Epidemiological and Clinical Features of Anaphylaxis: Single Center Experience with 109 Children

Abstract

There has been increasing data on pediatric anaphylaxis. In this study, we aim to determine demographics and atopic status of patients, etiology, and clinical feature of anaphylaxis, its management and follow-up over the 9-year period. We made a retrospective medical chart review of patients diagnosed as anaphylaxis in the Pediatric Allergy and Asthma Department of Gazi University Hospital between January 2003 and May 2012. Diagnosis of anaphylaxis was reviewed by 2 pediatric allergists and those compatible with the criteria according to the second symposium on the definition and management of anaphylaxis were included in the analysis. During the study period, 109 patients (66 male, 43 famale) were diagnosed with anaphylaxis. The median age was 72 months. Fourteen patients (12.8%) had more than one episode before diagnosis. Anaphylactic episode was severe in 28 patients (25.7%). Cutaneous symptoms were the most frequent symptoms (91.7%). Blood pressure measurement had been done in 47 patients (43.1%). Treatment of anaphylaxis included antihistamines in 105 patients (96.3%), corticosteroids in 101 patients (92.7%), and adrenaline in 50 patients (45.9%). The most common cause of anaphylaxis differed according to age groups: food in infants (85%), drugs in older children (43.8%). Sixty-six patients were prescribed autoinjector. In follow-up, 10 patients (9.2%) experienced a second episode of anaphylaxis. Nine of them had adrenaline autoinjector, 3 of them carried the autoinjector with them but only one patient used it. Major etiologic factors of anaphylaxis differed according to the age of children. There were inadequancies in management of anaphylaxis related to physicians, such as blood pressure measurement and acute treatment of anaphylaxis in medical centers and related to patients as uncompliances to carry and use adrenaline autoinjector.

Introduction

Anaphylaxis is a severe, potentially fatal, systemic allergic reaction that occurs suddenly after contact with an allergen.¹ Though the exact incidence is not known, its frequency is estimated at a life-time prevalence of 0.05%–0.2%.^2–4 Retrospective studies on anaphylaxis in children has increased in recent years and data from them indicate an increase in anaphylaxis in children.^5–7 Even though the first drug of choice is intramuscular adrenaline, there are still inadequancies in doctors and in patients who have self-injectable adrenaline devices.^8,9

The purpose of this study is to determine the demographics and atopic status of patients, etiology, clinical features of anaphylaxis, its management and follow-up over the 9-year period at a tertiary care center in Ankara.

Materials and Methods

We made a retrospective medical chart review in a 9-year period between January 2003 and May 2012. The study included patients whose medical records were available. Cases were referred from pediatric emergency department (PED), inpatient and outpatient pediatric clinics of our hospital for allergic reaction, anaphylaxis, anaphylactic reaction, or shock to our department. Patients who were seen at the allergy department earlier on were given a call after 72 h to be questioned about any biphasic reactions. Medical records of the patients were retrospectively reviewed by 2 pediatric allergists separately. Children whose anaphylaxis diagnosis were confirmed by the 2 allergists and fulfilled the criteria of anaphylaxis according to the second symposium on the definition and management of anaphylaxis (Table 1)¹ were included in the final analysis. The severity of the anaphylaxis episode was determined according to the position paper of the European Academy of Allergy and Clinical Immunology on the management of anaphylaxis in childhood.¹⁰ A biphasic reaction is defined as a recrudescence of symptoms within several hours (as late as 72 h) after resolution of anaphylaxis had occurred.¹¹ Demographics, triggers, number of previous anaphylaxis episodes, clinical manifestations, the interval between exposure, and the onset of anaphylaxis, the location of reaction, treatment of the acute episode, biphasic nature, diagnostic evaluations, comorbid diseases, and long-term management were recorded. Diagnostic testing was always based on the history and done by skin prick tests and/or serum specific IgE levels. Each patient with a diagnosis of anaphylaxis was given a scheduled a control visit within 6 months after the initial visit at the allergy department. The study was approved by the Ethics Comittee of Gazi University (approval number 153/11.05.2011).

Table 1.

Clinical Criteria for Diagnosing Anaphylaxis ¹

Anaphylaxis is highly likely when any one of the following 3 criteria are fulfilled:
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips- tongue-uvula) and at least one of the following
a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia)
b. Reduced BP or associated symptoms of end-organ dysfunction [eg, hypotonia (collapse), syncope, incontinence]
2. Two or more of the following that occur rapidly after exposure to a likely allergen for that patient (minutes to several hours):
a. Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen lips-tongue-uvula)
b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia)
c. Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, incontinence)
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
3. Reduced BP after exposure to known allergen for that patient (minutes to several hours):
a. Infants and children: low systolic BP (age specific) or greater than 30% decrease in systolic BP^*
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that person's baseline

Low systolic blood pressure for children is defined as less than 70 mm Hg from 1 month to 1 year, less than [70 mm Hg + (2×age)] from 1 to 10 years, and less than 90 mm Hg from 11 to 17 years.

