Introduction

Anaphylaxis is a term used to describe the sudden onset of a potentially fatal, severe systemic hypersensitivity reaction (1). The actual frequency of this disorder remains unknown. However, it is widely believed to be higher than previously reported, particularly since anaphylaxis is associated with a spectrum of manifestations ranging from mild symptoms, which are underreported, to very severe and fatal presentations. The prevalence of anaphylaxis in the general population, regardless of triggering agent, is estimated to be between 0.05-2%, with a higher reported frequency in children (2,3). Results of recent studies point to an increase in the frequency of anaphylaxis over the years, particularly in the young (4). Data on the characteristics of anaphylaxis in Turkey is sparse (5-8). The aim of this study was to share our experience as a tertiary pediatric center with anaphylaxis, with reference to demographic characteristics, clinical course, triggering agents and approach to treatment.

Materials and Methods

We used ICD-10 diagnostic codes to identify all children (under 18) presenting to the our outpatient clinic between 01.01.2010 and 31.12.2012, with an anaphylaxis. These codes included T78.2 (anaphylactic shock, undefined), T78.0 (anaphylactic shock due to adverse food reactions), T80.5 (anaphylactic shock due to serum), T88.6 (anaphylactic shock due to drugs). A diagnosis of anaphylaxis was made based on criteria put forth by the National Institute of Allergy and Infectious Disease and the Food Allergy and Anaphylaxis Network (Table 1) (9). Details regarding patient demographics, presenting symptoms (dermatological, respiratory, cardiovascular, gastrointestinal, neurological, etc.), their onset and duration, triggering agent, underlying allergies, clinical course, presence of a biphasic reaction, recurrence rates and laboratory tests utilized were recorded. Patients with an identifiable trigger were subject to a skin prick test and/or specific immunoglobulin E (IgE) measurements after at least 6 weeks from an anaphylactic attack. Provocation tests were not performed due to ethical concerns. The study was approved by the Local Ethics Committee of the Zeynep Kamil Woman and Children’s Diseases Training and Research Hospital (Date: 07.06.2013, No: 59) and adhered to the principles of Helsinki Declaration. Oral informed consent was obtained from all subjects and their parents. Skin Prick Test The Quantitest used for the skin tests (92160) consisted of common aeroallergens (house dust, grass and tree pollen, molds, danders, and cockroaches) as well as suspected food allergens. In the event of a borderline result with any of the food allergens, a prick-to-prick test was performed directly from the suspected food. For patients with a suspicion of a drug allergy, intradermal testing was performed using custom-made solutions containing the offending drug. All skin prick tests were applied on the anterior surface of the forearm. Histamine (10 mg/mL) and physiologic saline were used as positive and negative references, respectively. Skin reactions were evaluated 20 minutes after application of the skin test, and an induration of ≥3 mm was considered indicative of a positive reaction. Blood Sampling and Measurement of Serum Specific Immunoglobulin E and Tryptase Levels Measurements of specific IgE were made using a immunoCAP system (Pharmacia Diagnostic AB, Uppsala, Sweden). A value greater than class 0 (<0.35 kU/L) was considered significant. Serum tryptase level was measured when the onset of symptoms was less than 3 hours. Serum tryptase levels were estimated by UniCAP (System ImmunoCAP Tryptase®, Pharmacia & Upjohn). According to the manufacturer, the interassay variability for tryptase levels between <1 and 100 mg/L is <5% and the upper 95th percentile for healthy nonallergic subjects is 11.4 kU/L. Levels above 11.4 kU/L was considered high. Statistical Analysis Data analysis was performed using the Statistical Package for Social Sciences for Windows 11.0 (Chicago, USA) packet program. Values for continuous variables were given as either mean ± standard deviation or as median, based on normality of distribution. The chi-square and Mann Whitney U tests were used to compare means, where applicable. A p-value of <0.05 was considered indicative of statistical significance.

