor is necessary to elicit anaphylaxis such as exercise and alcohol or exercise and ASA.

Drugs as cofactors of anaphylaxis

  1. Top of page
  2. Abstract
  3. Exercise as cofactor of anaphylaxis
  4. Drugs as cofactors of anaphylaxis
  5. Alcohol as cofactor of anaphylaxis
  6. Infections as cofactors of anaphylaxis
  7. Conclusion
  8. Conflict of interest
  9. Author contributions
  10. References

NSAID

Some groups of drugs can modulate the onset of anaphylactic reactions triggered by allergens independent of a drug-specific sensitization. In this respect, evidence is best for a role of NSAID as cofactors of anaphylaxis with the first report published in 1984 [39]. Epidemiological data—even though relatively sparse—suggest that NSAID trigger anaphylaxis in 1.2–4.7% of all reported anaphylactic events (Table 1). Mechanisms underlying ‘idiosyncrasy’ (nonimmunological hypersensitivity) to NSAID probably contribute to its role as cofactor of type I allergy, but underlying mechanisms are still incompletely understood. Experimental data, however, prove NSAID's role in augmenting type I allergic reactions. Flemström et al. [40] investigated a model of dextran allergy in passively sensitized guinea pigs. While intragastric dextran administration alone caused no reaction, addition of ASA triggered anaphylaxis. These results suggest that similar to exercise, intestinal absorption of antigen can be upregulated by administration of ASA. Indeed, investigating the absorption of gliadin in humans with and without concomitant intake of ASA demonstrated that ASA increased the amount of serum gliadin 30 min after wheat consumption by fivefold [30]. As one possible underlying mechanism, a dysregulation of tight junctions establishing the intestinal barrier in the gastrointestinal epithelium was postulated [30, 40]. Indeed, treatment with 5 mM ASA decreased production of the tight junction protein claudin-7 and significantly increased dextran permeability in an in vitro model [41].

Of note, idiosyncratic reactions in response to NSAID such as urticaria or gastrointestinal symptoms are thought to be related to the nonselective blockade of cyclooxygenase 1 and cyclooxygenase 2 by NSAID. As compensation, synthesis of leukotriene A4 from arachidonic acid via the 5-lipoxygenase is increased. The activation of the LTC4 synthase then results in an enhanced release also of other leukotrienes derived from leukotriene A4. Susceptible patients display idiosyncrasy to NSAID, some of them based on a polymorphism in the promotor region of the leukotriene C4 synthase [42, 43]. The pattern of symptoms in patients with idiosyncrasy such as generalized urticaria, angioedema, and dyspnea resembles that of anaphylactic reactions and idiosyncrasy of the gastrointestinal tract, even though less well known, is frequent. This indicates that the mechanisms of NSAID idiosyncrasy may also be underlying changes in the gastrointestinal barrier postulated in cofactor-induced anaphylaxis. In addition to these effects, in vitro pretreatment of mast cells with ASA directly modulated FcεRI-dependent mast cell degranulation and LTC4 release following FcεRI stimulation [44, 45]. Moreover, several studies could show that also in humans, systemic administration of ASA triggers increased skin test reactions to different allergens [30, 32], supporting the concept that ASA next to modulating the intestinal absorption of allergens also directly modulates effector cell function in cofactor-induced anaphylaxis.

Other drugs relevant to anaphylaxis

In general, it can be assumed that drugs that are able to cause mediator release from mast cells and basophils are potential triggering factors of IgE-mediated anaphylactic reactions and thus may act as cofactors of anaphylaxis. Important examples of such drugs are X-ray contrast media (in general, iodinated contrast media, most frequently iomeprol and iopromide) [46], muscle relaxants (most frequently suxamethonium) [47], certain antibiotics like DNA gyrase inhibitors, and some opioids [48, 49]. Another mechanism of triggering anaphylaxis may be supporting allergen persistence. H2-receptor antagonists and the so-called proton pump inhibitors (PPI) blocking or inducing long-lasting suppression of the gastric acids may lead to allergen persistence, especially of degradable allergens. Gastric acid digests and thereby modulates or inactivates protein allergens. Both drugs interfere with these functions by increasing the gastric pH. This results in less efficient inactivation of food allergens, and otherwise, labile allergens may reach the intestine and induce local or systemic allergic reactions. Indeed, studies in mice confirmed that the use of PPI increases the risk of sensitization to food allergens and the risk to develop anaphylaxis [50]. Even in humans, it was shown that 25% of all patients tested developed clinically relevant IgE against food allergens while being on PPI [51]. This is especially relevant for patients with oral allergy syndrome to acid-sensitive allergens that are at risk to develop systemic type I reaction following high allergen intake while being on PPI [51, 52].

