What is the clinical presentation in a typical case of anaphylaxis?

What is the underlying pathophysiologic process?

What conditions should be considered in the differential diagnosis?

There are a number of factors that might have triggered this reaction. Although the list of potential causes of IgE-mediated anaphylaxis is long and continues to expand, agents that deserve special mention include venomous insect stings, foods, injection of allergy extracts (allergy shots), latex, and medications of any type but particularly antibiotics and heterologous proteins. Non–IgE-mediated anaphylaxis is most often caused by radiocontrast media, opioids, NSAIDs, and physical stimuli such as exercise-induced and food-related anaphylaxis.

IgE-mediated allergies to venoms or foods are common causes of anaphylaxis in all age-groups. In the absence of a known sting or injection of allergen, foods and medications should be immediately considered. The foods most commonly implicated in children are milk, eggs, and peanuts and in adults are peanuts, tree nuts, shellfish, and fin fish but virtually any food is a potential cause in a sensitized person. Typical reactions begin within minutes but may occur after several hours.

Most cases of drug-induced anaphylaxis are IgE-mediated and are often due to penicillin antibiotics, although almost any drug can be etiologic. In the surgical setting, anaphylactic reactions are most often due to muscle relaxants and latex but can also be due to hypnotics, antibiotics, opioids, colloids, and other agents. Aspirin and NSAIDs are potent inhibitors of the cyclooxygenase pathway of arachidonic acid metabolism, reportedly causing serious reactions in up to 10% of individuals with asthma and in 1% of the general population. In asthmatic patients, the reaction consists of severe bronchospasm; individuals who do not have asthma may have urticaria, angioedema, and anaphylaxis. Reactions to these drugs are usually not mediated by IgE. The mechanism responsible for causing them is poorly understood, but is possibly related to the inhibition of cyclooxygenase and the shifting of arachidonate metabolism to the lipoxygenase pathway. There are no immunologic tests that can detect this sensitivity, and challenge tests, which require the use of strict precautions, remain the only reliable method to identify aspirin- and NSAID-sensitive patients. However, as with any drug, IgE-mediated reactions can also occur.

Exercise can cause a limited array of systemic reactions, particularly a type of urticaria (hives) called cholinergic urticaria, and rarely exercise-induced anaphylaxis. An unusual syndrome of exercise-induced and food-related anaphylaxis is not uncommon wherein the patient can eat a specific food and exercise without problems. But if the food is eaten within as many as several hours before exercise,
the patient will experience anaphylaxis. Systemic mastocytosis is a rare disease characterized by a “gain of function” mutation in the receptor for stem cell factor and a resultant overgrowth of mast cells. Typically, these patients have frequent manifestations of mast cell degranulation such as flushing and hives but can present with isolated anaphylaxis. Finally, a few patients have idiopathic anaphylaxis, that is, they have one or more episodes of anaphylaxis that remain unexplained after a thorough evaluation.

In this particular case, there was no history of ingestion of a medication and no exposure to a venomous insect. However, many of the other diagnoses mentioned are possible explanations for the patient’s episode and the true etiology may only become apparent over time. It is important to consider an allergic reaction to soy because tofu was ingested shortly before the anaphylactic episode, was a new food for her, and there is adequate opportunity to become sensitized to soy through a number of common foods. Of course a “stir fry” contains many foods in addition to the tofu and any of these are potential culprits. In the event that the results of all diagnostic evaluations are negative, this episode may indeed be idiopathic.

