Etiology

The most common causes of anaphylaxis in children are different for hospital and community settings. Anaphylaxis occurring in the hospital results primarily from allergic reactions to medications and latex. Food allergy is the most common cause of anaphylaxis occurring outside the hospital, accounting for about one half of the anaphylactic reactions reported in pediatric surveys from the USA, Italy, and South Australia (Table 143-1). Peanut allergy is an important cause of food-induced anaphylaxis, accounting for the majority of fatal and near-fatal reactions. In the hospital, latex is a particular problem for children undergoing multiple operations, such as patients with spina bifida and urologic disorders, and has prompted many hospitals to switch to latex-free products. Patients with latex allergy may also experience food-allergic reactions from homologous proteins in foods such as bananas, kiwi, avocado, chestnut, and passion fruit.

Epidemiology

The overall annual incidence of anaphylaxis in the United States is estimated at 50 cases/100,000 persons/yr, totaling >150,000 cases/yr. An Australian parental survey found that 0.59% of children 3-17 yr of age had experienced at least 1 anaphylactic event.

Pathogenesis

Principal pathologic features in fatal anaphylaxis include acute pulmonary hyperinflation, pulmonary edema, intra-alveolar hemorrhaging, visceral congestion, laryngeal edema, and urticaria and angioedema. Acute hypotension is attributed to vasomotor dilation and/or cardiac dysrhythmias.

Most cases of anaphylaxis are the result of activation of mast cells and basophils via cell-bound allergen-specific IgE molecules. Patients initially must be exposed to the responsible allergen to generate allergen-specific antibodies. In many cases, the child and the parent are unaware of the initial exposure, which may be due to passage of food proteins in maternal breast milk. When the child is reexposed to the sensitizing allergen, mast cells and basophils and possibly other cells such as macrophages release a variety of mediators (histamine, tryptase) and cytokines that can produce allergic symptoms in any or all target organs. Clinical anaphylaxis may also be caused by mechanisms other than IgE-mediated reactions, sometimes termed anaphylactoid reactions, including direct release of mediators from mast cells by medications and physical factors (morphine, exercise, cold), disturbances of leukotriene metabolism (aspirin and nonsteroidal anti-inflammatory drugs), immune aggregates and complement activation (blood products), and probable complement activation (radiocontrast dyes, dialysis membranes).

Clinical Manifestations and Diagnosis

The onset of symptoms may vary somewhat depending on the cause of the reaction. Reactions from ingested allergens (foods, medications) are delayed in onset (minutes to 2 hr) compared with those from injected allergens (insect sting, medications) and tend to have more gastrointestinal symptoms. Initial symptoms vary with the etiology and may include any of the following constellation of symptoms: pruritus about the mouth and face; a sensation of warmth, weakness, and apprehension (sense of doom); flushing, urticaria and angioedema, oral or cutaneous pruritus, tightness in the throat, dry staccato cough and hoarseness, periocular pruritus, nasal congestion, sneezing, dyspnea, deep cough and wheezing; nausea, abdominal cramping, and vomiting, especially with ingested allergens; uterine contractions (manifesting as lower back pain; not uncommon); and faintness and loss of consciousness in severe cases. Some degree of obstructive laryngeal edema is typically encountered with severe reactions. Cutaneous symptoms may be absent in up to 20% of cases, and the acute onset of severe bronchospasm in a previously well asthmatic person should suggest the diagnosis of anaphylaxis. Sudden collapse in the absence of cutaneous symptoms should also raise suspicion of vasovagal collapse, myocardial infarction, aspiration, pulmonary embolism, or seizure disorder. Laryngeal edema, especially with abdominal pain, suggests hereditary angioedema (Chapter 142).

Laboratory Findings

Laboratory studies may indicate the presence of IgE antibodies to a suspected causative agent, but this result is not definitive. Plasma histamine is elevated for a brief period but is unstable and difficult to measure in a clinical setting. Plasma β-tryptase is more stable and remains elevated for several hours but often is not elevated, especially in food-induced anaphylactic reactions.