The inhibition of beta-adrenergic signals on effector cells of anaphylaxis, such as mast cells and basophilic granulocytes, by beta-adrenoceptor antagonists leads to inhibition of the cyclic AMP system and consequently to a destabilization of these cells [53]. In addition, beta-adrenoceptor antagonists inhibit important blood pressure regulating mechanisms, both facilitating the induction and severity of anaphylaxis. However, the significance of these mechanisms for triggering anaphylaxis is still a matter of debate. A recent multicenter study failed to confirm that treatment with beta-adrenoceptor antagonists is a predictive parameter for the occurrence of severe anaphylactic reactions in a cohort of hymenoptera venom allergic patients [9].

Consequences for the clinician

Emerging evidence indicates that different drugs can act as cofactors of anaphylaxis. Especially NSAIDs are frequently identified as cofactors of anaphylaxis. Consequently, NSAIDs are to be included in diagnostic measures and patients should be informed about their relative risk. It should be especially recommended to avoid the combined intake of identified food allergens and NSAIDs. If muscle relaxants or X-ray contrast media are suspected to induce anaphylaxis or anaphylactoid reactions, they should either be avoided or premedication with corticosteroids and antihistamines should be recommended. In case of PPI medication, patients with oral allergy syndrome should be informed about the possible role of PPIs to act as cofactors of anaphylaxis through incomplete acid-dependent digestion. Beta-adrenoceptor antagonists are used in patients with myocardial infarction, cardiac arrhythmias, and severe heart failure, and the risk associated with avoiding beta-adrenoceptor antagonist treatment may outweigh the risk of anaphylaxis. The decision of avoiding beta-adrenoceptor antagonists has to be taken on an individual basis.

Alcohol as cofactor of anaphylaxis

  1. Top of page
  2. Abstract
  3. Exercise as cofactor of anaphylaxis
  4. Drugs as cofactors of anaphylaxis
  5. Alcohol as cofactor of anaphylaxis
  6. Infections as cofactors of anaphylaxis
  7. Conclusion
  8. Conflict of interest
  9. Author contributions
  10. References

Alcohol consumption was shown to facilitate the manifestation of food allergies in about 10% of patients and to also trigger FDEIA [54]. According to data from European anaphylaxis registries, alcohol was reported as a cofactor of anaphylaxis even in up to 15.2% of patients (Table 1).

Like ASA, alcohol relaxes tight junctions in gut epithelium suggesting consecutive increase in intestinal protein absorption [25]. Especially for small proteins, an alcohol-dependent increase in the intestinal absorption seems to be an underlying mechanism for anaphylaxis [55, 56]; however, experimental evidence is still sparse.

Consequences for the clinician

To make the diagnosis of alcohol-triggered anaphylaxis, it is obligatory to perform oral provocation tests. Often, including additional cofactors such as ASA or exercise helps to confirm the diagnosis of alcohol-induced anaphylaxis.

