Background: Hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) is a rare inherited disease. In most HAE-affected subjects, defined trigger factors precede angioedema attacks. Mechanisms of how trigger factors stimulate the contact activation pathway with bradykinin generation are not well elucidated. In recent studies, hypersensitivity reactions and food were stated as relevant triggers. We investigated HAE affected people for possible hypersensitivity reactions or intolerances and their relation in triggering angioedema attacks. Methods: A questionnaire was filled in, recording date of birth, gender, and self-reported angioedema attacks associated with the ingestion of foodstuffs, administration of drugs, hymenoptera stings and hypersensitivity reactions against inhalation allergens. All participants performed a skin prick test against inhalation allergens and food. In patients who stated an association of possible hypersensitivity with angioedema, a serological ImmunoCAP test was also performed. Results: From the 27 women and 15 men analyzed, 79% stated trigger factors. From those food was mentioned in 36%. The suspected food included tomato, green salad, fish, citrus fruits, apple, onion, garlic, cheese, chili, kiwi, milk, tree nuts, strawberry, pineapple, shrimps, bread, banana, leek, chicken and alcohol, and were associated with abdominal angioedema. Neither the skin prick test nor the ImmunoCAP-test turned out positive for the tested food allergens. Conclusion: Food seems to be a relevant trigger factor, causing angioedema in HAE affected patients. The reason, however, is not IgE-mediated hypersensitivity, but most probably an intolerance reaction to food products. Keywords: Hereditary angioedema (HAE), Trigger factors, Allergy, Intolerance Background submucosal swelling affecting extremities, trunk, geni- Hereditary angioedema with C1 inhibitor deficiency tals, and face, and might be life threatening when upper (C1-INH-HAE) is a rare inherited disease, due to muta- airways and abdomen are affected [4, 5]. Although it is a tions of the SERPING1 gene. Two different variants have systemic activation process, frequency and localization been described. Type I is characterized by a quantitative of angioedema are highly variable, depending on the decrease in C1-INH protein, in Type II, the C1-INH trigger factors and the upregulation of bradykinin recep- protein has a normal level, but is dysfunctional [1, 2]. tors 1 and 2 (B1R, B2R) on the endothelium [6, 7]. In 56 C1-INH inhibits factors of the contact system including to 91% of HAE-affected subjects, defined factors or cir- FXII and kallikrein, and controls the generation of vaso- cumstances may trigger angioedema attacks [8, 9]. The active peptides such as bradykinin . C1-INH-HAE is most frequent trigger factors are emotions, mechanical characterized by episodic attacks of subcutaneous and trauma, infections, and, in women, hormonal causes, such as menstruation, pregnancy or intake of estrogen pills. In recent studies food ingestion has also been sug- * Correspondence: Urs.Steiner@usz.ch gested to cause angioedema attacks in HAE [8–10]. Department of Clinical Immunology, University Hospital Zurich, Zurich, Switzerland Mechanisms of how food could trigger angioedema Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Steiner et al. Orphanet Journal of Rare Diseases (2018) 13:90 Page 2 of 8 attacks have not yet been elucidated. Patients who are Serologic tests affected by angioedema induced by food, drugs or Serum samples were tested with the multitest Phadiatop hymenoptera stings interpret the cause most often as an Sx1 (timothy grass, birch, cultivated rye, mugwort, dog IgE-mediated hypersensitivity reaction. Recent studies dander, cat dander, Cladosporium herbarum, D. pteronyssi- have demonstrated an interaction of activated mast cells nus) and the multitest Fx5 (egg white, cow’smilk, fish(cod), by an allergen and the contact activation pathway resul- wheat flour, peanut, soy bean). Specific IgE (sIgE) and total ting in the production of bradykinin [11–13]. IgE were determined by ImmunoCAP FEIA (Thermo Fisher The aim of this study was to evaluate the influence of Scientific/Phadia, Uppsala, Sweden) according to the manu- atopy or IgE-mediated hypersensitivity reactions to specific facturer’s directions for use. SIgE levels > 0.35 kUA/L (RAST food, drugs or hymenoptera stings on angioedema attacks class ≥1) were considered positive. In one patient IgA and in HAE affected subjects. We assessed the prevalence of anti-transglutaminase IgA was performed (Thermo Fisher atopy in 42 HAE affected patients in correlation with the Scientific/Phadia, Uppsala, Sweden). frequency of angioedema