Case Based Pediatrics For Medical Students and Residents
Department of Pediatrics, University of Hawaii John A. Burns School of Medicine
Chapter V.2. Anaphylaxis and Other Acute Allergic Reactions
Todd T. Kuwaye, MD, MS
November 2002

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A 12-year-old boy is brought to the emergency department after being stung by a bee. He had been well until he was stung on his right forearm, while playing in the yard. He initially complained of localized pain and swelling. Fifteen minutes later, he began to complain of shortness of breath. His parents observed him to be wheezing. He also said that he felt very weak and dizzy. His parents brought him immediately to the local emergency department.

Exam: VS T 37.1, P 120, R 39, BP 69/45. He is in mild respiratory distress. He is drowsy and pale, but awakens when you talk to him. He has generalized urticaria. He has no conjunctival edema. His lips and tongue are not swollen. His voice sounds normal. Heart tachycardic without murmurs. His lung examination shows mild wheezing and fair aeration with minimal retractions. His abdomen is soft and non-tender. His face is moderately pale. The bee sting site on his right forearm is unremarkable with no foreign body seen.

He appears to in early anaphylactic shock and he is immediately given subcutaneous epinephrine and an albuterol updraft with improvement of his symptoms. An IV is started, but since his condition is improving, he is not given IV epinephrine. He is given diphenhydramine IV, cimetidine IV, methylprednisolone IV, and an IV fluid bolus of normal saline. His urticaria resolves, his blood pressure normalizes and his lungs sound clear. After being observed in the ER for three hours, he feels as if he is back to normal. He is discharged from the ER on oral diphenhydramine and prednisone.


Anaphylaxis is a clinical syndrome involving the circulatory and respiratory systems. There are no specific criteria for anaphylaxis. Anaphylaxis is a word that is poorly defined. According to one dictionary, it means an exaggerated allergic reaction, while others have defined anaphylaxis as being more severe, involving the respiratory and/or cardiovascular systems. Allergists and immunologists define anaphylaxis as an immediate systemic reaction caused by IgE mediated release of potent mediators from tissue mast cells and peripheral blood basophils. This definition, however, does not allow the clinician to differentiate anaphylaxis from other less severe allergic conditions. This definition does differentiate anaphylaxis from anaphylactoid reactions, but to the physician this is arbitrary since both will be managed the same. Most clinicians will agree that anaphylaxis is a severe, potentially life-threatening allergic response to a repeat exposure to an allergen. Symptoms may include swelling, urticaria, angioedema, hypotension, bronchospasm, airway obstruction/edema, shock, loss of consciousness and ultimately death if help is not received.

Due to a lack of specific clinical criteria for anaphylaxis there is no accurate data on its occurrence. In the United States, it is estimated that more than 40 people per year die from insect sting anaphylaxis (1).

Clinical manifestations include rapid onset of symptoms, 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. Cutaneous findings include erythema, flushing, pruritus, angioedema and urticaria. GI findings include: nausea, emesis, abdominal cramping and diarrhea. Patients with anaphylaxis may have any combination of the above.

After the onset of the initial symptoms, symptoms may recur despite initial treatment. This recurrence of symptoms has been called biphasic anaphylaxis. In adults, the rates of biphasic anaphylactic reactions are between 5-20% and in children 6% (2,3). The differential diagnosis for anaphylaxis includes asthmatic attacks, vasovagal reactions, Scombroid fish poisoning (a histamine reaction), hereditary angioedema, systemic mastocytosis, vocal cord dysplasia, shock, metastatic carcinoid, serum sickness, panic attacks as well as the less severe acute allergic reactions.

