Data from the anaphylaxis registry of the German-speaking countries

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ScienceDirect www.sciencedirect.com Revue française d’allergologie 55 (2015) 452–455

State of the art

Data from the anaphylaxis registry of the German-speaking countries Données du registre de l’anaphylaxie des pays germanophones M. Worm ∗ , S. Dölle , W. Francuzik Department of Dermatology and Allergy, Allergy Center Charité, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany Received 31 July 2015; accepted 29 September 2015

Abstract The anaphylaxis registry in German-speaking countries has been initiated in 2006 and since 2011 several other European countries started to participate as well. More than 7848 cases have been registered and the data give information on the elicitor profile cofactors, gender distribution, time of onset of reaction and treatment. Peanuts and tree nuts are frequent elicitors of anaphylaxis in particular in children and in adults these are venom and drugs. Several cofactors can contribute to the relative risk for severe reactions and besides alcohol, menstruation, psychological burden the concomitant intake of drugs (ACE inhibitors and beta-blockers) are relevant. The data from the anaphylaxis registry indicate an impact of age which is similar to the profile which is observed in allergic asthma. The data also clearly show that the time of onset of reaction is very short. Analysis of treatment modalities indicates that adrenaline which is the first choice of drug for the treatment of severe reactions is under represented. The anaphylaxis registry is an important tool. A better understanding of the elicitors and cofactors of anaphylaxis are releasing into treatment modalities and build therefore the basis to develop better awareness campaigns. © 2015 Elsevier Masson SAS. All rights reserved. Keywords: Anaphylaxis; Anaphylaxis registry; Food allergy; Elicitors; Cofactors; Treatment

Résumé Le registre des anaphylaxies destiné aux pays germanophones a été créé en 2006 et depuis 2011 plusieurs autres pays européens y ont contribué. Plus de 7848 cas ont été rapportés et les informations portent sur les cofacteurs de la réaction, le sexe du patient, le délai d’apparition de la réaction et le traitement institué. Les arachides et les fruits à coque sont des agents pathogènes fréquents chez l’enfant, et chez l’adulte les plus fréquents sont les venins et les médicaments. Plusieurs cofacteurs peuvent majorer le risque relatif de réactions sévères. Ce sont la consommation d’alcool, la période menstruelle, des facteurs psychologiques puis la prise de médicaments (inhibiteurs de l’ACE et bêta-bloquants). Les données du registre de l’anaphylaxie indiquent que la pyramide des âges est comparable à ce qui est noté pour l’asthme allergique. Les données indiquent également clairement que le délai d’apparition de la réaction est très court. L’analyse des schémas thérapeutiques montre que l’adrénaline, qui est le médicament de première intention pour les réactions sévères, est sous-utilisée. Le registre de l’anaphylaxie est un outil important. Une meilleure connaissance des allergènes responsables de l’anaphylaxie et des cofacteurs permet de mieux définir les options thérapeutiques et donc d’optimiser les campagnes d’information. © 2015 Elsevier Masson SAS. Tous droits réservés. Mots clés : Anaphylaxie ; Facteur déclenchant ; Cofacteur ; Traitement

1. Introduction

∗

Corresponding author. E-mail address: [email protected] (M. Worm).

http://dx.doi.org/10.1016/j.reval.2015.09.007 1877-0320/© 2015 Elsevier Masson SAS. All rights reserved.

The anaphylaxis registry in German-speaking countries has been initiated in 2006 [1]. Initially several centres throughout Germany participated in a pilot phase in order to explore the feasibility of a standardised data entry from anaphylaxis

M. Worm et al. / Revue française d’allergologie 55 (2015) 452–455 Table 1 Cofactors and risk factors of anaphylaxis.

50% 41% 40%

Drugs

31% 30% Pre-existing diseases

19%

20% 10%

6%

4%

Patient-specific factors Lifestyle factors

0% insects

453

food

drugs

unkown

other

Fig. 1. Elicitor groups for anaphylaxis cases (data from the anaphylaxis registry, n = 7484, data set 2006 – March 2015).

patients using an online system. The online questionnaire covers questions regarding patient demographics, symptoms, elicitors, cofactors and treatment modalities. Until to date in German-speaking countries 113 centres actively participate in the register, among these 92 in Germany, 12 in Austria and 9 in Switzerland. Since 2011, several other European countries started to participate in the register and we initiated a collaboration with the French network (CICBAA). 2. Elicitor profile: impact of age Until to date more than 7000 cases have been reported to the register and the latest data analysis from March 2015 included a data set of 7848 registered cases when cases from all European countries which participate since 2011 in the register are considered. Among these 4121 were female and 3727 were male patients. The elicitor profile of anaphylaxis is age dependent. If data from the German-speaking countries are considered in children, peanuts (n = 242) and tree nuts (n = 183) among milk (n = 83) and egg (n = 87) were the most frequent elicitors of anaphylaxis. In contrast in adults, venom (n = 2669) and drugs (n = 1083) were the most frequent elicitors followed by food (n = 794) (Fig. 1). In children milk and egg are most frequently inducing anaphylaxis considering the age between one and three years whereas peanuts and tree nuts occur as elicitors of an anaphylaxis more frequently in early childhood (3 to 10 years). Among food allergens the most frequent elicitors in adults are cereals (n = 132), legumes (n = 97) and shellfish (n = 71) [data not shown]. If drugs are triggers of anaphylaxis – as shown in other data sets previously [2] – antibiotics and non-steriodal antiphlogistics are major causes of anaphylaxis. Besides studying elicitors inducing anaphylaxis the register can also provide information on rare elicitors. These are for example broccoli, parsnip or polyethylene glycol [3]. Moreover, we learnt from the register that not only one agent can induce anaphylaxis. We also observed and registered cases where anaphylaxis was induced only when several elicitors were present. Such reports from the register have also been proven in a cohort of adult anaphylaxis patients [4]. In this cohort consisting 93 adult patients with suspected food-induced anaphylaxis