Infections as cofactors of anaphylaxis

  1. Top of page
  2. Abstract
  3. Exercise as cofactor of anaphylaxis
  4. Drugs as cofactors of anaphylaxis
  5. Alcohol as cofactor of anaphylaxis
  6. Infections as cofactors of anaphylaxis
  7. Conclusion
  8. Conflict of interest
  9. Author contributions
  10. References

Clinical experience shows that especially early phases of infectious diseases and also clinically mild infections can effectively augment anaphylaxis. Next to case reports [10, 57], the best evidence showing a role of infectious diseases acting as cofactors of anaphylaxis comes from anaphylaxis registries, reporting a relevance of concomitant infection in 2.5–3% of anaphylactic reactions in children and in 1.3–11% in adults (Table 1). Most often, clinicians observed an association of infections and anaphylactic reactions following specific immunotherapy (SIT) with pollen or hymenoptera venoms. Although usually well tolerated, episodes of anaphylaxis occur after SIT in combination with infection and consequently patients undergoing SIT must not suffer from infections [5, 11, 57]. In addition, the role of infections as cofactors of anaphylaxis is well documented in clinical trials with patients suffering from food allergy. Staden et al. [58] reported that 12 of 25 type I allergic children developed cofactor-induced anaphylaxis during oral tolerance induction with milk or eggs with the most common augmentation factor being ‘infection’ next to exercise.

Consequently, current guidelines for specific immunotherapy and manufacturers' recommendations advise doctors to discontinue SIT in case of infection [11]. Underlying mechanisms of how ‘infections’ act as cofactors of anaphylaxis are still not understood. Obviously and in contrast to other cofactors, provocation tests with and without infection as cofactor cannot be performed in humans and animal models suitable to elucidate the underlying mechanism on the cellular and molecular level were not yet established. Components of the ‘adaptive immune system’ were mostly addressed as mediators of enhanced type I allergy. Structures of pathogens leading to sensitization and IgE production or cross-reactivity with existing IgE could serve as allergens themselves [59-61]. IgE antibodies, but even more important IgM and IgG antibodies, also form soluble multimeric antibody–antigen immune complexes. Under physiological conditions, this is an important way of antigen elimination. However, if phagocytosis is insufficient, immune complexes can cause damage by initiating complement activation resulting in formation of ‘anaphylatoxins’ C3a and C5a and other pro-inflammatory and chemotactic components [62]. Besides FcεRI, basophils and mast cells also express activating FcγR, which can promote degranulation [63]. Indeed, FcγRI-dependent degranulation of human mast cells mediated by antibodies of the IgG1 subclass is very similar to FcεRI stimulation in regard to the amount and the pattern of released mediators [64, 65]. Thus, IgG production induced by ‘infection’ could also determine the outcome of anaphylaxis.

Alternatively but not yet addressed in detail, components of the ‘innate immune system’ could take part in the elicitation of type I allergy. This concept is especially intriguing, because substances from bacteria, fungi, or viruses generally known as ‘pathogen-associated molecular patterns’ (PAMP) can directly bind to pathogen recognition receptors (PRR) leading to cell activation and immune modulation without the need of previous sensitization [66, 67]. It is well established that mast cells and basophils express PRR and are activated by different PAMP [68, 69], which could alter their responsiveness [70]. Indeed, it was shown that the PAMP peptidoglycan (PGN) can induce degranulation in human [71] and murine mast cells [72]. In addition, some PAMP can also modulate and inhibit mast cell degranulation pointing toward a well-balanced system of innate mast cell stimulation [73]. Pathogens also lead to activation of the complement system resulting in generation of the so-called anaphylatoxins C3a and C5a. Several studies could demonstrate that both C3a and C5a trigger histamine release from mast cells, C5a being much more potent than C3a [74]. However, the activating role of anaphylatoxins is restricted to certain subpopulations of mast cells because mucosal mast cells fail to express anaphylatoxin receptors [75] and their contribution to anaphylaxis is still unclear [76]. In summary, bacterial or viral products can be sensed by receptors on mast cells and basophils and—under certain conditions—trigger or enhance mast cell degranulation. A model allowing to investigate how microbial factors act as cofactors of anaphylaxis is still lacking and research in this respect is ongoing.

Consequences for the clinician

Knowing about the role of infections as cofactors of anaphylaxis is most important in the context of SIT. SIT must be paused or continued with a reduced dose in case of infection. In case of infection-triggered anaphylaxis in a patient's history, other cofactors like ASA or exercise should be used as surrogates in the test protocol.

