Introduction
Anaphylaxis is an acute life-threatening hypersensitivity reaction resulting from the release of inflammatory mediators from mast cells and basophils, following exposure to an offending agent.1 As a growing public health issue and given the unpredictable and possibly lethal nature of anaphylaxis, it is crucial for healthcare providers to promptly recognize and manage this medical emergency. Epinephrine constitutes the cornerstone of anaphylaxis treatment and should be administered without any delay.1
Infancy has been the least investigated age group.2.3 In infants, anaphylaxis is likely to be under-recognized, as diagnosis is challenging due to a variety of factors, such as lack of age-specific diagnostic criteria, inability of infants to verbalize their symptoms, and atypical and nonspecific manifestations that may overlap normal infant’s behavior.4–7 Moreover, in most countries, the limited number of premeasured doses of epinephrine autoinjectors has led to the undertreatment of anaphylaxis in this age group, especially in infants weighting <15 kg.2,8
The aim of this study is to provide an overview of the characteristics of anaphylaxis in infants as well as specific challenges regarding its diagnosis and treatment in this age group, with a view to increasing awareness of this medical emergency that may lead to improved management and prevention of recurrences. Raising awareness among healthcare professionals is fundamental to promptly recognize and manage anaphylaxis in infants, contributing to proper and comprehensive care of this vulnerable age group.
Epidemiology of Infant Anaphylaxis
It is difficult to precisely estimate the incidence and prevalence of anaphylaxis as there is heterogeneity among studies due to differences in definitions used, study methodology, and geographical areas. A 2019 systematic review conducted by Wang et al. focusing on children reported that global incidence rates of anaphylaxis vary widely, ranging from 1 to 761 per 1,00,000 person-years, while the prevalence estimates of anaphylaxis is 0.04–1.8%.9
Recent evidence suggests a global increase in both emergency department (ED) visits and hospitalizations due to anaphylaxis over the past two decades, particularly for food-induced reactions, aligned with a parallel increase in food allergies over the past years.2,9–11 According to different studies, the highest incidence rates of anaphylaxis are recorded during the first years of life, especially in children aged 0–2 years.10–12
In infants, the exact prevalence of anaphylaxis is unknown, as the data available are limited, but it is reported to be increasing.6 Variable range of anaphylaxis rates were observed among different studies. A study done by Samady et al. reported that 13% of food-induced anaphylaxis cases presenting to ED between 2015 and 2017 occurred in infants aged <12 months.13 A 2-year nationwide study in the Greek pediatric population noted that 26.8% of anaphylactic reactions occurred in infants up to 2 years,14 while a retrospective study conducted by Jiang et al. revealed that 57.6% (102/177) of the first episode occurred at the age group 0–2 years.15 Moreover, according to another study, the number of infant anaphylaxis cases in South Korea quadrupled from 2009 to 2013, and this could be attributed to an increase in food allergies, and thus increase in food-induced anaphylaxis and increased awareness among patients and guardians regarding anaphylaxis.16
Triggers of Anaphylaxis in Infants
The leading triggers of anaphylaxis globally are foods, drugs and insect venoms. During infancy, food allergens account for the majority of anaphylaxis cases. Virtually, any food could be implicated in anaphylaxis, but cow’s milk and hen’s egg comprise the most frequently reported culprits during the first year of life. It is noteworthy that there are variable distributions in food allergens due to different eating habits among countries (Table 1).
Table 1 Common triggers of anaphylaxis in infants.
