Pediatric Anaphylaxis

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.^[2]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.^[3]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.^[4]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.

References

Common Triggers of Pediatric Anaphylaxis

In 2021, 27.2% of children had one or more selected allergic conditions. About 1 in 5 children had a seasonal allergy (18.9%), 1 in 10 had eczema (10.8%), and 1 in 20 had a food allergy (5.8%).^[1]Studies have shown that food is the most common cause of anaphylaxis in children,^{[5, 6, 7]} followed by insect stings.^[6]

The foods most commonly implicated include peanuts, hen’s egg, cow’s milk, seafood (shell and fin fish), tree nuts, soy, and wheat^{[5, 8, 9]}
Common non-food triggers include the following:^{[8, 10, 11, 12]} medications (beta-lactam antibiotics, nonsteroidal anti-inflammatories) and insect stings (especially bees and wasps)
Less frequent and rarer triggers include latex,^{[6, 8]} vaccines,^[12] and exercise^[12]
There may be times where no cause is identified, ie, idiopathic^{[5, 8, 12]}

References

Epidemiology of Anaphylaxis in Children

The true prevalence of anaphylaxis is difficult to obtain because of different definitions and reporting variations in different regions worldwide, different study populations, and different issues related to the collection of national health data sets.^{[8, 13, 14, 15]} Over the years a variety of definitions of anaphylaxis have been suggested, which may have influenced determining actual prevalence.^{[5, 16, 17]} For example, while similar, variations in definition can be as subtle as defining anaphylaxis as “serious allergic reaction”^[16]to “life threatening.”^[6] Data collection can be affected by different diagnostic terminology used in various versions of the International Classification of Diseases. The United States version (ICD-10-CM) (National Center for Health Statistics, Centers for Disease Control and Prevention [CDC])^[18]uses both “anaphylactic reaction” and anaphylactic shock,” whereas the World Health Organization (WHO) uses “anaphylactic shock” in ICD-10^[19]and “anaphylaxis” in ICD-11.^[20]

A previous systematic review by Panesar et al of 49 eligible studies observed that the incidence rates for anaphylaxis ranged from 1.5 to 7.9 per 100,000 person-years in the European population. Additionally, there was a peak incidence rate of 313.58 per 100,000 person-years in children aged 0-4 years.^[21]A more recent study by Wang et al showed a wider range of anaphylaxis of 1 to 761 per 100,000 person‐years, and 1 to 77 per 100,000 person‐years for food‐induced anaphylaxis in children.^[7]

Studies have shown increasing emergency visits for anaphylaxis. A 10-year review of the United States national administrative claims database noted an overall increase in emergency department (ED) visits for anaphylaxis, with the greatest increase in 5- to 17-year-olds (11.9 per 100,000 to 35.2 per 100,000).^[22] The rate of ED visits of infants and toddlers has been shown to be 15-32 visits per 100,000 population.^[23] A study in Spain of ED visits by children with a diagnosis of anaphylaxis found an incidence of 1.2 cases of anaphylaxis per 100,000 patients.^[24]

There is a trend for an increase in pediatric encounters in the ED for anaphylaxis for food-induced reactions. A 10-year review of US national claims data revealed a 214% increase from 6.40 per 100,000 to 20.05.^[25] The same study noted the largest increase in infants and toddlers (27.3 per 100,000). A report from the US Centers for Disease Control and Prevention (CDC) indicated that 5.8% of children nationwide had a food allergy in 2021. The percentage of children with a food allergy increased with age, from 4.4% in children 0–5 years old to 5.8% in children 6–11 years old, and 7.1% in children 12–17 years old.^[1]

References

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.^{[5, 6, 26]} Skin and mucosal cutaneous symptoms (eg, hives, pruritus, facial swelling) will occur 80-90% of the time.^{[5, 26]} 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.^{[5, 6, 26]}

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.^[16] However, these criteria have been modified by three major allergy groups. The differences in criteria are listed in the table below.

Table

View Table

See Table

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. About half of these patients may experience a recurrence of symptoms (biphasic reaction) 6-12 hours after the initial presentation.^[5] The overall risk of biphasic reactions appears to be < 1% to 20%.^[6]

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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.^[27]Additionally, the verbal child may not be able to identify the triggering agent (eg, food) even when known to the parent or caretaker.

References

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.

