Department of Pediatrics, Allergology, and Gastroenterology, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland
Introduction and objectives: The aim of the study was to determine the frequency of food-induced anaphylaxis, analyze the symptoms, and the trigger factors in the group of the youngest children. The additional aim of the study is to estimate the frequency of anaphylaxis episodes in the population of children in the Kuyavian–Pomeranian Voivodeship.
Methods: Retrospective analysis of medical records of 29 children aged 0–3 years that presented symptoms of food-induced anaphylaxis. Medical charts were reviewed using a collection of documents with the clinical data.
Results: The frequency of anaphylaxis was determined to be 0.3% of all hospitalized children aged 0–3 years and 1.9% of children suspected of food allergy. The mean age of an anaphylactic reaction was 12 ± 9 months. The most common symptom was mild-moderate urticaria. The respiratory symptoms were significantly more prevalent in toddlers than in infants (p = 0.148). Cardiac symptoms occurred only in the infant group, that is, in two (11%) infants. As a possible cause of the symptoms, in 18 (62%) cases, parents most often indicated the consumption of milk or milk-rice porridge. Anaphylaxis as the first manifestation of food-allergy was significantly more prevalent in infants than in older children (p = 0.0002).
Conclusions: The incidence of anaphylactic reactions rated at 0.3% of all children hospitalized at this age. The most common symptoms of anaphylactic reaction were skin lesions. The primary cause of allergic reactions was cow’s milk after first exposure at home. Anaphylaxis has different patterns of symptoms depending on the age of the child.
Key words: allergen, allergy, anaphylaxis, atopy, children, cow’s milk, epinephrine, food, infants, specific IgE
*Corresponding author: Julia Gawryjołek, Department of Pediatrics, Allergology, and Gastroenterology, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 9 Skłodowskiej-Curie St., 85-094 Bydgoszcz, Poland. Email address: email@example.com
Received 22 January 2021; Accepted 2 February 2021; Available online 1 July 2021
Copyright: Gawryjołek J and Krogulska A
License: This open access article is licensed under Creative Commons Attribution 4.0 International (CC BY 4.0). http://creativecommons.org/licenses/by/4.0/
By definition, anaphylaxis is a severe, potentially life-threatening systemic hypersensitivity reaction, which is characterized by rapid onset with life threatening airway, breathing, or circulatory problems and is usually, although not always, associated with skin and mucosal changes.1
Anaphylaxis can be triggered by a variety of agents, of which the most common cause is food.2–7 More than 120 foods that can cause anaphylactic reaction have been described, although the most often sensitizing ones are: peanuts, tree nuts, cow’s milk, eggs, fish, shellfish, wheat, and soya.8 It is well documented that the triggers of anaphylaxis and the course of the disease in the pediatric population are different from the adult patients.9
The role of individual food allergens as causative agents of anaphylaxis depends on eating habits in different countries. For example, the most common food allergen in Asia is shellfish, while peanut allergy is extremely low compared with the Western countries.10 However, according to worldwide data, the most common allergens in infants are hen’s eggs and cow’s milk.10–13
In some cases, the allergenic properties of food are affected by thermal processing. This is well documented in milk and egg allergens.14 Most children reacting to unprocessed milk, tolerate it in baked form.15 Regular intake of processed milk accelerates the acquisition of tolerance to unheated food.16,17 Extensive heating also results in allergenicity changes in peanut proteins.
The clinical criteria for anaphylaxis are well defined.1,9 In everyday medical practice, the diagnosis is based on sudden onset, characteristic symptoms and typical signs such as urticaria, flushing, edema, cough, wheezing, stridor, abdominal pain and vomiting.1 Vital signs (heart rate, respiratory rate, blood pressure) need to be interpreted according to the age of the patient. The clinical presentation of anaphylaxis in infants and toddlers is more different than in older children and adults. Small children cannot report subjective symptoms such as pruritus, throat tightness, nausea, or abdominal pain. On the other hand, some of the signs, like irritability, inconsolable crying, or somnolence are difficult to interpret in infants.4 Some of the symptoms (regurgitation, irritability, and so on) can also be observed in healthy infants.