| Authors | Study | Study period | Age | Number of patients (N) | Triggers |
|---|---|---|---|---|---|
| Gaspar et al. (2021)17 | Nationwide notification system for anaphylaxis by SPAIC (Portugal) | 2007-2017 | 0-2 years | 149 | Cow’s milk (62%) Hen’s egg (19%) Fish (13%) |
| Jiang et al. (2021)15 | Retrospective study in a tertiary hospital (China) | 2014-2020 | 0-2 years | 134 | Cow’s milk (32.9%) Hen’s egg (21.4%) Wheat (20.7%) |
| Kahveci et al. (2020)18 | Retrospective analysis of medical records in hospitals (Turkey) | 2015-2020 | <12 months | 160 | Cow’s milk (51.4%) Tree nuts (16.6%) Hen’s egg (15.4%) |
| Pouessel et al. (2020)5 | Retrospective study of cases recorded by AVN (France) | 2002-2018 | ≤12 months | 61 | Cow’s milk ( 59%) Hen’s egg (20%) Wheat (6%) |
| Jeon et al. (2019)16 | Retrospective study in 23 secondary or tertiary hospitals (South Korea) | 2016- 2018 | 0-2 years | 338 | Cow’s milk (43.8%) Hen’s egg (21.9%) Walnut (8.3%) |
| Samady et al. (2018)13 | Retrospective study in ED of a tertiary hospital (USA) | 2015-2017 | <12 months | 47 | Hen’s egg (28%) Cow’s milk (17%) Peanut (13%) |
| Topal et al. (2017)3 | Retrospective study in ED (Turkey) | 2007-2011 | <12 months | 23 | Cow’s milk (61%) Hen’s egg (21%) Walnut (9%) |
| Misirlioglu et al. (2017)7 | Prospective study on patients visiting an allergy clinic (Turkey) | 2010-2015 | 0-2 years | 63 | Cow’s milk (40.4%) Hen’s egg (25%) Tree nuts (25%) |
AVΝ: Allergy Vigilance Network; SPAIC: Portuguese Society of Allergology and Clinical Immunology.
Less commonly, anaphylaxis in infants may be triggered by drugs (mostly antibiotics and nonsteroidal anti-inflammatory drugs), natural rubber latex found in bottle nipples, pacifiers, rubber bands, and some toys as well as vaccinations.19
Risk factors
Comorbidities and cofactors of anaphylaxis are not well defined in infancy. There are comorbidities that possibly increase the risk of developing severe anaphylactic reactions, such as atopy, mastocytosis, and respiratory diseases, such as asthma, bronchiolitis, and croup.4,6,19 Additionally, cofactors that may contribute to severity of the reaction include acute upper respiratory tract infections, fever, physical exertion, and emotional stress.6,19–21 More studies are needed to better specify risk factors during infancy in order to prevent possible recurrences in future.
Diagnosis of Anaphylaxis in Infants
The diagnosis of anaphylaxis is primarily based on clinical presentation and history of a recent exposure to an offending agent because there is no specific laboratory test for accurate diagnosis.
No age-specific anaphylaxis diagnostic criteria are available, and it is therefore suggested to use the current criteria of National Institute of Allergy and Infectious Diseases–Food Allergy and Anaphylaxis Network (NIAID/FAAN)22 or the recently published World Allergy Organization’s (WAO)1 anaphylaxis criteria to establish the diagnosis of anaphylaxis in all age groups, including infants (Table 2).
Table 2 Anaphylaxis criteria of World Allergy Organization (WAO).1
Anaphylaxis is highly likely when any of the following criteria is fulfilled1:
|
In case of anaphylaxis, the infant age group presents a diagnostic challenge, and hence a high index of suspicion is needed to make correct diagnosis during infancy. First, infants cannot describe their symptoms, such as pruritus, throat tightness, lightheadedness, or feeling of impending doom, which makes diagnosis of anaphylaxis difficult.6,20 Additionally, in infants, it is difficult to interpret some of the symptoms of anaphylaxis, as they are nonspecific and could easily be attributed to normal infant’s behavior, including behavioral changes, such as irritability, inconsolable crying, regurgitation, or incontinence (Table 3). A study conducted among caregivers of infants who experienced food-induced anaphylaxis reported that signs such as eye rubbing and ear pulling were present in about 40% and 16% of cases, respectively.18 Of equal importance is the interpretation of vital signs, such as heart rate, respiratory rate, and blood pressure, which must be done according to the age of the patient. In particular, measuring of blood pressure is a difficult procedure in infants, and it is usually omitted, as referred by studies.6,7,19,23
Table 3 Clinical manifestations of anaphylaxis in infants.4,20,24
| Specific symptoms | Nonspecific symptoms |
|---|---|
