2007 Vol.27 Issues 2 Anaphylaxis

Immunol Allergy Clin N Am
27 (2007) xi–xii
Foreword
Rafeul Alam, MD, PhD

Consulting Editor
Anaphylaxis is one of the most dramatic acute medical conditions that the
medical professional deals with. Its treatment, especially its prevention, re-
mains an important challenge. No other medical specialty deals with anaphy-
laxis as much as the allergy and immunology subspecialty. Immunotherapy,
one of the most important therapeutic interventions of our subspecialty, is in-
herently linked to the risk of anaphylaxis. Preventive measures work well when
the trigger is known, as in the case of immunotherapy. When the trigger is un-
known, as in idiopathic anaphylaxis, the preventive intervention becomes se-
riously limited. Thus, the identification of etiologic factors for anaphylaxis
remains a major challenge.
We have a new trend in drug development in the pharmaceutical industry.
Instead of the archetypal small molecule–based drug discovery approach, the
companies are increasingly focusing on development of antibody-based bio-
logics. The introduction of biologics, especially, the antibody-based therapies,
has increased the risk of iatrogenic anaphylaxis in the patient population. This
biologics-based treatment calls for an added anaphylaxis surveillance. Some
of these biologics have been reported to induce a delayed anaphylaxis outside
the typical time frame of an immediate hypersensitivity reaction. The mecha-
nism is unclear and needs further investigations. Because of the increasing
prevalence, anaphylaxis is a timely topic and deserves a dedicated issue of this
journal. We have invited recognized experts in the field, led by Dr. Phil Lieber-
man, who has dedicated his entire professional life to expanding our knowl-
edge on anaphylaxis. The updated information on epidemiology, etiologic
factors, pathophysiology, and the management of anaphylaxis should benefit
0889-8561/07/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.iac.2007.03.012 immunology.theclinics.com
xii FOREWORD
not only allergy and immunology specialists but all clinicians and health care
providers.
Rafeul Alam, MD, PhD

National Jewish Medical and Research Center
Division of Allergy & Immunology
1400 Jackson Street, Denver, CO 80206, USA
E-mail address: alamr@njc.org
27 (2007) xiii–xiv
Preface
Phil Lieberman, MD
Guest Editor
It could be argued that the first description of anaphylaxis spawned the

birth of allergy immunology. Anaphylaxis, which remains almost the sole
purview of the allergist, is still of vital interest to our discipline. In this issue,
we intend to bring to the reader an update of the latest advances in our
knowledge regarding the pathogenesis, prevention, and treatment of poten-
tially fatal allergic reactions. The articles selected cover a wide spectrum of
areas related to anaphylactic episodes and include epidemiology; pathophys-
iology; prevention and management of episodes; the mediators involved;
and articles on the various agents that commonly produce anaphylaxis, in-
cluding foods, insect stings, allergen immunotherapy, and episodes occur-
ring perioperatively. We have chosen well-known experts in each segment
to author these articles and have not limited our participants to allergists,
but incorporated emergency room physicians as well.
The volume is clearly intended for the allergist/immunologist subspecial-
ist, and its information will be useful for emergency room physicians,
xiv PREFACE
anesthesiologists who deal with reactions during the perioperative period,

and primary care physicians as well.
Phil Lieberman, MD
University of Tennessee
College of Medicine
Memphis, TN 38163, USA
Allergy & Asthma Care
7205 Wolf River Blvd., Ste. 200
Germantown, TN 38138, USA
E-mail address: aac@allergymemphis.com
27 (2007) 145–163
Epidemiology of Anaphylaxis
Sunday Clark, MPH, ScD,
Carlos A. Camargo, Jr, MD, DrPH*
Department of Emergency Medicine, Massachusetts General Hospital,
Harvard Medical School, 326 Cambridge Street, Suite 410, Boston, MA 02114, USA
Anaphylaxis first was described in the early 1900s by Portier and Richet
[1], who induced anaphylactic reactions in dogs as they were attempting to
immunize them against jellyfish stings using repeated injections of sea anem-
one toxin [2]. One century later, at a recent symposium jointly sponsored by
the National Institute of Allergy and Infectious Disease (NIAID) and the
Food Allergy and Anaphylaxis Network (FAAN), a multidisciplinary group
suggested a broad definition of anaphylaxis that would be helpful for med-
ical professionals and lay people, stating that ‘‘anaphylaxis is a serious aller-
gic reaction that is rapid in onset and may cause death’’ [3,4].
The epidemiology of anaphylaxis has been difficult to quantify, with es-
timates varying widely [5]. A major problem in determining the burden of
anaphylaxis has been the lack of universal consensus on the definition of
anaphylaxis or of the best criteria for diagnosing anaphylactic reactions
[5–8]. The recent NIAID/FAAN symposia may have broken this logjam
by proposing [3] and then refining [4] simple clinical criteria for identifying
and diagnosing anaphylaxis (Box 1) [3,4]. Using a consistent definition to
identify anaphylaxis would allow for uniform reporting of cases and more
accurate estimates of the burden of disease.
Other epidemiologic challenges include difficulty in distinguishing ana-
phylaxis from other disorders and often selection bias based on hospital pre-
sentation [7,9,10]. Anaphylaxis researchers contribute to uncertainty by
using different measures of disease occurrence to estimate disease burden
(such as prevalence and incidence). In addition to the use of varying
* Corresponding author. EMNet Coordinating Center, Department of Emergency

Medicine, Massachusetts General Hospital, 326 Cambridge Street, Suite 410, Boston, MA
02114.
E-mail address: ccamargo@partners.org (C.A. Camargo).
146 CLARK & CAMARGO
Box 1. Clinical criteria for diagnosing anaphylaxis

Anaphylaxis is highly likely when any one of the following
three criteria are fulfilled:
Acute onset of an illness (minutes to several hours) with
involvement of the skin, mucosal tissue, or both (eg,
generalized hives, pruritus or flushing, swollen
lips-tongue-uvula) and at least one of the following:
Respiratory compromise (eg, dyspnea,
wheeze–bronchospasm, stridor, reduced peak
expiratory flow (PEF), hypoxemia)
Reduced blood pressure (BP) or associated symptoms of end
organ dysfunction (eg, hypotonia [collapse], syncope,
incontinence)
Two or more of the following that occur rapidly after exposure to
a likely allergen for that patient (minutes to several hours):
Involvement of the skin–mucosal tissue (eg, generalized hives,
itch–flush, swollen lips, tongue, uvula)
Respiratory compromise (eg, dyspnea,
wheeze–bronchospasm, stridor, reduced PEF, hypoxemia)
Reduced BP or associated symptoms (eg, hypotonia [collapse],
syncope, incontinence)
Persistent gastrointestinal (GI) symptoms (eg, crampy
abdominal pain, vomiting)
Reduced BP after exposure to known allergen for that patient
(minutes to several hours):
Infants and children: low systolic BP (age-specific) or greater
than 30% decrease in systolic BPa
Adults: systolic BP of less than 90 mm Hg or greater than 30%
decrease from that person’s baseline
Abbreviation(s): BP, blood pressure; PEF, peak expiratory flow.

a
Low systolic blood pressure for children is defined as less than 70 mm Hg
from 1 month to 1 year, less than (70 mm Hg 1 [2 age]) from 1 to 10 years, and
less than 90 mm Hg from 11 to 17 years.
From Sampson HA, Munoz-Furlong A, Campbell RL, et al. Second symposium
on the definition and management of anaphylaxis: summary report–Second
National Institute of Allergy and Infectious Disease/Food Allergy and Anaphy-
laxis Network symposium. [reprint in Ann Emerg Med. 2006 Apr;47(4):373–80].
J Allergy Clin Immunol 2006;117(2):391–7; with permission.
EPIDEMIOLOGY OF ANAPHYLAXIS 147
measures, the epidemiologic terminology frequently is misused. For exam-

ple, prevalence and incidence often are used interchangeably or incorrectly.
A recent commentary by the American College of Allergy, Asthma and
Immunology (ACAAI) Epidemiology of Anaphylaxis Working Group sum-
marized key articles in the medical literature and estimated a lifetime prev-
alence of approximately 0.05% to 2.0% [11]. The present article covers
a larger number of articles while focusing on the epidemiology of anaphy-
laxis occurring outside of the hospital. The authors suggest approaches
for more comprehensive and consistent identification of cases and encourage
more research on this relatively neglected topic.
Methods
The authors performed a qualitative review of articles published between
1966 and September 2006 describing the frequency of anaphylaxis. Studies
solely focused on cases of anaphylaxis occurring in the inpatient setting
were not included in this article. Potential references were identified using
the free text search string ‘‘anaphylaxis AND (prevalence OR incidence)’’
and ‘‘anaphylaxis AND epidemiology’’ in MEDLINE using PubMed. In
addition, the authors included abstracts known to the authors if applicable.
The review is divided into population-based estimates, emergency medical
services, emergency department (ED) visits, and hospital admissions.
Population-based estimates
Many population-based studies have evaluated the burden of anaphy-
laxis due to any cause, while others have focused on anaphylaxis caused
by specific allergens. The use of different case definitions in different popu-
lations, along with the reporting of different measures of occurrence, all con-
tribute to the wide range in estimates in the medical literature.
All-cause reactions
Yocum and colleagues [12] undertook a study to describe the epidemiol-
ogy of anaphylaxis in Olmsted County, Minnesota, between 1983 and 1987.
The investigators reviewed the medical records of 1255 residents in the Ro-
chester Epidemiology Study. Cases of anaphylaxis were identified by a com-
puter-linked, medical diagnostic indices program. During the 5-year study
133 residents experienced 154 anaphylactic reactions. The annual occurrence
rate of anaphylaxis in this population was 30 per 100,000 person–years, and
the annual incidence rate was 21 per 100,000 person–years. The observed
case fatality rate was low at 0.65%, with only one individual experiencing a
fatal reaction.
Boros and colleagues [13] estimated the prevalence of parent-reported al-
lergy and anaphylaxis in children aged 3 to 17 years. Parents of children
with already identified allergies were surveyed to obtain details about the
148 CLARK & CAMARGO
child’s allergic history. Among 4173 children, the rate of allergy was 7.3 per
100 children, and the rate of anaphylaxis was 0.59 per 100 children. Al-
though this survey was performed in subjects outside the clinical setting,
it focused on children known to have allergies (ie, it was not a true popula-
tion study with everyone proportionally represented). A similar study in-
cluding all children, regardless of allergic history, would be useful for
estimating the true national burden of anaphylaxis.
Simons and colleagues [14] used a novel approach to identify anaphylaxis
in their population-based study of anaphylaxis prevalence in Manitoba. In
brief, the authors used an administrative claims database to assess dispens-
ing data for all injectable epinephrine formulations prescribed for out-
of-hospital treatment over a 5-year period in an area with a population of
1.15 million. During the 5-year period, 0.95% of the population was dis-
pensed out-of-hospital injectable epinephrine. Simons and colleagues [15]
performed a similar analysis among children younger than 17 years. During
this 4-year study, epinephrine was dispensed to 3340 children or 1.2% of
children younger than 17 years.
Neugut and colleagues [5] estimated the overall incidence of anaphylaxis
by reviewing the literature for articles assessing four subtypes of anaphylaxis
(food, drugs, latex, and insect stings). Estimates were calculated using data
from the identified studies assessing the burden of each type of anaphylaxis.
Using the 1999 United States population of 272 million, the authors esti-
mated that between 3.3 and 43 million Americans were at risk for an ana-
phylactic reaction because of food, medications, latex or insect stings,
including approximately 1500 fatal reactions. This resulted in United States
prevalence estimates ranging from 1.21% to 15.04%, and 0.002% for a fatal
event.
In 2003, Mullins [9] reported a prospective study of 432 patients referred
to a community-based specialist practice in Australia for an anaphylactic
reaction between 1995 and 2000. Anaphylaxis was defined as the presence
of two or more of the following symptoms: urticaria/angioedema, bron-
chospasm, GI symptoms or hypotension. Mullins estimated a minimum
incidence (new reactions) of 9.9 cases per 100,000 patient years and a
minimum occurrence (new and subsequent reactions) of 12.6 per
100,000 patient years. The author cautions that these estimates do not
take into account patients managed by other practitioners or in the ED,
those whose diagnosis was missed, and those who did not seek medical at-
tention, thus leading to the potential for great underestimation of the true
problem.
Bohlke and colleagues [6] identified cases of anaphylaxis among children
and adolescents enrolled in a large health maintenance organization (HMO)
in the United States between 1991 and 1997. Cases were identified using di-
agnosis codes for anaphylaxis (International Classification of Disease
[ICD]-9 codes 995.0, 995.6, 999.4, and 995.4), and medical records were re-
viewed further to determine timing and treatment details for all suspected
cases. Using a definition of anaphylaxis of 1 organ system (mucocutaneous,