The prevalence of food-induced anaphylaxis among the youngest children is unknown, although increasing frequency is reported.2 Worldwide the youngest children (age 0–4 years) have the highest hospital admission rates for food-induced anaphylaxis.18–22
The aim of the study was to assess the rate of the hospitalization because of the anaphylaxis and analyze the cause and course of the episodes of food-induced anaphylaxis in children aged 0–3 years.
Food allergy was defined as an adverse reaction to food mediated by an immunological mechanism, involving specific IgE (IgE-mediated), cell-mediated mechanisms (non-IgE-mediated), or both IgE-mediated and cell-mediated mechanisms (mixed IgE-mediated and non-IgE-mediated).1 Diagnosis of food allergy was made based on the clear medical history of the patient, sensitivity to food allergen, and positive food challenge.
Anaphylaxis was diagnosed based on the criteria of European Academy of Allergy and Clinical Immunology’s (EAACI) Guidelines for Food Allergy and Anaphylaxis.1
Food-related anaphylaxis was diagnosed in patients with symptoms of anaphylaxis triggered by food allergens.
For the analysis of the personal and familial medical history of concomitant atopic diseases the following criteria were adapted:
AD—the diagnosis was made using the Hannifin and Rajka criteria for atopic AD.22
Asthma—was diagnosed based on the Global Initiative for Asthma (GINA) criteria; for children below 5 years, the Modified Asthma Predictive Index was used to establish diagnosis.23
allergic rhinitis—the diagnosis was based on ARIA criteria.24
Anaphylaxis episode was graded using the criteria of World Allergy Organization criteria.2
We conducted a retrospective analysis of medical records of 29 children aged 0–3 years that presented symptoms of food-induced anaphylaxis. The analysis comprised children hospitalized in the Department of Pediatrics, Allergology, and Gastroenterology between the period 01.01.2015 and 31.12.2018. During this period, 9667 children were hospitalized aged 0–3 years with infectious diseases and for allergy, gastroenterological and nephrological diagnostics.
Among this group:
out of 1527 children who were admitted to the Department of Pediatrics, Allergology, and Gastroenterology for food allergy diagnosis, 19 children met the criteria for food-induced anaphylaxis.
out of 22 children who were admitted to the Department of Pediatrics, Allergology and Gastroenterology because of the suspected food-induced anaphylaxis, 10 children met the criteria for the food-induced anaphylaxis.
All of the patients with the episodes of food-induced anaphylaxis were examined by a doctor immediately after the onset of anaphylaxis—full medical examination was performed. All of the patients underwent diagnostic procedure in the next month after the episode of anaphylaxis. The results of the diagnostic workup were all obtained from chart review. All patients with anaphylaxis have a clear cause–effect relationship with food intake. In the years 2015–2018, none of the children aged 0–3 years was hospitalized because of the anaphylaxis triggered by other factors than food.
Medical charts were reviewed from a collection of documents with the following clinical data; demographic data, symptoms of anaphylaxis, exam findings and vital signs, past medical history, type of food triggering reaction, coexistence of allergic disease, family, and perinatal history.
The diagnostic workup included specific IgE (sIgE), measured by using PolyCheck (Emma, Berlin). The concentration of sIgE was defined as positive for the results above the detection limit (>0.15 kU/l). The tests were conducted at least 1 month after the occurrence of anaphylaxis, but not later than 3 months. The results of skin prick tests were not included in the study, because they were performed only in some patients—most of the children were receiving antihistamines and/or had skin lesions that made it impossible to perform the test.
When sIgE was positive and the history of the patient was compatible, the food was defined as susceptible for the anaphylactic reaction. In other cases, an open oral food challenge (OFC) was performed in accordance with current guidelines.1,2
For the purpose of the study, the children were divided into two groups: infants from birth to 12 months of life and children from 13 months to 3 years of age.
