9.

Anaphylaxis
F. Estelle R. Simons, MD, FRCPC Winnipeg, Manitoba, Canada

This activity is available for CME credit. See page 6A for important information.

Anaphylaxis is an acute-onset, potentially fatal systemic allergic

reaction. It is usually triggered by an agent such as an insect Abbreviations used
sting, food, or medication, through a mechanism involving IgE CNS: Central nervous system
and the high-affinity IgE receptor on mast cells or basophils. PAF: Platelet-activating factor
Less commonly, it is triggered through other immunologic
mechanisms, or through nonimmunologic mechanisms. It often
occurs in community settings. Anaphylaxis episodes range in
severity from those that are mild and resolve spontaneously to Ninth Revision codes for the diagnosis and clinical manifesta-
those that are fatal within minutes. The clinical diagnosis is tions of anaphylaxis fail to capture all individuals with the
based on a meticulous history and physical examination, disease.4
sometimes, but not necessarily, supported by a laboratory test Epidemiologic studies suggest that anaphylaxis now occurs
such as an elevated serum total tryptase level. Sensitization to more commonly in community settings than in health care
allergen triggers suggested by the history needs to be confirmed settings. The rate of occurrence is increased in individuals living
by skin testing and measurement of allergen-specific IgE. In in good socioeconomic circumstances. The largest number of
some sensitized individuals, additional tests are needed to assess incident cases is among children and adolescents.3 Until age 15
the risk of future anaphylaxis episodes. Prompt injection of years, there is a predilection for males, but after age 15 years,
epinephrine is life-saving. H1-antihistamines and inhaled there is a predilection for females. Different trigger factors pre-
b2-adrenergic agonists cannot be depended on to prevent dominate in different age groups; for example, fatalities from
fatality. Long-term risk reduction is an integral part of food-induced anaphylaxis peak in adolescents and young
management. (J Allergy Clin Immunol 2008;121:S402-7.) adults,5,6 and fatalities from anaphylaxis triggered by insect
Key words: Anaphylaxis, allergic reaction, mast cell, basophil, IgE, stings, diagnostic agents, and medications predominate in mid-
FceRI, histamine, tryptase, food allergy, venom allergy, medication dle-aged and older adults.7 There are few studies of the role of ge-
allergy, epinephrine, adrenaline, H1-antihistamine netic factors in anaphylaxis.2

Anaphylaxis is an acute-onset, potentially fatal systemic PATHOGENESIS

allergic reaction. Anaphylactic and anaphylactoid reactions do In many individuals with anaphylaxis, IgE plays a pivotal
not need to be distinguished with regard to diagnosis and acute role. Synthesized in response to allergen exposure, it becomes
treatment. The term anaphylactoid is no longer recommended for fixed to FceRI on the surface membranes of mast cells and
use.1 Nevertheless, it remains critically important to understand basophils. Aggregation of receptor-bound IgE molecules on
the effector mechanisms involved in the pathogenesis of anaphy- re-exposure to the allergen results in cell activation, mediator
laxis in order to develop optimal risk reduction strategies and pre- release, and the immediate hypersensitivity response. IgE also
vent recurrence2 (Fig 1, A and B). contributes to the intensity of anaphylaxis through mechanisms
The true rate of occurrence of anaphylaxis from all triggers is that go beyond sensitizing, priming, activation, and mediator
unknown,3 but it appears to be increasing. Lifetime prevalence is release; for example, it enhances expression of FceRI on mast
estimated as 0.05% to 2%. In prospective studies, underreporting cells and basophils.2,8-10
likely occurs, because anaphylaxis may be underdiagnosed in Other potential immunologic mechanisms in anaphylaxis
individuals who present with mild or partially treated episodes. include involvement of immune aggregates, IgG, IgM, platelets,
In retrospective studies involving chart reviews from emergency and T cells; shift in eicosanoid metabolism toward leukotriene
departments or clinics, International Classification of Diseases, formation; and activation of the complement or coagulation
systems.2 In some individuals described as having idiopathic an-
aphylaxis, FceRI receptors may be aggregated through autoim-
From the Section of Allergy and Clinical Immunology, Department of Pediatrics and mune mechanisms. Nonimmunologic factors, which activate
Child Health, the Department of Immunology, and the Canadian Institutes of Health mast cells by mechanisms not yet fully understood, include exer-
Research National Training Program in Allergy and Asthma, Faculty of Medicine, cise, cold air or water exposure, radiation, ethanol, insect venom
University of Manitoba.
constituents, radiocontrast media, and medications such as
Disclosure of potential conflict of interest: The author has declared that she has no
conflict of interest. opioids and vancomycin.2 A few triggers—for example, insect
Received for publication May 30, 2007; revised August 15, 2007; accepted for publica- venoms, radiocontrast media, and some medications—potentially
tion August 16, 2007. act through more than 1 mechanism2 (Fig 1, A).
Reprint requests: F. Estelle R. Simons, MD, FRCPC, 820 Sherbrook Street, Winnipeg, Regardless of the immunologic or nonimmunologic triggering
Manitoba, Canada R3A 1R9. E-mail: lmcniven@hsc.mb.ca.
0091-6749/$34.00
mechanisms, and regardless of whether FceRI or other receptors
Ó 2008 American Academy of Allergy, Asthma & Immunology such as G protein–coupled receptors or Toll-like receptors are
doi:10.1016/j.jaci.2007.08.061 activated, mast cells and basophils play an important role in