Conclusion

  1. Top of page
  2. Abstract
  3. Exercise as cofactor of anaphylaxis
  4. Drugs as cofactors of anaphylaxis
  5. Alcohol as cofactor of anaphylaxis
  6. Infections as cofactors of anaphylaxis
  7. Conclusion
  8. Conflict of interest
  9. Author contributions
  10. References

The elicitation and severity of anaphylaxis depends on a variety of factors including the character of the allergen itself, the allergen dose, the sensitization status of the patient, and the affinity of the patient's IgE for the respective allergens. In addition, it was increasingly recognized that co- or augmentation factors of anaphylaxis potently modulate the clinical response. Such cofactors of anaphylaxis are physical exercise, alcohol, NSAID, and infectious diseases [5]. Strikingly, up to 39% of severe anaphylactic reactions are triggered by cofactors according to epidemiological studies with ‘physical exercise’ being the most frequent, followed by ‘alcohol’, ‘NSAID and other drugs’, and ‘infectious diseases’ (Table 1). Given the importance of cofactors for elicitation and severity of anaphylaxis, these cofactors need to be included into diagnostic measures and patients' management. Provocation tests with or without cofactors are the gold standard for individual risk assessment. By definition, cofactors make patients become susceptible to lower allergen doses triggering anaphylaxis and increased allergen bioavailability or susceptibility to activation are believed to be the underlying causes (Table 2). Although we begin to understand the mechanisms underlying the most important cofactors of anaphylaxis, for a more complete understanding further research is urgently needed. Only the understanding of the processes leading to cofactor-triggered anaphylaxis will allow us to develop new and better treatments for those patients at risk and to give better advice to our patients.

Conflict of interest

  1. Top of page
  2. Abstract
  3. Exercise as cofactor of anaphylaxis
  4. Drugs as cofactors of anaphylaxis
  5. Alcohol as cofactor of anaphylaxis
  6. Infections as cofactors of anaphylaxis
  7. Conclusion
  8. Conflict of interest
  9. Author contributions
  10. References

There are no conflicts of interest according to the ICMJE Form for Disclosure of Potential Conflicts of Interest. The above-mentioned form was submitted for each author.

Author contributions

  1. Top of page
  2. Abstract
  3. Exercise as cofactor of anaphylaxis
  4. Drugs as cofactors of anaphylaxis
  5. Alcohol as cofactor of anaphylaxis
  6. Infections as cofactors of anaphylaxis
  7. Conclusion
  8. Conflict of interest
  9. Author contributions
  10. References

The article was written by Florian Wölbing and Tilo Biedermann. Jörg Fischer, Martin Köberle and Susanne Kaesler each substantially contributed to the conception of the article as well as to acquisition, analysis, and interpretation of the data, critically revised the drafts of the article, and approved the final version for publication.

