Anaphylaxis

Abbreviations used:

FceR1: High-affinity IgE receptor

IgE: Immunoglobulin E

IgG: Immunoglobulin G

NSAID: Non-steroidal anti-inflammatory drug

NPV: Negative predictive value

PPV: Positive predictive value

RAST: Radioallergosorbent test

Introduction

Anaphylaxis is a relatively common and potentially life-threatening occurrence in the pediatric population. Fortunately, anaphylactic deaths are rare with potentially life-saving early intervention.

Anaphylaxis was described in 1902 by Frenchmen Richet and Portier. In their efforts to immunize dogs to sea anemone toxin, some dogs who previously tolerated sub-lethal doses died after receiving even smaller doses. They coined the term “anaphylaxis” (“without protection”), literally the opposite of prophylaxis. Richet received the 1913 Nobel Prize in Medicine for their work.

The incidence of anaphylaxis increased in the late 20th century with rates as high as 50/100,000 person-years. The prevalence of anaphylaxis in North America is about 1%. Every year in the United States an estimated 150 anaphylactic deaths are attributable to food, 50 to venom, and up to 600 from medications. The incidence and prevalence appear to be highest in children and decrease with age.

This review will stress the importance of early recognition and treatment of anaphylaxis and identify its most common causes.

Recognition and Mechansims of Anaphyalxis

Anaphylaxis was defined in the 2010 practice parameter as one of three clinical scenarios:

1. Acute onset (minutes-hours) of a reaction involving skin and/or mucosal tissue AND either respiratory compromise, hypotension OR symptoms of end-organ dysfunction.
2. Two or more of the following occurring rapidly after exposure to a likely allergen: skin/mucosal tissue, respiratory compromise, reduced blood pressure or associated symptoms, and/or persistent GI symptoms.
3. Reduced blood pressure after exposure to a known allergen.

The definition is inclusive with several key points to be made. The condition may occur without an identifiable trigger (scenario 1). Scenarios 1 and 2 also indicate the essential clinical point that anaphylaxis usually involves more than one body system and has a very rapid onset and evolution. The only scenario in which the diagnosis is made when only one body system is involved is hypotension after exposure to a known allergen (scenario 3).

The definition from the 2004 practice parameter was more succinct and combined all of the above scenarios into one sentence: "An acute multi-system reaction caused by the rapid release of mediators from tissue mast cells and peripheral blood basophils.” The older definition also stresses the rapid multi-system nature of anaphylaxis. Furthermore, it introduces the concept that mediator release from tissue mast cells and circulation basophils is responsible for the signs and symptoms of anaphylaxis.

The earlier document specifies that immunologic mechanisms may be IgE-mediated or non-IgE mediated and that non-immunologic mechanisms also cause anaphylaxis. As a result, we no longer use the terms “anaphylactoid” or “pseudo-allergic” (Figure).

Figutre 1 : Mechanisms of anaphylaxis: Anaphylaxis can be triggered by IgE-mediated (Gell and Coombs type 1 hypersensitivity reactions), non-IgE-mediated reactions (Gell and Coombs type 2 and 3 hypersensitivity reactions), or by non-immunologic mechanisms. In idiopathic anaphylaxis, activation of mast cells via immunologic mechanisms can sometimes be demonstrated.

IgE mediated reactions are those with which practitioners and patients are most familiar. Cross-linking of IgE bound to the high-affinity IgE receptor (FceR1) on the surface of tissue mast cells and circulating basophils initiates a signaling cascade that results in the rapid release of preformed mediators including histamine and tryptase. Synthesis and release of newly formed mediators follows. Because mast cells also have receptors for complement split products, complement activation has the potential to activate mast cells. IgE mediated episodes of anaphylaxis tend to be more severe and have more rapid onset than other immunologic mechanisms.

The trigger but not the mechanism of physical causes of anaphylaxis is obtained by history. Other triggers to anaphylaxis include non-specific mast cell activators (e.g., opioids, intravenous contrast, vancomycin) and over exposure to mast cell mediators as in systemic mastocytosis and scombroid poisoning.

Idiopathic anaphylaxis has no identifiable preceding trigger. Just as some chronic urticaria are caused by an IgG autoantibody to the a-subunit of FceR1, it is theoretically possible the same could cause anaphylaxis by cross linking the receptor or by activating complement locally.

Signs and symptoms of anaphylaxis

Most mast cells live at surfaces that interface with the outside world (skin, eyes, respiratory tract, gastrointestinal tract, and to a lesser extent bladder and uterus). The signs and symptoms of anaphylaxis reflect mast cell activation at those sites (Table).