S402
J ALLERGY CLIN IMMUNOL SIMONS S403
VOLUME 121, NUMBER 2

FIG 1A. Summary of the pathogenesis of anaphylaxis. Other potential triggers include occupational
allergens, inhalants such as horse dander or grass pollen, allergen immunotherapy, vaccines to prevent
infectious diseases, hormones, colorants, and enzymes. Some triggers may act through more than
1 mechanism. Individuals with anaphylaxis, by definition, usually have involvement of 2 or more body
systems concurrently; the occasional exceptions are those with isolated hypotension after exposure to a
known trigger.

initiating and amplifying the acute allergic response.2,8-15 They involvement might be more readily characterized, thanks to iden-
release mediators of inflammation, including histamine, proteases tification of a mAb directed against an intermediate form of
such as tryptase, mast cell carboxypeptidase A3 and chymase, pro–major basic protein 1.14 Anti-IgE antibody might play a ther-
lipids such as platelet-activating factor (PAF), prostaglandins apeutic role by depleting free IgE, with consequent downregula-
(PGD2), and leukotrienes (LTC4), as well as chemokines, and cy- tion of FceRI receptors on mast cells and basophils and deflation
tokines (Fig 1, A). Once activated, the mast cell response is regu- of the intracellular activation signal triggered by IgE/FceRI
lated by the balance of positive and negative intracellular aggregation.15
molecular events that extend beyond the traditional kinases and Animal models provide information that is potentially relevant
phosphatases.10 New discoveries in mast cell biology have the po- to human anaphylaxis. For example, in murine anaphylaxis, 2
tential to improve the diagnostic and therapeutic approach to hu- main immunologic pathways have been described: (1) a classic
man anaphylaxis. For example, stem cell factor and its receptor pathway involving a small amount of antigen, FceRI on mast cells
Kit are important in IgE/antigen-induced mast cell degranulation and basophils and release of histamine, leukotrienes, serotonin,
and cytokine production.11 Inhibitory sialic acid–binding immu- and PAF; and (2) a pathway involving a relatively large amount of
noglobulin-like lectins (Siglecs) are extensively expressed on hu- antigen, IgG–antigen complex-induced activation of macro-
man mast cells.12 Sphingosine kinases are reported to be phages by cross-linking of FcgRIII, and release of mediators,
determinants of mast cell responsiveness.13 In the future, basophil predominantly PAF.16
S404 SIMONS J ALLERGY CLIN IMMUNOL
FEBRUARY 2008