respiratory, cardiovascular, or GI) with no more than 4 hours between ex-
posure and onset of symptoms that were treated or two or more organ sys-
tems with no more than 4 hours between exposure and onset (treated or
untreated), or at least 4 hours between exposure and onset that was treated.
They found an incidence rate of 10.5 anaphylaxis episodes per 100,000
person–years. After further review of a sample of other allergy diagnoses
(ICD-9 codes 708.0, 708.9, 995.1, 995.3, and 695.1), Bohlke and colleagues
estimated that the true incidence is likely closer to 68.4 cases per 100,000
person–years.
Helbing and colleagues [16] assessed the incidence of anaphylaxis with
circulatory symptoms during a 3-year period in Swiss Canton Bern. All
medical records were reviewed from the two allergy clinics. In addition,
seven board-certified allergists in the Foederatio Medicorum Helveticorum
and all 17 EDs in the area were contacted to identify cases of anaphylaxis
not referred to the two allergy units. During the 3-year study period, 226 in-
dividuals contributed 246 episodes of severe life-threatening anaphylaxis
with cardiovascular symptoms, yielding an incidence of 7.9 to 9.6 per
100,000 inhabitants per year. Death caused by anaphylaxis occurred in three
individuals, resulting in a case fatality rate of 0.0001%.
A recent study by the authors’ research team evaluated the rate of pre-
scriptions for EpiPen and EpiPen Jr. in the United States [17]. During
2004 there were 1,511,534 EpiPen prescriptions, averaging 5.71 EpiPens pre-
scribed per 1000 persons. In addition to state-by-state variation in the rate
of EpiPen prescriptions, a marked north–south gradient was observed
(Fig. 1). This strong regional variation within the United States may provide
insight into the causes of anaphylaxis and merits further study.
In summary, estimates from studies of all-cause reactions in the general
population are wide ranging. Varying populations, different methods of
identification of cases, and diverse classifications of anaphylaxis contribute
to the divergent estimates. Novel approaches to identifying study samples
that are representative of the general population, such as assessing prescrip-
tions for self-injectable epinephrine [14,15], and using a more consistent def-
inition of anaphylaxis would help to quantify the burden of anaphylaxis.
Food-induced reactions
Food-induced anaphylaxis occurs across all age groups but is of particular
concern in children [18]. Food allergies are thought to affect approximately
2% of the United States population [18], resulting in nearly 100 deaths
each year [19]. Many recent studies have looked at food-induced anaphylaxis
attributable to any food, and several have looked at specific food allergens.
Any foods
MacDougall and colleagues [20] performed a retrospective study among
children age 0 to 15 years to assess the incidence of fatalities caused by food
150 CLARK & CAMARGO
Fig. 1. Regional differences in EpiPen prescriptions per 1000 persons. (Data from Camargo CA
Jr, Clark S, Kaplan MS, et al. Regional differences in EpiPen prescriptions in the United States
[abstract]. J Allergy Clin Immunol 2006;117(2):S139.)
reactions in the United Kingdom and Ireland between 1990 and February
1998. Cases were identified by multiple means, including pediatrician report-
ing and searching the British Paediatric Surveillance Unit for deaths caused
by food-induced anaphylaxis. ICD-9 codes 995.0, 995.3, 988, E865, and
693.1 were used to identify cases. During the study period, eight children
died from a food-induced reaction (0.006 deaths per 100,000 children 0 to
15 years). During a 2-year prospective arm with similar case identification
methods, six (0.02 per 100,000 children) near-fatal reactions and 49 (0.19
per 100,000 children) severe reactions were identified. The authors con-
cluded that if 5% of the child population had food allergy, they would ex-
pect fatal reactions at a rate of 1 per 800,000 per year.
In 2002, Moneret-Vautrin and colleagues [21] reported preliminary re-
sults from the introduction of the French Allergy Vigilance Network. Iden-
tified by the 100 members participating in the network, 163 cases of severe
anaphylaxis were reported to the network. Forty-six percent of cases were
among children. Looking only at the cases reported by the 91 French par-
ticipants, the authors extrapolated their results to the general population
in France. With 91 participating allergists and approximately 800 to 1500
allergists in France, they estimated that there would be approximately
15,000 to 30,000 severe allergic reactions each year in France.
In a subsequent publication, Moneret-Vautrin and colleagues [22] re-
ported that 107 cases of anaphylaxis caused by food were identified in
2002 through the French Allergy Vigilance Network. Among these 107 cases
identified by 302 allergists who subscribed to the French Allergy Vigilance
Network and reported all cases of severe anaphylaxis they treated, 84

(59.8%) were considered anaphylactic shock.
Peanuts/tree nuts
Peanuts and tree nuts are a common cause of food-induced allergic reac-
tions and anaphylaxis. Tariq and colleagues [23] performed a 4-year pro-
spective study of children age 4 or younger to assess peanut and tree nut
sensitization. Mothers were enrolled before the birth of the child. Children
underwent routine skin prick tests, and mothers were interviewed when the
child was 4 years old to assess the occurrence of anaphylactic reactions. Skin
prick tests were performed in 981 (80.5%) of the 1218 enrolled children. The
cumulative prevalence of nut allergy was 1.2%. Maternal report revealed
that three children (0.25%) experienced an anaphylactic reaction because
of peanuts or tree nuts.
Sicherer and colleagues [18] determined the prevalence of peanut and tree
nut allergy in the United States by random-digit dial. Among 7036 house-
holds contacted, 4374 (67%) agreed to participate in this survey, resulting
in the inclusion of allergy history information for 12,032 individuals. In
151 households, 164 individuals were peanut or tree nut allergic. Correcting
for allergies that could not be confirmed, a prevalence of 1.1% was esti-
mated by the authors. Among these individuals, 68 reported involvement
of two or more organ systems, yielding a prevalence of anaphylaxis to pea-
nuts or tree nuts of approximately 0.57% (calculated).
In 2003 Sicherer and colleagues [24] reported on a 5-year follow-up study
to re-evaluate the prevalence of peanut and tree nut allergy. United States
households again were contacted for participation using random-digit
dial. Adjusting for reported reactions that could not be verified, the preva-
lence of peanut and tree nut allergy in the United States in 2002 was 1.04%.
Individuals reporting a reaction involving two or more organ systems allows
for an estimation of a prevalence of 0.95% for peanut or tree nut-induced
anaphylaxis (calculated).
Emmett and colleagues [25] performed a two-stage study to assess the
prevalence of peanut allergy in the general population in England. In the
first stage 2000 households participated in in-person interviews between No-
vember 1995 and January 1996. Stage two involved more in-depth inter-
views with all individuals who reported peanut allergy. During stage 1,
16,434 individuals were interviewed. Anaphylactic shock was defined as
breathing difficulty, wheezing, blue round lips, and fainting/loss of con-
sciousness. Anaphylactic shock was reported by 43 of the 124 individuals
who had confirmed peanut allergy or 0.2% of the total population in
England.
Seafood
Sicherer and colleagues [26] also performed a random-digit dial survey to
estimate the prevalence of seafood allergy in the United States. Among 5529
152 CLARK & CAMARGO
participating households (67.3%), representing a total of 14,948 individuals,

fish or seafood allergy was reported 2.3% of individuals. Although details
were not provided to allow for an estimate of the prevalence of anaphylaxis
based on self-report or symptoms, 0.4% (16% of 336 with seafood allergy)
of individuals received epinephrine for an allergic reaction.
In summary, food-induced anaphylaxis estimates vary by study. As with
studies looking at all cause anaphylaxis, studies looking specifically at the
epidemiology of food-induced anaphylaxis report varying estimates of the
burden of disease. Anaphylactic reactions caused by food have been identi-
fied by physician reports, parental reports, and ICD-9 codes with varying
classifications for an anaphylactic reaction. Although one cannot expect
that different groups will adopt one common approach to the diagnosis of
anaphylaxis, future work could incorporate the NIAID/FAAN clinical cri-
teria in addition to whatever approach is used to classify study outcomes. If
all studies included the same extra outcome that would greatly facilitate
comparison across studies.
Insect sting-induced reactions

Insect stings also are a common cause of anaphylaxis around the world.
Although Hymenoptera stings are common in many places, ant stings are
common in certain geographic areas. Valentine [27] estimated that anaphy-
laxis caused by insect stings occurs in 0.5% to 5% of the population.
In 1971 Abrishami and colleagues [28] reported on a survey of girl scouts
to assess the occurrence of Hymenoptera allergy. Health cards of girl scouts
aged 7 to 16 years were reviewed. All cards suggesting a possible bee sting
allergy were collected, and parents were sent a questionnaire to obtain
more information about the possible allergy. Anaphylaxis to Hymenoptera
was classified as any reaction resulting in nausea, vomiting, perspiration, or
a shock-like state (the latter only occurred in one child). Among 2010 girl
scouts, the prevalence of Hymenoptera allergy was 0.35%. Only one case
of anaphylaxis was identified, yielding a prevalence of 0.05%. These results
are similar to results reported in a similar study by Settinpane and col-
leagues [29] in 1970. Using similar methods as those employed by Abrish-
ami, but evaluating the health cards of boy scouts, they observed
a prevalence of Hymenoptera allergy of 0.8%, although they did not differ-
entiate anaphylactic reactions in this study.
Kalyoncu and colleagues [30] surveyed cellulose paper factory workers
and their families in Turkey to investigate the status of bee and wasp sting
allergy in the region. The cumulative lifetime sting rate in this population
was 94.5%. Severe reactions were those reactions that were potentially
life-threatening, possibly including cutaneous symptoms in addition to la-
ryngeal, and/or respiratory, and/or cardiovascular symptoms, affecting
2.2% of the populations.
Incorvaia and colleagues [31] surveyed factory workers and foresters in

northern Italy to assess the prevalence of allergic reactions to Hymenoptera.
All participants were asked about their lifetime history of systemic reactions,
which were subdivided further into non-life-threatening (skin and gastroin-
testinal signs and symptoms) and life-threatening (respiratory and cardio-
vascular signs and symptoms) reactions. Among 462 factory workers, 13
(2.8%) reported systemic reactions. Ten reactions were non-life-threatening,
and three (0.6%) were life-threatening. Foresters, considered a high-risk
group, reported 5 (4.5%) systemic reactions out of 112 reactions; three
(2.7%) were non-life-threatening, and two (1.8%) were life-threatening.
In summary, studies evaluating insect sings often focus on systemic reac-
tions caused by insect stings, with many not distinguishing anaphylaxis from
less severe systemic reactions. Implementing the clinical criteria introduced
by the NIAID/FAAN symposia [3,4] would allow for comparisons across
studies and a clearer picture of the severity of insect sting-induced reactions.
Medication and vaccine-induced reactions

