Whether in an office setting or within an emergency department (ED), advanced practice nurses are often the first health care provider to triage infants and children who may be experiencing anaphylaxis—an acute, potentially fatal allergic reaction with rapidly developing symptoms that appear within minutes to a few hours following exposure to an allergic trigger (de Silva, Mehr, Tey, & Tang, 2008; Sampson et al., 2006). In infants (birth to 2 years of age), anaphylaxis is primarily triggered by direct ingestion of food, whether deliberate or unintentional (Simons, 2007). Although first-line treatment of anaphylaxis for any age group is intramuscular epinephrine injection (Simons et al., 2011), the first step in a successful clinical outcome is the proper diagnosis of this life-threatening hypersensitivity reaction.
Symptoms of anaphylaxis often include respiratory compromise (e.g., dyspnea, wheezing, bronchospasm) combined with skin and mucosal changes (e.g., hives, swollen mucosa) or gastrointestinal effects (e.g., vomiting, diarrhea, abdominal cramping), yet anaphylaxis can be difficult to diagnose—particularly in infants who are unable to verbally describe symptoms or report their exposure to potential or known allergens. Further, symptoms in infants are often underrecognized because they may be mistaken for other illness or even normal findings in this age group, such as drooling, loose stools (particularly if breastfed), or irritability (Dosanjh, 2013; Simons, 2007). Given the serious consequences of misdiagnosis, the importance of proper identification and timely treatment of anaphylaxis cannot be overstated.
Nurse practitioners are often the first-line providers for infants in clinical settings and it is important to educate them about the inherent challenges of diagnosing and treating infant anaphylaxis. The primary aims of this review are to provide an overview of the published literature that will help facilitate the recognition of infant anaphylaxis by nurse practitioners and to identify and summarize options for an effective course of treatment and patient follow-up.
How common is anaphylaxis?
Anaphylaxis can occur at any age, with an overall age- and sex-adjusted incidence rate in the United States of 42 per 100,000 person-years; in children younger than 10 years, food-related anaphylaxis is most common (21 per 100,000 person-years) (Lee et al., 2017). The overall incidence of pediatric anaphylaxis in the United States seems to be increasing, particularly in those younger than 5 years (Koplin, Mills, & Allen, 2015), with rates estimated as high as 10–29% per annum (Dyer, Lau, Smith, Smith, & Gupta, 2015; Lee et al., 2017). Anaphylaxis diagnoses in children younger than 18 years rose from 23 per 10,000 in 2010 to 47 per 10,000 in 2016, representing a 104% increase over a 7-year period; the corresponding rate of ED visits due to anaphylaxis increased from 1.4 visits to 3.5 visits per 10,000 children, equivalent to 150% growth (Blue Cross Blue Shield Association, 2018). However, it is unclear whether the increasing rate of diagnosis is a consequence of an improvement in health care provider education and identification of pediatric anaphylaxis or a true reflection of an increasing incidence of anaphylactic episodes overall.
The actual incidence of infant anaphylaxis has been challenging to discern primarily due to the difficulty in properly identifying anaphylaxis in this age group. The most recent estimates of anaphylaxis in infants range from 25% to 34% of all pediatric anaphylaxis cases, with an incidence somewhat higher among male infants (56–69%) than female infants (Jeon et al., 2019; Rudders, Banerji, Clark, & Camargo, 2011; Samady, Trainor, Smith, & Gupta, 2018; Silva, Gomes, Cunha, & Falcao, 2012). Although these estimates may seem alarmingly high, it is important to note that anaphylaxis in the pediatric population as a whole is rare, accounting for only 0.1–0.2% of all pediatric ED encounters (Alvarez-Perea et al., 2017; Ben-Shoshan et al., 2013; Huang, Chawla, Jarvinen, & Nowak-Wegrzyn, 2012).