Results

Out of the 39.371 children who presented to our outpatient clinic between 2010 and 2012, we reviewed the medical records for 241 children which were entered the above mentioned ICD-10 codes. Sixty-six (49 male, 17 female) of these cases met criteria for anaphylaxis, with a mean age of 8.9±5.3 years (0.9-18). The frequency of anaphylaxis in our clinic is thus 66/39.371 for two years. In 37 of our patients (56.1%) the anaphylactic attack occurred at home, with 6 patients (9.1%) developing anaphylaxis in the hospital. In the remaining 23 patients (33.8%), anaphylaxis occurred in outdoors. The mean age of onset of anaphylaxis was 81.9±63.7 (2-208) months. Twenty-seven patients (40.9%) had a previous history of an atopic disorder (12 of the patients with asthma, 11 of the patients with allergic rhinitis, 9 of the patients with atopic dermatitis) while a family history was present in 25 patients (37.9%). Dermatological symptoms were the most commonly reported presenting complaints in our patient population (65/66, 98.5%), followed by respiratory symptoms (55/66, 83.3%), cardiovascular symptoms (21/66, 31.8%), gastrointestinal symptoms (16/66, 24.2%) and neurological symptoms (11/66, 16.7%). A summary of presenting findings is provided in Table 2. A probable cause of anaphylaxis could be identified in all patients except for five (61/66, 92.4%). Food allergens were the recognized cause of anaphylaxis in 25 (37.9%) of the patients, followed by a hymenoptera sting in 22 (33.3%) patients and drugs in 14 (21.2%) patients. Beta-lactam antibiotics were the most common cause of drug-related anaphylaxis, whereas milk and dairy products were the most frequently encountered food allergens. Vespula spp were responsible for anaphylaxis in 20 (90.9%) of the patients who developed a reaction due to a hymenoptera. About half of the cases of drug-related anaphylaxis occurred in the hospital. A summary of triggers of anaphylaxis is shown in Table 3. The most common causes of anaphylaxis according to age groups are foods, hymenoptera sting and drugs (respectively 0-3 years, 4-14 years and over the age of 14) (Figure 1). Twenty-nine of our patients (43.9%) had a previous history of anaphylaxis with the identified allergen (15 of the patients with a food-related anaphylaxis-milk is the most common, 8 of the patients with venom-associated anaphylaxis, and 6 of the patients with drug-related anaphylaxis). The mean time between the manifestation of symptoms and exposure to the allergen was 28.6±27.9 minutes (2-120, median: 20). A biphasic reaction was observed in four of the patients, whose symptoms recurred hours (most within 10 hours) after resolution of the initial phase. All patients received an antihistamine (mostly pheniramine maleate IM), followed by a corticosteroid (mostly Methyl prednisolone IM, Dexamethasone IM) in 64 (97.0%) patients, oxygen in 42 patients (63.6%), intravenous fluids in 29 patients (43.9%), epinephrine in 21 patients (31.8%), and a nebulized salbutamol in 17 patients (25.8%). Thirty of the patients (45.5%) required hospitalization, with a mean duration of stay of 33.2±26.4 hours (8-120). Only seven patients required observation for more than 24 hours. Overall, it took anaphylactic symptoms an average of 87.2±69.8 minutes (10-480) to resolve. Tryptase measurement was made in 9 patients, and an elevated level of 11.4 kU/L was observed in only two of them (due to anesthetic and hymenoptera). An epinephrine auto-injector had been prescribed for all patients.