Signs and symptoms of mast cell activation.

The skin (~90%) and respiratory systems (40-70%) are the two most common body systems affected in anaphylaxis, especially in children. Adults are more likely than children to have cardiovascular involvement. Interestingly, patients who become hypotensive as an early sign of anaphylaxis are less likely to develop cutaneous symptoms (clinical scenario 3).

Temporal patterns of anaphylaxis:

There are three recognized patterns of anaphylaxis. The most common is a uniphasic reaction in which the episode is completely resolved once treated.

Biphasic reactions are ones in which symptoms recur 6-12 hours after apparent resolution. Biphasic reactions occur in up to 20% of patients (highest in adults) and typically have a similar presentation as the initial episode. Risk factors for biphasic reactions include ingested allergens, slower onset of severe symptoms, patients who require more than one dose of epinephrine, and a delay in its administration during the initial presentation. Co-factors such as poorly controlled asthma, anxiety, and ß-blocker use may also increase the risk. Many emergency departments have protocols requiring patients with anaphylaxis to be observed for at least 8-12 hours because of the risk of biphasic reactions.

Rarely, patients have protracted anaphylaxis with symptoms persisting for 2 or more days. These unfortunate patients respond incompletely and only briefly to emergency treatments.

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 the urgency in 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 of anaphylaxis. Antibiotics, NSAIDS, quaternary 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 quaternary 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 a 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 of their interpretation. A positive test does not indicate an allergy. It merely reflects sensitization, the presence of specific antibodies. 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 is 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 a 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 an 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 within Vitro tests, extensive testing without a supportive history is inappropriate. A larger positive skin test indicates a 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

Treatment of Anaphylaxis

The onset and progression of anaphylaxis is rapid. One retrospective study of anaphylactic deaths from medication, food, and venom found that nearly all patients had their first cardiac arrest within 20-45 minutes of exposure (with the onset of symptoms even faster). Patients with the earliest onset of symptoms, parenteral exposure, delay in initiating treatment, concurrent ß-blocker use, and underlying cardiovascular or respiratory disease were at greatest risk of anaphylactic death.

Epinephrine is the treatment of choice for anaphylaxis because of its rapid onset of action (within seconds). Intramuscular epinephrine administration is preferred because higher and faster peak serum levels are achieved than after subcutaneous administration,

Many practitioners (and even emergency rooms) start treatment with other classes of medication. Independent of the route of administration (IM, IV, or PO), antihistamines’ onset of action is at least 20-30 minutes. Antihistamine administration should be delayed until after epinephrine. Corticosteroids have never been shown to decrease the incidence of biphasic or protracted anaphylaxis. Their onset of action is 4-6 hours after administration, also independent of the route. While they probably don’t help, it is unlikely that a single short course of steroids will have any significant adverse effect. If the practitioner wishes to treat with steroids, it is not necessary that they are given quickly.

Depending on how severe the reaction is, basic life support measures might be required as recommended by the American Red Cross (“Circulation-Airway-Breathing”). In anaphylaxis, epinephrine should be administered as soon as it is available during basic CPR measures. In addition, when there is hypotension intravenous fluids should be given as soon as possible.

Patient Education

After the Anaphylaxis

Accidents are never planned, so patients and their families need to be prepared in case anaphylaxis recurs. When the trigger is identified, methods of avoidance and mechanisms of cross-contamination (especially food) should be reviewed. Patients should be educated to recognize their symptoms early and to treat themselves quickly rather than waiting to see if symptoms progress. All patients with anaphylaxis should have an epinephrine auto-injector and receive instructions in their use. Children who are old enough to understand and all their caretakers (including parents, babysitters, extended family, teachers) should receive the same education even if it is “passed down” from the parents.

Anaphylaxis Management Plans are useful for schools and homes. The written plan should include the triggers and symptoms to look for. It should identify the order in which medications should be administered and the correct doses. Schools should clearly note where medications are stored and what personnel other than the nurse should do in the event of a severe reaction (e.g., call emergency services, crowd control, etc.). Physicians should consider having “mock code” anaphylaxis drills in their offices including the same components of care.

Conclusion

Anaphylaxis is a rapidly progressive, potentially life-threatening condition requiring immediate treatment. Physicians should be prepared to treat anaphylaxis and to educate their patients in the event of a recurrence. A detailed history and judicious testing frequently identify the trigger allowing patients to actively avoid re-exposure.