PEF, peak expiratory flow; BP, blood pressure.

Statistical analysis

Statistical Package for Social Sciences (SPSS) 15.0 software (SPSS, Inc., Chicago, IL) was used for the statistical analysis. A descriptive analysis was used for the characterization of patients. Qualitative variables were described in frequency and percentage, while quantitative variables were expressed in medians. Comparison between severity of anaphylaxis groups was done by Pearson chi-square test and a 2-sided P<0.05 was considered statistically significant.

Results

Demographics

During the study period, 129 patients were diagnosed with anaphylaxis at the Pediatric Allergy and Asthma Departmant of Gazi University Faculty of Medicine. The study included 109 patients (66 male, 43 famale) whose medical records were complete. Fifty-four of these patients (49.5%) were referred from the PED, ambulatory care, and/or from the pediatric wards at Gazi University Faculty of Medicine, while the rest were outpatients from different hospitals. There was male predominance in cases ≤2 years old and venom-related ones (Table 2). At the time of the reaction, the median age was 72 months (range: 5 to 204 months) and the median follow-up period was 18 months (range: 1 to 51 months). Fourteen patients (12.8%) had more than one attack before diagnosis. Blood pressure was measured in 47 patients (43.1%).

Table 2.

Age and Sex Distribution of Patients (n=109)

	n (%)	Male, n (%)
Age range (years)
≤2	23 (21.1)	17 (73.9)
2–5	25 (22.9)	15 (60)
6–11	35 (32.1)	20 (57.1)
≥12	26 (23.9)	14 (53.8)
All age	109	66 (60.6)
Etiology
Food	32 (29.4)	19 (59.4)
Drug	41 (37.6)	23 (56.1)
Venom	25 (22.9)	17 (68)
Other^a	11 (10.1)	7 (63.6)

Idiopathic, exercise-induced, latex, and transfusion-related.

Etiology and diagnostic work-up

The 3 most common causes of anaphylaxis were drugs in 41 (37.6%), food in 32 (29.4%), and hymenoptera venoms in 25 (22.9%) cases. Food was the major etiologic factor in infants; drugs and venoms were the predominant etiologic factors in children (Fig. 1). Triggers of anaphylaxis in 109 patients were shown in Table 3. A diagnostic work-up (skin testing, serum-specific IgE antibodies) for the etiology of anaphylaxis was carried out in 85 patients (78%). Sixty-one of them (71.8%) were found positive with skin tests (epidermal and intradermal) and/or serum-specific IgE antibodies. Results of diagnostic work-up was related with history in all patients with venom induced anaphylaxis (n=23), in 31 of the 32 tested patients with food induced anaphylaxis, in 6 of 21 patients with drug induced anaphylaxis and in 1 patient with latex induced anaphylaxis.

FIG. 1.

Association between the age and etiology of anaphylaxis.

Table 3.

Causes of Anaphylaxis in 109 Patients

Causative agent	n (%)	Specific agent
Food	32 (29.4)	Cow's milk (15)
		Hen's egg (6)
		Fish (3)
		Walnut (3)
		Lentil (2)
		Peanut (1)
		Peach (1)
		Pomegranate (1)
Drugs	41 (37.6)	Antibiotics (18)
		Penicillin (8)
		Cephalosporins (8)
		Vancomycin (1)
		Gentamycine (1)
		NSAIDs (12)
		Chemotherapy Drugs (2)
		Carboplatin (1)
		Cyclophosphamid (1)
		Enzyme replacement therapy (4)
		Alpha-L-iduronate (1)
		Idursulfase (1)
		Alglucosidase alfa (1)
		Galsulfase (1)
		General anesthetics agents (4)
		Vitamin-B complex (1)
Venoms	25 (22.9)	Vespids (21)
		Apids (4)
Latex	1 (0.9)
Exercise-induced anaphylaxis	1 (0.9)
Transfusion-related	2 (1.8)^a
Idiopathic	7 (6.4)

Fresh frozen plasma and intravenous immunoglobulin.

NSAIDs, nonsteroidal anti-inflammatory drugs.

Severity of anaphylaxis episode

Anaphylaxis episode was mild in 38 patients (34.9%), moderate in 43 patients (39.4%) and severe in 28 patients (25.7%). The etiology of anaphylaxis was drug in 64.3% of patients, insect sting in 17.9% of patients, food in 14.3% of patients, and exercise in 3.6% of patients with a severe episode. The biphasic reaction occured in only one case (0.9%) who had been administered adrenaline. There were no fatal cases.