The study was approved by the appropriate IRB (Komisja Bioetyczna Collegium Medicum UMK).
Statistical analysis was performed using the Statistica 13.1 statistical package from Dell Inc. Evaluation of the correlation of qualitative variables was performed with the chisquare test, and the Fisher exact test was used for 2x2 tables and the expected number was n < 5. The value of the test probability p < 0.05 was considered statistically significant.
In the period 2015–2018 years, 9383 children aged 0–3 years were hospitalized in the department, including 1.527 (16.3%) because of suspected food allergy. Over the studied period, anaphylactic reactions after food intake was observed in 29 (0.3%) of all hospitalized patients; 1.9% of all children with suspected food allergy.
The mean age of the child at the time of an anaphylactic reaction was 12 ± 9 months. The characteristics of the study group are presented in Table 1.
Most reactions 27/29 (93%) occurred while at home. There was one episode of anaphylaxis reported in a coffee shop and one in the hospital.
Table 1 Patient characteristics.
|Parameter||Total N = 29 (100%)||Infants N = 18 (62%)||Toddlers N = 11 (38%)||p|
|Male, n (%)||21 (72)||14 (78)||7 (64)||P > 0.05|
|First pregnancy, n (%)||11 (38)||7 (39)||4 (36)||P > 0.05|
|Birth on time, n (%)||26 (90)||18 (100)||8 (73)||P > 0.05|
|Birth weight, g mean±SD||3436 ± 546||3524 ± 323||3294 ± 787||P > 0.05|
|Apgar scale, points mean min–max||9.65 6–10||9.9 9–10||9.27 6–10||P > 0.05|
|Way of birth, n (%): natural cesarean section||13 (45) 16 (55)||8 (45) 10 (55)||5 (45) 6 (55)||P > 0.05|
It was found that 13 (45%) children had a positive family history for atopic diseases. None of the families of the patients had a history of anaphylaxis.
Further, 16 (55%) children had a personal history of concurrent atopic disease (Figure 1). The most frequent symptom reported in the study group, independently of age, was AD (5 infants and 11 toddlers). Asthma was reported in one infant and six toddlers. Anaphylaxis as the first manifestation of food-allergy, without previous atopic history, was significantly more prevalent in infants than in older children (p = 0.0002).
Figure 1 Personal atopic history in the infant and toddler group.
Symptoms observed in children during the episodes of anaphylaxis are presented in Figure 2. Vital signs parameters were measured only in nine (31%) of the examined children.
Figure 2 Symptoms observed in children during the episodes of anaphylaxis.
In 11 (38%) patients, symptoms on their skin/mucosal tissue and respiratory system were observed. Six (21%) patients had symptoms of skin/mucosal, respiratory, and gastrointestinal system. In the next six children (21%), skin/mucosal and gastrointestinal symptoms were present. Two patients (7%) presented with skin, behavioral, and gastrointestinal symptoms. In two patients (7%), skin, behavioral, and respiratory symptoms were observed. One (3.5%) child had symptoms on their skin, respiratory, behavioral, and gastrointestinal system. One child (3.5%) presented with respiratory, behavioral, and gastrointestinal symptoms.
The most common skin manifestation was urticaria: generalized in 10 (34%) patients and local in 19 (66%) patients. Other reported symptoms were pruritus and erythema/flush. Gastrointestinal symptoms were vomiting (n = 14, 48%), abdominal pain (n = 5, 17%) and diarrhea (n = 3, 10%).
Up to 62% (n = 18) of children reported symptoms in the respiratory tract, most commonly wheezing (n = 10, 34%) and cough (n = 9, 31%). The respiratory symptoms were significantly more prevalent in toddlers than in infants (p = 0.148).
