Pediatric Anaphylaxis

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Overview

Anaphylaxis is an acute, potentially life-threatening syndrome — with multisystemic manifestations due to the rapid release of inflammatory mediators. In children, foods can be a significant trigger for immunoglobulin E (IgE)-mediated anaphylaxis. Milk, eggs, wheat, and soy (MEWS) as a group are the most common food allergens; however, peanuts and fish are among the most potent. In fact, children can develop anaphylaxis from the fumes of cooking fish or residual peanut in a candy bar.

Other common triggers include preservatives (in food and drugs), medications (antibiotics), insect venom (bee sting), and bioactive substances (eg, blood, blood products). Environmental allergens such as pollens, molds, and dust mites are a less common and infrequent cause of anaphylaxis. Non-IgE triggers include infection, opiates, radiocontrast dye, and exercise.

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Anaphylaxis vs anaphylaxis syndrome

Although the clinical presentation and management are the same, the term anaphylaxis generally refers to IgE-mediated reactions, whereas the term anaphylactoid generally refers to non–IgE-mediated reactions. The term anaphylaxis syndrome is best used to describe clinical symptoms and signs.

Pathophysiology

IgE- and Non–IgE-Mediated Reactions

Both IgE and non-IgE activation of mast cells and basophils ignites a cascade that results in the release and production of several inflammatory and vasoactive substances. These bioactive materials include histamine, tryptase, heparin, prostaglandins (PGD2, PGF2), leukotrienes (LTC4, LTD4, and LTE4), cytokines (TNF‑α), and platelet-activating factor (PAF). In anaphylaxis, these substances most commonly involve the skin, respiratory, cardiovascular, and gastrointestinal systems. As a result, urticaria, angioedema, bronchospasm, bronchorrhea, laryngospasm, increased vascular permeability and decreased vascular tone, and bloody diarrhea can develop.

The most common cause of mediator release is due to an IgE-mediated reaction. A previously sensitized B lymphocyte produces IgE against a specific antigen. The IgE resides on the mast cells and basophils. When the specific antigen, or one similar to it, binds to the high affinity FcεRI-α receptor of the immunoglobulin, mast cell and basophil degranulation occurs.

Non-IgE mediator release can be triggered by several different mechanisms including stimulation of the complement cascade to produce C3a, C4a, and C5a anaphylatoxin, neuropeptide and cytokine activity, and direct stimulation of the kallikrein-kinin system by certain agents (eg, opiates, radiocontrast media).

Activation of Histamine Receptors

Many of the clinical presentations seen in anaphylaxis are due to activation of multiple histamine receptors.[1] For example, acute bronchospasm (wheezing, dyspnea) is a result of the interaction between H1 and H2 receptor activity; bronchial smooth muscle constriction and increased mucus viscosity from H1 receptor activity and H2 activity causes increased mucus production. The combination of H1 and H2 receptor stimulation results in increased vascular permeability, flushing, hypotension, tachycardia, and headache. H1 and H3 activity results in cutaneous itch and nasal congestion.

Other Precipitating Agents in Anaphylaxis

Histamine, however, is not the only agent to cause symptoms in anaphylaxis.[2] Prostaglandins, leukotrienes, and PAF all contribute to the bronchoconstriction, vascular changes, and changes in vascular capacitance (increased vascular permeability and vasodilatation). One study showed an inverse correlation between PAF acetylhydrolase activity and the severity of anaphylaxis.[3] Compared with a placebo group, patients with anaphylaxis due to peanuts who had low PAF acetylhydrolase activity were more likely to have a fatal outcome.

Common Triggers of Pediatric Anaphylaxis

Foods are the most common trigger of anaphylaxis in children, with peanuts being the most frequent primary cause.[4] The following list is only meant to be illustrative of the more common anaphylactic triggers and therefore should not be considered an exhaustive listing. These triggering agents may cause an IgE- or non–IgE-mediated anaphylaxis:

Epidemiology of Anaphylaxis in Children

Although Bohlke and colleagues estimated the rate of anaphylaxis in children at 10.5 per 100,000 person-years,[6] the Rochester Epidemiology Project showed a rate of 75.1 per 100,000 person-years in children aged 9 years and 65.2 per 100,000 person-years in children aged 10-19-years old.[7] Furthermore, anaphylaxis appears to be more common in boys until the age of 15 years; a female preponderance then continues through adulthood.[8, 9] Infants younger than 12 months of age with anaphylaxis will more often have a history of atopic dermatitis.[10]

While asthma is more prevalent and has a higher mortality rate in black children, race does not appear to affect the likelihood of developing anaphylaxis.[11]