Kids at risk: triggers and risk factors in infant anaphylaxis
Pediatric anaphylaxis is most often associated with exposure to food, a fact that also holds true for infants. The most common specific food triggers in children include peanuts (12–31%), tree nuts (9–19%), cow's milk (6–40%), and egg (3–24%), although anaphylactic reactions have been reported after exposure to many other food items, including fruits and vegetables, meat, seafood, wheat, and seeds (de Silva et al., 2008; Huang et al., 2012; Rudders et al., 2011; Samady et al., 2018; Simons, 2007; Vetander et al., 2012). In infants younger than 12 months, cow's milk (17–61%) and egg (22–38%) are the most common triggers, followed by peanuts (13%) (Samady et al., 2018; Topal et al., 2013). Seafood, although a common trigger in older children, is rarely identified as a trigger in infants (Grabenhenrich et al., 2016; Huang et al., 2012; Rudders et al., 2011; Silva et al., 2012). Food-triggered anaphylaxis can occur in response to ingestion by direct feeding, transfer of an antigen through breast milk, or opportunistic sampling, such as an infant finding food on the floor (Simons, 2007). Dermal contact and inhalation of aerosolized food particles are rarely sufficient to cause anaphylaxis (Simons, 2007).
It is important to note that food allergies associated with anaphylaxis are immunoglobulin E (IgE) mediated. An unknown proportion of food allergies are non-IgE mediated (Nowak-Wegrzyn, Katz, Mehr, & Koletzko, 2015), but these do not cause anaphylaxis, are not treated with epinephrine, and are rarely life-threatening. Non–IgE-mediated food allergies are more prevalent in children than adults, with the most common being food protein-induced allergic proctocolitis, food-protein enteropathy, food protein-induced enterocolitis syndrome, and eosinophilic esophagitis, all of which can result in gastrointestinal distress (Mehr & Brown-Whitehorn, 2019; Meyer et al., 2019). Unlike the symptoms of the more common IgE-mediated food allergies, which typically develop within minutes of exposure, the symptoms of non–IgE-mediated food allergies tend to be subacute and chronic, developing over hours or days after exposure to the allergen (Caubet, Szajewska, Shamir, & Nowak-Wegrzyn, 2017; Meyer et al., 2019). Thus, the temporal profile of symptom development may prove useful in differentiating the two categories of IgE- and non–IgE-mediated food allergy.
Although food allergies account for the majority of infant and child anaphylaxis, other known triggers in children up to 18 years of age include insect sting venom (3–27%) and medications such as antibiotics and nonsteroidal anti-inflammatory drugs (5–9%) (Braganza, Acworth, McKinnon, Peake, & Brown, 2006; de Silva et al., 2008; Worm et al., 2014). Less commonly, anaphylaxis may be triggered by natural rubber latex found in bottle nipples, pacifiers, rubber bands, and some toys; vaccinations; and even cold exposure (Dinakar, 2012; Freishtat & Goepp, 2002; Landwehr & Boguniewicz, 1996; Romita, Mascia, Calogiuri, & Foti, 2017; Simons & Sampson, 2015). In perhaps 10–30% of cases in children, specific triggers cannot be identified, and anaphylaxis remains idiopathic (Braganza et al., 2006; Greenberger & Lieberman, 2014; Hogan, Kelly, & Wilson, 1998). In infants up to 2 years of age, information on the rates of anaphylaxis due to non–food-related triggers is limited; one study reported insect sting (0.6%), medication (3%), and unknown cause (3%) as triggers of anaphylaxis in infants (Jeon et al., 2019).
Clinicians and health care providers should be aware that the risk of infants developing severe anaphylactic reactions may be increased by a number of comorbid diseases, including atopy, urticaria pigmentosa/mastocytosis, and respiratory ailments such as asthma, bronchiolitis, and croup (Simons, 2007). Cofactors that may increase the severity of anaphylaxis in infants include acute upper respiratory tract infections, fever, physical exertion, and emotional stress (Simons & Sampson, 2015). When possible, wellness of the caretaker should also be evaluated because substance abuse, depression, Munchausen syndrome by proxy or other mental illness may hinder recognition or accurate reporting of anaphylactic symptoms in the infant (Simons, 2007).
