Which of the following agents are responsible for causing the most serious anaphylactic reaction?

The editors and current authors would like to thank and acknowledge the significant contribution of the previous author of this chapter from the 2004 first edition, Dr. Todd T. Kuwaye. This current second edition chapter is a revision and update of the original author's work.

A previously healthy 12-year-old boy is brought to the emergency department after being stung by a bee on his right forearm. He initially complained of localized pain and swelling. Fifteen minutes later, he began to complain of shortness of breath and was observed by his parents to be wheezing. He reported feeling weak and dizzy.

In the emergency department, VS: T 37.1 C, P 120, R 39, BP 69/45. Exam: He is drowsy and pale, but able to answer questions. Generalized urticaria is present. He has no conjunctival edema and his lips and tongue are not swollen. His voice sounds normal. He is tachycardic and hypotensive. Respiratory examination reveals mild wheezing, with fair aeration and mild subcostal retractions. Abdomen is soft and non-tender. His capillary refill time is delayed. The bee sting site on his right forearm shows moderate swelling without visualization of a foreign body.

A diagnosis of anaphylactic shock is made, and he is given intramuscular epinephrine and albuterol via nebulizer with subsequent improvement of his symptoms. An IV is started, and he is given diphenhydramine, ranitidine, methylprednisolone, and a fluid bolus of normal saline. IV epinephrine is considered but his status has rapidly improved since the IM epinephrine. His urticaria resolves, his blood pressure normalizes, and his wheezing resolves. After being observed in the ED for six hours, he feels �back to normal.� He is subsequently discharged from the ED on oral diphendramine, ranitidine, and prednisone. His parents are advised of the possibility of a late phase reaction that could result in worsening, so they are advised to monitor his condition carefully and return to the ED if his conditions worsens. He is also prescribed an epinephrine autoinjector and instructed in its use.

Anaphylaxis is a clinical syndrome in which there is a systemic reaction following antigen exposure in a sensitized person. It is rapid in onset and can lead to death. Reflecting the varied and potentially atypical presentations of anaphylaxis, three diagnostic criteria exist; fulfillment of any one criterion is diagnostic:

1) Acute onset (minutes to hours) of a reaction involving the skin and/or mucosal tissue (e.g., flushing, pruritis, hives, swollen lips, tongue, or uvula), and at least one of the following:
. . . . . Respiratory compromise (e.g., dyspnea, wheeze, hypoxia) or
. . . . . Reduced blood pressure or
. . . . . Symptoms of end-organ dysfunction (e.g., syncope, hypotonia, incontinence)
2) Two or more of the following, occuring rapidly after exposure to a likely allergen for that particular patient:
. . . . . Involvement of the skin/mucosal tissue (e.g. flushing, pruritis, hives, swollen lips, tongue, or uvula)
. . . . . Respiratory compromise (e.g., dyspnea, wheeze, hypoxia)
. . . . . Reduced blood pressure or associated symtpoms (syncope, incontinence)
. . . . . Persistent gastrointestinal symptoms (abdominal pain, nausea, emesis)
3) Reduced blood pressure after exposure to a known allergen for that particular patient (using age-specific blood pressure criteria, e.g., less than 70 mmHg for infants 1 to 12 months in age, less than 70 mmHg + 2 times the age in years for 1 to 10 years of age, and less than 90 mmHg for children 11 years of age and up).

Anaphylaxis remains underreported. Current estimates indicate that the incidence of life-threatening anaphylaxis is about 10 per 100,000 persons. In 2006, a group of international experts estimated the incidence of anaphylaxis to be as high as 2%, which was based on the number of prescriptions of automatic epinephrine injectors. A Massachusetts study examining the use of epinephrine for anaphylaxis in schools found that up to 24% of anaphylaxis episodes occurred in children who did not have a prior history of life-threatening allergies. According to more recent studies, the incidence is rising, especially in younger age groups. Those same studies also suggest that anaphylaxis-related hospitalizations and fatalities are also increasing. Current data estimates that approximately 1500 deaths occur each year from anaphylaxis in the United States.