attacks and investigated trigger factors including food, drugs or hymenoptera venoms for Data handling specific IgE antibodies. Clinical information was collected in each study center and transmitted to the administration site of the respon- sible researcher. Data were entered into the electronic Methods database. If data were incomplete, the participant was Patients contacted for specific clarification. The final dataset was Patients from the Division of Haematology of the pseudonymised and prepared for analysis. The pseudo- Cantonal Hospital Lucerne and from the Allergy nymisation key is stored at the administration site. Units of the University Hospitals of Berne and Zurich For evaluating attack frequency we considered the re- were included. They all fulfilled the diagnostic criteria sults from the Swiss HAE cohort study  and assumed for HAE . All patients included are part of the that sensitization patterns and attack frequency at the Swiss HAE cohort study . time point of the 2012-evaluation were stable. A questionnaire was sent to all participants: patients’ personal data, details of hypersensitivities/intolerances Results and symptoms (e.g.rhinoconjunctivitis, asthma, vomit- The analysis was based on 42 consenting patients (27 ing, stomach pain, diarrhea) were recorded. All partici- women and 15 men) with a mean age of 45 years (SD pating patients gave their written informed consent. The 16.1), all completed the questionnaire, conducted a skin protocol of this study received Ethics Committee ap- test and consented to provide blood samples. proval from the Northwest - and Central Switzerland ethics committee. The study was conducted according Trigger factors to the principles of good clinical practice and adhered Trigger factors causing HAE were indicated by 79% (23 strictly to the ethical standards outlined in the Declar- women, 10 men). The most frequent trigger was emo- ation of Helsinki . tion with 79.% (18 women, 8 men) followed by trauma with 55% (12 women, 6 men) food 36% (10 women, 2 men), drugs 6% and hymenoptera stings 6% with 2 Skin tests women each. Patient characteristics and trigger factors Skin prick tests (SPT) with 7 commercially available aero- are presented in Table 1. allergens (birch, ash, grass, mugwort, Alternaria alternata, house dust mite and cat dander) and 13 food antigen Atopy in HAE affected patients extracts (soy, hen’segg,cow’s milk, celery, apple, codfish, Atopy documented by positive skin prick tests was iden- shrimp, peanut, walnut, curry, chili, rye flour, and wheat tified in 29% (9 women, 3 men). Grass and tree pollen flour) were tested (ALK-Abello, Hørsholm, Denmark). For were the most prevalent allergen sources, followed by banana and pine apple a prick-to-prick test was per- house dust mites, cat dander and mugwort. Ten of the formed. If the wheal diameter was ≥3 mm the test reaction 12 sensitized subjects were symptomatic with rhinocon- was considered to be positive as recommended in the junctivitis (Table 1). European standards for skin prick testing . For the SPT with medications the drug powder dis- Association of self-reported hypersensitivity- or solved in 0.9% saline was applied onto the skin of the intolerance reaction and angioedema forearms. If a wheel of at least 5 mm in diameter with Trigger factors were interpreted by the subjects them- surrounding erythema after 20 min was evident, the test selves in 57% (11 women, 2 men), as an IgE-mediated was found positive . hypersensitivity reaction. Four of these 13 subjects were Steiner et al. Orphanet Journal of Rare Diseases (2018) 13:90 Page 3 of 8 Table 1 Characteristics of 42 patients suffered from acute, inducible (physical) and aspirin induced urticaria (AIU) each. The one with AIU Parameter Number (men/women) mentioned an association with urticaria and HAE typical Patients 42 (15/27) angioedema. The other three did not observe an associ- mean age (years) 45 (SD 16.1) ation between their urticaria and angioedema. HAE variants Type I 41 (0/41) Frequency of angioedema in atopic and non-atopic Type II 1 (1/0) subjects Trigger factors There was no difference in the incidence of HAE attacks in atopic and non-atopic subjects (Table 3). Emotions 26 (8/18) Trauma / Mechanical trigger 18 (6/12) Discussion Hormones 17 (0/17) We investigated 42 participants (31%) of the Swiss HAE Infection 13 (3/10) cohort for suspected self-reported hypersensitivity or Food 12 (2/10) intolerance reactions as trigger factors for their angio- Drugs 2 (0/2) edema attacks . The majority of the participating indi- viduals (79%) stated that trigger factors preceded Bee/Wasp sting 2 (0/2) angioedema attacks. Emotions, followed by trauma, were Total 33 (10/23) mentioned most