Evaluation of Pediatric Anaphylaxis

Signs and Symptoms

Anaphylaxis involves a range of signs and symptoms from hives, wheezing and angioedema to cardiovascular collapse and death.[12, 13] More than 80% of the patients will present with cutaneous symptoms (eg, hives, pruritus, facial swelling). Generally, at least 2 organ systems (skin, respiratory, cardiovascular, gastrointestinal systems) are involved; however, anaphylaxis can present with a low systolic blood pressure for age or decrease in systolic blood pressure by more than 30% after known allergen exposure alone.[14]

The Second National Institute of Allergy and Infectious Disease (NIAID) / FAAN symposium proposed diagnostic criteria that would identify at least 95% of the patients with anaphylaxis.[14] The primary clinical diagnostic criteria include the acute onset of skin and/or mucosal symptoms along with either respiratory compromise (eg, bronchospasm, stridor, shortness of breath) and/or persistent gastrointestinal symptoms (crampy abdominal pain, vomiting) and/or reduced blood pressure or associated symptoms of end-organ dysfunction (eg, hypotonia, syncope, incontinence).

Usually, cutaneous symptoms present first. Often, a history of exposure to a known trigger is given, (eg, bee sting, peanut ingestion, antibiotic administration). At times, the inciting agent may be unknown or unclear. Symptoms may develop slowly and insidiously over several hours or may rapidly progress over several minutes. Parenteral agents generally have a faster onset of symptoms than ingested ones.

Anaphylaxis may result in respiratory failure, shock, multiorgan system failure, and disseminated intravascular coagulation. Between 5% and 20% of patients may experience a recurrence of anaphylaxis 8-12 hours after the initial presentation.[15] Prolonged symptoms can last up to 32 hours despite treatment.[12]

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Special challenges

Initial symptoms may include an awareness that "something isn't right"; a tingling sensation in the mouth; itchy, watery nose and eyes; and/or the feeling of being warm and flushed. However, children and especially infants may not be able to verbally express the initial subjective symptoms of anaphylaxis. Infants may be more likely to have crying, persistent vomiting and irritability than older children.[10] Additionally, the verbal child may not be able to identify the triggering agent (eg, food) even when known to the parent or caretaker.

Differential Diagnosis

Angioedema

Asthma

Bee and Hymenoptera Stings

Carcinoid Tumor

Exercise-Induced Anaphylaxis

Serum Sickness

Shock

Shock, Cardiogenic

Shock, Hypovolemic

Status Asthmaticus

Syncope

Toxicity, Seafood

Anaphylaxis is essentially a clinical diagnosis. The primary clinical diagnostic criteria include the acute onset of skin and/or mucosal symptoms along with either respiratory compromise (eg, bronchospasm, stridor, shortness of breath) and/or persistent gastrointestinal symptoms (crampy abdominal pain, vomiting) and/or reduced blood pressure or associated symptoms of end-organ dysfunction (eg, hypotonia, syncope, incontinence).

Other problems to be considered include mastocytosis, physical urticaria, "red man syndrome" (related to the intravenous administration of vancomycin), and vocal cord dysfunction.

Diagnosis of Pediatric Anaphylaxis

Laboratory tests generally are not useful for the acute diagnosis of this condition, although serum histamine and tryptase may be of limited help in confirming the diagnosis retrospectively; other tests (eg, specific antigen testing following recovery) may provide some clues to triggering agents.[16]

Serum Histamine and Tryptase levels

Serum histamine level rises quickly with the onset of symptoms but does not remain elevated after 30-60 minutes.

Serum tryptase level peaks 60-90 minutes after the onset of symptoms and remains elevated for up to 5 hours. β-tryptase is released with degranulation of mast cells, whereas α-tryptase is secreted constitutively by the mast cells. The ratio of total tryptase to β-tryptase can help distinguish systemic mastocytosis from anaphylaxis. A ratio ≤10 implies anaphylaxis, whereas a ratio ≥20 is consistent with systemic mastocytosis.[17]

C1INH, VMA, RAST, and Cutaneous Antigen Testing

Other tests that may be useful in distinguishing anaphylaxis from the differential diagnosis include C1 inhibitor functional assay (C1INH) (hereditary angioedema) and urine vanillylmandelic acid (VMA) and serum serotonin levels (carcinoid syndrome).

Radioallergosorbent test (RAST) or cutaneous antigen testing (preferably by a specialist) can be used after recovery to try to identify the inciting antigen.

Treatment of Children With Anaphylaxis

Overview

The early use of epinephrine is the most important step in managing anaphylaxis.[18, 19] Administration in the anterolateral thigh appears to provide superior absorption compared with deltoid and subcutaneous injections.

Prehospital care should be directed at stabilization of the airway, breathing, and circulation (the "ABCs"). In addition, intravenous (IV) access should be obtained; intraosseous (IO) access should be considered when IV access cannot be quickly obtained in unstable patients.