References

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.^[28]

Serum tryptase levels

The diagnosis of anaphylaxis is principally a clinical one. However, measurements of serum tryptase may be helpful in confirming the diagnosis. Levels may increase as soon as 15 minutes after onset of symptoms and can peak in up to 3 hours. Levels return to baseline in about 6–8 hours after onset of symptoms. A normal value does not rule out anaphylaxis, as tryptase levels tend not to increase in children with food-induced anaphylaxis.^{[5, 6]} Although studies have shown a high sensitivity (88%) and positive predictive factor (93%), they also note a low sensitivity (28%) and negative predictive value (17%).^[29]

The Allergy Immunology Joint Task Force on Practice Parameters (JTFPP) recommends that clinicians obtain a baseline serum tryptase (bST) level in patients presenting with a history of recurrent, idiopathic, or severe anaphylaxis, particularly those presenting with hypotension.^[30]

The JTFPP suggests drawing an acute-phase tryptase level as early as possible during a suspected anaphylactic event (ideally within 2 hours after onset of symptoms). The JTFPP also suggests a second tryptase measurement at a later time as a baseline for comparison to determine whether there was a significant acute elevation.^[30]

Clinicians should consider evaluating HαT in patients with elevated bST level (8 ng/mL or greater).

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.

References

Treatment of Children With Anaphylaxis

Overview

It cannot be stressed enough that intramuscular (IM) administration of epinephrine is the only first-line treatment for anaphylaxis.^{[5, 6, 26]} Its use should not be delayed by giving other medications such as antihistamines beforehand. Administration in the anterolateral thigh provides superior absorption compared with deltoid and subcutaneous injections. Because of the risk of potentially fatal dysrhythmias, intravenous (IV) and intraosseous (IO) administration should be limited to low-dose infusions under closely monitored conditions for patients with refractory reactions. Since delay in administration may lead to more prolonged symptoms, epinephrine should be administered even when patients present with potential anaphylactic symptoms, whether mild or moderate in severity. There are no absolute contraindications to epinephrine use in the treatment of anaphylaxis.

Prehospital care should be directed at stabilization of the airway, breathing, and circulation (the "ABCs") and administration of IM epinephrine.

Patients with signs of poor perfusion 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.

ED consultation with a pediatric emergency or 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:

Significant clinical presentation or those requiring prolonged treatment
History of atopic disease
Unclear trigger or inciting agent
Recurrent episodes of anaphylaxis

Few patients will present in shock. Most will 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.

Although crystalloid fluids and nebulized beta-agonists may be helpful with clinical symptoms, the role of antihistamines (H₁ and H₂ blockers) and corticosteroids have come into question 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. The amount of observational time should be based on factors including the severity of presentation, time to first dose of epinephrine, need for more than one dose of epinephrine, and inciting trigger. A period of 2–6 hours is appropriate in most circumstances. Some children, nonetheless, may require up to 24 hours with certain triggers, eg, bee stings, or treatment, eg, multiple doses of IM epinephrine. In any case, the patient must be observed until all symptoms have cleared.

Children who require fluid resuscitation, continuous epinephrine infusion, 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.

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 his or her 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. Nebulized epinephrine may be used for stridor secondary to laryngeal edema.

Epinephrine administration

The Allergy Immunology Joint Task Force on Practice Parameters (JTFPP) published a 2023 practice parameter update for anaphylaxis.

Because there are no criteria specific to infants and toddlers, the JTFPP suggests that clinicians use current National Institute of Allergy and Infectious Disease and Food Allergy and Anaphylaxis Network (NIAID/FAAN) or World Allergy Organization (WAO) anaphylaxis criteria to assist in the diagnosis of anaphylaxis in infants/toddlers.

Epinephrine is the first drug of choice. The JTFPP suggests that clinicians prescribe either the 0.1-mg or the 0.15-mg epinephrine autoinjector (EAI) dose for infants/toddlers weighing less than 15 kg.^[30]

A dose of 0.01 mg/kg (1:1000 strength = 1 mg/mL) should be administered into the anterolateral portion of the thigh. Subcutaneous and deltoid administration are not recommended.^{[6, 26]} The IM epinephrine may be repeated at 5- to 15-minute intervals for unresponsive symptoms.

Because there is wide use of prefilled epinephrine syringes, a simplified IM dosing regimen can be used based on the child’s weight:

7.5–15 kg: 0.1 mg (0.1 mg/0.1 mL)
15–30 kg: 0.15 mg (0.15 mg/0.15 mL)
> 30 kg: 0.3 mg (0.3 mg/0.5 mL)

A low dose, continuous epinephrine infusion starting at 0.1 mcg/kg/min (1 mcg/kg/min maximum) may also be used in patients unresponsive to multiple IM doses. Because of the potential severe side effects of IV instead of IM epinephrine, use should be limited to those patients with hypotension unresponsive to IV fluids or in cardiovascular collapse at a dose of 0.01 mg/kg over 5 minutes. IV administration should only be performed in a facility capable of close monitoring and with appropriate expertise.