frequently, which is in line with the Atopy current literature [8, 9]. Hypersensitivities or intoler- Patients 12 (3/9) ances to food, medications or hymenoptera stings were Grass pollen 10 (1/9) stated by almost half of the patients with trigger factors Tree pollen 10 (3/7) (Table 1). IgE-mediated hypersensitivity with mast cell activation House dust mite 5 (2/3) can be associated with heparin release and a consequent Cat dander 3 (1/2) bradykinin generation [11–13, 17, 18]. Almost one third Mugwort 3 (1/2) of our cohort was atopic. This proportion reflects the Self reported hypersensitivities/intolerances inducing angioedema general population’s prevalence of atopy in Northern Atopic 4 (0/4) Europe and in industrialized countries [19–21]. In our Non atopic 9 (2/7) cohort no difference of attack frequency was docu- mented between atopic and non atopic subjects. With menstruation, pregnancy or intake of estrogen pills regard to the question of whether suspected hypersensi- indeed confirmed to be atopic (Tables 1 and 2). In all tivity or intolerance is associated with angioedema, there the twelve subjects with food as a trigger, abdominal an- was no relevant difference between atopic (33%) gioedema was induced. The included food were tomato compared to non-atopic subjects (30%). Based on our (1), green salad (1), fish (2), citrus fruits (2), apple (3), data, atopy does not predispose HAE affected subjects to onion (3), garlic (3), cheese (2), chili (2), kiwi (1), milk suffer from more frequent angioedema attacks (Table 3). (3), tree nut (1), peanut (1), strawberry (2), pineapple (3), Interestinglyinall 12 subjects thespecificfood which shrimps (1), bread (1), banana (1), leek (1), chicken (1), was mentioned as a trigger factor seemed to induce abdo- chamomile (1) and alcohol (1). However skin prick test minal angioedema attacks (Table 2). However, in none of for the specific food was negative in all 12 participants them specific IgE against the indicated food products could and none of the 11/12 tested patients with multitest fx5 be documented, neither by SPT nor by serological tests. and single food proteins had specific IgE (Table 2). Two Therefore, food induced abdominal angioedema attacks in women each mentioned bee/wasp venom, and drugs as these subjects are triggered most probably by an intolerance a trigger. No specific IgE to the recombinant venom reaction due to unknown mechanisms. Most of the food allergens of Api m1, Api m10 or Vesv5 were detected. In mentioned by the investigated subjects such as cheese, alco- the two subjects with assumed drug induced angio- holic beverages, fish, tomatoes, strawberries, pineapples, edema, SPT of acetylsalicylic acid (ASS) in one and ASS nuts, citrus fruits and kiwis contain or release histamine combinations Pretuval®, NeoCitran® and the antidepres- . Therefore a histamine intolerance reaction is probably sant Deroxat® (paroxetin) in the other patient resulted associated with the induction of angioedema. However, a negative. Drug intake was not concomitant with reac- clear allocation of food inducing histamine intolerance re- tions to hymenoptera venoms (Table 2). Four subjects mains difficult and a reliable laboratory test for objective complained of urticarial episodes. One atopic patient diagnosis is lacking [23–25]. Three patients suffered from a suffered from acute urticaria, 3 non atopic patients known lactose intolerance and they stated a clear Steiner et al. Orphanet Journal of Rare Diseases (2018) 13:90 Page 4 of 8 Table 2 Self reported hypersensitivity- and intolerance reactions associated with angioedema (AE) in atopic and non atopic subjects Patients Self reported hypersensitivity/intolerance SPT Phadiatop Sx1, fx5; sIgE; (CAP class 1–6) Localisation AE induced by of AE a b Inhalation allergens Food Drug Bee−/wasp- Aeroallergns Food /drug Aeroallergens Food Bee stings allergens −/wasp allergens Atopic, associated with AE (n =4) Female trees, tomato, positive for: all negative positive for: negative nd abdomen food grass, green salad grass, grass (4), for fx5, hdm, ash, birch (1), tomato, cat cat rye (3), cat dander (2) Female trees, grass fish, citrus positive for: all negative positive for: negative nd abdomen food fruits grass, grass (1), for: fx5 birch rye (1) Female hdm apple, bee- and positive for: all negative positive for: negative negative abdomen food onion, wasp sting hdm hdm (1) for: fx5, for: Bee−/wasp garlic, onion, rApim1/ sting cheese, chili apple, 10, chili rVes v5 Female trees, grass, hdm, cat kiwi,onion, bee and positive for: all negative positive for: negative negative abdomen food chili, fondue wasp sting birch, ash, grass (3), for: fx 5, for: Bee−/wasp grass, hdm