Etiologies of anaphylaxis include food, insect stings, antibiotics, vaccines, latex and idiopathic causes. Common foods that trigger anaphylaxis include tree nuts, peanuts, shellfish and dairy products. The pathogenesis of anaphylaxis involves prior exposure to an allergen (such as mentioned above). Upon first exposure of the offending allergen, a specific IgE antibody is produced against the allergen. These IgE antibodies attach themselves to the outer surface of mast cells. Upon re-exposure to the offending allergen, the allergen complexes with the IgE antibodies on mast cells. This interaction between the specific IgE antibody and the allergen sets into motion the degranulation of tissue mast cells and blood basophils. The mast cell releases potent inflammatory mediators such as histamine, proteases and chemotactic factors such as tumor necrosis factor. In addition to these primary mediators, there are secondary mediators such as prostaglandins and leukotrienes that are also produced. These potent mediators have the effect of producing the symptoms of anaphylaxis. The main inflammatory mediator is histamine, which causes initial erythema (vasodilatation), edema (vasopermeability) and secondary flare (axon reflex with arteriolar dilation) (4). Anaphylactoid reactions produce a similar inflammatory response, but the primary difference is that the reaction is not IgE mediated. Examples of anaphylactoid reactions are those caused by radiocontrast media, anesthetics, and exercise.

The diagnosis of anaphylaxis is made clinically. Thus, it is important to rule out disorders mentioned in the differential diagnosis. There is some evidence that measuring a serum tryptase within 2 hours of an anaphylactic episode is helpful to diagnose anaphylaxis. However, the test is not available and is limited to research labs. The difference between anaphylaxis and anaphylactoid reaction to the clinician is not important since both are treated the same.

The primary immediate treatment of anaphylaxis is epinephrine. If a patient has a history of a previous severe reaction, then it is recommended that the epinephrine may be given immediately after contact or ingestion, with no waiting periods to see if a severe reaction will occur (5). Pediatric dosage for epinephrine is 0.01mg/kg up to a max dose of 0.5mg per dose or 0.5ml of 1:1000 SQ/IM Q15minutes for two doses and then Q4 hours as needed. The adult dosage is 0.2-0.5ml of a 1:1000 epinephrine solution. IM administration is faster than subcutaneous (SQ) (6). 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 in the circulation unless it is given IV. It is usually recommended to prepare a dilute infusion of epinephrine calculated as 0.1 to 1.0 mcg/kg/min. This is cumbersome, time consuming and impractical for the patient who needs IV epinephrine immediately. 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, allowing the clinician to titrate the dose. Epinephrine is a dangerous drug, which will cause severe palpitations and/or dysrhythmias if it is given too fast. You could calculate the SQ/IM dose and administer only this dose IV between 2 to 10 minutes depending on the severity of the patient.

Patients with a previous history of anaphylaxis are usually given epinephrine autoinjectors for home use (e.g., EpiPen 0.3 mg, EpiPen Junior 0.15 mg). All patients receiving epinephrine should immediately go to the emergency department or call 911 (5).

Adjunctive therapy for anaphylaxis includes antihistamines. H1 blockers appear to be effective. Diphenhydramine (H1 blocker) is the most commonly used drug given parenterally. A combination of H1 and H2 blockers (such as diphenhydramine and cimetidine) given together may have more benefit than a single antihistamine in treating severe allergic reactions (7). However no study has shown the addition of H2 blockers to provide additional benefit in the treatment of anaphylaxis. Corticosteroids are not effective in the treatment of anaphylaxis in the acute period. There is some discussion that it may be effective in the biphasic phase of anaphylaxis. Although corticosteroids are commonly given in anaphylaxis and other severe allergic reactions, there are no studies that clearly demonstrate its effectiveness. In fact, in a study by Lee, 5 of 6 biphasic cases of anaphylaxis received corticosteroids initially at time of presentation (2). Bronchodilators are effective for patients developing wheezing and bronchospasm, although epinephrine alone may be sufficient.

Finally glucagon may be helpful in those patients on beta-blockers who develop anaphylaxis. There are no studies documenting effectiveness and only anecdotal accounts in the literature. The management of anaphylaxis also requires hospitalization or observation for 24 hours because of the possibility of biphasic anaphylaxis. All patients require at least observation since one cannot predict which patient will develop the biphasic response of anaphylaxis. However, if the parents are reliable observers and they are able to get to the hospital quickly, then the observation time in the emergency department can be shortened.