Discussion

Anaphylaxis is defined as a potentially fatal serious hypersensitivity reaction of sudden onset (1). It is the most serious clinical consequence of allergy, which can cause death when diagnosis and treatment of anaphylaxis is delayed. Anaphylaxis is an underdiagnosed condition since some of its features are shared by other clinical conditions. There are very few studies from Turkey on anaphylaxis (5-8). Most of our cases (74.2%) were male, with particular prominence in patients under the age of 15 years, while in older patients, females were more prominent (10). A similar male predominance was reported in other studies (5,6,6,7,8,6,7,8,9,10,11,6,7,8,9,10,11,12). Annual frequency of anaphylaxis for our outpatient pediatric allergy clinic was 0.084%. Previously, the prevalence of anaphylaxis in the general population, regardless of the trigger, was estimated to be between 0.05-2% (2). However, in a more recent study it has been reported that all-cause anaphylaxis affects 6.7-70/100000 individuals annually (13). In a recent study, the frequency of anaphylaxis in patients admitted to the emergency room was found as 3.3/100000/year (14). Anaphylaxis is known to occur more commonly in children (3). In a study by Decker et al. (3), the reported annual prevalence of anaphylaxis for all ages was 49.8/100000 individuals, compared to 70/100000 individuals in patients under the age of 19 years. Recent studies have shown an increasing trend in the frequency of anaphylaxis, particularly in the very young (4). In two studies by the same work group, an increase in the annual frequency of anaphylaxis from 21/100000 individuals between 1983-1987 to 49/100000 individuals between 1990-2000 was observed (3,4,5,6,7,8,9,10,11,12,13,14,15). More than half of our cases with anaphylaxis occurred at home, which is an expected result considering young children tend to spend most of their time indoors. This is similar with the results of other studies (11,12,13,14,15,16,12,13,14,15,16,17). An allergic disorder was present in 40.9% of our patients with anaphylaxis, similar to the rate of 40.3% reported by Thong et al. (18), and lower than the 58.8% rate reported by Decker et al. (3). In our patient group, dermatological, respiratory, cardiovascular, gastrointestinal and neurological symptoms occurred with decreasing frequency, a result was consistent with findings of other studies in the literature, with reported rates of 80-90%, 70%, 45%, 30-45% and 15%, respectively. Urticaria and angioedema were the most common presenting symptoms (13,14,15,16,17,18,19). Food allergens were the most commonly identified cause of anaphylaxis in our patient population, with milk and dairy products at the forefront, followed by hazelnuts, eggs, lentils and wheat. Numerous other studies have also reported food as being the most common cause of anaphylaxis (3,4,5,4,5,6,7,8,9,10,11,4,5,6,7,8,9,10,11,12,4,5,6,7,8,9,10,11,12,13,14,15). Triggering food allergens differ according to the dietary habits of the population studied. For example, while De Swert et al. (11) reported peanuts to be the most common cause of anaphylaxis in their study population, in another study by Thong et al. (18) crustacean shellfish was the most frequently identified triggers. On the other hand, milk and fish were mainly implicated in a study by Novembre et al. (17). Hymenoptera stings were the second most frequent cause of anaphylaxis in our study. In two studies by Decker et al. (3) and Orhan et al. (5), hymenoptera stings were the most common cause of anaphylaxis. Drugs were the third most frequent cause of anaphylaxis in our study, with beta lactam antibiotics at the top of the list, followed by nonsteroidal anti-inflammatory drugs (NSAID), anesthetics, and vaccines. Unlike in children, drugs are the leading cause of anaphylaxis in adults, occurring mainly in middle-aged individuals and the elderly. Similarly in our study, drugs are the most common cause of anaphylaxis over the age of 14. Antibiotics, particularly beta-lactams, along with NSAIDs are the main allergens implicated as a cause of anaphylaxis (13). While some studies in the literature list drugs as the second most frequent cause of anaphylaxis (11,12,13,14,15,16,17,12,13,14,15,16,17,18,19,20), other investigators like Pumphrey and Roberts (22) and Cianferoni et al. (23) reported drugs to be the leading cause in patients with fatal anaphylaxis or those hospitalized for anaphylaxis. Half of the drug related anaphylaxis in our study required hospitalization due to anaphylaxis. About half of our patients gave a previous history of anaphylaxis, particularly in those for whom a food allergen was the identified cause of the reaction. De Swert et al. (11) also reported on similar findings in their study, where they stressed on the importance of patient education with regard to the avoidance of the offending allergen. The times between the development of anaphylaxis symptoms and exposure to the offending allergen observed in our study (2-120 minutes) is consistent with those reported in the literature (11,12,13,14,15,16,17,12,13,14,15,16,17,18,19,20,21,22). Symptoms of anaphylaxis usually manifest within 5-30 minutes of parenteral introduction of an allergen, however this period may sometimes extend beyond 1 hour. With oral exposure, symptoms usually develop within the first two hours (21). Anaphylactic symptoms may recur hours after apparent resolution of initial symptoms. This is defined as a biphasic reaction, which has been reported to mostly occur within 10 hours of the initial attack. The reported incidence of biphasic reactions is between 1-23% (24). In our study, such a reaction was observed in 6.1% of patients. Antihistamines were the most commonly used drugs for the treatment of anaphylaxis, a result similar to findings from previous studies (2,3,4,5,3,4,5,6,3,4,5,6,7,8,9,10,11,3,4,5,6,7,8,9,10,11,12,13,14). Even though antihistamines are considered a second line treatment option for the management of anaphylaxis, this group of drugs are still widely used as the first treatment of choice in our country (5,6). Adrenalin was used in nearly third of our patients. Adrenalin was reported to have been used in 32.3% of patients studied by Orhan et al. (5) and 44.4% of patients in a study by Vezir et al. (7). Epinephrine was mainly used to treat drug-related anaphylaxis, or in attacks that developed in the hospital. Failure to inject epinephrine promptly in patients with anaphylaxis occurs because of a lack of recognition of signs and symptoms, delayed diagnosis, perception that the episode is mild, preference for using an oral H1-antihistamine, and fear of side effects. Epinephrine should be administered as soon as the diagnosis of anaphylaxis is suspected. Due to the lack of controlled studies how long patients with anaphylaxis will be observed, is undefined. The duration of follow-up differs with every patient, and a decision should be made taking into consideration the patient’s general condition and the proximity of his/her place of residence to a healthcare facility. Some authors suggest that patients with moderate-severe anaphylaxis, those with active asthma, a history of a biphasic reaction and/or continuing risk of drug absorption should be followed up for 8-24 hours (21). While 45.5% of our patients required hospitalization, duration of stay was longer than 24 hours in only 7 patients. Recently a multicenter study containing twelve centers with a number of 137 patients, two hundred and twenty-four anaphylactic events was reported. They reported 43.8% of the episode occurred at home. The symptoms, triggers and treatment of the patients of the study were similar to our patients. The difference with our study was occurrence of death (5). Laboratory tests may be useful to confirm a diagnosis of anaphylaxis or to exclude the presence of other disorders that may mimic anaphylaxis. Measurement of serum tryptase, which should ideally be performed within moments of an anaphylactic attack, was performed in only 9 of our patients, and elevations were observed in only two patients. This may be attributed to inadequate blood sampling technique, as specimens needed to be centrifuged and extracted serum samples to be frozen almost immediately to obtain accurate measurements. On the other hand, serum tryptase levels are seldom increased when anaphylaxis is triggered by food or when hypotension or shock is absent (13).