Drug- and vaccine-induced anaphylactic reactions are thought to be com-
mon. Although there are many studies describing anaphylactic reactions
caused by medications and vaccines in the hospital setting, this article dis-
cusses only reactions identified from outside of the hospital setting.
Bohlke and colleagues [32] identified cases of potentially vaccine-associ-
ated anaphylaxis among four HMOs in the western United States. Cases
were identified using ICD-9 codes 995.0, E948.0 through E948.9, and
E949.0 through E949.9. Only five cases of vaccine-associated anaphylaxis
were identified after administration of 7,644,049 vaccine doses, or 0.65 cases
per million doses. Cases were considered anaphylaxis if there was:
Involvement of one organ system (mucocutaneous, respiratory, cardio-
vascular, or GI) with no more than 4 hours between exposure and symp-
tom onset that required treatment or
Involvement of two or more organ systems with no more than 4 hours
between exposure and onset (treated or untreated), or at least 4 hours
between exposure and onset that required treatment
Kelso and colleagues [33] assessed anaphylaxis caused by yellow fever
vaccine using the Vaccine Adverse Event Reporting System between 1990
and 1997. Of 243 reports, 40 were classified as probable or possible anaphy-
laxis. These 40 cases would yield a yellow fever vaccine-related anaphylaxis
rate of 40 in 5,236,820 or 1 in 131,000 vaccinations. Probable reactions were
those occurring within 4 hours of vaccination and including dermatologic
signs and symptoms and respiratory signs and symptoms. Possible reactions
included dermatologic or respiratory signs and symptoms (not both) or der-
matologic and/or respiratory signs and symptoms more than 4 hours after
vaccine.
154 CLARK & CAMARGO
Lenler-Petersen and colleagues [34] performed a retrospective study to

determine drug-related fatal anaphylactic shock in Denmark between 1968
and 1990. Reviewing the Danish Committee on Adverse Drug Reactions
and the Central Death Register, the authors identified 30 cases of drug-
induced fatal anaphylactic shock. They concluded that drug-induced fatal
anaphylactic shock is rare, accounting for 0.3 cases per million inhabitants
per year. They noted that review of the Committee on Adverse Drug Reac-
tions reports produced 1252 diagnoses of anaphylactic shock, anaphylactic
reaction, and allergic reaction. This would yield approximately 11.2 (calcu-
lated) cases of anaphylactic shock, anaphylactic reaction, or allergic reaction
per 1 million inhabitants per year. Although the authors suspected that these
results were underestimates of the true burden of drug-induced anaphylaxis
and fatal anaphylactic shock, they noted that had they used only the cause
of death to identify cases, they would have underestimated the burden of
disease severely.
Sakaguchi and colleagues [35] estimated the minimum incidence of ana-
phylaxis to live virus vaccines including gelatin in Japan during April
1994 to March 1997. The authors identified cases of anaphylaxis caused
by the following vaccinations (all per 1 million doses containing gelatin):
measles (6.84), rubella (7.31), mumps (4.36), and varicella (10.3). These re-
sults were similar to those observed by another Japanese study, where there
were 11.9 cases of anaphylaxis per 1 million doses of measles vaccine, 6.52
cases for rubella, and 18.5 cases for mumps [36]. A United States study as-
sessing anaphylaxis caused by the measles, mumps, rubella vaccine, how-
ever, showed only 0.5 cases per million doses [37].
Van der Klauw and colleagues [38] reported the results of a 20-year ret-
rospective study between 1974 and 1994 based on all reports of anaphy-
laxis through the voluntary reporting system of the Drug Safety Unit
(DSU) of the Dutch Inspectorate for Health Case. All reports of anaphy-
laxis, anaphylactic shock or reaction, anaphylactoid shock or reaction, al-
lergic reaction, facial edema, or peri-orbital or eyelid edema, made through
the DSU voluntary drug safety reporting system were included. Reports
then were classified according to degree of probability of anaphylaxis.
Probable anaphylaxis was considered a reaction that involved two or
more systems (cardiovascular, respiratory, skin/conjunctiva, and GI)
with a known temporal relationship (eg, symptoms occur within 1 hour
of causative agent). Possible anaphylaxis involved two or more systems
but with an unknown temporal relationship or only one system involved
but temporal relationship known. Among the 936 reports that were able
to be classified, 345 were considered probable anaphylaxis, and 485 were
possible anaphylaxis. The Dutch population during the study period was
approximately 13,000,000 to 15,000,000, resulting in a frequency of ap-
proximately 0.01% (calculated based on information presented by au-
thors). Because of the voluntary nature of this registry and pervious
work showing a low proportion of cases actually are reported, the authors
concede that these results are gross underestimates of the burden of drug-
induced anaphylaxis in the Netherlands.
In summary, many countries have implemented registries to try to quan-
tify the magnitude drug- or vaccine-induced anaphylaxis. Many of the reg-
istries are voluntary, leading to underestimations of the number of reactions
in a given population. Reactions to drugs and vaccines not only differ be-
cause of classifications used to identify anaphylaxis, but also by type of
drug or vaccine.
Emergency medical services

Although many cases of anaphylaxis undoubtedly are seen by prehospital
personnel, surprisingly few studies have examined the epidemiology of ana-
phylaxis in this setting. In 2004 Kane and Cone [39] reported data on emer-
gency medical services (EMS) runs for acute allergic reactions and
anaphylaxis across the United States. Among nine EMS system databases,
there were more than 2.8 million runs. Among these runs between 0.34%
and 0.82% were for allergic reactions or anaphylaxis. Data on deaths caused
by anaphylaxis were inconsistent across the EMS systems, ranging from 0%
to 0.94%. A limitation of this study is that case definitions for anaphylaxis
varied across the nine EMS systems.
Emergency department visits

A recent population-based study suggests that 71% of anaphylactic reac-
tions are treated in the ED [6]. Although occasional studies over the past 15
years have assessed the occurrence of anaphylaxis presenting to the ED, the
topic is a recent focus of increased investigation. Unfortunately, and as was
the case in population-based studies, ED-based studies have yielded widely
varying estimates of the epidemiology of anaphylaxis.
In 1992, Bock [40] surveyed 73 Colorado EDs over a 2-year period to
identify severe allergic reactions caused by food. In these 73 EDs, 25 severe
food reactions were reported. Bock extrapolated these results to estimate
a minimum of 950 severe reactions caused by food in the United States dur-
ing a 1-year period.
Klein and Yocum [7] reported an incidence of anaphylaxis of 0.09% over
a 4-month period in a single ED in rural Minnesota. Cases were classified as
anaphylaxis if the patient had acute mucocutaneous signs and involvement
of another organ system. The authors note that the occurrence of anaphy-
laxis is relatively uncommon, but caution methodology using ICD-9 codes
to identify cases, because most of the cases identified for inclusion in this
study would have been missed if cases were identified by ICD-9 code.
In 1996, Stewart and Ewan [41] reported the results of their retrospective
study. Among 55,000 visits, 24 (0.4%) were for generalized allergic
156 CLARK & CAMARGO
reactions, and nine (0.16%) were for severe reaction. The authors suggest
that the results obtained in this study are likely underestimates of the true
disease occurrence. Coding used in their hospital, as in most, is likely to
miss cases of anaphylaxis.
Sheikh and Alves [42] identified cases of anaphylaxis treated in the ED in
England. Cases were identified through the National Health Services (NHS)
hospitals. Among 13.5 million ED visits, there were 2323 visits for anaphy-
laxis, for an average of 17 cases of anaphylaxis per 100,000 ED visits in
London between 1991 and 1995.
Brown and colleagues [43] evaluated 142 patients treated for anaphylaxis
in an Australian ED over a 1-year period. These 142 visits accounted for
0.2% of all ED visits. The ED serves a local population of 485,000. If the
ED sees all ED visits for anaphylaxis, these 142 cases of anaphylaxis would
account for a population estimate of 0.029%.
Pastorello and colleagues [44] evaluated the incidence of anaphylaxis in
a Milan, Italy ED. During a 2-year period there were 140 (0.4%) ED visits
for anaphylaxis, classified as multisystem organ involvement. Among these
140 cases, 13 were classified as severe anaphylaxis.
Bellou and colleagues [45] performed a retrospective study during 1998 in
a university hospital in the French Lorraine region. Among 32,400 ED visits
during 1 year, 324 (1%) patients were treated in the ED for allergic reac-
tions, and 12 (0.037%) were treated for anaphylactic shock.
Smit and colleagues [46] identified 282 cases of anaphylaxis during a
6-year period in Hong Kong, resulting in 4.41 cases per 100,000 ED visits
per year. Patients were identified through the resuscitation room log book
that is populated by experienced resuscitation room nurses. Cases were in-
cluded with various allergic disease complaints. The estimate of 4.41 cases
per 100,000 ED visits is based on patients who had involvement of more
than one organ system.
More recently, Braganza and colleagues [47] reported an incidence of 9.3
per 1000 ED visits for generalized acute allergic reactions and 1 per 1000 ED
visits for anaphylaxis. A recent study by the authors’ group showed that
there were 12.4 million allergy-related ED visits between 1993 and 2004,
representing 1% of all ED visits, or 1.03 million ED visits per year [48].
In addition, two studies by the Emergency Medicine Network (www.emnet-
usa.org) evaluated the management of food-induced and insect sting-
induced acute allergic reactions and found that 51% of food allergy patients
treated in the ED and 31% insect sting patients were classified as having
anaphylaxis by using the multisystem organ involvement definition [49,50].
In summary, ED-based studies of anaphylaxis rely on ICD-9 codes and
physician designation of anaphylaxis. The diagnosis of anaphylaxis is often
inconsistent and does not follow a standardized approach to classifying ana-
phylactic reactions. Many studies have concluded that although the occur-
rence of anaphylaxis represents a small proportion of all ED visits, these
estimates are considerably underestimated because of the difficulty in
accurately identifying reactions. Applying the NIAID/FAAN clinical crite-

ria to ED patients with suspected allergic reactions or anaphylaxis [3,4]
would allow for greater insight into the number of anaphylactic reactions
treated in the ED setting.
Hospital admissions
Many population-based studies also have attempted to assess the epidemi-
ology of anaphylaxis by reviewing hospital admissions for anaphylaxis in cer-
tain hospital catchment areas. For example, Sorensen and colleagues [8]
reported a retrospective study in 1989 that identified all cases of anaphylactic
shock occurring in a hospital catchment area between January 1973 and De-
cember 1985. Cases were considered for inclusion with a discharge diagnosis
of collapsus anaphylacticus, allergic and toxic reactions, adverse reactions to
drugs, and shock not caused by cardiovascular disease or trauma. Twenty pa-
tients were included in the study and were identified from a relatively constant
population of approximately 48,500 residents, with one death occurring be-
fore arrival to the hospital. The investigators estimated an incidence of 3.2
per 100,000 inhabitants and a mortality rate of 5 per 100 cases.
In 2000, Sheikh and Alves [10] reported trends in hospital admission for
acute anaphylaxis between 1991 and 1992 and 1994 and 1995 in England.
Patients were identified by ICD-9 code for anaphylactic shock (995.0) or
anaphylactic shock caused by serum (999.4). During this 4-year study, there
were 2424 hospital discharges with a primary code for anaphylaxis among
32.4 million hospital discharges or 7.48 per 100,000. The authors observed
an increase in anaphylactic hospitalizations rising from 5.6 per 100,000 from
1991 to 1992 to 10.2 per 100,000 in 1994.
Wilson [51] reported a retrospective study during 1998 and 1999 to con-
tribute as an update to the report by Sheikh and Alves. Wilson included all
hospital admissions with a primary admission diagnosis of anaphylaxis as
identified by ICD-10 code (T78.0, T78.2, T80.5, T88.6). Cases were included
regardless of exposure. Overall, he observed 1202 hospital admissions for
anaphylaxis (11.05 per 100,000). Wilson concluded that these results further
strengthen the need for more detailed research into the increasing trends in
anaphylaxis and into long-term outcomes.
More recently, Peng and Jick [52] estimated the incidence of anaphylaxis
in the United Kingdom using the General Practice Research Database
(GPRD), a database of more than 4 million registrants the United King-
dom. Hospital admissions were recorded, allowing for assessment of the fre-
quency of anaphylaxis in England, which typically results in a hospital visit.
Among approximately 8 million person–years in the GPRD between Janu-
ary 1994 and December 1999, 675 cases of anaphylaxis were identified. The
authors estimated the incidence to be 8.4 per 100,000 person–years. Peng
and Jick caution that the observed results still may underestimate the true
158 CLARK & CAMARGO
burden of anaphylaxis. If cases of anaphylaxis occurring in the hospital set-