One factor that has the potential to decrease the incidence of anaphylaxis in infants is the change in recommended infant feeding practices suggested by recent studies on oral tolerance induction. Data from several clinical trials indicate that a window of opportunity exists after the introduction of solid food and before the development of allergies during which high-risk infants may benefit from an oral tolerance induction program (Fisher, Du Toit, Bahnson, & Lack, 2018). The Learning Early About Peanut Allergy (LEAP) study showed early introduction of peanuts to infants younger than 11 months reduced peanut sensitization at 5 years of age (Du Toit et al., 2015). Similarly, introduction of egg protein to infants at 4–6 months has recently been shown to reduce subsequent egg allergy (Natsume et al., 2017; Wei-Liang Tan et al., 2017). Although it remains unclear whether oral tolerance induction in infants is a viable approach to other food allergies, meta-analyses of available data support the early introduction of peanuts and egg to infants to lower the risk of developing childhood allergies to these foods (Al-Saud & Sigurdardottir, 2018; Ierodiakonou et al., 2016). In the United States, following the release of the LEAP study, the National Institute of Allergy and Infectious Disease (NIAID) released addendum guidelines recommending introduction of peanuts at 4–6 months of age in high-risk infants with severe eczema and/or egg allergy and at around 6 months of age in those with mild to moderate eczema (Togias et al., 2017). Although such guidelines are offered in an effort to reduce the incidence of pediatric food allergies, adoption of such recommendations will likely result in more infants being exposed to potentially allergenic foods, which could lead to an increased incidence of anaphylaxis in this age group. Of course, in many cases, initial introduction of the potential allergen to infants at risk is likely to be performed in a clinical setting where the infant can be monitored for developing symptoms, and knowledge of the purposeful exposure to the allergen will facilitate diagnosis.
Factors unique to infants (e.g., their inability to verbally describe symptoms or exposure to potential triggers) make diagnosis of anaphylaxis particularly challenging in this age group. The clinical presentation of anaphylaxis in infants can vary widely. Potential signs, such as inconsolable crying, drooling, and regurgitation, are often shared with other childhood illnesses or conditions or are observed in healthy infants, further complicating diagnosis (Rudders et al., 2011; Simons & Sampson, 2015). Such aspects likely contribute to the underdiagnosis of pediatric anaphylaxis in the ED setting, with the resulting misdiagnosis potentially leading to suboptimal courses of treatment and negatively affecting outcome (Thomson, Seith, & Craig, 2018).
Basic diagnostic criteria
The accurate diagnosis of anaphylaxis is made difficult by the rapid onset of symptoms in multiple organ systems. The NIAID and the Food Allergy and Anaphylaxis Network (FAAN) have systematically developed a set of three diagnostic criteria for anaphylaxis in patients of all ages (Figure 1) (Sampson et al., 2006). Different criteria are invoked depending on the known allergic status of the patient, with more stringent requirements associated with less complete knowledge of that status. In cases in which the patient has a known allergic history or has been exposed to a likely or known allergen, the criteria are based on the acute onset of specific symptoms in at least two of four defined organ systems (skin/mucosa, respiratory, cardiovascular, and gastrointestinal). When it is unknown whether exposure to an allergen has occurred, a diagnosis of anaphylaxis requires presentation with skin and/or mucosal reactions accompanied by symptoms of respiratory compromise and/or end-organ disfunction. Although the rapid onset of symptoms and the involvement of multiple organ systems means there are numerous different ways in which anaphylaxis may present in the clinic, a retrospective assessment of diagnostic accuracy demonstrated that 97% of diagnosed cases were captured by the NIAID/FAAN criteria (Campbell et al., 2012). Because most anaphylaxis cases involve acute skin reactions (Braganza et al., 2006; Brown, 2004; Grabenhenrich et al., 2016), 87% of diagnosed cases were captured by criterion 1 alone (Figure 1) (Campbell et al., 2012). However, more than 18% of patients who met one or more of the NIAID/FAAN criteria were ultimately determined not to have anaphylaxis (Campbell et al., 2012); thus, alternative diagnoses should always be considered.