In six patients (21%), behavioral symptoms were observed: anxiety (n = 3, 10%), somnolence (n = 2, 7%), and irritability (n = 1, 3, 5%).
Cardiac symptoms occurred only in the in two (11%) infants. Both children presented with tachycardia and hypotension referring for the age, confirmed by physician examination.
The differences in the clinical manifestation of anaphylaxis between the group of infants and toddlers are presented in Figure 3.
Figure 3 Anaphylaxis symptoms according to the age of studied children.
All infants were classified as mild-moderate anaphylaxis. Two toddlers had severe type of reaction.
There were no differences between the course of mild and moderate anaphylaxis in infants and toddlers (p > 0.05). The performed statistical analysis did not show a statistically significant relationship between the severity of the reaction and the patient’s age (p = 1). None of the children experienced a biphasic reaction.
As a possible cause of the symptoms, in 18 (62%) cases parents most often indicated the consumption of milk or milk-rice porridge, introduced as a new food to the child’s diet or consumed in a random manner. The other possible reported triggers were: hen’s eggs, wheat, peanuts, apple juice, and pumpkin seeds. In three children aged 2 years, there was anaphylactic reaction after consumption of processed food possibly contaminated with the trace amounts of milk, eggs, or nuts. In 11 (38%) cases, the anaphylaxis occurred after the first consumption of cow’s milk based formula. The trigger of the anaphylactic reaction was already known and had been previously diagnosed in 14 (48%) cases. In all of the children with previously diagnosed allergy, the allergic food was consumed accidentally or in a trace amount. More than 50% (n = 15) of the children had been breastfed when the incidence of anaphylaxis occurred. In all breast-fed children, the occurrence of the anaphylaxis was directly related to the introduction of new food into the diet or feeding with milk-based formula. In 27 patients (93%), the time between exposure and onset of symptoms was less than 15 min; two (7%) patients reported a reaction with 1 h. Milk was consumed as liquid food and egg was consumed in boiled form.
Sensitization has been demonstrated in all children. Most of the children were sensitized to cow’s milk (n = 25, i.e., 86%). The majority of them (n = 20, i.e., 69%) were sensitized to casein.
The majority of patients (n = 24, i.e., 83%) had polysensitization, five (17%) of them had sensitization only to milk. All of the children with sensitization only to milk were infants up to 5 months. We found significantly higher sIgE concentration to milk and hazelnuts in toddlers than in infants (147 kU/l vs 1.1 kU/l; 11 kU/l vs 0.64 kU/l, respectively) (Table 2).
Table 2 Sensitization to main allergens in the infants and toddlers group.
|Food allergen||sIgE concentration, median, min–max, kU/l||P|
|Total N = 29 (100%)||Infants N = 18 (62%)||Toddlers N = 11 (38%)|
|Milk||2.1 0.18–693||1.1 0.18–448||147 2–693||0.012|
|Egg white||2.0 0.18–374||0.91 0.18–320||2.0 0.29–374||P > 0.05|
|Egg yolk||0.27 0.16–431||0.19 0.16–431||11.50 0.23–20||P > 0.05|
|Wheat||1.45 0.35–228||0.56 0.35–228||1.75 0.65–30||P > 0.05|
|Soya||0.42 0.17–150||0.39 0.17–45||1.0 0.18–150||P > 0.05|
|Peanuts||2.1 0.17–547||7.1 0.17–547||0.5 0.3–300||P > 0.05|
|Hazelnut||5.6 0.26–500||0.64 0.63–150||11 0.26–500||0.032|
|Sesame||3.00 0.18–200||0.43 0.18–189||3.0 0.18–200||P > 0.05|
|Almond||1.4 0.18–8.5||3.9 0.18–8.5||1.175 0.18–150||P > 0.05|
The statistical analysis did not show a significant difference between the mean concentration of sIgE in the group of patients with mild, moderate, or severe reactions (Table 3). Anaphylaxis also occurred in children with low concentration sIgE; in four (14%) children sIgE was lower than 0.35 kU/l and in five (17%) children sIgE was 0.35–0.7 kU/l.