Place of occurrence, time lapse between exposure and onset of symptoms and clinical features

Anaphylaxis occurred at home in 52 patients (47.7%), at a medical facility in 34 patients (31.2%), outdoors in 23 patients (21.1%). Ninety-three percent of food induced anaphylaxis occured at home, 88% of venom induced anaphylaxis occured at outdoors, and 73.2% of drug induced anaphylaxis occured in the hospital. The reaction occurred in 1–5 min in 42 patients (38.5%), within 5–30 min in 50 patients (45.9%), and within 30 min–2 h in 10 patients (9.2%). The reaction time was unknown in 7 cases (6.4%) with idiopathic anaphylaxis. The reaction occurred in the first 30 min in 96.9% of food-related, in 96% of venom-related, and in 82.9% of drug-related (65.8% I.V/I.M route and the rest by oral route) anaphylaxis. Symptoms and signs of anaphylaxis were shown in Table 4. Cutaneous symptoms were the most frequent (91.7%) followed by the respiratory symptoms (87.2%).

Table 4.

Incidence of Signs and Symptoms in Anaphylactic Reactions (n=109)

	n (%)
Cutaneous	100 (91.7)
Angioedema	64 (58.7)
Urticaria	64 (58.7)
Flushing	37 (33.9)
Pruritus	28 (25.7)
Respiratory	95 (87.2)
Stridor	39 (35.8)
Dsypnea	38 (34.9)
Cough	27 (24.8)
Wheezing	15 (13.8)
Cyanosis	15 (13.8)
Hoarseness	12 (11)
Rhinore	10 (9.2)
Cardiovascular	24 (22)
Hypotension	20 (18.3)
Syncope	17 (15.6)
Arrest	5 (4.6)
Gastrointestinal	14 (12.8)
Persistent vomitting	13 (11.9)
Abdominal pain	1 (0.9)

Co-morbid allergic and systemic diseases

Fourty five patients (41.3%) had comorbid allergic diseases (Table 5). Fifteen patients (13.8%) had systemic disease (solid or hematologic malignancies: 5, metabolic diseases requiring enzyme replacement: 5, liver and gastrointestinal tract diseases: 4, endocrinologic disease: 1).

Table 5.

Comorbid Allergic Diseases (n=45)

	n (%)
Asthma	21 (46.7)
Allergic rhinitis	13 (28.9)
Eczema	6 (13.3)
Food allergy	18 (40)
Drug allergy	9 (20)

Acute management and follow up

At the acute anaphylaxis episode, 86 patients (78.9%) were observed in ED ward. Six patients (5.5%) were admitted to pediatric intensive care unit where 3 of them needed intubation. Seventeen patients (15.6%) had already been hospitalized in one of the inpatient wards due to associated systemic diseases at the time of anaphylaxis. Acute treatments included antihistamines in 105 (96.3%), corticosteroids in 101 (92.6%), adrenaline in 50 (45.9%), oxygen in 62 (56.9%), intravenous (IV) fluid in 40 (36.7%), and beta 2 agonist in 24 patients (22.0%). Thirty-nine percent of patients with mild-moderate anaphylaxis (32/81) and 64% of patients with severe anaphylaxis (18/28) were treated with adrenaline in the acute episode of anaphylaxis (P=0.041). Ten patients (9.2%) had experienced a second episode after diagnosis of anaphylaxis. The etiology of anaphylaxis in these recurrent cases were food (n=5), venom (n=4), and drug (n=1). Sixty-six of 109 patients were prescribed adrenaline auto-injector. Thirty-two for food (48.5%), 25 for hymenoptera venom (37.9%), 7 for idiopathic (10.6%), 1 for latex (1.5%), and the other 1 for exercise (1.5%) induced anaphylaxis. Nine of the 10 patients with recurrent anaphylactic episodes had been prescribed adrenaline autoinjector (Epipen). Three of them carried the autoinjector with them but only one had used it at the time of reaction.

Discussion

This study showed that the etiology of anaphylaxis differed according to age. Food was the major trigger in children ≤2 years old which decreased thereafter and was substituted by drugs and venoms. Severe anaphylaxis was more frequently observed with drugs compared to food and venom. There were still inadequancies in management of anaphylaxis especially in blood pressure measurement and in adrenaline administration during acute treatment.

Male to female ratio in this study was 1.5:1 which showed similarities to previous studies.^5,7,12,13 Novembre et al.¹³ found out male predominance of 2:1 and hypothesized that it might be attributable to the larger number of boys with hymenoptera sting or exercise-induced anaphylaxis. In our study, male predominancy was obvious in venom induced anaphylaxis (68%) and in children ≤2 years old (74%). Similar to the results of our study, Orhan et al.⁷ also concluded the predominance of male gender in infants.