Most clinical manifestations of anaphylaxis occur within minutes to hours of exposure to an allergen. On rare occasions, delayed reactions, with symptoms presenting many hours later may occur. The most common manifestations are cutaneous (pruritus, urticaria, angioedema, flushing), occurring in 80-90% of children. Children may also present with a feeling of impending doom, weakness, dizziness, confusion, loss of consciousness and seizures. Airway and pulmonary findings include congestion, sneezing, rhinorrhea, swelling of the lips and tongue, stridor, hoarseness, dyspnea and wheezing. Cardiovascular findings include light-headedness, syncope, tachycardia, hypotension, pallor, arrhythmia and complete cardiovascular collapse. Although uncommon, patients may present with cardiovascular symptoms before cutaneous manifestations. In a retrospective analysis, 15% of patients presented with chest pain and 7% presented with arrhythmia. Gastrointestinal findings include nausea, emesis, abdominal cramping and diarrhea. Patients with anaphylaxis may have any combination of cutaneous, GI or cardiac findings described above. Given the broad range of potentially non-specific symptoms, diagnostic criteria as described above must be used.

Following initial presentation and treatment, symptoms may recur despite appropriate managment. This recurrence of symptoms is known as biphasic anaphylaxis, and is defined as symptom recurrence 1 to 72 hours after resolution of the initial symptoms despite no further exposure to the trigger. Biphasic anaphylactic reactions occur in up to 20% of fatal and near-fatal food reactions. The rates of biphasic anaphylactic reactions are between 5% and 20% in adults, and about 6% in children. Recent studies have reported an increased incidence of biphasic reactions, which portends an increased risk of fatal anaphylaxis.

The differential diagnosis for anaphylaxis includes asthmatic attacks, vasovagal reactions, Scombroid fish poisoning (a histamine reaction), hereditary angioedema, systemic mastocytosis, vocal cord dysplasia, shock (secondary to other causes), serum sickness, panic attacks, and less severe acute allergic reactions.

Etiological agents may potentially include food, arthropod stings, antibiotics, vaccines, latex, or may be idiopathic and unidentifiable. In the outpatient setting, food remains the most common cause of anaphylaxis, affecting about 6% of young children in North America. While any food may trigger an anaphylactic reaction, peanuts and tree nuts (walnuts, pecans, cashews, pistachios, macadamias) account for the majority of reactions, followed by shellfish. Milk, eggs, and sesame are also common triggers. Allergies to peanut, tree nuts, fish and shellfish are likely to be life-long, whereas allergies to milk, egg, soy, and wheat are usually outgrown within the first decade of life. Thus, it is important for these children to have yearly evaluations by an allergist to determine which patients may be eligible for oral food challenges and determine if allergies have been outgrown.

Low-molecular-weight medications induce an IgE-mediated reaction after combining with a carrier protein and producing a complete multivalent antigen. Penicillin is the most common cause of drug-induced anaphylaxis. Cephalosporins share the beta-lactam ring, but confer a lower risk of cross-reactivity. The degree of cross-reactivity between penicillin and carbapenems also appears to be low. Non beta-lactam antibiotics, aspirin, nonsteroidal anti-inflammatory drugs, and chemotherapy agents also may trigger anaphylaxis. Patients with penicillin allergies or cephalosporin allergies should consult with an allergist to discuss possible interventions such as graded challenge or drug desensitization.

Anaphylaxis to insect stings may be fatal in 1% of children, even on first exposure. The most common causes of insect anaphylaxis are wasps, hornets, bumblebees, honeybees, and red fire ants. Most insults do not require treatment; however large local reactions can still lead to future anaphylaxis. Children under 16 years of age who experience solely cutaneous symptoms (urticaria, angioedema, flushing) have about a 5-10% risk for future anaphylaxis, whereas children who have organ-specific symptoms (cardiovascular, respiratory, gastrointestinal) have a 20-40% risk for future anaphylaxis, suggesting an allergy to the insect venom. Venom immunotherapy may reduce the risk to less than 5%.

Latex allergy affects a high proportion of those who have spina bifida and 10% to 15% of health-care workers. In patients with spina bifida it is believed that early and frequent exposure to latex due to multiple surgeries early in life, frequent bladder catheterizations, and manual rectal disimpactions all contribute to development of latex allergies.

Anaphylaxis after routine vaccination is rare, with an estimated risk of 0.65 cases per 1 million doses. Vaccine components that have been implicated include latex in vial stoppers, egg, gelatin, yeast, and antimicrobial agents, such as neomycin. Inactivated influenza vaccine is grown in the ovalbumin of chick embryos. However, it should still be administered to all patients except for those who have a documented history of true anaphylaxis. The measles component of MMR is grown in chick fibroblast cultures that do not contain egg antigens. Many of those who have reactions to the MMR vaccine do not have egg allergies and have been shown to be sensitive to other agents, including gelatin or neomycin. Yellow fever vaccine presents the greatest potential risk for reaction, as it is grown in chick embryos.