Table 3 Concentration of milk, eggs, and peanut sIgE according to the severity of anaphylaxis.
|Severity of anaphylaxis N = 29 (100%)||Type of sensitization||sIgE concentration, kU/l|
|Mean ± SD||Median||Min–Max|
|Mild||Peanut||79.05 ± 158.5||0.31||0.03–547|
|N = 16 (55.2%)||Cow’s milk||110.81 ± 210.51||1.80||0–693|
|Casein||32.31 ± 69.11||1.30||0–206|
|Egg white||63.30 ± 133.89||0.04||0–374|
|Moderate||Peanut||1.79 ± 3.54||0.18||0–11.00|
|N = 12 (41.3%)||Cow’s milk||29.97 ± 59.39||58.67||0–164.00|
|Casein||6.05 ± 10.04||9.86||0–25.00|
|Egg white||4.65 ± 12.73||12.65||0–45.00|
|N = 1 (3.5%)||Cow’s milk||13.00||13.00||13.00|
P > 0.05.
The basis for identifying the allergen was a medical history taken from the caregivers.
In 19 children (65%), the clear medical history and clinical data made it possible to establish a diagnosis without OFC.
In 10 (35%) children, OFC was performed to determine the causative factor. In total, 10 OFC were carried out—eight with milk, eight with rice, three with egg, and two with wheat. There were 10 positive OFC, including seven patients with milk, two patients with egg, and one patient with wheat. As an outcome of the OFC, anaphylaxis was observed in one patient, epinephrine was used.
Summarizing, milk was identified as a causative factor of the episodes of anaphylaxis in 19 (65%) children. Other elicitors of anaphylaxis were hen’s eggs: n = 4 (14%), wheat: n = 1 (3%), peanuts: n = 1 (3%), and pumpkin seeds: n = 1 (3%). In three (10%) children with food polysensitization, who consumed food possibly contaminated with multiple allergens, until now the causative factor of anaphylaxis could not be determined.
Most of the children received treatment: antihistamine drug (n = 21, 72%), glucocorticoids (n = 13, 45%), salbutamol (n = 6, 21%), and epinephrine (n = 2, 7%). There were no significant differences between the treatment in infants and toddlers (p > 0.05). Part of the children (n = 8, 28%), after the episode, attended hospital and received no treatment yet fulfilled the criteria for anaphylaxis. None of the children required intensive care.
Food-induced anaphylaxis is increasingly reported in all age groups, although the highest increase is observed in children and young adults. According to the epidemiologic data, a seven-fold increase in hospitalization in children due to food-induced anaphylaxis has been observed in Europe in the recent years.26 According to the US data, the hospitalization of food-induced anaphylaxis in children has more than doubled from 2000 to 2009.19 Also, in Australia the anaphylaxis fatality rates have increased over the last 20 years by 6.2% per year.22,24
The true prevalence of anaphylaxis in infancy is unknown—the frequency is estimated with the variation from 0.19–30 cases per 100,000 children/year.27 The incidence of anaphylaxis in children worldwide varied widely, ranging from 1 to 761 per 100,000 person-years for total anaphylaxis and 1 to 77 per 100,000 person-years for food-induced anaphylaxis.28 The epidemiology studies conducted in 2006 reported the lifetime prevalence of anaphylaxis as 0.05%–2.0%.6
In our study, the frequency of episodes of anaphylaxis was determined to be 0.3% of all hospitalized children aged 0–3 years, during 3 years period and 1.9% of children suspected of food allergy among hospitalized patients. The estimated frequency of anaphylaxis is probably overstated due to the profile of the department.
