Mitchell Lester
Diagnosing Anaphylaxis and Identifying Its Trigger
As the definition implies, the diagnosis of anaphylaxis is made on clinical grounds. The diagnosis relies on identifying the signs and symptoms of mast cell activation. In the acute setting it is important to quickly recognize anaphylaxis so treatment can be started immediately. The differential diagnosis of anaphylaxis includes c1-esterase inhibitor deficiency (hereditary angioedema), vasovagal reactions and other causes of syncope, hypoglycemia, sudden infant death syndrome, and psychiatric conditions (panic attacks, hyperventilation syndromes, anxiety). More frequently in adults than children, the differential diagnosis also includes aspirin-exacerbated respiratory disease (Samter’s Triad), cardiac arrhythmias, and flushing syndromes.

Because of the acuity of anaphylaxis and urgency its management, the trigger is often not identified until after treatment. By far, the most important tool for identifying the trigger of anaphylaxis is a thorough history. Because the signs and symptoms of anaphylaxis start soon after exposure to the trigger, the history should focus on exposures and ingestions shortly before the onset of symptoms (up to 1-2 hours, but usually within 30 minutes). Co-factors including exercise, NSAID use, and occasionally menses should be considered, particularly in teenagers and adults. When the trigger is not identified and there are recurrent episodes, detailed diary-keeping is an essential tool to identify potential consistent preceding exposures and to rule out triggers that do not consistently cause reactions. When in doubt, review the history and diary again.

Documenting the timing and sequence of symptoms, treatments provided, and their effectiveness helps in the design of the anaphylaxis management plan.

Common causes of IgE mediated anaphylaxis

Food is the most common cause of anaphylaxis in childhood. At least 90% of reactions triggered by food in very young American children are by cow’s milk, egg, soy, or wheat. In older children and adults, peanut, tree nuts, shellfish, and finned fish account for more than 90% of new-onset systemic food reactions. Any food can cause allergy, however, so careful history taking is necessary.

Medications are also common triggers to anaphylaxis. Antibiotics, NSAIDS, quarternary ammonium muscle relaxants, and latex are common IgE-mediated triggers. Penicillins are frequently implicated because they are commonly prescribed and are good haptens making them more allergenic than other classes of medication. The quarternary ammonium compounds are large molecules that easily cross link mast-cell bound IgE molecules triggering mast cell activation.

Hymenoptera stings (honey bees, yellow jackets, wasps, hornets, and fire ants) cause anaphylaxis in adults more commonly than children. Insect bites are a rare cause of any form of systemic reaction.

Laboratory testing in anaphylaxis

When laboratory testing is necessary for trigger identification, the tests requested must be driven by and dependent on the clinical history. Tests for specific IgE are useful to confirm or refute diagnostic suspicion only after a detailed history (therefore, the clinician must have a diagnostic suspicion before ordering tests).

Testing for specific IgE

The true value of tests for specific IgE comes with an understanding their interpretation. A positive test does not indicate allergy. It merely reflects sensitization, the presence of specific antibody. IgE-mediated allergy is sensitization resulting in mast cell activation after exposure; that is, there must be symptoms. Hence, the physician should only request tests for specific IgE to allergens suggested by the history (rather than a “panel”). By so doing, the statistical value (sensitivity, specificity, positive [PPV] and negative predictive values [NPV]) of the tests improves.

In vitro tests (colloquially called RASTs [radioallergosorbent tests]) are easily accessible to any practitioner. RASTs are rarely used these days. Instead, in vitro tests using the same immunologic principles but a different solid medium are preferred. The newer tests are more sensitive and specific than RASTs and in some cases the sensitivity approaches that of skin tests. The degree of elevation of an in vitro specific IgE level does not indicate severity of allergy; it indicates greater likelihood of allergy. Only the clinical reaction itself is predictive of severity. In vitro tests are more expensive than skin tests and take longer to get results. Because of the range of levels reported, they can also be harder to interpret. However, they are not influenced by antihistamine use, skin disease, or behavior of patents resistant to testing.

Skin testing is more specific and often easier to interpret than in vitro tests, but some of the same caveats apply. As with in vitro tests, a positive in vivo test indicates sensitization, not allergy. Food skin tests have a high NPV for IgE mediated reactions, but without a supportive history positive tests to food have <50% PPV. As with in vitro tests, extensive testing without a supportive history is inappropriate. A larger positive skin test indicates greater likelihood of allergy, but not the severity of the allergy. In contrast to in vitro tests, antihistamines and tricyclic antidepressants must be withheld before testing. Patients with atopic dermatitis and dermatographism are more likely to have irrelevant or false positive skin tests.

Testing in non-IgE-mediated anaphylaxis

When there is no IgE-mediated trigger, the diagnosis is in doubt, or there are recurrent episodes without identifiable trigger, tests for mast cell mediators may be useful. Histamine has a very short serum half-life, with levels peaking in minutes after mast cell degranulation and returning to normal within 30-60 minutes. Unless the episode is witnessed, plasma histamine levels are usually normal by the time a patient reaches medical care and blood is drawn.

Tryptase is a mast cell specific enzyme. After mast cell activation, serum tryptase levels rise more slowly than histamine, peak later (30-120 minutes), and decrease more gradually (over 3-5 hours). Therefore, the practitioner has a longer window of opportunity for its use. In addition, if blood was drawn within a few hours after onset of symptoms a tryptase level can be added later if the lab has any remaining serum.

Tryptase levels are specific (93% PPV) but not sensitive (52% NPV) measures of mast cell activation. Therefore, a normal serum tryptase level does not rule out mast cell activation. Because mucosal mast cells contain less tryptase than connective tissue mast cells, serum tryptase might be a less useful tool in the diagnosis of food-induced anaphylaxis.

In systemic mastocytosis, a-tryptase and histamine are constitutively expressed. Upon activation, mast cells release ß-tryptase. Commercial labs report total (a+ß) tryptase levels. When mast cell activation syndromes are suspected, a serum tryptase level should be measured when the patient is clinically well and compared to the acute level. Other useful tests to identify chronic mast-cell activation are 24-hour urine collections for N-methylhistamine (a histamine metabolite) and the mast cell specific prostaglandin D2.

In rare instances, tests for complement abnormalities including c1-esterase level and function are indicated, but that is beyond the scope of this article

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