COX 1/2 inhibitors ACE inhibitors Beta-blockers Increased basal tryptase Mastocytosis Bronchial asthma Sex Advanced age Active infections Physical exertion Added substances Alcohol

Modified according to [6].

double-blind placebo-controlled food challenges with the suspected allergens and cofactors were performed. Among these 27 reacted after exposure to single food allergen, but in 15 patients a reaction occurred only if a combination of one or two food allergens with and without cofactors were given. 3. Cofactors Among cofactors of anaphylaxis exercise has been reported previously in many cases [5] but until to date exercise has never been studied in a prospective controlled manner. Besides exercise other cofactors like alcohol, menstruation or psychological burden as well as the concomitant intake of certain drugs have been reported (Table 1) [6]. Among such drugs, which can either enhance the risk for onset of reaction or increase its severity, NSAID but also cardiovascular drugs like ACE inhibitors and beta-blockers have been discussed. Data from the anaphylaxis registry have indicated that the intake of beta-blocker but also ACE inhibitors increases the risk of severe reactions more than twofold (relative risk factor for ACE inhibitor = 1.96 and relative risk factor for beta-blocker = 2.08) [7]. Moreover, if both drugs were taken by one patient the relative risk for a severe reaction is further increasing. Although the intake of these drugs and their role in anaphylaxis has been a matter of debate [8,9] we could recently show that in a mouse model the severity of an anaphylactic reaction was enhanced if these animals were treated with ACE inhibitors or beta-blockers or both [7]. This increased severity of anaphylaxis was characterised by an increased drop of temperature in these animals, which was associated with an enhanced mediator release including histamine and serotonin. Further investigation of mast cells in the context of these drugs shows that both drugs increased the releasability of mast cells in vitro and can thereby promote the severity of anaphylaxis [7]. Data on the mechanisms of other cofactors like physical exercise or psychological burden are still unknown and need to be further explored in the future. 4. Gender and anaphylaxis The impact of gender on the onset and severity of anaphylaxis is only partly understood. It is well known that like other

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Fig. 2. Adrenaline use as first-line treatment, by country. Modified according to [18].

IgE-dependent diseases as asthma or food allergy [10,11] anaphylaxis occurs more frequently during childhood in boys which is reverted after puberty and equalising again above the age of 55. Hormones are relevant in the sensitisation, but also elicitation process of an IgE-dependent allergy [12]. Estrogens have been shown to play an important role for B cell differentiation, but can also alter mast cell releasability and other effector organ systems. A recent publication indicated a contribution of estrogens in anaphylaxis through regulation of endothelial nitric oxide synthase expression and nitric oxide production thereby promoting vascular hyperpermeability [13].

labelling but also educational measures including teaching the affected individuals how to realise a diet excluding the offending allergen in daily life. By contrast venom-induced anaphylaxis occurs most frequently according to the natural exposure outside and particularly during the summer time. Drug-induced anaphylaxis is most frequently observed in hospitals indicating that improvement regarding the allergological workup in hospitalised patients is required. Among repetitive reactions food-induced anaphylaxis has the highest rate of recurrent reactions, however this is also although to a lesser extent observed due to venom- and drug-induced anaphylaxis (food: n = 990, insect: n = 1204, drug: n = 551) [15].

5. Time of onset of reaction 6. Treatment In the online questionnaire data on the time of the onset of the reaction are assessed as well as the place where the reaction occurs. According to the literature the shortest time interval between exposure and the onset of symptoms is given when drugs are the elicitating agents [14]. Although in venom-induced anaphylaxis the time of onset is rather quick whereas foodinduced anaphylaxis may develop most frequently between 0 and 2 hours but also late phase reactions may occur. However, overall most of the severe reactions occur fast within < 10 minutes indicating the necessity for a prompt treatment (Table 2). An anaphylactic reaction can occur everywhere. Most interesting a large proportion of reactions particularly if food is induced occur at home. This indicates the need of a better food Table 2 Interval between exposure and anaphylactic reaction, by eliciting agent (data from the anaphylaxis registry, n = 5403, data set 2006 – March 2015). Time between exposure and reaction

Relative frequency (%)

< 10 min 11–30 min 31–60 min 1–2 h 2–4 h more than 4 h

52.97 26.60 8.73 5.39 3.00 3.31

According to the guidelines the first-line treatment of severe allergic reactions is adrenaline given intramuscular [16,17]. Other, although second-line treatment measures, are the application of antihistamines and corticosteroids as well as supportive measures like oxygen and fluids. The data from the German-speaking countries reveal that adrenaline is not used according to the guidelines [15] as the quote percentage of adrenaline use in the anaphylaxis cohort from the register is below 20%. By contrast the most frequent given drugs in the severe anaphylactic patients are antihistamines and corticosteroids. However, if a comparative analysis among the German-speaking countries and also other European countries is performed differences of the use of adrenaline are visible [18] (Fig. 2). However, the rate of its use never reaches more than 50%. If the rate of adrenaline use is related to the grade of severity an increase of this rate can be determined indicating that at least the most severe anaphylactic cases (anaphylactic shock) are treated with adrenaline in the majority of cases. The data concerning self-injectable autoinjectors indicate that the use by patients or laypersons is low. Particularly in adults in comparison to children autoinjectors are seldomly used by patients. However, if these data are looked at for the last years an increase can be determined suggesting a fruitful realisation of awareness and education.

M. Worm et al. / Revue française d’allergologie 55 (2015) 452–455

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