Exercise-induced anaphylaxis (EIA) and food-dependent exercise-induced anaphylaxis (FDEIAn) generally occur in older children. In FDEIAn, anaphylaxis only occurs when a food allergen is consumed within hours to minutes prior to exercise. The reaction usually does not occur in the setting of food consumption without exercise or vice versa. Foods most commonly associated with FDEIAn are wheat, grains, and nuts in Western populations, and with wheat and shellfish in Asian populations. EIA typically occurs in the setting of moderate exercise; however, it can occur with minimal exercise, such as walking.

The pathogenesis of anaphylaxis involves prior exposure to an allergen (such as mentioned above). Upon first exposure to the offending allergen, a specific IgE antibody is produced against the allergen. These IgE antibodies become affixed to receptors on tissue mast cells and peripheral blood basophils. Upon re-exposure, the allergen cross-links specific IgE antibodies on mast cells. This cross linkage initiates a cascade of biochemical events that leads to degranulation of tissue mast cells and blood basophils, allowing release of inflammatory mediators such as histamine, proteases and chemotactic factors (tumor necrosis factor), and production of secondary mediators, such as prostaglandins and leukotrienes. These potent mediators have the effect of producing the symptoms of anaphylaxis, having physiologic effects on multiple organ systems. The main inflammatory mediator is histamine, which causes initial erythema (vasodilatation), edema (vasopermeability), and secondary flare (axon reflex with arteriolar dilation). The severity of anaphylactic reactions is proportional to the amount of mediator release and the time for mediator degradation. Other mediator cascades are also responsible for the symptoms of anaphylaxis. These include, but are not limited to, clotting and complement cascades and other non-mast cell derived mediators. This was most recently described in studies where patients, unresponsive to epinephrine, responded to tranexamic acid (in anaphylaxis associated with intravascular coagulation) or methylene blue (in anaphylaxis associated with hypotension). Anaphylactoid reactions produce a similar inflammatory response, though these reactions are not IgE-mediated and do not require immunologic memory. Thus degranulation of mast cells occurs upon first exposure to the allergen. Examples of anaphylactoid reactions are those caused by radiocontrast media, anesthetics, and exercise.

Epinephrine is the first-line of therapy and administration should not be delayed. Frequently caregivers administer antihistamines first, particularly because children often present initially with cutaneous symptoms. Any clinical improvement after administration of antihistamines is likely due to endogenous compensatory mechanism because drug absorption of antihistamines may be slow. Patients with a previous history of anaphylaxis are usually given epinephrine autoinjectors for home use (EpiPen 0.3 mg, EpiPen Junior 0.15 mg).

Since most anaphylaxis events occur at home or in school, intramuscular administration - typically in the lateral thigh - is the suggested route and site. The recommended pediatric dosage for intramuscular epinephrine (1:1000 dilution) is 0.01 mg/kg up to a max dose of 0.5 mg per dose. Another option is a dose of 0.5 ml of 1:1000 IM every 15 minutes for two doses and then every 4 hours as needed. Epinephrine auto-injectors come in 0.15 mg in the EpiPen Junior, for children who weigh between 15 and 30 kg, or 0.3 mg doses in the EpiPen for patients greater than or equal to 30 kg. All patients receiving epinephrine should immediately go to the emergency department or call 911, as there is a 20% incidence of biphasic latent reactions after administration of epinephrine.

The adult dosage is 0.2-0.5 ml of a 1:1000 epinephrine solution. IM administration is faster than subcutaneous (SQ). IV epinephrine is given for severe reactions in which patients are in severe shock. When in severe shock, the skin and muscle may not be adequately perfused, so SQ or IM epinephrine will not be absorbed sufficiently unless it is given IV. Additionally IV fluid boluses may be required to compensate for the marked peripheral vasodilation and third spacing that may occur with anaphylaxis. IV epinephrine should be given as a dilute infusion calculated as 0.1 to 1.0 mcg/kg/min. Another practice is to utilize the 1 mg 1:10,000 epinephrine injector (1 mg diluted in 10cc), and inject this VERY slowly into the IV line (0.5 mL per minute = 50 mcg per minute which would be OK for adult but this would be too much for a small child), allowing the clinician to titrate the dose, and to prevent palpitations and/or dysrhythmias associated with rapid administration.