DIAGNOSIS increased by factors such as stinging insect species, recent stings

Diagnosis of anaphylaxis depends primarily on a meticulous leading to mast cell or basophil priming, concurrent disease such
clinical history: ascertaining exposure to potential triggering as asthma, COPD, or mastocytosis, and concurrent use of medi-
agents or events, time elapsed between exposure and symptom cations such as nonselective b-blockers.7,24-27
onset, and evolution of the episode over minutes or hours. Among Food-induced anaphylaxis is commonly triggered by cow’s
individuals recognized as having anaphylaxis, target organs milk, egg, peanut, tree nuts, finned fish, shellfish, wheat, soy, or
include skin (90% of episodes), respiratory tract (70%), gastro- sesame; however, any food may be implicated, including other
intestinal tract (30% to 45%), cardiovascular system (10% to seeds, fruits, vegetables, gums, and spices. Selection of foods for
45%), and central nervous system (CNS; 10% to 15%; Fig 1, A). skin prick testing or in vitro testing should be guided by the his-
Diagnosis is impeded when symptoms are not recognized, and tory, because sensitization to food occurs in as many as 60% of
when skin signs are absent. As reflected in the clinical criteria individuals in the general population, most of whom do not de-
supporting the new anaphylaxis definition, many individuals velop anaphylaxis from foods. Intradermal tests to foods are con-
with anaphylaxis never develop hypotension or shock,1,5-7 and traindicated. Few commercial food allergens are standardized.
respiratory tract obstruction is often the predominant cause of Testing with fresh foods is often performed. Identification of
death.6,7 The differential diagnosis of anaphylaxis is age- food-specific IgE levels with greater than 95% predictive risk
dependent.2,17 values for clinical reactivity (positive challenge) has been an im-
Laboratory tests available to support the clinical diagnosis of portant advance (ImmunoCap; Phadia AB, Uppsala, Sweden).
anaphylaxis include plasma histamine levels and serum or plasma These levels are defined for cow’s milk (15 kU/L), egg (7
total tryptase levels, which do not necessarily correlate with each kU/L), peanut (14 kU/L), tree nuts (15 kU/L), and fish (20
other, in part because of the different time courses of their kU/L); in infants, lower values have been established for milk
appearance in, and disappearance from, the circulation. Hista- (5 kU/L) and egg (2 kU/L).2,28,29
mine should be measured in blood samples obtained within 15 to Individuals with a convincing history of anaphylaxis to a
60 minutes of onset; tryptase, in samples obtained within 15 to specific food, and evidence of sensitization (positive skin prick
test or elevated specific IgE level) to that food, need no further
180 minutes. Even in optimally timed samples, histamine and
testing. Others might require a physician-monitored incremental
tryptase levels may be within normal limits; in particular, tryptase
oral food challenge, conducted in an appropriately staffed and
levels are seldom elevated in food-triggered anaphylaxis, in
equipped healthcare facility, in order to predict clinical reactivity.
which basophil involvement possibly predominates over mast cell
Challenges are time-consuming and not without risk. Additional
involvement. Measurement of serial tryptase levels, or of baseline
approaches to distinguishing between sensitization and clinical
levels in postevent serum or stored serum, might be helpful. In the
risk are therefore being developed. Determination of specific IgE-
future, more widespread availability of measurement of addi-
binding epitopes on an allergen such as peanut or milk potentially
tional mast cell and basophil activation markers such as mature b-
provides increased ability to determine the risk of, and the
tryptase, mast cell carboxypeptidase A3, chymase, and PAF, or a severity of, a future reaction. For example, individuals with IgE
panel of such markers, might be useful2,18,19 (Fig 1, A). antibodies binding to stable linear epitopes are more likely to have
The specific trigger implicated by the history of an anaphylaxis severe-persistent allergy, whereas those with IgE binding to
episode needs to be confirmed, so that it can be avoided and future conformational epitopes dependent on protein folding are more
episodes can be prevented.17,20 In individuals with IgE-dependent likely to have mild-transient allergy. Other approaches being
anaphylaxis, positive allergen skin tests and elevated quantitative tested include measurement of the rate of change of the allergen-
allergen-specific IgE levels indicate sensitization, which is a risk specific IgE level, the ratio of allergen-specific IgE to total IgE,
factor for anaphylaxis, but they are not diagnostic of anaphy- and upregulation of basophil surface activation markers after
laxis.2,8 Sensitization to novel triggers suggested by the history, stimulation with food antigen.2,28,29
for which there are no commercially available test antigens, can Any medication can trigger anaphylaxis, including those used
be identified through development of customized in vitro tests.2 in the treatment of allergic diseases, omalizumab and other mAbs
Individuals with Hymenoptera sting–triggered anaphylaxis (rituximab, trastuzumab, alemtuzumab), and chemotherapy drugs
should be evaluated by an allergy/immunology specialist, be- (platins, taxenes). For most medications, antigenic determinants
cause of the complexities involved in assessment and the high po- have not been characterized or validated; indeed, the relevant
tential for cure when appropriate treatment is instituted.17,20-22 immunogens, including haptens, metabolites, and unidentified
Positive intradermal tests to venom and/or elevated venom-spe- degradation products, are unknown. If IgE is involved in the
cific IgE levels occur in as many as 25% of adults in the general pathogenesis—for example, in b-lactam antibiotic-triggered
population, most of whom do not develop anaphylaxis after an in- anaphylaxis—skin tests and medication-specific IgE levels are
sect sting. Positive tests therefore do not necessarily predict the helpful. Tests involving measurement of upregulation of basophil
risk of, or the severity of, future venom-triggered anaphylaxis ep- activation marker expression after stimulation with medication
isodes, and it is critically important that they be interpreted in the are in clinical use in some countries. Physician-monitored
context of the clinical history. Measurement of upregulation of challenge tests performed in specialized centers remain the gold
basophil surface activation markers such as CD63 and CD203c standard in assessment.2,20,30,31
after stimulation with venom is used in the clinical evaluation
of these individuals in some countries, but remains a research
tool in North America.23 Cross-reacting compounds among MANAGEMENT
venoms (such as hyaluronidases), and cross-reacting carbohy- When anaphylaxis occurs in a healthcare facility, rapid assess-
drate derivatives between venom and nonvenom allergens, may ment of airway, breathing, circulation, and orientation is manda-
account for some positive tests. Clinical risk of anaphylaxis is tory; in addition, the skin should be examined and body weight
J ALLERGY CLIN IMMUNOL SIMONS S405
VOLUME 121, NUMBER 2