| Skin: Hives, rashes, itching, and angioedema. Gastrointestinal: Vomiting, diarrhea, and abdominal pain. Respiratory: Cough, wheezing, and tachypnea. Cardiovascular: Hypotension and fainting. |
Skin: Eye rubbing, itching, or redness, ear scratching, tongue thrusting, tongue pulling, repetitive lip licking, or licking of hands. Gastrointestinal: Spitting up/regurgitation, back arching, bringing knees to chest, colicky abdominal pain, hiccups, and loose stools. Respiratory: Hoarse voice/crying, putting fingers in ears, ear pulling. Cardiovascular: Skin mottling and cyanosis. Neurologic: Sudden behavioral changes (crankiness, inconsolable crying, withdrawn/clingy). |
Symptoms of Anaphylaxis in Infants
Several studies have reported that there are age-related differences in the clinical presentation of anaphylaxis in children.7,13 During infancy, most common symptoms involve the skin (generalized urticaria, flushing, and angioedema), the GI system (vomiting), and the respiratory system (cough, wheezing, and stridor). Less frequently observed symptoms of infant anaphylaxis are cardiovascular symptoms (tachycardia and hypotension) and neurologic symptoms (change in behavior and irritability) (Figure 1).
Figure 1 Comparison of manifestations of infant anaphylaxis by organ systems in reported studies.3,13,5,7,15,16,18
Differential Diagnosis
The differential diagnosis of anaphylaxis in infancy is often complicated due to the fact that many of the symptoms are common with other childhood illnesses or conditions (Table 4).
Table 4 Differential diagnosis of anaphylaxis in infants.19,20
| Skin: Urticaria, urticaria pigmentosa/mastocytosis, contact dermatitis, viral exanthem, and hereditary angioedema. |
| Respiratory (upper or lower respiratory tract): Obstruction, congenital (e.g., laryngeal web, vascular ring, or malacias) or acquired (e.g., aspiration of foreign body, croup, bronchiolitis, or asthma), asphyxiation/suffocation, and breath holding. |
| Gastrointestinal: Obstruction, congenital, including pyloric stenosis and malrotation, or acquired, including food protein- induced enterocolitis syndrome with acute presentation, and intussusceptions. |
| Shock: Septic, cardiogenic, hypovolemic, distributive. |
| Central nervous system (CNS): Seizures, postictal state, stroke, trauma, child abuse, and increased intracranial pressure. |
| Metabolic disorders: Infectious diseases, such as pertussis, gastroenteritis, meningitis. Ingestion of poison or toxin (e.g., food, drug, or plant); drug overdose. Munchausen syndrome by proxy. Sudden infant death syndrome, apparently a life-threatening event. |
Treatment of Anaphylaxis in Infants
Regardless of the patient’s age, intramuscular administration of epinephrine is the cornerstone of anaphylaxis treatment and must be administered without delay, even in suspicion of impending anaphylaxis, because delayed use of adrenaline is related to increased rates of hospitalization and fatalities.1,25,26
The recommended dose of epinephrine is 0.01 mg/kg (max 0.3–0.5 mg/kg) and can be administered as an injection drawn up from an ampule containing 1 mg/mL by using a 1-mL syringe or by using an EAI. In most countries, EAI are available in two doses: 0.15 mg for children weighing <30 kg, and 0.30 mg for children and adults weighing ≥30 kg; however, most infants weigh between 10 and 15 kg. In 2018, the US Food and Drug Administration (US FDA) approved a dose of 0.1-mg EIA for children weighing 7.5–15 kg; however, it is available only in the United States.6,27 Globally, the 0.15-mg EIA is often prescribed for infants, as this is the lowest available dose, but this may provide up to double the recommended dose in case of infants weighing <7.5 kg. However, this dose is recommended due to the unavailability of 0.1-mg dose and the favorable benefit–risk ratio of epinephrine in this life-threatening allergic reaction. Furthermore, using an EIA minimizes the risk of dosing errors and delays in the administration of injectable epinephrine, especially for caregivers without medical training.1,6,18
Given the ambiguity of symptoms of anaphylaxis during infancy and the fact that many clinical manifestations of anaphylaxis could be confused with normal infant’s behavior, infants could be more vulnerable to delayed administration of epinephrine than children of other age groups.6,28