The FDA approved an intranasal dosage form of epinephrine in August 2024 for emergency treatment of type I allergic reactions, including anaphylaxis in patients weighing at least 30 kg. The mean plasma concentration-time profile for intranasal administration was similar to that of needle syringe administration. The intranasal administration peak plasma time was 30 minutes, compared with the auto-injector at 8 minutes.^[31]

Blood pressure management

Patients with hypotension unresponsive to positioning and epinephrine should receive a 20 mL/kg rapid crystalloid fluid bolus. Additional medications should be considered for patients not responding to 60 mL/kg of crystalloid fluids and continuous epinephrine infusion.

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.^[32]A systolic pressure of less than the 5th percentile for age would indicate uncompensated shock, which correlates to the following:

< 70 mm Hg in children aged 1–12 months
< 70 mm Hg + (2× age in years) in children aged 1–10 years
< 90 mm Hg in children aged ≥ 10 years

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:

Epinephrine (0.1–1 mcg/kg/min IV) should be considered as the initial vasopressor in children. Doses at < 0.3 mcg/kg/min will tend to have more β-activity, whereas α-action becomes more pronounced at higher doses.
Dopamine (2–20 mcg/kg/min IV) may be used in addition to epinephrine. Greater α-activity is seen at higher doses.
Norepinephrine (0.1–2 mcg/kg/min IV) is a potent vasopressor. It is usually considered in children unresponsive to epinephrine.

Treatment of cutaneous symptoms

Cetirizine is currently the only second-generation IV H1 antihistamine approved for use in the United States. Studies have shown its efficacy in acute urticaria,^[33] and by extension its potential use in anaphylaxis.^[34] However, the CDC have recommended its use in Covid vaccine–related anaphylaxis.^[35]

Recommended dosing is as follows:

- 6 months to 5 years of age: 2.5 mg IV
- 6 to 11 years of age: 5–10 mg IV
- 12 years of age and older: 10 mg IV
- 6 months to 5 years of age: 2.5 mg
- 6 years of age and older: 5-–10 mg

In those circumstances when cetirizine is not available, diphenhydramine 1 mg/kg (not to exceed 50 mg/dose) may be given IV/IM/PO.

H2 antihistamine use has fallen out of favor for the most part, because these receptors have limited vascular smooth muscle distribution and have a minor place in anaphylaxis.^{[6, 36]}

Treatment of late phase reaction

The place of glucocorticoids has come under question. Their use in anaphylaxis has been extrapolated from their effects in asthma. Current World Allergy Organization, European Academy of Allergy, Clinical Immunology, and Joint Task Force on Practice Parameters are no longer recommending the routine use of glucocorticoids to prevent a biphasic response. The time it takes for these medicines to be bioavailable is such that they also have no apparent effect on the initial phase of anaphylaxis.^[37]

References

Outcomes in Pediatric Anaphylaxis

The prognosis is good, especially if anaphylaxis is treated early with epinephrine. Although the overall fatality rate in children is very low (1 per 100,000 per population),^[14] those who have a delay in receiving epinephrine, have hypotension or prolonged respiratory symptoms, or are unresponsive to treatment are at the greatest risk.

Delayed/biphasic anaphylactic response

The overall risk of biphasic reactions appears to be < 1% to 20%.^[6] The secondary response may be milder, the same, or more severe than the initial presentation. Those at greatest risk, with certain triggers (eg, bee stings) or treatment (eg, multiple doses of IM epinephrine), may require up to 24 hours of observation. All patients with anaphylaxis, even with mild symptoms, should be monitored. Most will suffice with a 2–6-hour period of observation. In any event, the patient must be observed until the symptoms have resolved.

References

Patient Follow-up for Pediatric Anaphylaxis

Patients and their caregivers should be provided with education about exposure risk, early management, and access to medical care.

All patients should be discharged with a prescription for an epinephrine auto-injector. Patients and caregivers should be advised to call 911 or seek immediate medical attention after epinephrine self-administration. Two to three days of cetirizine may be helpful for residual cutaneous symptoms.

Discharge guidance should include an in-person follow-up with the patient’s primary care provider within a week. Those with more than mild symptoms should be referred for evaluation by an allergist.

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

References

Author

Jeffrey F Linzer, Sr, MD, MICP, FAAP, FACEP, Professor of Pediatrics and Emergency Medicine, Division of Pediatric Emergency Medicine, Emory University School of Medicine; Medical Director for Compliance and Business Affairs, Senior Advisor for Emergency Medical Services and Disaster Preparedness, Consulting Staff for Children's Sedation Service, Children's Healthcare of Atlanta