Diagnosis

A National Institutes of Health (NIH)–sponsored expert panel has recommended an approach to the diagnosis of anaphylaxis (Table 143-2). The differential diagnosis includes other forms of shock (hemorrhagic, cardiogenic, septic), vasopressor reactions including flush syndromes such as carcinoid syndrome, excess histamine syndromes (systemic mastocytosis), and ingestion of monosodium glutamate (MSG), scombroidosis, and heriditary angioedema. In addition, panic attack, vocal cord dysfunction, pheochromocytoma, and red man syndrome (due to vancomycin) should be considered.

Treatment

Anaphylaxis is a medical emergency requiring aggressive management with intramuscular or intravenous epinephrine, intramuscular or intravenous H₁ and H₂ antihistamine antagonists, oxygen, intravenous fluids, inhaled β-agonists, and corticosteroids (Table 143-3). The initial assessment should ensure an adequate airway with effective respiration, circulation, and perfusion. Epinephrine is the most important medication, and there should be no delay in its administration. If an intravenous line is not available, epinephrine should be given by the intramuscular route (0.01 mg/kg; max 0.3-0.5 mg). For children ≥12 yr, many recommend the 0.5-mg intramuscular dose. The intramuscular dose can be repeated 2 or 3 times at intervals of 5 to 15 minutes if an intravenous continuous epinephrine infusion has not yet been started and symptoms persist. Intraosseous infusion is an alternative if an intravenous line is not available (this is an uncommon route). Fluids are also important in patients with shock. Other drugs (antihistamines, glucocorticosteroids) have a secondary role in the management of anaphylaxis. Patients may experience biphasic anaphylaxis, which occurs when anaphylactic symptoms recur after apparent resolution. The mechanism of this phenomenon is unknown, but it appears to be more common when therapy is initiated late and symptoms at presentation are more severe. It does not appear to be affected by the administration of corticosteroids during the initial therapy. More than 90% of biphasic responses occur within 4 hr, so patients should be observed for at least 4 hr before being discharged from the emergency department.

Table 143-3 MANAGEMENT OF A PATIENT WITH ANAPHYLAXIS

DRUG CLASSIFICATION	INDICATION(S) AND DOSAGE(S)	COMMENTS; ADVERSE REACTIONS
PATIENT EMERGENCY MANAGEMENT (DEPENDENT ON SEVERITY OF SYMPTOMS)
Epinephrine (adrenaline)	Rx of anaphylaxis, bronchospasm, cardiac arrest	Tachycardia, hypertension, nervousness, headache, nausea, irritability, and tremor
0.01 mg/kg up to 0.3 mg	EpiPen Jr (0.15 mg) IM 8-25 kg Twinject Jr (0.15 mg) IM