hdm (3) onion, rApim1/ sting kiwi, chili 10, rVes v5 Non atopic associated with AE (n =9) Female yes, ns strawberry, negative negative Sx1 negative negative chamomile, nd chamomile, for: fx5, strawberry, pineapple pineapple abdomen food Female garlic, negative negative Sx1 negative negative nd abdomen food shrimps, for: fx5, milk shrimp, garlic Female grass milk, bread negative negative Sx1 negative negative nd abdomen food for: fx5, anti tg- IgA Female cheese, negative negative nd nd nd abdomen food apple, banana, garlic, onion, leek Female grass, trees, walnut, ASS negative negative for Sx1 negative negative nd ASS: mouth, drugs hdm pineapple, food for: fx5, eyelid food: food chicken allergens, chicken, abdomen Steiner et al. Orphanet Journal of Rare Diseases (2018) 13:90 Page 5 of 8 Table 2 Self reported hypersensitivity- and intolerance reactions associated with angioedema (AE) in atopic and non atopic subjects (Continued) Patients Self reported hypersensitivity/intolerance SPT Phadiatop Sx1, fx5; sIgE; (CAP class 1–6) Localisation AE induced by of AE a b Inhalation allergens Food Drug Bee−/wasp- Aeroallergns Food /drug Aeroallergens Food Bee stings allergens −/wasp allergens ASS pine apple, walnut Female yes, ns pineapple, negative negative Sx1 negative negative strawberry, nd peanut, for: fx 5, orange, apple, apple, pine apple orange, strawberry abdomen food face extremities Male alcohol, negative negative Sx1 negative fx 5 nd alcohol: food milk negative extremities, genitals, abdomen milk: abdomen Male fish negative negative Sx1 negative fx5 nd abdomen food negative Female Paroxetin®, negative negative for Sx1 negative nd nd face, drugs Pretuval®, Paroxetin®, abdomen Neo-citran® Pretuval®, Neo-citran® AE angioedema, SPT skin prick test, hdm house dust mites, ASS acetylsalicylic acid, ns not specified, nd not done SPT: 7 aeroallergens: birch, ash, grass, mugwort, Alternaria alternata, house dust mite and cat dander SPT 14 food allergen extracts: soy, hen’s egg, cow’s milk, celery, apple, codfish, shrimp, peanut, walnut, pepper, curry, rye flour, and wheat flour (aeroallergen extract and food allergen extract by ALK-Abello, Hørsholm, Denmark). Only positive results mentioned Multitest Sx1: Specific IgE for: timothy grass, birch, cultivated rye, mugwort, dog dander, cat dander, Cladosporium herbarum, D. pteronyssinus Multitest fx5: Specific IgE for: egg white, cow’s milk, fish (cod), wheat flour, peanut, soy bean ( ): CAP class 1–4 of allergen specific IgE in kU/l: 0: < 0.35; 1: 0.35–0.7; 2: 0.71–3.5; 3: 3.51–17.5; 4: 17.5–50 Anti tg IgA-Ab: anti transglutaminase IgA antibodies (marker for celiac disease) Steiner et al. Orphanet Journal of Rare Diseases (2018) 13:90 Page 6 of 8 Table 3 Frequency and distribution of attacks per year stratified for male vs female and atopy vs non-atopy Female (n = 27) * p-value Male (n = 15) No atopy (n = 18) Atopy (n = 9) No atopy (n = 12) Atopy (n =3) No attacks (# subjects) 2 1 5 3 Rare attacks (# subjects) 4 2 0.029 5 - # attacks (range) 1.5 (1–3) 4 (4–4) 4 (2–6) - Moderate attacks (# subjects) 8 5 0.854 2 - # attacks (range) 25.1 (15–37) 26 (12–36) 12 (12–12) - Frequent attacks (# subjects) 4 1 - - # attacks (range) 89.5 (53–136) 93 - - * t-test: The p-values are for the comparison of attack frequency among atopic and non-atopic subjects within one specific category of attacks, where feasible no attacks: < 1/year; rare attacks: < 1/month; ≥ 1/year; moderate attacks: < 1/week; ≥ 1/month; frequent attacks: ≥1/week association between HAE attacks and intake of cow’smilk different subtypes of urticaria and pseudoallergy with a products. In lactose intolerance the unabsorbed lactose subsequent potential to induce the contact activation leads to osmotic diarrhea and gas production causing flatu- pathway with bradykinin release. lence and abdominal pain. In these subjects also a height- Two patients who stated a local reaction and an ab- ened activity of the innate mucosal immune system with dominal angioedema attack induced by hymenoptera increased counts of mast cells and lymphocytes is described stings, showed no sensitization to the major allergens [26, 27]. Which of these mechanisms are influencing the rApi m1/10 and rVes v5 involved. In these patients, it formation of angioedema in HAE remains to be analyzed was not allergy, but rather the pain of the sting and the further. For one subject, who declared bread as a cause of stress that triggered the angioedema attacks. angioedema celiac disease was excluded with a negative test Severe IgE-mediated hypersensitivity reactions most for anti-tissue transglutaminase IgA-antibodies. probably can induce bradykinergic angioedema attacks This study corroborates