ting are not recorded by participating practitioners in the GPRD, these
cases will be missed, leading to an underestimate of the burden of the inci-
dence of anaphylaxis.
Also in 2004, Gupta and colleagues [53] preformed a retrospective, na-
tion-wide survey and identified 1964 hospital admissions for anaphylaxis
with 3.8 hospital admissions for anaphylactic shock among 100,000 admis-
sions. Only one death caused by anaphylaxis was identified from 1990 to
2000; however, on further review, 12 deaths had some mention of anaphy-
laxis as a contributing cause of death between 1991 and 1995. Although the
investigators observed an increase in allergic reactions as a whole, anaphy-
laxis, and food-induced allergic reactions had the most notable increases in
incidence during the duration of the study.
In summary, studies of hospitalizations for anaphylaxis vary for several
reasons. Many studies identify cases based on ICD-9 code, but they often
use different codes to identify cases for study inclusion (Table 1). Addition-
ally, some studies report their results based on the number of anaphylaxis
cases per inhabitant, and others report cases based on the number of hospi-
tal admissions. The use of simple clinical criteria (see Box 1) for classifying
anaphylaxis resulting in hospital admission is particularly attractive,
Table 1
Codes used by studies reporting case identification by International Classification of Disease-9
codes
Study ICD-9 codes used to identify cases
Population-based studies
All-cause reactions
Bohlke (2004) [6] Anaphylaxis: 995.0, 995.4, 995.6, 999.4
Other allergy: 695.1, 708.0, 708.9, 995.1, 995.3
Food-induced reactions
Macdougall (2002) [20] 693.1, 995.0, 995.3, 988, E865
Medication and vaccine-induced reactions
Bohlke (2003) [32] 995.0, E948.0–E948.9, E949.0–E949.9
Emergency department visits
Sheikh and Alves (2001) [42] 999.4, 999.5
Braganza (2006) [47] Cases identified cases by ICD-9 codes for allergy,
allergic (reaction), anaphylactic shock,
angioedema, and urticaria, but specific codes not
reported
Clark (2004) [49] 693.1, 995.0, 995.3, 995.60–995.69
Clark (2005) [50] 989.5, 995.0, 995.3
Clark (2006) [48] 995.0, 995.1, 995.2, 995.3, 995.6
Hospital admissions
Sheikh and Alves (2000) [10] 999.4, 999.5
Wilson (2000) [51]a T78.0, T78.2, T80.5, T88.6
Gupta (2004) [53] Some cases identified by ICD-9 code, but specific
codes not reported
a
ICD-10 codes used.
because this setting allows for detailed collection of events surrounding the
reaction and timing of the exposure and subsequent signs and symptoms.
Discussion
Studies on the occurrence of anaphylaxis occurring outside of the hospi-
tal inpatient setting suffer from varying methodologies and varying means of
identifying and classifying cases of anaphylaxis. The divergent estimates of
the occurrence of anaphylaxis likely are caused in part by these methodolog-
ical differences. In addition, studies have been performed in numerous dif-
ferent geographic locations. Because of the differences in allergen exposure
in these locations, estimates may be expected to differ from one place to
another. In addition, many of the epidemiologic studies of anaphylaxis in-
clude small sample sizes that then are extrapolated, with the expected impreci-
sion, to produce national statistics [5].
Identifying cases of anaphylaxis in the general population can be chal-
lenging for numerous reasons. It may be difficult to obtain a sample of
a population that is representative of the larger population, so generalizing
results may be difficult. Moreover, a sample that is representative of a larger
local population may not be representative of people in different geographic
locations. Collectively, epidemiologic research could be much more consis-
tent in terms of methodology and case definition, but data still would need
to be collected from varying parts of the world to allow a true understanding
of the burden of anaphylaxis at local, national, and international levels.
Studies identifying cases of anaphylaxis based on hospital admission or
ED visits may be at particular risk of underestimating the occurrence of ana-
phylaxis. These studies rest on an assumption that all cases of anaphylaxis
present to the ED or require hospital admission and thus are included for
evaluation. If cases occurring outside of the hospital do not present for med-
ical attention, they will be lost to the study investigators. Although admission
rates have varied across studies, ranging from 3% to 41% [7,43,45–
47,49,50], studies by the authors’ group have found that more than 95%
of patients were discharged to home [48–50]. Thus, studies identifying
cases based on hospital admission only (ie, inpatients only) will miss the
vast majority of anaphylaxis cases. Likewise, fatal reactions that occur
in the community setting may not be brought to the ED or hospital. Re-
quiring that deaths caused by anaphylaxis be reported to state depart-
ments of health may be one way to gain greater understanding of
fatalities caused by anaphylaxis.
The study of anaphylaxis in the ED has been complicated for several rea-
sons. First, the definition has been highly variable, as a useful clinical defi-
nition was lacking until recently [3,4]. Clinicians can fail to differentiate
between the singular presence of mucocutaneous signs and the additional
occurrence of cardiovascular and respiratory symptoms, as in anaphylaxis.
Similarly, when symptoms do not appear life-threatening, physicians are
160 CLARK & CAMARGO
more likely to categorize even multisystem complaints as either acute aller-

gic reaction or urticaria.
In addition, the classification of anaphylaxis has evolved over the years.
New codes to describe fatal anaphylactic reactions including ‘‘anaphylactic
shock due to adverse food reaction’’ and ‘‘anaphylactic shock, unspecified’’
were developed in 2003 [3,4]. Research, however, has indicated that these co-
des are widely underused [3,4] and also has suggested that ICD codes might
be limited in their ability to identify specific allergic reactions in the ED [54].
Furthermore, newly introduced allergen-specific codes (such as those cate-
gorizing food allergies) do not account for other patient characteristics,
such as the complexity or severity of the reaction.
There is another limitation to using the ICD-9 and ICD-10 coding sys-
tems to identify cases of anaphylaxis, due to specified or unspecified causes,
as anaphylactic shock (eg, ICD-9 code 995.6 indicates anaphylactic shock
due to food). It is not realistic to expect physicians (or health statistics) to
code anaphylactic reactions defined as multisystem organ involvement,
but not shock, with codes specifically including shock. As a better under-
standing of anaphylaxis is gained, and clinical criteria develop to include
multisystem organ involvement, the coding systems used to record and iden-
tify these reactions also need to change.
Research on these recently identified criteria is encouraged. Symptom-
based approaches to identifying anaphylaxis have been useful for research
purposes, and are likely to be useful for clinical management. Newly devel-
oped clinical criteria for anaphylaxis are expected to be useful for both re-
search purposes and clinical management, but they have not been tested
rigorously against expert judgment. As recommended by the NIAID/
FAAN symposium, research efforts focused on evaluating the usefulness
of these criteria are greatly needed [4].
In summary, greater use of a consistent simple definition for anaphylaxis,
such as the symptom-based approach advocated by the authors’ group [48–
50] and others [3,4,6,7,12,32,44] would help to simplify research on the ep-
idemiology of anaphylaxis. This would allow comparisons across diverse
study designs and studies and across diverse geographic locations. The com-
pilation of such data would all epidemiologists and other population-based
researchers to better define the epidemiology of this serious, and potentially
fatal, allergic reaction.
References
[1] Portier P, Richet C. De l’action anaphylactique de certains venins. Soc Biol (Paris) 1902;54:
170–2.
[2] Cohen SG, Zelaya-Quesada M. Portier, Richet, and the discovery of anaphylaxis: a centen-
nial. J Allergy Clin Immunol 2002;110(2):331–6.
[3] Sampson HA, Munoz-Furlong A, Bock SA, et al. Symposium on the definition and manage-
ment of anaphylaxis: summary report. J Allergy Clin Immunol 2005;115(3):584–91.
[4] Sampson HA, Munoz-Furlong A, Campbell RL, 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. [reprint in Ann
Emerg Med. 2006 Apr;47(4):373–80]. J Allergy Clin Immunol 2006;117(2):391–7.
[5] Neugut AI, Ghatak AT, Miller RL. Anaphylaxis in the United States: an investigation into
its epidemiology. Arch Intern Med 2001;161(1):15–21.
[6] Bohlke K, Davis RL, DeStefano F, et al. Epidemiology of anaphylaxis among children and
adolescents enrolled in a health maintenance organization. J Allergy Clin Immunol 2004;
113(3):536–42.
[7] Klein JS, Yocum MW. Underreporting of anaphylaxis in a community emergency room.
J Allergy Clin Immunol 1995;95(2):637–8.
[8] Sorensen HT, Nielsen B, Ostergaard Nielsen J. Anaphylactic shock occurring outside hospi-
tals. Allergy 1989;44(4):288–90.
[9] Mullins RJ. Anaphylaxis: risk factors for recurrence. Clin Exp Allergy 2003;33(8):1033–40.
[10] Sheikh A, Alves B. Hospital admissions for acute anaphylaxis: time trend study. BMJ 2000;
320(7247):1441.
[11] Lieberman P, Camargo CA Jr, Bohlke K, et al. Epidemiology of anaphylaxis: findings of the
ACAAI epidemiology of anaphylaxis working group. Ann Allergy Asthma Immunol 2006;
97(5):596–602.
[12] Yocum MW, Butterfield JH, Klein JS, et al. Epidemiology of anaphylaxis in Olmsted
county: a population-based study. J Allergy Clin Immunol 1999;104(2 Pt 1):452–6.
[13] Boros CA, Kay D, Gold MS. Parent-reported allergy and anaphylaxis in 4173 South Aus-
tralian children. J Paediatr Child Health 2000;36(1):36–40.
[14] Simons FE, Peterson S, Black CD. Epinephrine dispensing for the out-of-hospital treatment
of anaphylaxis in infants and children: a population-based study. Ann Allergy Asthma Im-
munol 2001;86(6):622–6.
[15] Simons FER, Peterson S, Black CD. Epinephrine dispensing patterns for an out-of-hospital
population: a novel approach to studying the epidemiology of anaphylaxis. J Allergy Clin
Immunol 2002;110(4):647–51.
[16] Helbling A, Hurni T, Mueller UR, et al. Incidence of anaphylaxis with circulatory symp-
toms: a study over a 3-year period comprising 940,000 inhabitants of the Swiss Canton
Bern. Clin Exp Allergy 2004;34(2):285–90.
[17] Camargo CA Jr, Clark S, Kaplan MS, et al. Regional differences in EpiPen prescriptions in
the United States. J Allergy Clin Immunol 2007, in press.
[18] Sicherer SH, Munoz-Furlong A, Burks AW, et al. Prevalence of peanut and tree nut allergy
in the US determined by a random-digit dial telephone survey. J Allergy Clin Immunol 1999;
103(4):559–62.
[19] Sampson HA, Metcalfe DD. Food allergies. JAMA 1992;268(20):2840–4.
[20] Macdougall CF, Cant AJ, Colver AF. How dangerous is food allergy in childhood? The in-
cidence of severe and fatal allergic reactions across the UK and Ireland. Arch Dis Child 2002;
86(4):236–9.
[21] Moneret-Vautrin DA, Kanny G, Parisot L. First survey from the Allergy Vigilance Net-
work: life-threatening food allergies in France. Allerg Immunol (Paris) 2002;34(6):194–8.
[22] Moneret-Vautrin DA, Kanny G, Morisset M, et al. Severe food anaphylaxis: 107 cases reg-
istered in 2002 by the Allergy Vigilance Network. Allerg Immunol (Paris) 2004;36(2):46–51.
[23] Tariq SM, Stevens M, Matthews S, et al. Cohort study of peanut and tree nut sensitisation by
age of 4 years. BMJ 1996;313(7056):514–7.
[24] Sicherer SH, Munoz-Furlong A, Sampson HA. Prevalence of peanut and tree nut allergy in
the United States determined by means of a random-digit dial telephone survey: a 5-year fol-
low-up study. J Allergy Clin Immunol 2003;112(6):1203–7.
[25] Emmett SE, Angus FJ, Fry JS, et al. Perceived prevalence of peanut allergy in Great Britain
and its association with other atopic conditions and with peanut allergy in other household
members. Allergy 1999;54(4):380–5.
162 CLARK & CAMARGO
[26] Sicherer SH, Munoz-Furlong A, Sampson HA. Prevalence of seafood allergy in the United
States determined by a random telephone survey. J Allergy Clin Immunol 2004;114(1):
159–65.
[27] Valentine MD. Anaphylaxis and stinging insect hypersensitivity. JAMA 1992;268(20):
2830–3.
[28] Abrishami MA, Boyd GK, Settipane GA. Prevalence of bee sting allergy in 2010 girl scouts.
Acta Allergol 1971;26(2):117–20.
[29] Settipane GA, Boyd GK. Prevalence of bee sting allergy in 4992 boy scouts. Acta Allergol
1970;25:286.
[30] Kalyoncu AF, Demir AU, Ozcan U, et al. Bee and wasp venom allergy in Turkey. Ann
Allergy Asthma Immunol 1997;78(4):408–12.
[31] Incorvaia C, Senna G, Mauro M, et al. Prevalence of allergic reactions to Hymenoptera
stings in northern Italy. Allerg Immunol (Paris) 2004;36(10):372–4.
[32] Bohlke K, Davis RL, Marcy SM, et al. Risk of anaphylaxis after vaccination of children and
adolescents. Pediatrics 2003;112(4):815–20.
[33] Kelso JM, Mootrey GT, Tsai TF. Anaphylaxis from yellow fever vaccine. J Allergy Clin Im-
munol 1999;103(4):698–701.
[34] Lenler-Petersen P, Hansen D, Andersen M, et al. Drug-related fatal anaphylactic shock in
Denmark 1968–1990. A study based on notifications to the Committee on Adverse Drug Re-
actions. J Clin Epidemiol 1995;48(9):1185–8.
[35] Sakaguchi M, Nakayama T, Fujita H, et al. Minimum estimated incidence in Ja-
pan of anaphylaxis to live virus vaccines including gelatin. Vaccine 2000;19(4–5):
431–6.
[36] Nakayama T, Aizawa C, Kuno-Sakai H. A clinical analysis of gelatin allergy and determi-
nation of its causal relationship to the previous administration of gelatin-containing acellular
pertussis vaccine combined with diphtheria and tetanus toxoids. J Allergy Clin Immunol
2001;103(2 Pt 1):321–5.
[37] Businco L. Measles, mumps, rubella immunization in egg-allergic children: a long-lasting de-
bate. Ann Allergy 1994;72(1):25–8.
[38] van der Klauw MM, Wilson JH, Stricker BH. Drug-associated anaphylaxis: 20 years of re-
porting in The Netherlands (1974–1994) and review of the literature. Clin Exp Allergy 1996;
26(12):1355–63.
[39] Kane KE, Cone DC. Anaphylaxis in the prehospital setting. J Emerg Med 2004;27(4):371–7.
[40] Bock SA. The incidence of severe adverse reactions to food in Colorado. J Allergy Clin Im-
munol 1992;90(4 Pt 1):683–5.
[41] Stewart AG, Ewan PW. The incidence, aetiology and management of anaphylaxis presenting
to an accident and emergency department. QJM 1996;89(11):859–64.
[42] Sheikh A, Alves B. Age, sex, geographical and socio–economic variations in admissions for
anaphylaxis: analysis of four years of English hospital data. Clin Exp Allergy 2001;31(10):
1571–6.
[43] Brown AF, McKinnon D, Chu K. Emergency department anaphylaxis: A review of 142 pa-
tients in a single year. J Allergy Clin Immunol 2001;108(5):861–6.
[44] Pastorello EA, Rivolta F, Bianchi M, et al. Incidence of anaphylaxis in the emergency de-
partment of a general hospital in Milan. J Chromatogr B Biomed Sci Appl 2001;756(1–2):
11–7.
[45] Bellou A, Manel J, Samman-Kaakaji H, et al. Spectrum of acute allergic diseases in an emer-
gency department: an evaluation of one year’s experience. Emerg Med (Fremantle) 2003;
15(4):341–7.
[46] Smit DV, Cameron PA, Rainer TH. Anaphylaxis presentations to an emergency department
in Hong Kong: incidence and predictors of biphasic reactions. J Emerg Med 2005;28(4):
381–8.
[47] Braganza SC, Acworth JP, McKinnon DRL, et al. Paediatric emergency department ana-
phylaxis: different patterns from adults. Arch Dis Child 2006;91(2):159–63.
[48] Clark S, Pelletier AJ, Gaeta TJ, et al. Management of acute allergic reactions and anaphy-
laxis in the emergency department between 1993–2003 [abstract]. J Allergy Clin Immunol
2006;117(2):S307.
[49] Clark S, Bock SA, Gaeta TJ, et al. Multicenter study of emergency department visits for food
allergies. J Allergy Clin Immunol 2004;113(2):347–52.
[50] Clark S, Long AA, Gaeta TJ, et al. Multicenter study of emergency department visits for in-
sect sting allergies. J Allergy Clin Immunol 2005;116(3):643–9.
[51] Wilson R. Upward trend in acute anaphylaxis continued in 1998–9. BMJ 2000;321(7267):
1021–2.
[52] Peng MM, Jick H. A population-based study of the incidence, cause, and severity of anaphy-
laxis in the United Kingdom. Arch Intern Med 2004;164(3):317–9.
[53] Gupta R, Sheikh A, Strachan DP, et al. Burden of allergic disease in the UK: secondary anal-
yses of national databases. Clin Exp Allergy 2004;34(4):520–6.
[54] Clark S, Gaeta TJ, Kamarthi GS, et al. ICD-9-CM coding of emergency department visits
for food and insect sting allergy. Ann Epidemiol 2006;16(9):696–700.
27 (2007) 165–175
The Pathophysiology of Shock