References

  1. Top of page
  2. Abstract
  3. Exercise as cofactor of anaphylaxis
  4. Drugs as cofactors of anaphylaxis
  5. Alcohol as cofactor of anaphylaxis
  6. Infections as cofactors of anaphylaxis
  7. Conclusion
  8. Conflict of interest
  9. Author contributions
  10. References
  • 1
    Ring J, Brockow K, Behrendt H. History and classification of anaphylaxis. Novartis Found Symp 2004;257:616.
  • 2
    Lieberman P, Camargo CA Jr, Bohlke K, Jick H, Miller RL, Sheikh A et al. Epidemiology of anaphylaxis: findings of the American College of Allergy, Asthma and Immunology Epidemiology of Anaphylaxis Working Group. Ann Allergy Asthma Immunol 2006;97:596602.
  • 3
    Koplin JJ, Martin PE, Allen KJ. An update on epidemiology of anaphylaxis in children and adults. Curr Opin Allergy Clin Immunol 2011;11:492496.
  • 4
    Maulitz RM, Pratt DS, Schocket AL. Exercise-induced anaphylactic reaction to shellfish. J Allergy Clin Immunol 1979;63:433434.
  • 5
    Simons FE, Ardusso LR, Bilo MB, El Gamal YM, Ledford DK, Ring J et al. World Allergy Organization anaphylaxis guidelines: summary. J Allergy Clin Immunol 2011;127:587593.
  • 6
    Wölbing F, Biedermann T. Augmentation to anaphylaxis: the role of aspirin and physical exercise as co-factors. Acta Derm Venereol 2012;92:451453.
  • 7
    Pfeffer I, Fischer J, Biedermann T. Acetylsalicylic acid dependent anaphylaxis to carrots in a patient with mastocytosis. J Dtsch Dermatol Ges 2011;9:230231.
  • 8
    Worm M, Scherer K, Köhli-Wiesner A, Rueff F, Mahler V, Lange L et al. Nahrungsmittelanaphylaxie und Kofaktoren – Daten aus dem Anaphylaxie-Register. Allergologie 2011;34:329337. German.
  • 9
    Rueff F, Przybilla B, Bilo MB, Muller U, Scheipl F, Aberer W et al. Predictors of severe systemic anaphylactic reactions in patients with Hymenoptera venom allergy: importance of baseline serum tryptase-a study of the European Academy of Allergology and Clinical Immunology Interest Group on Insect Venom Hypersensitivity. J Allergy Clin Immunol 2009;124:10471054.
  • 10
    Mazur N, Patterson R, Perlman D. A case of idiopathic anaphylaxis associated with respiratory infections. Ann Allergy Asthma Immunol 1997;79:546548.
  • 11
    Kleine-Tebbe J, Bufe A, Ebner C, Eigenmann P, Friedrichs F, Fuchs T et al. Die spezifische Immuntherapie (Hyposensibilisierung) bei IgE-vermittelten allergischen Erkrankungen. Allergo J 2009;18:508537. German.
  • 12
    Cardona V, Luengo O, Garriga T, Labrador-Horrillo M, Sala-Cunill A, Izquierdo A et al. Co-factor-enhanced food allergy. Allergy 2012;67:13161318.
  • 13
    Hompes S, Köhli 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;22:568574.
  • 14
    Mullins RJ. Anaphylaxis: risk factors for recurrence. Clin Exp Allergy 2003;33:10331040.
  • 15
    De Swert LF, Bullens D, Raes M, Dermaux AM. Anaphylaxis in referred pediatric patients: demographic and clinical features, triggers, and therapeutic approach. Eur J Pediatr 2008;167:12511261.
  • 16
    Treudler R, Kozovska Y, Simon JC. Severe immediate type hypersensitivity reactions in 105 German adults: when to diagnose anaphylaxis. J Investig Allergol Clin Immunol 2008;18:5258.
  • 17
    Uguz A, Lackw G, Pumphreyz R, Ewan P, Warner J, Dickz J et al. Allergic reactions in the community: a questionnaire survey of members of the anaphylaxis campaign. J Clin Exp Allergy 2005;35:746750.
  • 18
    Cercle d'Investigations Cliniques et Biologiques en Allergologie Alimentaire [Internet]. Nancy: CICBAA [updated 2009 Jan 09; cited 2013 May 25]. Le reseau d'allergo-vigilance; [about 4 screens]. Available from: http://www.cicbaa.org/pages_fr/allergovigilance/index.html
