Anaphylaxis is an acute systemic type I (IgE-mediated) hypersensitivity
reaction mediated by histamine, leukotrienes, and other mast cell–derived
mediators.1 The estimated overall lifetime prevalence
of anaphylaxis from all causes is 0.5% to 2%,
and 0.7% to 2% of anaphylactic reactions are fatal.
Rapid recognition, diagnosis, and therapy of anaphylaxis are imperative to
prevent morbidity and mortality.
Although anaphylaxis can occur at any age, adolescents and young
adults are most at risk for serious anaphylaxis. Preexisting asthma
is a primary risk factor for fatal anaphylaxis, and delay in epinephrine
therapy has been strongly associated with anaphylaxis mortality.
Additional risk factors for poor outcomes with the occurrence of
anaphylaxis include concomitant therapy with β-adrenergic
or α-adrenergic antagonists, which blunts the effects
of epinephrine treatment, and angiotensin-converting enzyme inhibitors,
which interfere with physiologic compensatory mechanisms, thereby
leading to severe or protracted anaphylaxis.
Risk factors for anaphylaxis include parenteral antigen exposure
(ie, IV medications) and repeated, interrupted antigen exposure
(ie, medication or food ingestion). The most common causes of anaphylaxis
include (1) medications, (2) foods, (3) stinging insects, (4) latex,
and (5) blood products. Of these causes, medications and foods account
for the majority of serious anaphylactic reactions resulting in
emergency room visits or causing anaphylaxis mortality. The most
commonly implicated causative medications are β-lactam antibiotics
(penicillins and cephalosporins), other antibiotics, radiocontrast
agents (through direct mast cell stimulation), and neuromuscular
blocking agents. Among foods, peanuts, tree nuts, cow’s
milk, egg, and seafood (crustaceans, mollusks, fish) most commonly cause
anaphylaxis.2 Rarely, the temporal combination
of food ingestion and exercise may trigger anaphylaxis.3 This
food-dependent, exercise-induced anaphylaxis is best evaluated by
an allergy specialist. Other uncommon causes of anaphylaxis include
physical factors such as cold, heat, or ultraviolet light exposure.
Finally, idiopathic anaphylaxis occurs when no inciting allergen
can be identified by considering the patient’s history
or by diagnostic testing.
In the pediatric population, anaphylactic reactions to vaccines
are a concern. True IgE-mediated anaphylaxis to immunizations is
rare and more commonly involves IgE to vaccine components rather
than the immunizing antigen itself. Gelatin, added to vaccines as
a stabilizing agent, has been implicated in anaphylactic reactions
to measles, mumps, and rubella (MMR), varicella, influenza, and Japanese
encephalitis vaccines. Children with a history of allergy to egg
should be seen by an allergy specialist prior to receiving influenza and
yellow-fever vaccines, as egg protein used in these vaccines has
been implicated in anaphylactic reactions to these immunizations. IgE-mediated
reactions to the specific vaccine antigen is exceedingly rare, but
has been reported for diphtheria and tetanus.
Generally, previous exposure to an antigen is necessary for IgE
sensitization to occur in an individual. On subsequent exposure,
the triggering antigen cross-links antigen-specific IgE bound to
mast cells and basophils through high-affinity IgE (FcεRI)
receptors. Activated mast cells and basophils release preformed mediators,
including histamine, tryptase, chymase, and heparin. In addition,
lipid-derived mediators such as cysteinyl leukotrienes (LTC4, LTD4,
LTE4), prostaglandins, and platelet-activating factor are generated
by activated mast cells and basophils. This sudden release of mediators
into the circulation and tissues of the gastrointestinal and respiratory tract
results in the multisystem syndrome of anaphylaxis. Less commonly,
non-IgE mechanisms may lead to mast cell activation and symptoms
of anaphylaxis. Such non-IgE reactions are sometimes called “anaphylactoid” reactions,
as though they are clinically indistinguishable from IgE-mediated
anaphylactic reactions. Direct mast cell stimulation is likely a
primary mechanism responsible for immediate systemic reactions to
radiocontrast media. Other non-IgE alternative mechanisms leading
to anaphylactic symptoms include immune complex–mediated
complement activation, as occurs with blood products.
Anaphylaxis is a clinical diagnosis based on presenting signs
and symptoms, as well as a clinical history suggestive of allergen
exposure. Symptoms of anaphylaxis typically appear within minutes
of the antigen exposure, though occasionally symptom onset may be delayed
for several hours after oral ingestions. In severe cases, symptoms
progress rapidly and lead to fatal shock within 60 minutes of exposure.