Diagnostic issues in infants
Failure to accurately diagnose anaphylaxis can negatively impact the chances of infants and children receiving appropriate treatment, reducing the likelihood of receiving epinephrine, an adequate observation period, or post-event referral to an allergist (Thomson et al., 2018). Specific criteria for the diagnosis of anaphylaxis in infants have not been developed. Symptoms can be considerably more difficult to evaluate in infants than in older children, which necessarily may lead to greater uncertainty in the diagnosis and likely underdiagnosis of the condition in this age group. The primary difficulty in diagnosing anaphylaxis in infants stems from their inability to communicate verbally. Infants cannot accurately describe symptoms and cannot answer questions about symptom development or possible exposure to allergens. The inability to communicate verbally makes it particularly difficult to evaluate subjective symptoms, such as pruritus, localized pain, nausea, feelings of faintness, airway restriction, and difficulty breathing. Clinical judgment is needed to identify objective signs of what might constitute subjective symptoms in older children and adults (e.g., scratching as a sign of acute pruritus). It is important to note that although knowledge of a history of anaphylaxis in a patient can help focus the assessment of symptoms, more than 80% of pediatric ED anaphylaxis cases are an initial diagnosis (Topal et al., 2013).
A confirmatory laboratory test for anaphylaxis in infants has not been established. Although elevated plasma or serum total tryptase levels have proven useful in confirming a diagnosis of anaphylaxis in some patients, these tests have limited practical utility in infants (Sicherer, 2018; Simons & Sampson, 2015). The difficulties arise primarily from the facts that 1) basal tryptase levels are usually elevated in infants—particularly those younger than 9–12 months—potentially due to mast cell activation in the developing immune system (Belhocine et al., 2011) and 2) food-triggered anaphylaxis, by far the most common in infants, rarely increases tryptase levels outside the normal reference range (Sampson, Mendelson, & Rosen, 1992; Wongkaewpothong et al., 2014).
Of interest, an association between anaphylaxis and sudden infant death syndrome (SIDS) has been suggested by reports of elevated postmortem beta tryptase serum levels in some infants diagnosed with SIDS (Buckley, Variend, & Walls, 2001; Holgate et al., 1994; Platt et al., 1994). Although other groups have failed to replicate these findings (Hagan, Goetz, Revercomb, & Garriott, 1998; Nishio & Suzuki, 2004), the possibility remains that at least some cases of SIDS are undiagnosed anaphylaxis and, as such, are not represented in the prevalence data.
Diagnosis of anaphylaxis in infants is often complicated by the fact that many of the objective symptoms are shared with other childhood illnesses or conditions (Figure 2). For example, skin and mucosal reactions may result from infectious diseases or autoimmune disorders, and respiratory distress may stem from foreign body aspiration or asthma. Gastrointestinal symptoms may be indicative of obstruction or congenital defects, although reduced blood pressure may be the result of stroke, meningitis, or head trauma. Even after known exposure to common triggers, such as peanuts or tree nuts, respiratory irregularities may not be related to an allergic reaction because these foods also account for more than 40% of all aspirated foreign bodies in children (Tan et al., 2000). Similarly, symptoms of acute gastrointestinal distress, such as persistent vomiting or diarrhea after exposure to cow's milk, may be associated with a non–IgE-mediated reaction such as food protein-induced enterocolitis syndrome rather than anaphylaxis (Bingemann, Sood, & Jarvinen, 2018). Many of the most salient symptoms—such as flushing, vomiting, somnolence, and incontinence—are nonspecific and often occur in healthy infants. Some, such as drooling and scratching, are seen so frequently in infants that they may not be documented (Dosanjh, 2013).