in Anaphylaxis
Simon G.A. Brown, MBBS, PhD, FACEM
Emergency Medicine Research Unit, The University of Western Australia
and Fremantle Hospital, Alma Street, Fremantle, WA 6160, Australia
In one large study of deaths due to anaphylaxis, circulatory shock was

a prominent clinical feature in 54% of cases (67 of 125 cases), the sole
mode of death in half of these; in the other half, it was combined with upper
and/or lower airway obstruction [1]. In the same study, shock was more of-
ten a feature in lethal iatrogenic and venom anaphylaxis (61 of 87 cases,
70%) than in lethal food anaphylaxis (5 of 37 cases, 14%).
This article examines the current understanding of the pathophysiology
of shock in anaphylaxis and discusses the implications of this knowledge
for clinicians and researchers.
Clinical manifestations
A brief overview of the physiological determinants of blood pressure is
provided in Box 1. Shock does not necessarily equate with hypotension,
but is defined broadly as a condition where blood flow to vital organs is in-
sufficient to meet the metabolic demands of the body. In some forms of
shock, compensatory mechanisms maintain blood pressure and thus cere-
bral function at normal or near-normal levels for a time despite peripheral
circulatory failure and progressively worsening metabolic acidosis. During
severe anaphylaxis there is usually a rapid onset of hypotension, neurolog-
ical compromise, and cardiac arrest (median time to cardiac arrest 5 to 15
minutes after reaction onset) [1]. In nonlethal cases, hypotension during
anaphylaxis is associated with nausea, vomiting, dyspnea, dizziness (presyn-
cope), diaphoresis, collapse, unconsciousness, and incontinence [2].
There are four broad types of shock: hypovolemic, cardiogenic, distribu-
tive, and obstructive [3]. It generally is considered that shock in human ana-
phylaxis may comprise variable components of hypovolemia because of
E-mail address: simon.brown@uwa.edu.au
166 BROWN
Box 1. Determinants of blood pressure and cardiac output

1: Blood Pressure ðBPÞfCardiac output ðCOÞ
Systemic Vascular Resistance ðSVRÞ
SVR is determined by the tone of the precapillary arterioles

(resistance vessels).
2: COfHeart Rate Stroke volume
Preload Contractility
3: Stroke Volumef
Afterload
Preload = myocardial fiber length before contraction

(= ventricular end diastolic volume), which depends upon
venous return; which in turn depends upon blood volume
and the tone of the veins (capacitance vessels)
Afterload = tension in the ventricular wall during contraction,
which depends upon SVR (to resistance vessels), the size of
the ventricle according to Laplace’s law, and other obstructions
to flow such as aortic valve obstruction
Contractility = the inherent ability of the heart to contract,
independent of preload and afterload
capillary fluid leak [4–6], distributive shock caused by vasodilation [4,7–9],

and cardiogenic shock caused by reduced contractility [10,11] and perhaps
inappropriate bradycardia [12]. Pulmonary vasospasm also may introduce
an obstructive component, by reducing left ventricular filling [13–16]. These
multiple effects, reducing the ability of the body to compensate, probably
explain the rapid onset of severe hypotension and unconsciousness that is
characteristic of anaphylaxis.
A close examination of the literature, however, reveals numerous incon-
sistencies and unanswered questions. Few studies adequately investigate car-
diovascular parameters to define the precise cause of hypotension.
Hypotension can be caused by reduced cardiac output and/or reduced sys-
temic vascular resistance. As outlined in Box 1, a fall in cardiac output can
be caused by any combination of reduced venous return to the chest, in-
creased pulmonary vascular resistance reducing venous return to the left
heart, myocardial depression caused by a direct effect of mediators and
myocardial ischemia. Myocardial ischaemia may be caused by reduced cor-
onary blood flow (and/or severe hypoxemia), and increased systemic vascu-
lar resistance causing increased afterload on the myocardium.
PATHOPHYSIOLOGY OF SHOCK IN ANAPHYLAXIS 167
Animal models and the concept of anaphylactic shock organs

In addition to interspecies variations, complicating factors in the inter-
pretation of animal models include the methods of initial sensitization (eg,
passive versus active, type of antigen) and subsequent exposure (ingested, in-
travenous, or subcutaneous), and whether the animal is awake or anaesthe-
tized with blunted reflex responses. Nevertheless, some valuable insights into
potential pathophysiological mechanisms in people can be obtained from
animal studies.
Early studies found organ system involvement to vary between animal
models, with the major organ involved being termed the shock organ for
that particular species [17]. In the guinea pig, intense bronchospasm leading
to hypoxia was considered the principal cause of death [17,18], leading to sec-
ondary cardiac ECG abnormalities comparable to those caused by asphyxia
[19]. In rabbits, severe vasoconstriction in the pulmonary arterial system ap-
peared to cause hypoxia and circulatory collapse, and again cardiac ECG ab-
normalities were considered to be secondary to asphyxia [19]. In dogs, severe
hepatic congestion was considered the major cause of lethal shock.
Subsequently the manifestations of guinea pig anaphylaxis have been
shown to include, in addition to intense bronchospasm, progressive impair-
ment of atrioventricular conduction leading to complete block, increased
ventricular automaticity (including ventricular fibrillation) and cardiac con-
tractile failure in both intact whole-animal and isolated-heart models, indi-
cating that these occur independent of hypoxia [20,21]. Reduced coronary
blood flow caused by increased coronary vascular resistance also has been
demonstrated [22].
In a canine ragweed model of anaphylactic shock, increased pulmonary
vascular resistance and increased systemic vascular resistance have been
demonstrated, along with reduced venous return and reduced cardiac out-
put [14,23–25]; however in one recent study by the same group using the
same model, systemic vascular resistance appeared to fall in some dogs [26].
Increased pulmonary vascular resistance also has been demonstrated in
a monkey model [16], and in some monkeys, cardiovascular collapse can
be attributed to decreased venous return and pulmonary hypertension,
whereas in others, the decrease in cardiac output is more severe and seems
to be associated with reduced myocardial contractility [15].
Human cardiovascular collapse

Arguably the most important human study to date is a series of 205 episodes
of anaphylactic shock occurring under anesthesia, where the treating anesthe-
siologist was asked to provide detailed clinical and laboratory information im-
mediately after the event [5,6]. In this study, extravasation of up to 35% of
circulating blood volume within 10 minutes was evident by increases in hemat-
ocrit. Additionally, in 46 patients who had central and/or pulmonary artery
168 BROWN
placed before or soon after the onset of anaphylaxis, there was a significant fall
in filling pressures except in nine of 11 patients with cardiac disease, in whom
pressures were elevated. Even so, these patients appeared to need volume ex-
pansion to achieve a stable blood pressure. In all six patients who had balloon
pulmonary artery catheters, pulmonary arterial pressure rose initially and
then fell over the subsequent 10 minutes [6]. In a single case report of a patient
with iatrogenic anaphylaxis for whom systemic vascular resistance was deter-
mined using a pulmonary artery catheter and cardiac output measurements,
3 hours into a reaction, there was increased pulmonary vascular resistance,
reduced pulmonary capillary wedge pressure, reduced cardiac output, and
slightly elevated systemic vascular resistance [13].
What peripheral vascular changes occur during human
anaphylaxis?
The peripheral skin flushing and fall in diastolic blood pressure (widened
pulse pressure) and tachycardia seen early in human anaphylaxis are sugges-
tive of dilation of both resistance and capacitance vessels [12]. During this
time, a transient peak in histamine, a potent vasodilator of both arterioles
and veins, has been shown to occur [27]. Beyond these observation, the pre-
cise vascular events during anaphylaxis have not been characterized in peo-
ple. It generally is presumed on the basis of the sudden reduction of central
venous pressure at reaction onset seen in people, animal studies, and known
mediator effects, that venodilation (increased venous capacitance) leading to
reduced venous return is a significant feature of human anaphylaxis.
Severe vasodilation resistant to epinephrine (adrenaline) and responding
only to potent vasoconstrictors has been described in human case reports
[7,8]. Such reports, however, only can assume that vasodilation has occurred
on the basis of an apparent response to a selective vasopressor. Whether the
primary sites of vasopressor action in these cases were the capacitance
vessels, resistance vessels or both, is unknown.
Is the human heart a target organ during anaphylaxis?