There is a generally accepted protocol for treating anaphylactic syndromes. Epinephrine is the mainstay of treatment in anaphylaxis; it acts by inhibiting mediator release from mast cells and basophils, relaxing bronchial smooth muscle, and bolstering blood pressure. Often, all of the signs and symptoms of anaphylaxis resolve completely within minutes of a single injection of epinephrine but the underlying pathophysiologic events persist and symptoms recur after the epinephrine is metabolized. As soon as the diagnosis of anaphylaxis is strongly entertained, starting dose of 0.3mL of a 1:1,000 solution of epinephrine should be given intramuscularly, preferably in the thigh, for an adult and 0.01 mg/kg for a child. If no untoward side effects occur, the patient may receive repeated doses every 10 minutes until the symptoms improve. Rarely, 1 to 2 mL of a 1:10,000 dilution of epinephrine is given by intravenous (IV) route but this should be avoided if possible because it may cause potentially fatal cardiac arrhythmias. In a patient whose primary site of involvement is the upper airway (such as the one described here), inhaled 2% racemic epinephrine is a valuable adjunct to parenteral therapy (at a dose of 0.5 mL). In addition, an H₁ antagonist (e.g., diphenhydramine, 50 mg) should be given slowly by the IV route. Recent evidence shows that the addition of an H₂ blocker, such as ranitidine 150 mg by slow IV infusion leads to more rapid resolution of acute allergic events. If the patient has severe airway obstruction at presentation (cyanosis) or the obstruction worsens despite the prompt use of epinephrine, endotracheal intubation should be performed promptly using a small-bore tube (no. 4 or 5). If this is not possible because of the degree of edema, cricothyrotomy should be performed. In the example given, semielective intubation was chosen by a skilled ED physician to avoid the complications associated with emergency intubation of patients with swelling of the airway. The patient was extubated after 8 hours without sequelae.

Anaphylaxis in patients who are taking β-adrenergic antagonists may be particularly difficult to treat. If wheezing does not respond to initial epinephrine or inhaled
β-agonist therapy, glucagon should be administered. Patients with hypotension refractory to treatment with subcutaneous epinephrine, antihistamines, and parenter-al fluids may require parenteral dopamine, norepinephrine, and glucagon therapy.

In patients who have significant symptoms affecting any target organ system, IV corticosteroids (Solu-Medrol, 1 mg/kg) should be given immediately, followed by an oral dose 6 hours later. Patients who have a prolonged clinical course should continue to receive corticosteroids every 6 hours.

Initial therapy consisting of the interventions just described brings about complete and sustained relief of the signs and symptoms of anaphylaxis in 50% of patients. However, one fourth of the patients remain partially resistant to therapy for several hours and occasionally for several days (protracted anaphylaxis). The remaining 25% of the patients respond to initial therapy, but after a variable interval (up to 8 hours) without signs or symptoms, they experience recurrence of life-threatening complications (biphasic anaphylaxis). There is no reliable way to predict which patients will have such a relapse. Therefore, all patients with anaphylaxis should be observed by medical personnel for at least 8 hours after the onset of the episode.

All patients with a history of anaphylactic reaction, no matter what the cause, should be given preloaded syringes containing epinephrine for self-administration (e.g., EpiPen 0.3 mg or EpiPen Jr 0.15 mg Auto-injector, Dey Inc., Napa, California) and also diphenhydramine (25 mg capsules). Before they leave the ED, the patient and family members should be trained on how to administer the epinephrine and diphenhydramine and told to call 911 or proceed immediately to a nearby ED. Another important general measure to be implemented is the replacement of β-blocking drugs with a suitable alternative medication if possible in those individuals who are at possible risk for further episodes of anaphylaxis.

After acute treatment of the anaphylactic episode, the most likely cause of the reaction should be determined so that recommendations on future avoidance can be made. In the patient described here, food skin tests to all the ingredients in the meal preceding her reaction should be performed by an allergist/immunologist. Soy is particularly suspicious as a possible cause of her anaphylaxis. If the skin test results are positive to one or more foods, carefully monitored, graded, double-blinded, placebo-controlled (DBPC) food challenges can be performed to identify the etiologic agent. In the event that the food challenge results are negative, it is not necessary for the patient to avoid soy or any of the other implicated foods. In practice, most patients just avoid the suspect food or foods. This is suboptimal because there may be unnecessary changes in lifestyle and nutrition may be compromised. Patients with a history of food-induced anaphylaxis should always carry epinephrine and diphenhydramine (Benadryl) because of the possibility of inadvertent exposure. Patients with recurrent episodes of idiopathic anaphylaxis have been shown to benefit from daily administration of antihistamine and oral corticosteroid therapy. This type of therapy, however, is unwarranted in patients who have known avoidable causes of anaphylaxis.

The patient described here had a positive skin test to celery and a negative test to soy. The most likely diagnosis in her case is exercise-induced and food-related
anaphylaxis. So, she was advised to avoid exercising for 6 hours after eating celery, to carry her epinephrine and diphenhydramine, to never exercise alone, and to never exercise in remote settings.

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