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 an epinephrine syringe. Physicians should be responsible for demonstrating and training patients on the use of epinephrine syringes. 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). For example, patients who are allergic to peanuts will probably react to foods cooked in peanut oil and patients with dairy product allergy may need to avoid butter and foods cooked with butter. This can be extremely challenging and almost impossible to avoid, especially at restaurants. An instruction to the waiter of "no peanut oil", will often translate to "use corn oil instead" to the cooks in the back. However, if the pan used had some peanut oil on it for the previous dish that was cooked, this may still be sufficient to cause a reaction in the patient. 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 causing the release of 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. Urticaria that lasts less than 6 weeks is acute and more than 6 weeks is chronic. Acute urticaria is more common in children and young adults, while the peak incidence of chronic urticaria is during the third and fourth decades (4).

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 is idiopathic. Urticaria is treated with antihistamines. In most instances, the urticaria should be largely resolved within several hours. H1 blockers, such as diphenhydramine or the newer non-drowsy antihistamines such as loratadine, are the standard therapy, but H2 blockers, such as ranitidine and cimetidine, have variable degrees of success so routine use is controversial (8). Avoidance of known triggers of urticaria is probably the most important aspect in chronic management.

Angioedema is a similar process that occurs in the deeper subcutaneous layers of the skin or mucus membranes, giving rise to nonpitting, 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. Otherwise, angioedema is similar to urticaria with the main distinguishing feature of involvement into the dermis. Angioedema is treated similarly as urticaria.

Hereditary angioedema is an autosomal dominant disorder characterized by recurrent bouts of swelling typically affecting the face, extremities, respiratory and GI tract. This condition occurs because of the absence or abnormally functioning 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. The disorder is usually self-limited, however, severe laryngeal edema or GI involvement may occur. Treatment involves the use of androgens, which causes the production of sufficient amount of C1 esterase inhibitor to prevent C1 activation.

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 that 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 generally resolve on their own within about 2 weeks. Withdrawing the allergic substance is a good idea, but it is usually not possible to determine what the inciting cause was. 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. True/False: Anaphylaxis is well defined with its own clinical criteria.

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

3. What are some of the adjunctive therapies for anaphylaxis?

4. Two weeks following 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.

5. 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 an history of recurrent facial swelling. What is the probably diagnosis?
. . . . . a. Environmental allergen
. . . . . b. Hereditary angioedema
. . . . . c. Child abuse
. . . . . d. Anaphylaxis
. . . . . e. Urticaria


References

1. Valentine MD. Insect-sting Anaphylaxis. Ann Intern Med 1993;118(3):225-226.

2. Lee JS, Greenes DS. Biphasic Anaphylactic Reactions in Pediatrics. Pediatrics 2000;106(4):762-766.

3. Stark BJ, Sullivan TJ. Biphasic and Protracted Anaphylaxis. J Allergy Clin Immunol 1986;78(1 Pt 1):76-83.

4. Zacharisen MC. Pediatric Urticaria and Angioedema. Immunol Allergy Clin North Am 1999;19(2):363-382.

5. Bernhisel-Broadbent J. Diagnosis and management of food hypersensitivity. Immunol Allergy Clin North Am 1999;19(3);463-477.

6. Simons FE, Gu X, Simons KJ. Epinephrine absorption in adults: intramuscular versus subcutaneous injection. J Allergy Clin Immunol 2001 Nov;108(5):871-873

7. Lin RY, et al. Improved outcomes in patients with acute allergic syndromes who are treated with combined H1 and H2 antagonist. Ann Emerg Med 2000;36(5):462-468.

8. Greaves MW. Antihistamines. Dermatol Clin 2001;19(1):53-62.


Answers to questions

1. false

2. Epinephrine. Pediatric dosage for epinephrine is 0.01mg/kg up to a max dose of 0.5mg per dose or 0.5ml of 1:1000 SQ/IM Q15minutes for two doses and then Q4 hours as needed. The adult dosage is 0.2-0.5ml of a 1:1000 epinephrine solution.

3. Adjunctive therapies includes antihistamines, bronchodilators, and perhaps glucagon and corticosteroids.

4. e. This is erythema multiforme.

5. b


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