A 14 year-old girl comes into the emergency room presenting with lip swelling, throat tingling and rash several minutes after stepping foot on a public bus on which someone was eating peanut butter crackers. She reports that she's had these symptoms before to peanut butter exposure.

Simple enough, right? It sounds like an allergic reaction and her trigger is the ever infamous troublemaker, the most feared of the legumes, the peanut.

But, how do we know the severity of her allergic reaction, and is it possible that our patient is in anaphylaxis? How can we tell and what are the implications of the diagnosis?

Anaphylaxis is a diagnosis on the spectrum of allergic or hypersensitivity reactions, broadly defined as an acute-onset SEVERE allergic reaction that can potentially be fatal.

Importantly, its diagnosis is primarily CLINICAL, based on symptoms and good history of events prior to presentation. However, as with many other systemic immune-mediated processes, it's presentation can be both BROAD and HIGHLY VARIABLE, making it difficult for providers such as ourselves to distinguish anaphylaxis from less severe allergic reaction, and from other mimickers that may not be immune-mediated at all.

Clinicians were attune to the diagnostic challenges behind anaphylaxis and in 2006, the National Institute of Allergy and Infectious Disease in conjunction with the Food Allergy and Anaphylaxis Network published a consensus statement with formal definitions of anaphylaxis targeted to help clinicians identity anaphylaxis with high sensitivity.

Their statement came up with the following three accepted definitions of anaphylaxis, with all three definitions having to meet criteria for being acute-onset (minutes to several hours).

1) muco-cutaneous involvement AND one or more of the following:
-respiratory compromise
-reduced blood pressure or symptoms of associated end-organ dysfunction

2) in the presence of a LIKELY allergen, two or more of the following:
-muco-cutaneous involvement
-respiratory compromise
-reduced blood pressure or symptoms of associated end-organ dysfunction
-persistent GI symptoms

3) in the presence of a KNOWN allergen:
-reduced blood pressure, defined as SBP
A retrospective study of ED patients done in 2012 reported these diagnostic criteria to have a sensitivity of 97%, suggesting these criteria to be particularly useful for the ED setting and helping to validate them for wide adaption into clinical practice.

The 2006 criteria were made to help us think both broadly and specifically about the presentation of anaphylaxis, but what's happening in anaphylaxis that allows it to present in so many different ways?

As we know big picture-wise, anaphylaxis is an immune-mediated allergic reaction, with systemic involvement that makes it a diagnosis that may require resuscitation or potentially be fatal.

Taking a brief moment to sketch out the pathophysiology behind anaphylaxis can help us both to frame the presentations that we see, and to help us understand what guides our management.

Fundamentally, anaphylaxis is the result of basophil and mast cell activation with subsequent release of histamine that acts on H1 receptors located throughout the cardiovascular and respiratory systems, causing bronchoconstriction, systemic vasodilation and capillary permeability, while action on H2 receptors can cause increased secretions and GI symptoms, paired with the release of leukotrienes, additionally contributing to capillary permeability and sustained symptoms.

Importantly, histamine release is through preformed granules, while leukotrienes are produced through lipid breakdown, suggesting that there is a temporal association with the presentation of symptoms.

So, knowing that the primary pathophysiology behind anaphylaxis acts via histamine-mediated bronchoconstriction, capillary permeability, and vasodilatation, we can understand how epinephrine with its alpha1, beta1 and beta2 effects is essentially a targeted pathophysiology reversal and is thus the CORNERSTONE to treatment. Think ABCDE, with E as epinephrine. Management also includes histamine blockers, directly targeting the histamine release, beta-agonists to target bronchoconstriction, while glucocorticoids, with later onset of action, aim to target later leukotriene-mediated effects.

Although management addresses the pathophysiology behind anaphylaxis, a review of the current literature suggests that epinephrine is the ONLY treatment with life-saving outcomes, and that delay to epinephrine is associated with mortality. Thus all other therapy is considered adjunctive and should be given after assessing initial response to epinephrine.

Given that these adjunctive therapies have not been demonstrated to be life-saving, epinephrine MUST be prioritized. Studies suggest that over-reliance on these adjunctive therapies may account for failure to administer epinephrine promptly, resulting in the mismanagement and increased mortality seen in these patients.

Additionally, of note to ED management is the concept of anaphylaxis as a BIPHASIC REACTION, related to acute histamine release versus lipid-derived leukotrienes accumulation, producing early-phase and late-phase stages of anaphylaxis that compromise the biphasic reaction.

Given that leukotriene-mediated late-phase can present with the same life-threatening symptoms as early-phase, resolution of symptoms with early treatment should not reassure the clinician for discharge, but instead of the need to monitor for recurrence of symptoms. Currently no consensus exists on how long monitoring is required, but suggested guidelines state a minimum observation period of 4 to 8 hours for simple cases with immediate resolution with epinephrine, and longer periods of observation for protracted symptoms, or previous episodes of biphasic reaction.

Given that symptoms of anaphylaxis include hypotension and respiratory compromise, significant overlap exists with many other diagnoses in the scope of emergency medicine, and diagnoses such as asthma attack and causes of distributive shock should be ruled out.

Additionally, noting that other mediators can produce the similar effects as histamine and leukotrienes, can suggest less common diagnoses such as carcinoid syndrome or medullary cancer of the thyroid, with elevated serotonin and calcitonin respectively, or non-allergic causes of angioedema, which result in accumulation of bradykinin.

Our 14 year-old patient had experienced these symptoms before and had self-administered epinephrine with onset of her symptoms. She reported an initial chest tightness that reduced with its administration, and improving lip swelling and rash. Her diagnosis in this case would meet criteria for anaphylaxis with a likely allergen. She was treated with adjunctive therapies and observed for 6 hours before discharge.

1. Sampson 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
2. Boghner and Lichtenstein. Anaphylaxis. NEJM, 1991.
3. Campbell et al. Emergency department diagnosis and treatment of anaphylaxis:
a practice parameter. Ann Allergy Asthma Immunol, 2014.
4. "Anaphylaxis: rapid recognition and treatment" UptoDate, Feb 8, 2016