  • 19
    Wölbing F, Fischer J, Biedermann T. Kofaktoren der Anaphylaxie. Allergo J 2008;17:563568. German.
  • 20
    Porcel S, Sanchez AB, Rodriguez E, Fletes C, Alvarado M, Jimenez S et al. Food-dependent exercise-induced anaphylaxis to pistachio. J Investig Allergol Clin Immunol 2006;16:7173.
  • 21
    Fukunaga A, Shimizu H, Tanaka M, Kikuzawa A, Tsujimoto M, Sekimukai A et al. Limited influence of aspirin intake on mast cell activation in patients with food-dependent exercise-induced anaphylaxis: comparison using skin prick and histamine release tests. Acta Derm Venereol 2012;92:480483.
  • 22
    Morisset M, Richard C, Astier C, Jacquenet S, Croizier A, Beaudouin E et al. Anaphylaxis to pork kidney is related to IgE antibodies specific for galactose-alpha-1,3-galactose. Allergy 2012;67:699704.
  • 23
    Barg W, Medrala W, Wolanczyk-Medrala A. Exercise-induced anaphylaxis: an update on diagnosis and treatment. Curr Allergy Asthma Rep 2011;11:4551.
  • 24
    Biedermann T, Schopf P, Rueff F, Przybilla B. Exertion-induced anaphylaxis after eating pork and beef. Dtsch Med Wochenschr 1999;124:456458. German.
  • 25
    Robson-Ansley P, Toit GD. Pathophysiology, diagnosis and management of exercise-induced anaphylaxis. Curr Opin Allergy Clin Immunol 2010;10:312317.
  • 26
    Palosuo K, Alenius H, Varjonen E, Koivuluhta M, Mikkola J, Keskinen H et al. A novel wheat gliadin as a cause of exercise-induced anaphylaxis. J Allergy Clin Immunol 1999;103:912917.
  • 27
    Matsuo H, Kohno K, Niihara H, Morita E. Specific IgE determination to epitope peptides of omega-5 gliadin and high molecular weight glutenin subunit is a useful tool for diagnosis of wheat-dependent exercise-induced anaphylaxis. J Immunol 2005;175:81168122.
  • 28
    Matsuo H, Dahlstrom J, Tanaka A, Kohno K, Takahashi H, Furumura M et al. Sensitivity and specificity of recombinant omega-5 gliadin-specific IgE measurement for the diagnosis of wheat-dependent exercise-induced anaphylaxis. Allergy 2008;63:233236.
  • 29
    Park HJ, Kim JH, Kim JE, Jin HJ, Choi GS, Ye YM et al. Diagnostic value of the serum-specific IgE ratio of omega-5 Gliadin to wheat in adult patients with wheat-induced anaphylaxis. Int Arch Allergy Immunol 2011;157:147150.
  • 30
    Matsuo H, Morimoto K, Akaki T, Kaneko S, Kusatake K, Kuroda T et al. Exercise and aspirin increase levels of circulating gliadin peptides in patients with wheat-dependent exercise-induced anaphylaxis. Clin Exp Allergy 2005;35:461466.
  • 31
    Yano H, Kato Y, Matsuda T. Acute exercise induces gastrointestinal leakage of allergen in lysozyme-sensitized mice. Eur J Appl Physiol 2002;87:358364.
  • 32
    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;146:466472.
  • 33
    Romano A, Di Fonso M, Giuffreda F, Quaratino D, Papa G, Palmieri V et al. Diagnostic work-up for food-dependent, exercise-induced anaphylaxis. Allergy 1995;50:817824.
  • 34
    Barg W, Wolanczyk-Medrala A, Obojski A, Wytrychowski K, Panaszek B, Medrala W. Food-dependent exercise-induced anaphylaxis: possible impact of increased basophil histamine releasability in hyperosmolar conditions. J Investig Allergol Clin Immunol 2008;18:312315.
  • 35
    Wolanczyk-Medrala A, Barg W, Gogolewski G, Panaszek B, Liebhart J, Litwa M et al. Influence of hyperosmotic conditions on basophil CD203c upregulation in patients with food-dependent exercise-induced anaphylaxis. Ann Agric Environ Med 2009;16:301304.
  • 36