that food is a relevant trigger by induction of the contact activation pathway [12, 13]. factor for abdominal angioedema attacks in HAE Therefore if HAE affected subjects indicate triggers such affected subjects. However the underlying pathomechan- as food, hymenoptera stings or drugs, which have the isms for activation of the contact activation pathway potential to induce severe IgE-mediated hypersensitivity with bradykinin formation in the investigated subjects reaction, specific IgE antibodies must be excluded. How- seem to be intolerance reactions rather than ever intolerance reactions seem to be more important IgE-mediated hypersensitivity. In these patients a careful triggers than IgE-mediated mechanisms. individual nutritional counseling is recommended with the aim of a targeted avoidance of the food concerned. Strength and limitations Little data are available on urticaria in HAE [28, 29]. To our knowledge this is the first study that addresses The prevalence of urticaria in our cohort was 10%. This food as a trigger factor in patients with HAE. Although proportion was lower compared to the general popula- the selected cohort is small, we consider the results tion or a recently described survey of a HAE cohort, valid. Self-reporting of trigger factors and symptoms which is most probably explained by the small number carry the risk of reporting bias. A downside of this study of our investigated population [28, 30]. is that no provocation tests with the incriminated food, An association of urticaria with typical HAE was only suspected drug or a challenge sting test with a living corroborated by the patient with AIU. Acute and physical hymenoptera has been performed. urticaria did not seem to provoke HAE. These findings are emphasizing that mechanisms in AIU are different compared to acute or physical urticaria. In AIU most probably activated mast cells are involved but the exact Conclusion pathomechanism is still not clear . The drugs ASS, Food products can be important trigger factors for abdom- ASS combinations and Paroxetin® provoked peripheral, fa- inal angioedema attacks in HAE. The underlying pathome- cial and abdominal angioedema. According to the negative chanism most often is compatible with an intolerance skin test results, non IgE-mediated hypersensitivity reaction. IgE-mediated hypersensitivity reactions seem reaction (e.g. pseudoallergy) most probably induced the rarely cause angioedema in HAE. Studying trigger factors symptoms [32, 33]. Further investigations are required to in HAE is essential to obtain a better understanding of the analyze the threshold of mast cell activation in the disease mechanisms. Steiner et al. Orphanet Journal of Rare Diseases (2018) 13:90 Page 7 of 8 Abbreviations 9. Steiner UC, Weber-Chrysochoou C, Helbling A, Scherer K, Grendelmeier PS, AIU: Aspirin induced urticaria; ASS: Acetylsalicylic acid; C1-INH- Wuillemin WA. Hereditary angioedema due to C1 - inhibitor deficiency in HAE: Hereditary angioedema with C1 inhibitor deficiency; sIgE: Specific IgE; Switzerland: clinical characteristics and therapeutic modalities within a SPT: Skin prick test cohort study. Orphanet J Rare Dis. 2016;11:43. 10. Wais-Nocker B, Steiner U, Spath P, Wuillemin WA. Clinical facets of hereditary Funding angioedema among Swiss patients. Praxis (Bern 1994). 2010;99:1135–41. This study was supported by the Ulrich Müller-Gierok Foundation. 11. van der Linden PW, Hack CE, Eerenberg AJ, Struyvenberg A, van der Zwan JK. Activation of the contact system in insect-sting anaphylaxis: association Availability of data and materials with the development of angioedema and shock. Blood. 1993;82:1732–9. The datasets used and analysed during the current study are available from 12. Oschatz C, Maas C, Lecher B, Jansen T, Bjorkqvist J, Tradler T, et al. Mast cells the corresponding author on reasonable request. increase vascular permeability by heparin-initiated bradykinin formation in vivo. Immunity. 2011;34:258–68. Authors’ contributions 13. Sala-Cunill A, Bjorkqvist J, Senter R, Guilarte M, Cardona V, Labrador M, et al. US: carried out concept and design of the study, accumulation of data, Plasma contact system activation drives anaphylaxis in severe mast cell- analysis and interpretation of the data, performed writing/critical revision of mediated allergic reactions. J Allergy Clin Immunol. 2015;135:1031–43. e6 the manuscript. LK: accumulation of data, critical revision of the manuscript. 14. 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Published: Jun 5, 2018
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“My last article couldn't be possible without the platform @deepdyve that makes journal papers cheaper.”@JoseServera