A key factor in diagnosing anaphylaxis is the temporal profile of symptom development. As symptoms typically tend to develop rapidly, with a median time between exposure and anaphylaxis of 10 minutes for food allergens and 12–20 minutes for drug and insect toxin allergens (de Silva et al., 2008), it is important to obtain a detailed history of recent exposure to potential allergens and an accurate estimate of symptom presentation. However, temporal proximity of allergen exposure and symptom development is not universal because up to 15% of children with anaphylaxis develop biphasic anaphylaxis in which symptoms can reoccur hours or days after an initial anaphylactic reaction has resolved without reexposure to the allergen (Alqurashi et al., 2015; Mehr, Liew, Tey, & Tang, 2009).
In studies of ED admissions of children with food-related anaphylaxis, initial presentation in infants most commonly involved skin and mucosal reactions (92–98%; e.g., hives, swelling), respiratory difficulties (30–59%; e.g., labored breathing, wheezing), and gastrointestinal irregularities (56–77%; primarily vomiting) (Rudders et al., 2011; Samady et al., 2018). Although most of the children display cutaneous symptoms, respiratory symptoms are somewhat less common and gastrointestinal symptoms more common in infants than in the pediatric population as a whole (de Silva et al., 2008; Rudders et al., 2011; Samady et al., 2018; Topal et al., 2013). Although cardiovascular irregularities are reported less frequently than those in other organ systems, this likely reflects the paucity of blood pressure measurements taken in infants rather than a clinical characteristic of the condition in this population. Blood pressure readings were reported in only 13–22% of infants 12 months of age or younger compared with 54–90% of older children (Huang et al., 2012; Topal et al., 2013), in part due to the difficulty in obtaining accurate readings in crying infants. These results suggest that hypotension is likely underdiagnosed in infants and underused as a diagnostic criterion for anaphylaxis.
But first, epinephrine
The first-line treatment for anaphylaxis is intramuscular epinephrine, which should be administered as soon as possible to help avert the development of life-threatening symptoms (Lieberman et al., 2015; Simons et al., 2011, 2013). Use of H1- and/or H2-antihistamines is not a substitute for epinephrine and should be administered only as adjunctive therapy (Campbell, Li, Nicklas, & Sadosty, 2014). Epinephrine has both α- and β-adrenergic properties, which are responsible for increasing blood pressure, preventing and relieving hypotension and shock, and decreasing upper airway obstruction, acute urticaria, angioedema, and wheezing (Dinakar, 2012).
In health care settings, epinephrine is injected into the mid-anterolateral thigh at a dose of 0.01 mg/kg up to a maximum of 0.3 mg in children and 0.5 mg in adults (Sicherer & Simons, 2017; Simons et al., 2011). In community settings, epinephrine is most often administered via an epinephrine autoinjector (EAI), which is available in the United States in three dosage strengths: 0.3 mg for those weighing 30 kg or more, 0.15 mg for those weighing 15–30 kg (0.3 and 0.15 mg manufactured by Lineage Therapeutics, Inc, Horsham, PA; kaléo, Inc, Richmond, VA; Mylan Specialty LP, Morgantown, WV; Teva Pharmaceuticals USA, Inc, North Wales, PA; Adamis Pharmaceuticals Corp, San Diego, CA; Amedra Pharmaceuticals LLC, Horsham, PA), and 0.1 mg for those weighing 7.5–15 kg (kaléo, Inc, Richmond, VA).
Currently, an EAI for infants weighing less than 7.5 kg is not available. This leaves health care providers and caregivers with the option to draw epinephrine from an ampule with a syringe, but one study found this was impractical for at-home use by caregivers who were inexperienced with ampules (Simons, Chan, Gu, & Simons, 2001). Therefore, the health care provider should evaluate the risks and benefits of administering a higher-than-recommended dose of epinephrine during anaphylaxis in infants and use their clinical judgment to provide the caregiver with an EAI dose recommendation (Wang & Sicherer, 2017).