    Palosuo K, Varjonen E, Nurkkala J, Kalkkinen N, Harvima R, Reunala T et al. Transglutaminase-mediated cross-linking of a peptic fraction of omega-5 gliadin enhances IgE reactivity in wheat-dependent, exercise-induced anaphylaxis. J Allergy Clin Immunol 2003;111:13861392.
  • 37
    Teofoli P, Frezzolini A, Puddu P, De Pita O, Mauviel A, Lotti T. The role of proopiomelanocortin-derived peptides in skin fibroblast and mast cell functions. Ann N Y Acad Sci 1999;885:268276.
  • 38
    Baumgarten CR, Schmitz P, O'Connor A, Kunkel G. Effects of beta-endorphin on nasal allergic inflammation. Clin Exp Allergy 2002;32:228236.
  • 39
    Cant AJ, Gibson P, Dancy M. Food hypersensitivity made life threatening by ingestion of aspirin. Br Med J (Clin Res Ed) 1984;288:755756.
  • 40
    Flemstrom G, Marsden NV, Richter W. Passive cutaneous anaphylaxis in guinea pigs elicited by gastric absorption of dextran induced by acetylsalicylic acid. Int Arch Allergy Appl Immunol 1976;51:627636.
  • 41
    Oshima T, Miwa H, Joh T. Aspirin induces gastric epithelial barrier dysfunction by activating p38 MAPK via claudin-7. Am J Physiol Cell Physiol 2008;295:C800C806.
  • 42
    Sanak M, Simon HU, Szczeklik A. Leukotriene C4 synthase promoter polymorphism and risk of aspirin-induced asthma. Lancet 1997;350:15991600.
  • 43
    Mastalerz L, Setkowicz M, Sanak M, Rybarczyk H, Szczeklik A. Familial aggregation of aspirin-induced urticaria and leukotriene C synthase allelic variant. Br J Dermatol 2006;154:256260.
  • 44
    Mortaz E, Redegeld FA, Nijkamp FP, Engels F. Dual effects of acetylsalicylic acid on mast cell degranulation, expression of cyclooxygenase-2 and release of pro-inflammatory cytokines. Biochem Pharmacol 2005;69:10491057.
  • 45
    Suzuki Y, Ra C. Analysis of the mechanism for the development of allergic skin inflammation and the application for its treatment: aspirin modulation of IgE-dependent mast cell activation: role of aspirin-induced exacerbation of immediate allergy. J Pharmacol Sci 2009;110:237244.
  • 46
    Trcka J, Schmidt C, Seitz CS, Bröcker EB, Gross GE, Trautmann A. Anaphylaxis to iodinated contrast material: nonallergic hypersensitivity or IgE-mediated allergy? AJR Am J Roentgenol 2008;190:666670.
  • 47
    Moss J. Muscle relaxants and histamine release. Acta Anaesthesiol Scand 1995;106:712.
  • 48
    Brockow K, Ring J. Anaphylaxis to radiographic contrast media. Curr Opin Allergy Clin Immunol 2011;11:326331.
  • 49
    Thong BY, Yeow C. Anaphylaxis during surgical and interventional procedures. Ann Allergy Asthma Immunol 2004;92:619628.
  • 50
    Diesner SC, Knittelfelder R, Krishnamurthy D, Pali-Schöll I, Gajdzik L, Jensen-Jarolim E et al. Dose-dependent food allergy induction against ovalbumin under acid-suppression: a murine food allergy model. Immunol Lett 2008;121:4551.
  • 51
    Untersmayr E, Jensen-Jarolim E. The effect of gastric digestion on food allergy. Curr Opin Allergy Clin Immunol 2006;6:214219.
  • 52
    Untersmayr E, Jensen-Jarolim E. The role of protein digestibility and antacids on food allergy outcomes. J Allergy Clin Immunol 2008;121:13011308.
  • 53
    Toogood JH. Risk of anaphylaxis in patients receiving beta-blocker drugs. J Allergy Clin Immunol 1988;81:15.
  • 54
    Gonzalez-Quintela A, Vidal C, Gude F. Alcohol, IgE and allergy. Addict Biol 2004;9:195204.
  • 55
    Alcoceba BE, Botey FE, Gaig JP, Bartolome ZB. Alcohol-induced anaphylaxis to grapes. Allergol Immunopathol (Madr) 2007;35:159161.
  • 56
    Pastorello EA, Farioli L, Pravettoni V, Ortolani C, Fortunato D, Giuffrida MG et al. Identification of grape and wine allergens as an endochitinase 4, a lipid-transfer protein, and a thaumatin. J Allergy Clin Immunol 2003;111:350359.