Severe reversible cardiac dysfunction associated with nonspecific electro-
cardiogram changes and normal coronary arteries also has been described
during human anaphylaxis [10,11,27]. Numerous case reports have indicated
that intravenous glucagon [28], the phosphodiesterase inhibitor amrinone
[29], and intra-aortic balloon pump support [11] may be useful for treating re-
sistant anaphylactic shock where cardiac dysfunction is a problem because of
beta blockade, pre-existing impairment of left ventricular function, or cardiac
anaphylaxis. The author also has observed global ST segment changes in a pa-
tient without any cardiovascular instability, suggesting a direct mediator effect
on the human heart [12].
Nevertheless, cardiac dysfunction during anaphylaxis in people has been
considered to be exceptionally rare [30]. Even in closely monitored cases, an
obvious difficulty in determining the contribution of cardiac dysfunction to

anaphylactic shock in people lies with the problems in dissecting this com-
ponent from other pathological events [31]. In lethal cases, owing to a rapid
and unpredicted demise, few if any detailed clinical observations are possi-
ble. Therefore, although numerous animal studies and human observations
support the concept of anaphylactic mediators having direct effects on the
myocardium [32], the contribution of this cardiac anaphylaxis to morbidity
and mortality remains to be defined.
The presence of mast cells in human cardiac (mainly peri-vascular) tissue
is well-recognized [33–35]. ECG changes suggestive of myocardial ischemia
and enzyme changes indicating infarction also have been reported within
24 hours of anaphylaxis [27,36–38]. This raises the possibility of mediator-
induced plaque ulceration and/or coronary spasm, ischemia secondary to
hypotension, and a direct mediator effect on the myocardium. Also, high
catecholamine levels (either therapeutic or caused by endogenous release)
can have an adverse effect in the myocardium, including significant reduc-
tions in cardiac output, ischemic chest pain, and ECG changes in the ab-
sence of coronary artery disease [39]. All of these can be argued as
potential mechanisms. Although attempts have been made on the basis
of a few case reports to give this allergic coronary syndrome an eponym
[40–42], some cases simply may represent coincidence, and the underlying
mechanisms are speculative.
Relative bradycardia during anaphylaxis

While performing a randomized controlled trial of venom immunother-
apy, the author observed eight hypotensive anaphylactic sting reactions,
two of which were associated with severe bradycardia and treated with
intravenous atropine [43]. A careful review of these reactions revealed that
hypotension was preceded by a fall in diastolic blood pressure (suggesting
reduced systemic vascular resistance) with tachycardia. Following this, in
every case, the onset of hypotension was accompanied by a relative brady-
cardia. That is, rather than the heart rate further increasing to compensate
for falling blood pressure, it fell as the blood pressure fell. We postulated
that this may have been caused by a neurocardiogenic reflex, triggered by
cardiac mechanoreceptors, and enhanced by increased levels of serotonin,
catecholamines, prostaglandins, and nitric oxide that are known to potenti-
ate this reflex and also are elevated during anaphylaxis [12]. More recently,
C5a and adenosine have been implicated as a potential mediators of brady-
cardia during cardiac anaphylaxis in pigs [44].
Bradycardia also may be a nonspecific feature of severe hypovolemic–dis-
tributive shock in awake animals. Paradoxical bradycardia has been re-
ported as a common feature of traumatic hypotension in people [45], and
physiological studies of awake mammals have identified two phases of re-
sponse to hypovolemia, an initial phase of blood pressure maintenance by
170 BROWN
tachycardia and peripheral arteriolar constriction, followed by a second

phase with more severe hypovolemia characterized by bradycardia, reduced
peripheral arteriolar tone and a profound fall in blood pressure [46]. How-
ever, bradycardia has not been reported as a feature of anaphylaxis under
anesthesia, where tachycardia is the norm except when there has been prior
beta blockade or severe hypoxia [6]. This may be explained by the blunting
of central reflexes that occurs under anesthesia and/or different allergen
routes and dosage. One cannot be sure whether bradycardia during anaphy-
laxis is maladaptive, potentiated by various mediators, or an adaptive pro-
cess that triggers collapse to a supine position and a slower heart rate to
allow the heart to adequately fill between contractions when there is a severe
reduction in preload.
Biochemical mediators
In the early 20th century, histamine was thought to be the principal me-
diator of anaphylaxis [30]. Since then, a huge range of inflammatory medi-
ators has been implicated in anaphylaxis by human studies, in vitro cell
stimulation studies, and animal models. These include:
Preformed mediators, released immediately by mast cells and basophils:
histamine, heparin, tryptase, chymase, tumor necrosis factor a
(TNF-a);
Mediators generated over minutes by mast cells, basophils, and possibly
other cells: platelet-activating factor (PAF), nitric oxide (NO), TNF-a,
cyclo–oxygenase products of arachidonic metabolism (PGD2), and lip-
oxygenase products of arachidonic metabolism (leukotrienes LTC4,
LTD4, and LTE4);
Mediators generated over hours by mast cells, basophils and possibly
other cells: interleukin (IL)-4, IL-5, IL-13, and GM-CSF
Mediators generated by contact system activation: bradykinin, plasmin,
and complement pathway anaphylatoxins C3a and C5a
Although tissue mast cells and circulating basophils play a pivotal role,
other cells including platelets, eosinophils, monocytes/macrophages, endo-
thelial cells, and antigen presenting cells also have been implicated. The
large numbers of mediators provide for significant redundancy and positive
feedback mechanisms by which other effector cells are recruited to release
more mediators. This has led to the concept of a mast cell–leukocyte cyto-
kine cascade that initiates, amplifies, and perpetuates the allergic response
[29].
Many of these mediators variously may cause systemic venodilation, in-
creased capillary permeability, reduced myocardial contractility, and con-
striction of some vessels (eg, precapillary arterioles, coronary arteries, and
pulmonary vasculature). Analyzing their roles in people is difficult because
of the opportunistic nature of anaphylaxis research, not only because of
the near-impossibility of establishing causal relationships, but also because

much of the action occurs locally in the tissue where the reaction is initiated,
because the presence of some mediators in serum such as histamine is tran-
sient [30], and because of technical difficulties assessing the concentrations of
some mediators. Variability between individuals in patterns of mediator
release and target organ sensitivity also may complicate interpretation.
Platelet-activating factor, nitric oxide, and tumor

necrosis factor a
In mice, PAF and platelets appear to play a central role in the hypoten-
sion of anaphylaxis, and there is good reason to suspect a similar role in
people [47]. PAF is released by mast cells, basophils, and platelets upon
IgE-mediated activation, and it may exert its effects largely through the
activation of endothelial nitric oxide synthase (eNOS) and excessive NO
synthesis, causing intense venodilation and perhaps myocardial depression
[48,49]. PAF also promotes the synthesis of TNF-a, which in turn promotes
later PAF synthesis, and thus delayed-phase reaction recurrence [50].
Clinical perspective
A summary of key pathological mechanisms of human anaphylactic
shock classified as proven, likely, and uncommon is presented in Box 2.
The large number of mediators with redundant effects underlying these
mechanisms indicates that physiological antagonism with fluid resuscitation,
epinephrine and perhaps potent vasopressors will be more effective than
individual receptor antagonists such as antihistamines.
Canine studies indicate that epinephrine works predominantly by increas-
ing cardiac output through a direct beta effect on the heart rather than by
improving venous return, and that only the intravenous infusion works in
established shock, with subcutaneous and intramuscular injections being in-
effective, and intravenous boluses having only a transient effect [24,26]. It
should be noted, however, that these studies were in dogs in which severe
anaphylactic shock had been precipitated, In many human cases with reac-
tions of milder severity, epinephrine is likely to provide some vasoconstric-
tion. Prospectively evaluated protocols for the infusion of epinephrine in
people are available [12,51].
Aggressive fluid resuscitation (volume expansion, eg, 20 mL/kg of normal
saline over 3 to 5 minutes, infused under pressure through a wide-bore in-
travenous line and repeated if necessary) is a critical treatment adjunct. It
often is forgotten that resuscitation can be initiated by laying a patient
flat and elevating his or her legs. Conversely the upright position, by further
enhancing blood pooling in the lower extremities, can be lethal [52].
Anecdotally, some cases not responding to fluid resuscitation and epi-
nephrine respond to additional treatment with potent vasopressors such
172 BROWN
Box 2. Key pathophysiologic mechanisms of human

anaphylactic shock
Common/clearly demonstrated: supported by unambiguous
observations of human anaphylaxis
Fluid extravasation causing hemoconcentration, hypovolemia
and reduced venous return to the heart manifested as low
filling pressures and reduction in cardiac output
Likely: unproven but supported by animal studies, studies of
histamine infusion in volunteers, known mediator actions,
and/or indirect physiological observations during human
anaphylaxis
Venodilation and blood pooling, contributing to reduced venous
return
Impaired myocardial contractility contributing, along with
reduced venous return, to reduced in cardiac output
Relative bradycardia (neurally mediated) in awake patients,
contributing to reduced cardiac output
Early transient increase in pulmonary vascular resistance,
contributing to the reduction in cardiac output by obstructing
venous return to the left heart
Early arteriolar dilation manifested as a widened pulse pressure
and contributing to hypotension (however an increase in
systemic vascular resistance caused by increased arteriolar
tone may predominate after this early phase)
Uncommon/postulated: based on case reports, speculation,
plausible mechanisms
Severe global depression of myocardial contractility with
non-specific ST segment ECG changes (unresponsive to
adrenaline) possibly more likely in those with underlying
cardiac disease or taking beta blockers
Severe arteriolar dilation as well as venous dilation
Coronary ischemia caused by coronary vasospasm and plaque
ulceration
as metaraminol and vasopressin [7–9]. Presumably these work primarily by