Patients with signs of poor profusion should be placed in a modified Trendelenburg position with the legs elevated. Crystalloid fluids should be given rapidly if the patient is hypotensive or has other signs of shock.

Emergency department consultation with a pediatric critical care specialist should be obtained in unstable patients and those unresponsive to treatment. Outpatient consultation with an allergist is appropriate for most patients with anaphylaxis, especially those with the following factors:

Not all patients will present in shock. Most patients present with skin complaints (eg, urticaria, angioedema) along with respiratory, gastrointestinal, or cardiovascular symptoms. Primary attention is directed at the stabilization of the patient's airway, breathing, and circulation. If not already given, epinephrine (which acts as a physiologic antagonist) should be administered as soon as the diagnosis is suspected.

It cannot be stressed enough that the early use of epinephrine is the most important step in managing anaphylaxis.[12, 20, 21] An expert panel convened by the American College of Allergy, Asthma and Immunology urged that there are no contraindications for the use of epinephrine in treating anaphylaxis. Since delay in administration may lead to more severe cases, one should administer epinephrine when patients present with the possibility any allergic symptoms, whether mild or moderate in severity.[22, 23]

Antihistamines (H1 and H2 blockers), corticosteroids, crystalloid fluids, and other adrenergic agonists can also be beneficial in the management of this condition.

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Observation Versus Inpatient Monitoring

Even patients with mild symptoms should be observed for a minimum period of time. Although the time of observation should be individualized to the patient, a minimum of 4-8 hours appears appropriate.

Children who require fluid resuscitation, multiple doses of epinephrine, or repeated doses of a bronchodilator should be hospitalized. At a minimum, children who require vasopressors or glucagon should be admitted to a tertiary pediatric intensive care center (PICU).

Airway Management

If the patient is hypoxic or has respiratory complaints, high-flow oxygen (warm, humidified air is preferred) by nonrebreather mask should be given. In the awake child who is having some difficulty maintaining their airway, a nasopharyngeal (NP) airway is better tolerated than an oropharyngeal (OP) airway.

Continuous positive airway pressure (CPAP) may be considered before using an advanced airway (eg, noninvasive pharyngeal airway, endotracheal intubation) if the child is unable to maintain his or her airway, has decreased oxygen saturation, and/or has a decreasing level of consciousness. The use of noninvasive positive pressure (eg, CPAP) may help avoid the need for an advanced airway. In patients with signs of significant hypoxia, an advanced airway (eg, supraglottic airway device, endotracheal intubation) should be considered. The airway should be secured with an endotracheal tube early in cases of upper airway obstruction.

Nebulized albuterol (2.5-5 mg/dose) may be used for bronchospasm not responding to epinephrine. Although the addition of ipratropium to albuterol has been shown to be beneficial in severe asthma exacerbations in children, this combination in anaphylaxis has not been studied. Nebulized epinephrine has been used for stridor secondary to laryngeal edema but has not been studied in anaphylaxis.

Epinephrine Administration

Epinephrine is the first drug of choice. The 1:1000 strength should preferentially be administered intramuscularly (IM) in to the thigh. Subcutaneous (SC) administration is no longer recommended.[14, 20, 24] Because of the risk of potentially lethal dysrhythmias, IV/IO epinephrine (1:10,000) should be reserved for the patient with uncompensated shock.

The epinephrine dose may be repeated every 5-15 minutes. Administration in the anterolateral thigh appears to provide superior absorption compared with deltoid and SC injections.[25, 26] Subcutaneous injection is not recommended. For mild symptoms, diphenhydramine may be given orally via IM/IV administration.

Nebulized albuterol (2.5-5 mg/dose) may be used for bronchospasm not responding to epinephrine. Although the addition of ipratropium to albuterol has been shown to be beneficial in severe asthma exacerbations in children, this combination in anaphylaxis has not been studied. Nebulized epinephrine has been used for stridor secondary to laryngeal edema but has not been studied in anaphylaxis.

Blood Pressure Management

Patients with hypotension unresponsive to positioning and epinephrine should receive a 20 mL/kg rapid crystalloid fluid bolus (eg, lactated Ringer or isotonic sodium chloride). Repeat boluses up to 60-80 mL/kg may be necessary for correcting the hypovolemia.

Recall that children are more likely to have compensated shock in which tachycardia and signs of hypoperfusion (eg, decreased peripheral pulses, cool extremities) are present, but the blood pressure is normal.[27] A systolic pressure of less than the 5th percentile for age would indicate uncompensated shock, which correlates to the following:

Glucagon may help with refractory symptoms in the patient taking a beta-blocker. In children, administer 20-30 mcg/kg (not to exceed a cumulative dose of 1 mg) IV over 5 minutes, followed by an IV maintenance infusion and titrated to clinical effect at 5-15 mcg/min.