Adjunctive therapy for anaphylaxis includes antihistamines. Diphenhydramine is the most commonly used drug given parenterally. A combination of H1 (diphenhydramine or hydroxyzine) and H2 blockers (ranitidine, famotidine, or cimetidine) are commonly given together with the thought that they can be synergistic in their effect. While corticosteroids are not very effective in the treatment of anaphylaxis in the acute period, it may be effective in the biphasic phase of anaphylaxis, though this remains controversial. In fact, in a study by Lee (4), 5 of 6 biphasic cases of anaphylaxis received corticosteroids at time of presentation. Bronchodilators are effective for patients developing wheezing and bronchospasm, although epinephrine alone may be sufficient. All patients require at least some period of observation since one cannot predict which patient will develop the biphasic response of anaphylaxis. The length of time of observation remains controversial, but periods of up to 8 to 10 hours are often used.

In 2007, the American College of Allergy, Asthma and Immunology and the American College of Emergency Physicians recommended SAFE: a multidisciplinary approach to anaphylaxis education. The SAFE system encourages (S) seeking support, (A) allergen identification and avoidance, (F) follow-up for specialty care, and (E) epinephrine for emergencies. Physicians who identify a patient with a history of anaphylaxis should encourage their patient to obtain a Medic Alert bracelet or ID. The patient should be instructed on epinephrine use and dispensed two epinephrine autoinjectors. Physicians should be responsible for demonstrating and training patients on the use of epinephrine autoinjectors and making sure to mention the fluid contents should remain at room temperature, with avoidance of extremes of temperature. Epinephrine autoinjectors have a shelf life of 1-2 years and change color from clear to brown when they expire. However, considering the practical consideration that this epinephrine injector is not likely to be available (i.e., the patient won't have it) when their next reaction occurs, patients should also be taught the best means to obtain medical care depending on the severity of the reaction. Patients should also be prescribed an oral antihistamine, which should be taken immediately. Lastly, the management of anaphylaxis should be directed toward avoiding the offending agent and education of where the offending agent can be hidden (especially if it is a food item). Allergy testing may be useful to determine the cause of the allergy and desensitization therapy may be useful for some types of allergies.

Urticaria, also commonly known as hives, are raised erythematous, circumscribed, pruritic lesions. Urticaria occurs from focal mast cell degranulation, releasing histamine and other mediators. Individual lesions of urticaria generally do not remain in the same place for greater than 24 hours. Urticaria is divided into acute and chronic urticaria, with acute lasting less than 6 weeks and chronic lasting longer than 6 weeks. Acute urticaria is more common in children and young adults, while the peak incidence of chronic urticaria is during the third and fourth decades.

Urticaria can occur from food allergies, collagen vascular disease, infections, environmental factors such as heat, cold or pressure, and medications. Despite an extensive workup, most cases of chronic urticaria are idiopathic. Urticaria is treated with antihistamines. In most instances, the urticaria should be largely resolved within several hours. Second-generation H1 blockers, such as loratadine, are considered first-line therapy. This drug class has a better side effect profile (non-sedating) than first-generation H1 blockers. First-generation H1 blockers, such as diphenhydramine and hydroxyzine, should still be provided as a rescue antihistamine for "breakthrough" symptoms. H2 blockers, such as ranitidine, famotidine, and cimetidine, have variable degrees of success so routine use is controversial. Avoidance of known triggers of urticaria is probably the most important aspect in chronic management.

Angioedema is a localized subcutaneous or submucosal swelling, giving rise to non-pitting, stretched, colorless, well demarcated skin lesions. In contrast, urticaria lesions are typically raised, erythematous and pruritic. Characteristically, pruritus is absent in angioedema. There are fewer mast cells and sensory nerve endings in the deeper layers of skin involved. Most frequently, angioedema affects the scalp, lips, face, eyes, extremities and genitalia. Angioedema is treated similarly as urticaria.