  Cetirizine (liquid) Antihistamine (competitive of H₁ receptor) Hypotension, tachycardia, and somnolence (Zyrtec—5 mg/5 mL) 0.25 mg/kg up to 10 mg PO Alt: Diphenhydramine Antihistamine (competitive of H₁ receptor) Hypotension, tachycardia, somnolence, and paradoxical excitement (Benadryl—12.5mg/5mL) 1.25 mg/kg up to 50 mg PO Transport to an Emergency Facility EMERGENCY PERSONNEL MANAGEMENT (DEPENDENT ON SEVERITY OF SYMPTOMS) Supplemental oxygen and airway management Epinephrine (adrenaline) Rx of anaphylaxis, bronchospasm, cardiac arrest Tachycardia, hypertension, nervousness, headache, nausea, irritability, and tremor 0.01 mg/kg up to 0.3 mg EpiPen Jr (0.15 mg) IM 8-25 kg May repeat every 10-15 min EpiPen (0.3 mg) IM >25 kg   0.01 mL/kg/dose of 1 : 1,000 solution up to 0.3 mL IM   0.01 mL/kg/dose of 1 : 10,000 slow IV push For severe hypotension Volume expanders Crystalloids (normal saline or Ringer lactate) 30 mL/kg in 1st hour Rate titrated against blood pressure response Colloids (hydroxyethyl starch) 10 mL/kg rapidly followed by slow infusion Rate titrated against blood pressure response Diphenhydramine (Benadryl—12.5 mg/5 mL) Antihistamine (competitive of H₁ receptor) Hypotension, tachycardia, somnolence, and paradoxical excitement 1.25 mg/kg up to 50 mg IM   Alt: Cetirizine [liquid] (Zyrtec—5 mg/5 mL) Antihistamine (competitive of H₁ receptor) Hypotension, tachycardia, and somnolence Nebulized albuterol β-Agonist Palpitations, nervousness, central nervous system stimulation, tachycardia; use to supplement epinephrine when bronchospasm appears unresponsive; may repeat (0.83 mg/mL [3 mL]) via mask with O₂ Corticosteroids: Methylprednisolone Anti-inflammatory Hypertension, edema, nervousness, and agitation Solu-Medrol (IV) 1-2 mg/kg up to 125 mg IV   Depo-Medrol (IM) 1 mg/kg up to 80 mg IM   Prednisone Anti-inflammatory Hypertension, edema, nervousness, and agitation For oral use 1 mg/kg up to 75 mg PO   Ranitidine (Zantac—25 mg/mL) Antihistamine (competitive of H₂ receptor) Headache, mental confusion 1 mg/kg up to 50 mg IV Should be administered slowly Alt: Cimetidine (Tagamet—25 mg/mL) Headache, mental confusion Should be administered slowly POST-EMERGENCY MANAGEMENT H₁-antagonist Cetirizine (5-10 mg qd) or loratidine (5-10 mg qd) for 3 days   Corticosteroids Oral prednisone (1 mg/kg up to 75 mg) daily for 3 days   Preventive Treatment Follow-up evaluation to determine/confirm etiology Immunotherapy for insect sting allergy Prescription for EpiPen and antihistamine Provide written plan outlining patient emergency management (may download form from www.foodallergy.org) Patient Education Instruction on avoidance of causative agent Information on recognizing early signs of anaphylaxis Stress early treatment of allergic symptoms to avoid systemic anaphylaxis

IM, intramuscularly; IV, intravenously; PO, by mouth.

Prevention

Patients experiencing anaphylactic reactions to foods must be educated in allergen avoidance, including actively reading food labels and acquiring knowledge of potential contamination and high-risk situations, as well as in the early recognition of anaphylactic symptoms and ready administration of emergency medications. Any child with food allergy and a history of asthma, peanut or tree nut allergy, or a previous severe anaphylactic reaction should be given an epinephrine autoinjector (EpiPen, Twinject), liquid cetirizine (or alternatively, diphenhydramine), and a written emergency plan in case of accidental ingestion. A form can be downloaded from the Food Allergy and Anaphylaxis Network at www.foodallergy.org. Patients with egg allergy should be tested before receiving the influenza or yellow fever vaccine, which contain egg protein.

Children experiencing a systemic anaphylactic reaction including respiratory symptoms to an insect sting should be evaluated and treated with immunotherapy, which is more than 90% protective. In cases of food-associated exercise-induced anaphylaxis, children must not exercise within 2-3 hr of ingesting the triggering food and, like children with exercise-induced anaphylaxis, should exercise with a friend, learn to recognize the early signs of anaphylaxis (sensation of warmth and facial pruritus), stop exercising, and seek help immediately if symptoms develop. Any child who is at risk for anaphylaxis should receive emergency medications, education, and a written emergency plan in case of accidental ingestion.

Reactions to medications can be reduced and minimized by using oral medications in preference to injected forms. Hypo-osmolar radiocontrast dyes can be used in patients in whom previous reactions are suspected. The use of powder-free, low-allergen latex gloves or non-latex gloves and materials should be used in children undergoing multiple operations.