an effect on venous (capacitance vessel) tone. Atropine also may be required
when severe bradycardia is a feature [12], and phosphodiesterase inhibitor
inotropes (including glucagon) and mechanical circulatory support have
been reported to be effective in patients who have severely depressed myo-
cardial function [11,28,53,54].
Summary
Although human studies are difficult to perform, the balance of evidence
from human observations and animal studies suggests that the main patho-
physiological features of anaphylactic shock are a profound reduction in ve-
nous tone and fluid extravasation causing reduced venous return (mixed
hypovolemic–distributive shock) and depressed myocardial function. Ag-
gressive fluid resuscitation is required to ameliorate hypovolemic–distribu-
tive shock, and an intravenous infusion of epinephrine will increase
vascular tone, myocardial contractility, and cardiac output in most cases.
Where these measures fail, pathophysiological considerations and anecdotal
evidence support the consideration of selective vasoconstrictors as the next
step in treatment.
References
[1] Pumphrey RS. Lessons for management of anaphylaxis from a study of fatal reactions. Clin
Exp Allergy 2000;30(8):1144–50.
[2] Brown SGA. Clinical features and severity grading of anaphylaxis. J Allergy Clin Immunol
2004;114(2):371–6.
[3] Weil MH. Personal commentary on the diagnosis and treatment of circulatory shock states.
Curr Opin Crit Care 2004;10(4):246–9.
[4] Beaupre PN, Roizen MF, Cahalan MK, et al. Hemodynamic and two-dimensional transe-
sophageal echocardiographic analysis of an anaphylactic reaction in a human. Anesthesiol-
ogy 1984;60(5):482–4.
[5] Fisher M. Blood volume replacement in acute anaphylactic cardiovascular collapse related
to anaesthesia. Br J Anaesth 1977;49(10):1023–6.
[6] Fisher MM. Clinical observations on the pathophysiology and treatment of anaphylactic
cardiovascular collapse. Anaesth Intensive Care 1986;14(1):17–21.
[7] Heytman M, Rainbird A. Use of alpha-agonists for management of anaphylaxis occurring
under anaesthesia: case studies and review. Anaesthesia 2004;59(12):1210–5.
[8] Schummer W, Schummer C, Wippermann J, et al. Anaphylactic shock: is vasopressin the
drug of choice? Anesthesiology 2004;101(4):1025–7.
[9] Kill C, Wranze E, Wulf H. Successful treatment of severe anaphylactic shock with vasopres-
sin. Two case reports. Int Arch Allergy Immunol 2004;134(3):260–1.
[10] Hanashiro PK, Weil MH. Anaphylactic shock in man. Report of two cases with detailed
hemodynamic and metabolic studies. Arch Intern Med 1967;119(2):129–40.
[11] Raper RF, Fisher MM. Profound reversible myocardial depression after anaphylaxis.
Lancet 1988;1(8582):386–8.
[12] Brown SGA, Blackman KE, Stenlake V, et al. Insect sting anaphylaxis; prospective evalua-
tion of treatment with intravenous adrenaline and volume resuscitation. Emerg Med J 2004;
21(2):149–54.
[13] Silverman HJ, Van Hook C, Haponik EF. Hemodynamic changes in human anaphylaxis.
Am J Med 1984;77(2):341–4.
[14] Silverman HJ, Taylor WR, Smith PL, et al. Effects of antihistamines on the cardiopulmonary
changes due to canine anaphylaxis. J Appl Physiol 1988;64(1):210–7.
[15] Pavek K. Anaphylactic shock in the monkey: its hemodynamics and mediators. Acta Anaes-
thesiol Scand 1977;21(4):293–307.
[16] Patterson R, Fink JN, Wennemark J, et al. The biologic consequences of the immediate-type
hypersensitivity transferred from man to monkey. J Allergy 1966;37(5):295–310.
174 BROWN
[17] Melli G, Folli G, Mazzei D, et al. Shock organ and shock tissue in various animal species.
Acta Allergol 1963;18:188–210.
[18] Auer J, Lewis PA. Physiology of the immediate reaction of anaphylaxis in the guinea pig.
J Exp Med 1910;12:151–75.
[19] Criep LH. Electrocardiographic studies of the effects of anaphylaxis on the cardiac mecha-
nism. Arch Intern Med 1931;48:1098–108.
[20] Felix SB, Baumann G, Berdel WE. Systemic anaphylaxisdseparation of cardiac reactions
from respiratory and peripheral vascular events. Res Exp Med (Berl) 1990;190(4):239–52.
[21] Capurro N, Levi R. The heart as a target organ in systemic allergic reactions: comparison of
cardiac anaphylaxis in vivo and in vitro. Circ Res 1975;36(4):520–8.
[22] Regal JF, Heller LJ. Cardiac anaphylaxis in isolated guinea pig hearts perfused at constant
flow or constant pressure. Proc Soc Exp Biol Med 1987;185(2):193–200.
[23] Mink S, Becker A, Sharma S, et al. Role of autacoids in cardiovascular collapse in anaphy-
lactic shock in anaesthetized dogs. Cardiovasc Res 1999;43(1):173–82.
[24] Mink SN, Bands C, Becker A, et al. Effect of bolus epinephrine on systemic hemodynamics in
canine anaphylactic shock. Cardiovasc Res 1998;40(3):546–56.
[25] Mink SN, Becker A, Unruh H, et al. Effects of anaphylaxis mediators on partitioned pulmo-
nary vascular resistance during ragweed shock in dogs. J Appl Physiol 1998;84(3):782–90.
[26] Mink SN, Simons FE, Simons KJ, et al. Constant infusion of epinephrine, but not bolus
treatment, improves haemodynamic recovery in anaphylactic shock in dogs. Clin Exp
Allergy 2004;34(11):1776–83.
[27] Smith PL, Kagey-Sobotka A, Bleecker ER, et al. Physiologic manifestations of human ana-
phylaxis. J Clin Invest 1980;66(5):1072–80.
[28] Zaloga GP, DeLacey W, Holmboe E, et al. Glucagon reversal of hypotension in a case of
anaphylactoid shock. Ann Intern Med 1986;105(1):65–6.
[29] Otero E, Onufer JR, Reiss CK, et al. Anaphylaxis-induced myocardial depression treated
with amrinone. Lancet 1991;337(8742):682.
[30] Fisher M. Treating anaphylaxis with sympathomimetic drugs. BMJ 1992;305(6862):1107–8.
[31] Cooper DJ. Cardiac dysfunction during anaphylaxis in patients. Appl Cardiopulm Patho-
physiol 1993;5:9–18.
[32] Marone G, Bova M, Detoraki A, et al. The human heart as a shock organ in anaphylaxis.
Novartis Found Symp 2004;257:133–49 [discussion: 149–60, 276–85].
[33] Patella V, de Crescenzo G, Ciccarelli A, et al. Human heart mast cells: a definitive case of
mast cell heterogeneity. Int Arch Allergy Immunol 1995;106(4):386–93.
[34] Patella V, Genovese A, Marone G. What are human heart mast cells for? Chem Immunol
1995;62:171–86.
[35] Patella V, Marino I, Lamparter B, et al. Human heart mast cells. Isolation, purification,
ultrastructure, and immunologic characterization. J Immunol 1995;154(6):2855–65.
[36] Austin SM, Barooah B, Kim CS. Reversible acute cardiac injury during cefoxitin-induced
anaphylaxis in a patient with normal coronary arteries. Am J Med 1984;77(4):729–32.
[37] Levine HD. Acute myocardial infarction following wasp sting. Report of two cases and
critical survey of the literature. Am Heart J 1976;91(3):365–74.
[38] Quercia O, Rafanelli S, Emiliani F, et al. Anaphylactic reaction to cinoxacin: report of one
case associated with inferior acute myocardial infarction. Allerg Immunol (Paris) 2003;35(2):
61–3.
[39] Wittstein IS, Thiemann DR, Lima JA, et al. Neurohumoral features of myocardial stunning
due to sudden emotional stress. N Engl J Med 2005;352(6):539–48.
[40] Soufras GD, Ginopoulos PV, Papadaki PJ, et al. Penicillin allergy in cancer patients mani-
festing as Kounis syndrome. Heart Vessels 2005;20(4):159–63.
[41] Koutsojannis CM, Kounis NG. Lepirudin anaphylaxis and Kounis syndrome. Circulation
2004;109(22):e315, author reply e315.
[42] Kounis NG, Grapsas ND, Goudevenos JA. Unstable angina, allergic angina, and allergic
myocardial infarction. Circulation 1999;100(25):e156.
[43] Brown SGA, Wiese MD, Blackman KE, et al. Ant venom immunotherapy: a double-blind,
placebo-controlled, cross-over trial. Lancet 2003;361(9362):1001–6.
[44] Szebeni J, Baranyi L, Savay S, et al. Complement activation-related cardiac anaphylaxis in
pigs: role of C5a anaphylatoxin and adenosine in liposome-induced abnormalities in ECG
and heart function. Am J Physiol Heart Circ Physiol 2006;290(3):H1050–8.
[45] Demetriades D, Chan LS, Bhasin P, et al. Relative bradycardia in patients with traumatic
hypotension. J Trauma 1998;45(3):534–9.
[46] Schadt JC, Ludbrook J. Hemodynamic and neurohumoral responses to acute hypovolemia
in conscious mammals. Am J Physiol 1991;260(2 Pt 2):H305–18.
[47] Kasperska-Zajac A, Rogala B. Platelet function in anaphylaxis. J Investig Allergol Clin
Immunol 2006;16(1):1–4.
[48] Cauwels A, Janssen B, Buys E, et al. Anaphylactic shock depends on PI3K and eNOS-
derived NO. J Clin Invest 2006;116(8):2244–51.
[49] Lowenstein CJ, Michel T. What’s in a name? eNOS and anaphylactic shock. J Clin Invest
2006;116(8):2075–8.
[50] Choi IW, Kim YS, Kim DK, et al. Platelet-activating factor-mediated NF-kappaB depen-
dency of a late anaphylactic reaction. J Exp Med 2003;198(1):145–51.
[51] Brown SGA. Anaphylaxis: clinical concepts and research priorities. Emerg Med Australas
2006;18(2):155–69.
[52] Pumphrey RS. Fatal posture in anaphylactic shock. J Allergy Clin Immunol 2003;112(2):
451–2.
[53] Andjelkovic I, Zlokovic B. Protective effects of glucagon during the anaphylactic response
in guinea pig isolated heart. Br J Pharmacol 1982;76(3):483–9.
[54] Thomas M, Crawford I. Best evidence topic report. Glucagon infusion in refractory anaphy-
lactic shock in patients on beta blockers. Emerg Med J 2005;22(4):272–3.
27 (2007) 177–191
Anaphylaxis: Office Management

and Prevention
Matthew L. Oswalt, MD, Stephen F. Kemp, MD*
Departments of Medicine and Pediatrics, The University of Mississippi Medical Center,
768 Lakeland Drive, Building LJ, Jackson, MS 39216, USA
Anaphylaxis, an acute and potentially lethal multisystem allergic reac-

tion, occurs in various clinical scenarios and is almost unavoidable in med-
ical practice [1]. Immunologic reactions to foods, medications, and insect
stings cause most episodes, but any agent capable of producing a sudden,
systemic degranulation of mast cells or basophils can induce anaphylaxis
(Box 1) [2]. Lifetime risk of anaphylaxis is presumed to be 1% to 3% per in-
dividual, with a mortality rate of 1% [3–7]. Therefore, all physicians must be
able to recognize anaphylaxis, be sufficiently prepared to treat it promptly
and appropriately, and be able to provide preventive recommendations.
Clinical manifestations of anaphylaxis

Signs and symptoms of anaphylaxis vary, but cutaneous features (urti-
caria and/or angioedema) are the most common overall [2]. Clinically, ana-
phylaxis is considered likely to be present if any one of three criteria is
satisfied within minutes to hours:
Acute onset of illness with involvement of skin, mucosal surface, or both,
and at least one of the following: respiratory compromise, hypoten-
sion, or end-organ dysfunction
Two or more of the following occur rapidly after exposure to a likely al-
lergen: skin or mucosal involvement, respiratory compromise, hypo-
tension, or persistent gastrointestinal symptoms
Hypotension after exposure to known allergen for that patient: age-
specific low blood pressure or decline of systolic blood pressure of
greater than 30% compared with baseline [1]
* Corresponding author.
E-mail address: skemp@medicine.umsmed.edu (S.F. Kemp).
Box 1. Representative agents that cause anaphylaxis
Anaphylactic (IgE-dependent)
Foods (such as crustaceans, mollusks, peanuts, and tree nuts)
Medications (such as antibiotics)
Insect venoms (stinging ants, wasps, yellow jackets, others)
Allergen extracts
Latex
Exercise (possibly, in food- and medication-dependent events)
Hormones
Animal or human proteins
Colorants (insect-derived, such as carmine)
Polysaccharides
Enzymes
Anaphylactoid (IgE-independent)
Nonspecific degranulation of mast cells and basophils
Opioids
Muscle relaxants
Idiopathic
Physical factors, including exercise and temperature (cold, heat)
Disturbance of arachidonic acid metabolism
Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs)a
Immune aggregates
Intravenous immunoglobulin
Dextran (possibly)
Possibly antihaptoglobin in anhaptoglobinemia (in Asians)
Cytotoxic
Transfusion reactions to cellular elements (IgM, IgG)
Multimediator complement activation/activation of contact system
Radiocontrast media
ACE-inhibitor administered during renal dialysis with sulfonated
polyacrylonitrile, cuprophane, or polymethylmethacrylate
dialysis membranes
Ethylene oxide gas on dialysis tubing
Protamine (possibly)
Psychogenic
Factitious
Munchausen’s syndrome by proxy
Undifferentiated somatoform idiopathic anaphylaxis
a
Some authors suggest that reactions to NSAIDs should be classified as ana-
phylactic, even though there is no reliable or consistent detection of agent-specific
IgE. These reactions almost always are drug-specific (unlike the cross-reactivity ob-
served in aspirin-exacerbated respiratory disease [also known as aspirin triad or
Samter syndrome]); they require two or more previous specific drug exposures,
and the subject group characteristically has no underlying asthma or nasal polyps.
Modified from Stevenson DD. Anaphylactic and anaphylactoid reactions to
aspirin and other nonsteroidal anti-inflammatory drugs. Immunol Allergy Clin N
Am 2001;21:745–68; and Kemp SF, Lockey RF. Anaphylaxis: a review of causes
and mechanisms. J Allergy Clin Immunol 2002;110:341–8.
ANAPHYLAXIS 179
For practical purposes, delaying the diagnosis until end-organ features of

anaphylaxis are present is risky, because the ultimate severity of a reaction is
difficult to predict.
Respiratory compromise and cardiovascular collapse are responsible for
most fatalities [2,8]. An analysis of 202 anaphylaxis fatalities occurring over
10 years in the United Kingdom determined that the interval between initial
onset of food anaphylaxis symptoms and fatal cardiopulmonary arrest aver-
aged 25 to 35 minutes, which was longer than for drugs (mean, 5 minutes in
the hospital; 10 to 20 minutes prehospital) or insect stings (10 to 15 minutes)
[8].
Increased vascular permeability during anaphylaxis can shift 50% of
intravascular fluid to the extravascular space within 10 minutes [9,10]. A
patient’s intrinsic compensatory response to anaphylaxis (endogenous
catecholamines, angiotensin II, endothelin-1, and others) also influences
the extent of clinical manifestations and, when adequate, may be life-saving
independent of medical intervention.
Because antibodies attached to mast cells can trigger mast cell degranula-
tion, and mast cells accumulate at sites of coronary atherosclerotic plaques,
some investigators have suggested that anaphylaxis may promote plaque
rupture, thus risking myocardial ischemia [11,12]. Stimulation of the H1
histamine receptor also may produce coronary artery vasospasm [12,13].
Biphasic and protracted anaphylaxis