  • 57
    Bousquet J, Menardo JL, Velasquez G, Michel FB. Systemic reactions during maintenance immunotherapy with honey bee venom. Ann Allergy 1988;61:6368.
  • 58
    Staden U, Rolinck-Werninghaus C, Brewe F, Wahn U, Niggemann B, Beyer K. Specific oral tolerance induction in food allergy in children: efficacy and clinical patterns of reaction. Allergy 2007;62:12611269.
  • 59
    Grunewald SM, Hahn C, Wohlleben G, Teufel M, Major T, Moll H et al. Infection with influenza a virus leads to flu antigen-induced cutaneous anaphylaxis in mice. J Invest Dermatol 2002;118:645651.
  • 60
    Sharma BK, Talwar KK, Bhatnagar V, Kumar L, Ganguly NK, Mahajan RC. Recurrent anaphylaxis due to Plasmodium vivax infection. Lancet 1979;1:13401341.
  • 61
    Vuitton DA. Echinococcosis and allergy. Clin Rev Allergy Immunol 2004;26:93104.
  • 62
    Simons FE. Anaphylaxis: recent advances in assessment and treatment. J Allergy Clin Immunol 2009;124:625636.
  • 63
    Tkaczyk C, Okayama Y, Metcalfe DD, Gilfillan AM. Fcgamma receptors on mast cells: activatory and inhibitory regulation of mediator release. Int Arch Allergy Immunol 2004;133:305315.
  • 64
    Okayama Y, Hagaman DD, Metcalfe DD. A comparison of mediators released or generated by IFN-gamma-treated human mast cells following aggregation of Fc gamma RI or Fc epsilon RI. J Immunol 2001;166:47054712.
  • 65
    Okayama Y, Tkaczyk C, Metcalfe DD, Gilfillan AM. Comparison of Fc epsilon RI- and Fc gamma RI-mediated degranulation and TNF-alpha synthesis in human mast cells: selective utilization of phosphatidylinositol-3-kinase for Fc gamma RI-induced degranulation. Eur J Immunol 2003;33:14501459.
  • 66
    Volz T, Kaesler S, Biedermann T. Innate immune sensing 2.0 – from linear activation pathways to fine tuned and regulated innate immune networks. Exp Dermatol 2012;21:6169.
  • 67
    Kumar H, Kawai T, Akira S. Pathogen recognition by the innate immune system. Int Rev Immunol 2011;30:1634.
  • 68
    Fukata M, Vamadevan AS, Abreu MT. Toll-like receptors (TLRs) and Nod-like receptors (NLRs) in inflammatory disorders. Semin Immunol 2009;21:242253.
  • 69
    Metz M, Maurer M. Mast cells–key effector cells in immune responses. Trends Immunol 2007;28:234241.
  • 70
    Qiao H, Andrade MV, Lisboa FA, Morgan K, Beaven MA. FcepsilonR1 and toll-like receptors mediate synergistic signals to markedly augment production of inflammatory cytokines in murine mast cells. Blood 2006;107:610618.
  • 71
    Wu L, Feng BS, He SH, Zheng PY, Croitoru K, Yang PC. Bacterial peptidoglycan breaks down intestinal tolerance via mast cell activation: the role of TLR2 and NOD2. Immunol Cell Biol 2007;85:538545.
  • 72
    Supajatura V, Ushio H, Nakao A, Akira S, Okumura K, Ra C et al. Differential responses of mast cell Toll-like receptors 2 and 4 in allergy and innate immunity. J Clin Invest 2002;109:13511359.
  • 73
    Kasakura K, Takahashi K, Aizawa T, Hosono A, Kaminogawa S. A TLR2 ligand suppresses allergic inflammatory reactions by acting directly on mast cells. Int Arch Allergy Immunol 2009;150:359369.
  • 74
    Erdei A, Kerekes K, Pecht I. Role of C3a and C5a in the activation of mast cells. Exp Clin Immunogenet 1997;14:1618.
  • 75
    Ali H. Regulation of human mast cell and basophil function by anaphylatoxins C3a and C5a. Immunol Lett 2010;128:3645.
  • 76
    Windbichler M, Echtenacher B, Takahashi K, Ezekowitz RA, Schwaeble WJ, Jenseniuis JC et al. Investigations on the involvement of the lectin pathway of complement activation in anaphylaxis. Int Arch Allergy Immunol 2006;141:1123.