In our study, drugs mainly antibiotics and nonsteroid anti-inflammatory medications took the first place in the etiology of anaphylaxis rather than food which was determined as the first offending agent in other studies,^5–7,12. In a study carried out by Dibs and Baker¹⁴, food was the second trigger after latex. However, almost half of the patients in Dibs's study had anaphylactic episodes at the hospital and most of them had a history of hospital readmissions and surgical operations. We think the major reason for this unexpected finding is the low number of children ≤2 years old in our study which decreased the rate of food-related anaphylaxis. Another reason might be the data loss due to limiting our analysis only with patients whose medical records were complete. In addition, more than half of the drug induced anaphylaxis cases were severe and this rate was higher than those in food and venom induced anaphylaxis. In our study, almost 2 thirds of patients with drug induced anaphylaxis had taken the drug in intramuscular (IM) or IV route which might affect the severity of the reaction.

Milk was the major causes of food induced anaphylaxis in this study which was similar to some,^5,7 but not all studies.^6,12,13 Nuts and sea food took the first place as the major etiologic factor for anaphylaxis in a study by Huang et al.⁶ These disparities in the outcome can be explained by different eating behaviours and food in different countries and age groups, respectively.

One fifth of our patients had venom induced anaphylaxis which is more frequent compared to other studies^12,13. This may be explained by climate and the extent of rural regions in our country. In a multicenter study⁷ done previously in our country, more than a third of patients had venom induced anaphylaxis which further supports this hypothesis.

Blood pressure measurement seems to be the most neglected examination in children with anaphylaxis.^1,15,16 In our cases, blood pressure was measured in less than half of the children with anaphylaxis. Negligence in blood pressure measurement may cause misdiagnosis of anaphylaxis, underestimation of its severity and insufficient treatment of the patients. This situation might have also affected our results especially for underestimation of the severity and its acute treatment.

Anaphylaxis mostly manifests in cutaneous and respiratory symptoms. Similar to other studies,^7,12,13 cutaneous and respiratory symptoms were more frequent in our patients. Less than one fourth of the patients had cardiovascular and gastrointestinal symptoms. In other studies cardiovascular⁵ or neurologic⁷ symptoms follow the cutaneous and respiratory symptoms. The variability in the frequency of symptoms and the associated systems may be due to the differences in the methodology of the studies, definitions and assessments of the clinical findings and study populations.

Even though the drug of choice for anaphylaxis is IM adrenaline, it was given approximately to half of the patients, significantly more to patients with severe compared to mild-moderate anaphylaxis in our analysis. This rate was higher compared to some^7,17 and lower to other studies^5,6. In contrast, in almost all studies a considerable portion of physicians still prefer antihistamines and corticosteroids to adrenaline.^5,7,17 This is an important issue because adrenaline is the only life saving medication in anaphylaxis and is still a neglected treatment. In addition, major reasons for biphasic anaphylactic episodes are delay in its administration or administrating lower dose of adrenaline¹¹. In our study, one case (0.9%) with idiopathic anaphylaxis experienced a biphasic course, although she had been treated within 30 min with the appropriate dose in the first episode. In other studies biphasic reactions were reported between 1.4% to 6%.^6,7,12,18 In Lee's study,¹⁸ this rate was 6% which was explained by the fact that it took an average of 190 min until the first treatment.

Recurrence rates of anaphylaxis in previous studies were reported to be between 10.5% and 40%.^6,7 In our study, this rate was 9.2% and was similar to the results in Huang's study.⁶ In that study, Huang et al. indicated that food played a major etiologic role in patients readmitted to the emergency department with anaphylaxis attack. In our study, the recurrent episodes were majorly food and venom induced. Most recurrent anaphylactic episodes occur out of hospital where prompt administration of adrenaline autoinjector has a crucial role. Nine of our 10 patients with recurrent anaphylaxis had an adrenaline autoinjector, but only 3 of them carried it with them at the time of the recurrent episode and unfortunately only one had used it. The rates of carriage and usage of adrenaline autoinjector were also low in other studies^7,12,14 which points to the importance of educating patients and their caregivers about anaphylaxis management.

Retrospective nature of our study is the main limitation which is unfourtunately a common problem of the most anaphylaxis reports.^{5–7,12–15,17} Also we restricted data to the patients with complete medical records which might have affected our results.

In conclusion, triggers of anaphylaxis differ according to the age groups in children. Severe anaphylaxis is more frequent in drug induced cases compared to food and venom induced ones. There are still inadequencies in appropriate anaphylaxis management, such as blood pressure measurement and adrenaline administration as the first line drug. Incompetency of patients to carry and use adrenaline autoinjectors is another gap in this area. These facts all together denote the importance of increasing the perception and awareness of both patients and physicians as well as improvement of their education about management of anaphylaxis.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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