Many studies have reported that epinephrine is underutilized in general population, specifically in infants.18,19,23,29 In a prospective observational study of 512 infants aged 3–15 months with known or likely allergy to milk or egg, 11.4% of anaphylactic reactions were characterized as severe, yet only 29.9% of the infants received adrenaline.7 Another study that analyzed the medical records of infants aged 0–2 years diagnosed with anaphylaxis, demonstrated that almost half of the patients (46.8%) received epinephrine treatment as initial management.16 The low rates of epinephrine administration could be attributed to several factors, such as failure to recognize anaphylactic reactions, fear of possible adverse reactions in infants, or uncertainty about the necessity of medication.7,15,18,19,29
Even though epinephrine is the first-line treatment for anaphylaxis, other medications, such as corticosteroids and antihistamines, often replace epinephrine in acute treatment of anaphylaxis, although there is little convincing data available to establish the effectiveness of these medications for treating anaphylaxis.30 A retrospective review of a pediatric allergy department showed that of the 43 infants diagnosed with anaphylaxis in the first year of life, 68.3% received H1 antihistamines, 49.2% received corticosteroids, and only 36.5% received epinephrine as an acute treatment.3
Acute management
Acute treatment of anaphylaxis during infancy involves the following steps (Figure 2):
Additional medications, such as antihistamines, corticosteroids, or β-agonists, are prescribed as an acute treatment of anaphylaxis, although these are not first-line medications and will not rapidly lessen symptoms, such as laryngeal edema, bronchospasm, or hypotension.6,19
Long-term management
In case of all infants with a history of anaphylaxis, long-term management is of paramount importance. Implementation of measures to prevent and effectively treat possible future reactions must include prescription of a weight-appropriate EAI, a personalized written anaphylaxis emergency action plan, and training of caregivers regarding prompt recognition of anaphylaxis manifestations as well as correct injecting of epinephrine. Moreover, the patient should be referred to an allergist/immunologist for identification of the suspected trigger via skin prick tests or by measuring allergen-specific immunoglobulin E (IgE) levels, prevention of recurrences by strict avoidance of the trigger(s), and allergen immunotherapy (AIT) if indicated.19,31 Several studies have noted that EAIs are under-prescribed and underused in the treatment of anaphylaxis.7,19,32 Fleischer et al. reported that among 512 infants aged 3 to 15 months with documented or likely food allergy, only 29.9% with severe anaphylaxis received adrenaline injections.32 The possible reasons mentioned for not injecting epinephrine included the following: reactions not recognized by caregivers, unavailability of epinephrine, caregivers’ fear or uncertainty to inject epinephrine, or waiting for more symptoms to develop.32
Future Directions
Although several studies are published over the years about anaphylaxis in infancy, additional research is required to address knowledge gaps in epidemiology, diagnosis, management, and prevention of recurrences in this age group.
Foremost, since no age-specific diagnostic criteria are available, it is important to create new infant-specific diagnostic criteria, leading to prompt and accurate diagnosis of this medical emergency. Moreover, taking into consideration that anaphylaxis in the specific age group is often underdiagnosed and most of the data are underreported and do not reflect the real epidemiological pattern, a better understanding is of great importance regarding the true incidence of anaphylaxis in infants through more infant-specific and multi-institutional studies. Advance research is needed regarding identification of potential risk factors and cofactors that are crucial for proper management of patients with anaphylaxis, as they contribute to the development of personalized action plans to prevent possible recurrences in the future. As anaphylaxis is increasingly reported in infancy, healthcare professionals should focus on prevention of recurrences through parental education about avoidance of allergens, recognition of specific manifestations, and severity assessment of the allergic reaction as well as if indicated, appropriately epinephrine using an EIA. Last but not least, global availability of new types of autoinjectors containing 0.1-mg epinephrine is essential for its safe administration to infants.