A concern when using an EAI may be potential bone penetration due to the length of the exposed needle, which ranges from 11.7 to 16 mm for currently marketed 0.15-mg devices (Song, 2018). A recent study found that 43.1% of infants and children weighing 7.5–15 kg would be at risk of an accidental bone injection if using an EAI with a needle length of 12.7 mm (Kim et al., 2017). Penetration of the bone can lead to intraosseous delivery and systemic absorption rates that are similar to intravenous epinephrine delivery. Although inadvertent intravenous administration of an intramuscular or subcutaneous dose in the adult population is associated with a higher risk of cardiovascular complications (Kim et al., 2017), data regarding the pediatric population is limited; however, ventricular dysrhythmias and myocardial ischemia have been reported (Kim et al., 2017). Based on data from Kim et al., the appropriate EAI needle length for infants and children weighing 7.5–15 kg would measure approximately 7–8 mm (Kim et al., 2017). Therefore, an infant EAI option was released in 2018 with a needle length of 7.5 mm (kaléo, Inc, Richmond, VA).
Injections using EAIs in infants and children can also result in lacerations and embedded needles. In 22 cases of EAI-related injuries, 17 experienced lacerations and four experienced a needle stuck in the child's limb (Brown et al., 2016). It should be noted that this study was limited to participants who responded via two emergency medicine e-mail discussion lists and members of eight social media groups related to food allergies. To lessen the likelihood of injuries when administering to small children, injections using an EAI should follow the Food and Drug Administration–approved instructions that accompany each EAI prescription, including holding the child's leg firmly in place and limiting movement before and during injection.
All patients with a history of anaphylaxis should have an emergency management plan. Proper precautions for infant anaphylaxis include education of the family/caregivers regarding triggers and treatment when symptoms occur. If a food allergy is identified as the primary risk factor, then proper education regarding avoidance and safe feeding practices should be advised and reviewed regularly. Caregivers must be educated regarding the proper manner in which to read food labels and should be given a list of allergens and their synonyms, which can be overlooked in the list of ingredients (e.g., casein, whey). The patient should receive a prescription for a weight-appropriate EAI, and the caregiver should be properly trained on its use and instructed to keep the EAI within close proximity to the infant at all times. Because infants are nonverbal, wearing medical identification items (e.g., Velcro alert attached to clothing or wristbands for older infants) is recommended when infants are not in the care of their primary caregivers.
Anaphylaxis is a sudden onset of potentially life-threatening symptoms that is often underrecognized in infants either due to this being a first-time event, lack of recognition of symptoms, or misdiagnosis of another infantile disease. As first-line providers, it is critical that nurse practitioners be familiar with the diagnostic and treatment challenges of infant anaphylaxis. It is important that timely treatment is obtained. After an anaphylactic reaction, patients should be discharged with a management plan and a prescription for injectable epinephrine. With new guidelines that encourage early introduction of potentially allergenic foods, the incidence of infant anaphylaxis may increase. To further examine the epidemiology and proper diagnosis and treatment of infant anaphylaxis, additional studies should be conducted with results posted in a national registry.
A case of infant anaphylaxis
A 12-month-old boy transitioning from breast milk developed red itchy skin and nasal drainage following ingestion of 4 oz cow's milk. Child had a history of moderate eczema so changes in skin were not initially noted as a change from baseline. He was also teething, so the family thought his nasal drainage was related to him cutting teeth. About 20 minutes later, he developed emesis. Mother took him into the ED due to the vomiting. In the ED, he continued to have emesis, increase in nasal drainage and was digging at his skin. His lungs were clear on examination. Oxygen saturation level was 98% on room air and blood pressure was within normal range for his age. Due to the development of three body systems (skin, upper respiratory, and gastrointestinal system), he was given an EAI based on his weight. The five-minute reassessment showed resolution of itching and redness to skin, improvement in nasal symptoms and no additional episodes of emesis. The rest of his examination remained within normal range. He was also given cetirizine 2.5 mg and prednisolone 15 mg by mouth. He was monitored for an additional 4 hours with complete resolution of symptoms at discharge. He was sent home with an emergency anaphylaxis plan, a weight-based EAI with instruction on use, and a referral to an allergy clinic for further management of milk allergy.
Acknowledgments: Writing and editorial assistance was provided by Tom Stratford, PhD and Kristen Andersen, PhD of Prescott Medical Communications Group (Chicago, IL), and funded by kaléo , Inc.
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