Our study found statistically significant differences in previous personal atopic history between the groups of infants and toddlers. All of the children >12 months had been diagnosed with at least one atopic disease (predominantly AD) whereas for over 70% of infants’ anaphylaxis was the first manifestation of food allergy. Infants are frequently being introduced to new foods in their diet which can lead to developing anaphylactic reaction. However, the introduction of solid foods in infants is recommended. Few infants presented with symptoms of anaphylaxis after the first exposure to cow’s milk formula. All of the reactions were self-limiting and occurred in private homes. Other researchers had similar observations.29,30
According to previous studies, the symptoms of anaphylaxis differ depending on the age of the children.29,30 Samady et al. found that the most common presentation of anaphylaxis in infants involved the skin and the gastrointestinal system (i.e., vomiting).30 In the group of older children, similarly frequent symptoms were present in the skin, oropharyngeal, gastrointestinal system, and respiratory system. Misirlioglu et al. described cutaneous and respiratory system disorders in children <2 years old as the most frequent symptoms.29 The same conclusions were drawn by Jeon et al.31
Our data also supports the observation that the main manifestation of anaphylaxis in infants are skin symptoms, regardless of the causative factor. Like in other studies, we found that respiratory symptoms were significantly more common in older children.4 Comparing to other studies concerning children up to 18 years, we found cardiovascular symptoms to be rare (7% of all children with anaphylaxis).33 One of the reasons could be due to the difficulty of recognizing cardiovascular symptoms in infants.
The measurement of blood pressure and interpretation of the results are usually underused and underreported in infants.34 Like in other studies, we do not have complete data concerning vital signs measurements, including blood pressure, during anaphylaxis episodes. Conducted studies have shown that only 12.5% children younger than the age of 3 years with anaphylaxis had a blood pressure measurement.35 The ambiguity of symptoms makes it difficult to determine the final diagnosis of anaphylaxis, leading to underutilization of epinephrine, and a higher risk of death. In guidelines published in 2019, authors indicated that health care providers should be aware of the needs to improve the recognition, diagnosis, and management of infants with anaphylaxis.36
The family history of allergic disease was observed in 45% of the patients in our study that is the same frequency estimated also in other studies.37
Cow’s milk is the most frequent trigger food in our group. That is similar to what is reported worldwide for that age group.21,29 Some of the studies identify egg as the most common food trigger in infants.30
We found the concentration of sIgE for milk, casein, and hazelnut significantly higher for toddlers than infants. Most of the cases of anaphylaxis to cow’s milk occurred with low or very low concentration of sIgE, like in other studies.16,30 The concentration of sIgE allows to estimate the risk of an allergic reaction after contact with the allergen but does not allow the assessment of its severity.38 Long term follow-up could indicate how sIgE concentration changes over time.
The main drug used in anaphylaxis epinephrine. In our study, the commonly given group of drugs are antihistamines and steroids, even though according to the guidelines they are third-line drugs. Similar results are observed in other studies.20,35 According to current knowledge, the lack of administration or delaying the administration of epinephrine is associated with an increased risk of death. Tsuang et al. found that reactions triggered by milk are at higher risk for needing more than one dose of epinephrine.36 Although the guidelines strongly advise the use of epinephrine as the first-line drug in treatment of anaphylaxis,1 there is parental and doctor’s uncertainty about the severity of the reaction, fear of side-effects, and difficulties deciding which drug to use.37 Although usually associated with life-threatening anaphylaxis, none of the patients required Intensive Care Unit (ICU) treatment.
There are some limitations to our study: retrospective character of the analysis, bias (because of the profile of the department), only a small group of children, from one university hospital qualified for the study. The strength of the study is our material, that is, a group of infants and toddlers with symptoms of anaphylaxis.
The incidence of anaphylactic reactions in children up to 3 years of age rated at 0.3% of all children hospitalized at this age. The most common symptom of anaphylactic reaction was urticaria. The primary cause of allergic reactions was cow’s milk after first exposure at home. Anaphylaxis has different patterns of symptoms depending on the age of the child. Anaphylaxis can occur even with low concentration of sIgE.
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