Most anaphylactic reactions are uniphasic, though up to 20% show
a biphasic course with recurrent symptoms approximately 8 to 12
hours after the exposure; this may occur as late as 72 hours after
the initial anaphylactic phase. The mechanism of this clinical observation
has not been established, though it has historically been attributed
to mast cell cytokine production resulting in recruitment of eosinophils,
basophils, macrophages, and lymphocytes into tissues producing a
second phase of inflammation.
The most common symptoms of anaphylaxis are cutaneous, respiratory,
gastrointestinal, and cardiovascular. Skin symptoms may include
urticaria, angioedema, erythema, pruritus, and diaphoresis. Respiratory
symptoms of rhinitis, nasal congestion, wheezing, cough, chest tightness,
and dyspnea are common. Laryngeal edema may also occur, causing
stridor and airway compromise. Gastrointestinal symptoms are frequently
associated with anaphylaxis, including cramping, abdominal pain, nausea,
vomiting, and diarrhea. Cardiovascular features are less common
in children than adults. In the most severe or advanced stages,
hypotension occurs with reflex tachycardia. Syncope and shock may
result from the profound hypotension associated with severe anaphylaxis.
Respiratory arrest and/or cardiovascular collapse due to
hypotension are the common causes of death from anaphylaxis.
A number of common conditions may be confused with anaphylaxis.
These include vasovagal reactions, acute urticaria and/or
angioedema, acute asthma exacerbations, vocal cord dysfunction,
acute anxiety disorders, and epiglottitis or foreign body aspirations
resulting in respiratory distress. In addition to these common conditions,
rare disorders such as mastocytosis or basophilic leukemia may present with
systemic histamine-mediated symptoms.
While anaphylaxis is a clinical diagnosis based on the history
and constellation of presenting signs and symptoms, confirmatory testing
with serum histamine or tryptase levels is sometimes useful to confirm
systemic mast cell activation. Histamine is detectable in plasma
for only 15 to 30 minutes after the anaphylactic event, making appropriate
collection difficult. Tryptase, a protease specific to mast cells,
reaches a serum peak 30 to 120 minutes after the event and remains
elevated for approximately 6 hours making it more helpful to confirm
systemic mast cell activation. Thus, an elevated serum tryptase
level is useful to confirm systemic mast cell activation. A normal
serum tryptase level does not necessarily exclude anaphylaxis, particularly
with food-induced events, which are rarely associated with elevated
serum tryptase. After treatment of the acute anaphylactic episode,
additional diagnostic testing should include testing for allergen-specific
IgE to confirm the causative antigen. This can be performed by allergy
skin testing or serum-specific IgE testing to suspected allergens.
Evaluation by an allergy-immunology specialist is appropriate.
The approach to treating anaphylaxis should focus first on maintaining
the airway, breathing, and circulation. Mortality from anaphylaxis
results from asphyxiation due to upper airway angioedema, respiratory
failure from severe bronchial obstruction, or cardiovascular collapse.
The most important initial medical therapy is epinephrine, which
is most effective when administered within 30 minutes of symptom onset.4 Anaphylaxis
mortality is strongly correlated with delays in epinephrine therapy.
Any ongoing exposure to the suspected antigen should be discontinued
(ie, medication infusion). Hypotension requires aggressive large-volume
fluid resuscitation and, if persistent, vasopressor therapy. Supplemental
oxygen is recommended, and in the presence of respiratory compromise
or bronchospasm, inhaled bronchodilators such as albuterol should
be administered. Intubation and mechanical ventilation may be necessary.
H1- and H2-receptor antagonists are adjunctive medications that should
be given to reduce pruritus and urticaria, though antihistamines
without epinephrine are insufficient to adequately treat anaphylaxis. Corticosteroids
are frequently given to attenuate the potential late-phase inflammatory
response and thereby prevent recurrence of symptoms 8 to 12 hours
after the initial onset; corticosteroids are not effective for the
initial acute phase. Anaphylactic reactions that occur in patients
taking β-adrenergic antagonists may be particularly
refractory to epinephrine. In this setting, glucagon or atropine
administration should be considered. Whenever possible, patients
should be observed for 8 to 12 hours after an anaphylactic reaction
due to the possibility of recurrent symptoms from the late-phase
response occurring several hours after the initial event.
All patients should be discharged with injectable epinephrine
for home use, assuring that they receive appropriate instruction
in the use of an Epipen.5 Subsequent to treatment
of the acute episode, identification of the triggering antigen or
exposure should be pursued through diagnostic allergy skin testing
or serum IgE testing whenever possible. Patients should strongly
consider wearing medical alert identification detailing their specific
allergies if known.