FIG 1B. Summary of anaphylaxis management. Acute treatment is the same regardless of the mechanism
or trigger involved in anaphylaxis. In contrast, for long-term risk reduction, avoidance measures and
immunomodulation are trigger-specific; currently, immunomodulation is available only for a minority of
individuals with anaphylaxis. All at-risk individuals need to have comorbidities and comedications
assessed, to be taught the importance of emergency preparedness, and to be instructed in the use of
self-injectable epinephrine.
*The skin should be inspected, and weight estimation is important, especially in infants and children, and
also in overweight and obese teens and adults, in order to calculate an optimal dose of epinephrine and
other medications needed in treatment and resuscitation. **Supine position, as tolerated, to prevent empty
ventricle syndrome. ***Call 911/emergency medical services for anaphylaxis occurring in community
healthcare facilities such as medical, dental, or infusion clinics, where optimal backup might not be avail-
able for resuscitation. ACLS, Advanced cardiac life support; CPR, cardiopulmonary resuscitation; CVS, car-
diovascular; GI, gastrointestinal; ID, identification (eg, bracelet, wallet card); IV, intravenous.

(mass) should be estimated. This should be followed by prompt COPD, ischemic heart disease, and mastocytosis (symptomatic
intramuscular injection of epinephrine, administration of supple- or asymptomatic) potentially affect recognition and treatment, and
mental oxygen, establishment of an airway, placing the individual should be optimally managed. The relative benefits and risks of
in the supine position, and insertion of 1 or more large-bore medications such as nonselective b-blockers, angiotensin-con-
intravenous lines for fluid replacement and infusion of epineph- verting enzyme inhibitors, and angiotensin II receptor blockers
rine and additional medications, if needed17,20 (Fig 1, B). Pharma- that potentially impede the response to treatment should be
cologic interventions in anaphylaxis have changed little during reviewed2,5-7,17,20,25-27 (Fig 1, B).
the past 6 decades. Written, personalized information about avoidance of the
Long-term risk reduction measures include accurate risk documented trigger (stinging insect, food, medication, or other)
assessment, optimal management of comorbidities, and relevant should be provided, along with direction to additional up-to-date
specific preventive treatment such as avoidance of confirmed sources of information (Fig 1, B). Avoidance measures may neg-
triggers and/or immunomodulation. At-risk individuals should be atively affect quality of life.17
equipped with self-injectable epinephrine, a personalized Ana- In as many as 98% of individuals with anaphylaxis from a
phylaxis Emergency Action Plan, and medical identification17 Hymenoptera sting, an appropriate course of venom immunother-
(Fig 1, B). apy dramatically reduces the risk of anaphylaxis from a subse-
Comorbidities such as vision or hearing impairment, CNS quent sting. Immunotherapy is not indicated in children with
diseases, and use of prescription, nonprescription, and recrea- mild cutaneous systemic reactions, or in individuals of any age
tional drugs or ethanol potentially impede recognition of anaphy- with large local reactions.21,22 Agent-specific rapid desensitiza-
laxis triggers and symptoms. Comorbidities such as asthma, tion provides short-term immunomodulation for individuals at
S406 SIMONS J ALLERGY CLIN IMMUNOL
FEBRUARY 2008

risk for anaphylaxis from seminal fluid, or from therapeutic agents strategies will eventually be available for long-term risk
such as b-lactam antibiotics, fluoroquinolones, vancomycin, ace- reduction.
tylsalicylic acid and other nonsteroidal anti-inflammatory drugs,
insulin, platins, taxenes, and mAbs.20,30,31
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