Hereditary angioedema (HAE) is a rare autosomal dominant disorder characterized by recurrent bouts of swelling typically affecting the face, extremities, respiratory and GI tract in the absence of pruritis or urticaria. HAE has a reported prevalence of 1 in 10,000 to 1 in 50,000 individuals. This condition occurs because of the deficiency or dysfunction of C1 esterase inhibitor. C1 esterase inhibitor prevents complement activation. If CI esterase is not functioning or absent, then the activation of the classical complement pathway could be unchecked and allow for excessive bradykinin production, a potent vasodilatory mediator. The disorder is usually self-limited; however, severe laryngeal edema or GI involvement may occur. Untreated HAE patients are at risk for laryngeal edema or even death. Treatment to prevent attacks involves the use of prophylactic oral attenuated androgens in the postpubertal adolescent or young adult. Androgens cause the production of sufficient amounts of C1 esterase inhibitor to prevent C1 activation. In Europe, purified C1 esterase inhibitor concentrate is used in acute attacks and for surgery prophylaxis. Studies in the United States have shown similar results. Fresh frozen plasma has been shown to be safe and effective in acute attacks and prophylaxis.

Erythema multiforme may also resemble urticaria, especially in the early stages. However, erythema multiforme (EM) does not respond to antihistamines or corticosteroids. The lesions are varying in size and shape (multiformed) and some lesions have a target appearance with a rim of urticaria surrounding a central depression (target lesion). The most common presenting complaint is a case of "hives" which has not responded to an antihistamine. Serum sickness may present a similar clinical picture. Joint swelling may accompany both conditions. These conditions are generally self-resolving in about 2 weeks. If the inciting cause is known, then withdrawal of the allergic substance is the key component of treatment. Group A beta hemolytic streptococci, herpes simplex, and mycoplasma are known causes of EM, but there are numerous other causes as well. Stevens-Johnson Syndrome is a severe form of EM (also known as EM major) which requires hospitalization. Treatment is supportive, but corticosteroids may be beneficial.

Questions

1. What is the primary treatment of severe anaphylaxis and what is the appropriate dose?

2. What are the adjunctive therapies for anaphylaxis?

3. Two weeks after a viral illness, a teenage boy breaks out in an evolving rash that is remarkable for target lesions. What is the primary treatment?
. . . . . a. Epinephrine
. . . . . b. Glucagon
. . . . . c. Corticosteroids
. . . . . d. Antihistamines
. . . . . e. Symptomatic or supportive therapy depending on severity.

4. A girl is brought to her pediatrician by her mother because of recurrent bouts of non-pitting, non-pruritic facial swelling that have occurred three times prior. Her father also has a history of recurrent facial swelling. What is the probably diagnosis?
. . . . . a. Environmental allergen
. . . . . b. Hereditary angioedema
. . . . . c. Child abuse
. . . . . d. Anaphylaxis
. . . . . e. Urticaria

5. A 5 year old boy develops shortness of breath and hives after eating lunch at school. His lunch consisted of a banana, milk, and a peanut butter and jelly sandwich. Which of the foods was the most likely offending cause of his anaphylaxis?
. . . . . a. Milk
. . . . . b. Banana
. . . . . c. Jelly
. . . . . d. Bread
. . . . . e. Peanut Butter

References

1. Sampson HA, et al. Second symposium on the definition and management of anaphylaxis: summary report--Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol 2006;117(2):391-397.

2. Lieberman P, et al. Epidemiology of anaphylaxis: findings of the American College of Allergy, Asthma and Immunology Epidemiology of Anaphylaxis Working Group. Ann Allergy Asthma Immunol 2006;97(5):596-602.

3. Lieberman P, et al. The diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol 2010;126(3):477-480(e1-42).

4. Lee JM, Greenes DS. Biphasic anaphylactic reactions in pediatrics. Pediatrics 2000;106(4):762-766.

5. Waibel KH. Anaphylaxis. Pediatr Rev 2008;29(8):255-263.

6. Langley EW, Gigante J. Anaphylaxis, Urticaria, and Angioedema. Pediatr Rev 2013;34:247.

Answers to questions

1. Epinephrine. Pediatric dosage for epinephrine is 0.01 mg/kg up to a max dose of 0.5 mg per dose or 0.5 ml of 1:1000 SQ/IM every 15 minutes for two doses and then every 4 hours as needed. The adult dosage is 0.2-0.5 ml of a 1:1000 epinephrine solution.

2. Adjunctive therapies include antihistamines, bronchodilators, and perhaps glucagon and corticosteroids.

3. e. This is erythema multiforme. There is no good treatment. Treatment is largely symptomatic.

4. b. Hereditary angioedema.

5. e. Peanuts and tree nuts remain the leading causes of food-related anaphylaxis.

Which of the following agents are responsible for causing the most serious anaphylactic reactions?

What is the most common cause of anaphylactic reaction?

What drugs are most likely to cause anaphylaxis?