Treatment for Patients Unresponsive to Fluid Resuscitation

Patients unresponsive to fluid resuscitation should receive vasopressors as follows:

Treatment of Cutaneous Symptoms

The combination of H1 and H2 antihistamines appears to be more effective, especially for cutaneous symptoms.[14, 28] The onset of activity of these agents is slower than epinephrine and are considered next-in-line treatment. Second-generation H1 antihistamines (eg, cetirizine, loratadine) have not been studied in anaphylaxis.

Diphenhydramine 1 mg/kg (not to exceed 50 mg/dose) may be given IV/IM/PO or ranitidine, which has a beneficial side effect profile in children, 1 mg/kg (not to exceed 50 mg/dose IV or 150 mg/dose PO) may be given. The oral use of these agents should be restricted to mild cases.

Treatment of Late Phase Reaction

Corticosteroids do not have an immediate effect on the symptoms of anaphylaxis but may help reduce or prevent a biphasic "late phase" reaction. The choice of methylprednisolone (IV), prednisone, or prednisolone (PO) 1-2 mg/kg should be based on the patient's presentation and condition. The effect and time of onset are similar among these agents. The dose may be repeated at 6-hour intervals as indicated.

No published studies compare dexamethasone with other corticosteroids in the treatment of anaphylaxis. However, based on its use in other allergic conditions, a dose of dexamethasone 0.15-0.6 mg/kg IV would be appropriate.

Outcomes in Pediatric Anaphylaxis

The prognosis is good if anaphylaxis is treated early. The development of shock, however, is a poor prognostic indicator. In fact, the risk of death due to respiratory and cardiovascular complications is significant in anaphylaxis. Estimates of mortality from anaphylaxis vary from 100 to more than 500 cases per year in the United States; the estimated death rate is 0.002%.[29]

Delayed/biphasic anaphylactic response

A delayed or biphasic anaphylactic response may occur in 1-20% of patients.[30] The literature is unclear as to which patients are at greatest risk from having this condition. The secondary response may be milder, the same, or more severe than the initial presentation. Patients with greater risk of biphasic response should be observed a minimum of 12-24 hours. Severity of symptoms, delay in receiving epinephrine, and ingested antigen have been implicated as risk factors.

All patients who had more than mild symptoms and/or required more than 4 hours of observation should be given a prescription for an auto-injector of epinephrine. Patients and families should be advised to call 911 or seek immediate medical attention after epinephrine self-administration.

Patients should be continued on H1 and H2 blockers for 3 days after resolution of symptoms. A second generation H1 may be used as part of discharge care. A 3-day course of oral steroids may be warranted.

Patient Follow-up for Pediatric Anaphylaxis

Patients with anaphylaxis should follow up with their pediatrician and be given a referral for allergy evaluation and counseling. Moreover, patients and their caregivers should be educated about exposure risk, early management, and access to medical care.

Consider discharging patients with an action plan (such as those from the American Academy of Asthma, Allergy and Immunology [AAAAI] or Food Allergy and Anaphylaxis Network [FAAN]). Exposure to inciting agent, if known, should be avoided.

For excellent patient education resources, visit eMedicineHealth's Allergies Center. Also, see eMedicineHealth's patient education articles Severe Allergic Reaction (Anaphylactic Shock), Food Allergy, and Allergy: Insect Sting.

Author

Jeffrey F Linzer, Sr, MD, FAAP, FACEP, MICP, Professor of Pediatrics and Emergency Medicine, Division of Pediatric Emergency Medicine, Emory University School of Medicine; Associate Medical Director for Compliance and Business Affairs, EMS/Pre-Hospital Care Coordinator, Consulting Staff for Children's Sedation Service, Children's Healthcare of Atlanta

Disclosure: Nothing to disclose.

Chief Editor

Kirsten A Bechtel, MD, Associate Professor of Pediatrics, Section of Pediatric Emergency Medicine, Yale University School of Medicine; Co-Director, Injury Free Coalition for Kids, Yale-New Haven Children's Hospital

Disclosure: Nothing to disclose.

Acknowledgements

Kirsten A Bechtel, MD Associate Professor, Department of Pediatrics, Yale University School of Medicine; Attending Physician, Department of Pediatric Emergency Medicine, Yale-New Haven Children's Hospital

Kirsten A Bechtel, MD is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Wayne Wolfram, MD, MPH Associate Professor, Department of Emergency Medicine, Mercy St Vincent Medical Center

Wayne Wolfram, MD, MPH is a member of the following medical societies: American Academy of Emergency Medicine, American Academy of Pediatrics, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

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