Conclusions

Food allergens are the most common cause of childhood anaphylaxis in our study, with most cases occurring at home. But this frequency decreases with age and other factors (i.e drugs, venoms) become more common than food allergens. The usage of epinephrine rates for the treatment of anaphylaxis are quite low in Turkey, highlighting the need for doctor-oriented education aimed at raising awareness.

Ethics

Ethics Committee Approval: Zeynep Kamil Woman and Children’s Diseases Training and Research Hospital (Date: 07.06.2013, No: 59), Informed Consent: It was taken. Peer-review: Internally peer-reviewed. Authorship Contributions Surgical and Medical Practices: Mahmut Dogru, Handan Duman Senol, Tayfur Ginis, Concept: Mahmut Dogru, Ilknur Bostanci, Serap Özmen, Design: Mahmut Dogru, Ilknur Bostanci, Serap Özmen, Data Collection or Processing: Mahmut Dogru, Handan Duman Senol, Tayfur Ginis, Analysis or Interpretation: Mahmut Dogru, Ilknur Bostanci, Serap Özmen, Handan Duman Senol, Tayfur Ginis, Literature Search: Mahmut Dogru, Ilknur Bostanci, Serap Özmen, Writing: Mahmut Dogru, Ilknur Bostanci, Serap Özmen, Handan Duman Senol, Tayfur Ginis. Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study received no financial support.