Biphasic anaphylaxis occurs in 1% to 20% of anaphylaxis cases [14].
Signs and symptoms experienced during the recurrent phase may be equiv-
alent to or worse than those observed in the initial reaction and may occur 1
to 72 hours (most occur within 8 hr) after apparent remission. Data are in-
conclusive, but some investigators have suggested that risk factors might in-
clude relatively large doses of epinephrine administered during the initial
phase [15], lower doses of epinephrine and corticosteroids during initial
treatment [16], laryngeal edema during the initial phase [17], or slow symp-
tomatic onset (at least 30 minutes after antigen exposure) [17]. Protracted
anaphylaxis (anaphylaxis that may last from 5 to 32 hours) also has been
reported [17,18].
Severity of the initial phase of an anaphylactic reaction is not predictive
for either biphasic or protracted anaphylaxis. Because life-threatening man-
ifestations of anaphylaxis may recur, it may be necessary to monitor patients
24 hours or more after apparent recovery from the initial phase.
Diagnosis of anaphylaxis
Anaphylaxis remains a clinical diagnosis based on probability and
pattern recognition (see Box 1). No evaluation can prove causation of
180 OSWALT & KEMP
anaphylaxis conclusively without directly challenging the patient with the

suspected agent, a course of action that generally is contraindicated because
of ethical and safety concerns. Cause-and-effect often is confirmed histori-
cally in patients who experience objective findings of anaphylaxis upon in-
advertent re-exposure to the offending agent.
Diagnostic testing, where appropriate, may confirm the presence of aller-
gen-specific IgE or assist in narrowing the differential diagnosis. Elevated se-
rum tryptase, for example, reflects mast cell degranulation and might help to
confirm anaphylaxis. Levels of total tryptase peak 60 to 90 minutes after the
onset of anaphylaxis and can persist as long as 5 hours after the onset of
symptoms [19]. Tryptase levels obtained under ideal conditions, however,
occasionally may fall within the reference range for normality despite the
presence of anaphylaxis clinically. (This has been observed in some cases
of food anaphylaxis, for example.) Serial tryptase measurements might im-
prove diagnostic sensitivity, but further investigation is needed [1].
Differential diagnosis of anaphylaxis

Several systemic disorders share clinical features with anaphylaxis. The
vasodepressor (vaso–vagal) reaction probably is the most common. In vaso-
depressor reactions, however, urticaria and dyspnea are absent; the blood
pressure is usually normal or elevated, and the skin is typically cool and
pale. Although tachycardia is the rule, bradycardia also may occur in ana-
phylaxis. Thus, bradycardia may not be as helpful to differentiate between
the two syndromes as traditionally thought. Brown and colleagues [20] con-
ducted sting challenges in 19 patients known to be allergic to jack jumper
ants (Myrmecia). All eight patients who became hypotensive developed bra-
dycardia after an initial tachycardia. One of three subjects described by
Smith and colleagues [21] in their detailed analysis of the physiological man-
ifestations of anaphylaxis also experienced hypotension and bradycardia af-
ter initial tachycardia. Both reports exclusively involved venom-allergic
patients challenged with insect venom. Whether bradycardia in anaphylaxis
is a phenomenon more commonly observed in venom hypersensitivity is un-
clear. Conduction defects and sympatholytic medications also may produce
bradycardia.
Several conditions can cause abrupt and dramatic patient collapse and
potentially be confused with anaphylaxis. Among conditions to consider
are systemic mast cell disorders, myocardial dysfunction, pulmonary embo-
lism, foreign body aspiration (especially in children), acute poisoning, hypo-
glycemia, and seizure disorder. Specific signs and symptoms of anaphylaxis
can present singly in other disorders. Examples are urticaria–angioedema (in
the absence of other signs and symptoms suggestive of anaphylaxis), hered-
itary angioedema, asthma, and acute anxiety (eg, hyperventilation syndrome
or panic attack). Postprandial syndromes (eg, scombroidosis), flushing
ANAPHYLAXIS 181
syndromes (eg, metastatic carcinoid), and psychiatric disorders that can

mimic anaphylaxis also can contribute to diagnostic confusion [22].
Management of anaphylaxis
Practice parameters [22] and consensus emergency management guide-
lines [23–26] concerning anaphylaxis and its management have been pub-
lished. Similar to asthma and other diseases for which there are published
guidelines, however, providers may not apply them. In a standardized clin-
ical scenario of anaphylaxis as defined by United Kingdom Resuscitation
Council guidelines, in the judgment of investigators, 5% of 78 senior house
officers beginning emergency department responsibilities would administer
epinephrine appropriately and with the proper dose and route administra-
tion as outlined in the published guidelines [27]. Other reports have exam-
ined treatment patterns in the emergency department setting of civilian
[28] and military hospitals [29] and observed that epinephrine injections
were administered during acute anaphylaxis to 16% and 50% of patients,
respectively, where epinephrine was indicated by consensus guidelines.
Clinicians who perform procedures or administer medications in the of-
fice should have available the basic therapeutic agents used in the treatment
of anaphylaxis (Table 1). At a minimum, the following equipment and sup-
plies should be available [22,30,31]:
Stethoscope and sphygmomanometer
Tourniquets, tuberculin syringes, and large-bore needles (eg, 14-gauge
needles)
Injectable aqueous epinephrine 1:1000
Equipment for administering oxygen
Oral airway
Equipment for administering intravenous fluids
Injectable antihistamine (eg, diphenhydramine)
Corticosteroids for intravenous injection
A vasopressor (eg, dopamine)
Depending on the clinical setting, some clinicians might find desirable the
availability of glucagon, an automatic defibrillator, and a one-way valve
facemask with an oxygen inlet port (eg, Pocket-Mask [Laerdal Medical Cor-
poration, Gatesville, Texas] or similar device). The emergency kit should be
up-to-date and complete. Everyone directly involved in patient care should
be able to locate necessary supplies easily, rapidly assemble fluids for intra-
venous administration, and perform other necessary tasks.
When a patient should be transferred to an emergency facility depends on
the clinical severity of the reaction, response to treatment, and skill of the
individual clinician. The authors’ rule is ‘‘sooner better than later.’’
A sequential approach to management is outlined in Box 2, and a sample
treatment flow sheet is presented in Fig. 1. Judicious use of epinephrine and
182 OSWALT & KEMP
Table 1
Therapeutic agents for anaphylaxis in the office
Dose and route
Agent of administration Comments
Epinephrine 1:1000 0.2–0.5 mg IM thigh (adult); Give immediately and
0.01 mg/kg (up to 0.03 mg) repeat every 5–15 min as
IM thigh (child) needed. Monitor for
toxicity.
Volume expansion
Normal saline 1–2 L rapidly IV in adults Rate is titrated to pulse and
(5–10 mL/kg in first blood pressure. Insert the
5 min); 30 mL/kg in first largest catheter possible
h for children into the largest available
peripheral vein. Use
administration set that
permits rapid infusion of
fluids. Monitor for
volume overload.
Antihistamines
Diphenhydramine 25–50 mg IV (adults) Second-line agents; H1 and
1 mg/kg IV up to 50 mg H2 agents work better in
(children) combination than H1
agents alone. Identical
oral doses might be
sufficient for milder
episodes.
Ranitidine 1 mg/kg (adults) 12.5–50 mg
infused over 10 min
(children)
Corticosteroids
Methylprednisolone 1–2 mg/kg/day IV Exact dose not established;
Prednisone 0.5 mg/kg/day by mouth have no role in acute
anaphylaxis
Treatment complicated Initial dose, 1–5 mg slow Emesis precautions needed;
by b-blockade glucagon IV, then 5–15 mg/min titrate to blood pressure
infusion
Abbreviations: IM, intramuscularly; IV, intravenously.
the maintenance of adequate oxygenation and effective circulatory volume

are the most important considerations. Assessment and maintenance of air-
way, breathing, circulation, and mentation are essential, initial management
steps. Altered mentation may reflect underlying hypoxia. Measurement of
pulse oximetry and peak expiratory flow rate, where appropriate, may be
useful to guide therapy. Patients should be monitored continuously to facil-
itate prompt detection of any clinical changes or treatment complications.
The recumbent position is recommended strongly. Placement in the re-
cumbent position is roughly equivalent to auto-infusion (or preservation)
of 1 to 2 L of fluid into the central vascular compartment [32]. In a retrospec-
tive review of prehospital anaphylactic fatalities in the United Kingdom, the
postural history was known for 10 individuals [33]. Four of the 10 were
ANAPHYLAXIS 183
Box 2. Physician-supervised management of anaphylaxis

Immediate Intervention
Assessment of airway, breathing, circulation, and adequacy of
mentation
Administer epinephrine intramuscularly every 5 to 15 minutes,
as necessary, to control symptoms and blood pressure.
Possibly appropriate, subsequent measures depending on

response to epinephrine
Place patient in recumbent position and elevate lower extremities
(avoid Trendelenburg position).
Establish and maintain airway.
Administer oxygen.
Establish venous access.
Normal saline intravenously for fluid replacement
Specific measures to consider after epinephrine injections,

where appropriate
Consider epinephrine infusion (Please see anaphylaxis
parameter for specific details.)
H1 and H2 antihistamines
Nebulized albuterol for bronchospasm resistant to epinephrine
Consider dopamine.
Consider glucagon.
Consider systemic corticosteroids.
Consider atropine for symptomatic bradycardia.
Consider transportation to the emergency department or an
intensive care facility.
Interventions for cardiopulmonary arrest occurring during

anaphylaxis
High-dose epinephrine and prolonged resuscitation efforts are
encouraged, if necessary, because they are more likely to be
successful in anaphylaxis. (See anaphylaxis parameter for
specific details.)
Adapted from Lieberman P, Kemp SF, Oppenheimer J, et al. Joint Task Force
on Practice Parameters. The diagnosis and management of anaphylaxis: an
updated practice parameter. J Allergy Clin Immunol 2005;115:S483–523.
184 OSWALT & KEMP
Fig. 1. Anaphylaxis treatment record. (From Lieberman P, Kemp SF, Oppenheimer J, et al.
Joint Task Force on Practice Parameters. The diagnosis and management of anaphylaxis: an
updated practice parameter. J Allergy Clin Immunol 2005;115:S483–523; with permission.)
associated with assumption of an upright or sitting posture and postmortem

findings consistent with ‘‘empty heart’’ and pulseless electrical activity.
Epinephrine
Epinephrine is the treatment of choice for anaphylaxis [22–24,34]. Again,
the authors’ rule is ‘‘sooner better than later.’’ Fatalities in anaphylaxis usually
ANAPHYLAXIS 185
result from delayed or inadequate administration of epinephrine and from se-

vere respiratory and/or cardiovascular complications [8,22]. There is no abso-
lute contraindication to epinephrine administration in anaphylaxis [22]. All
subsequent therapeutic interventions depend on the initial response to epi-
nephrine. Development of toxicity or inadequate response to epinephrine in-
jections indicates that additional therapeutic modalities are necessary [22].
Epinephrine administered intramuscularly every 5 to 15 minutes, as nec-
essary, should be used to control symptoms and sustain or increase blood
pressure [22,25,26]. Comparisons of intramuscular to subcutaneous injec-
tions have not been done during anaphylaxis. Absorption, however, is com-
plete and more rapid and plasma levels are higher in asymptomatic adults
and children who receive epinephrine intramuscularly in the anterolateral
thigh [35,36]. Obesity or other conditions that accentuate the subcutaneous
fat pad may prevent or complicate intramuscular access and render such
considerations irrelevant clinically for a particular individual [37].
The a-adrenergic, vasoconstrictive effect reverses peripheral vasodilation,
which alleviates hypotension and also reduces angioedema and urticaria. It
also may minimize further absorption of antigen from a sting or injection.
The b-adrenergic properties of epinephrine cause bronchodilation, increase
myocardial output and contractility, and suppress further mediator release
from mast cells and basophils [38,39]. Epinephrine administered in low con-
centrations (eg, 0.1 mg/kg) paradoxically can be associated with vasodila-
tion, hypotension, and increased release of inflammatory mediators [40].
Epinephrine administration enhances coronary blood flow. Two mecha-
nisms are probably responsible: a vasodilator effect caused by increased
myocardial contractility and an increased duration of diastole compared
with systole. These effects usually offset vasoconstrictor effects of epineph-
rine on the coronary arteries [39].
Because of the risk for potentially lethal arrhythmias, epinephrine
(1:10,000 or 1:100,000 dilutions) should be administered intravenously
only during cardiac arrest or to profoundly hypotensive patients who
have failed to respond to multiple epinephrine injections and intravenous
volume replacement [22].
Oxygen and airway adjuncts

All patients who have anaphylaxis should receive oxygen at 6 to 8 L/min.
Oxygen administration is especially important in patients who have a history
of cardiac or respiratory disease, inhaled b2-agonist use, and who have re-
quired multiple doses of epinephrine [22]. Continuous pulse oximetry or ar-
terial blood gas determination (where available) should guide oxygen
therapy if the potential development of hypoxemia is a concern.
Because adequate oxygenation also depends on ventilation, it may be
necessary to establish and maintain an airway and/or provide ventilatory as-
sistance. Again, the authors’ rule is ‘‘sooner better than later.’’ One of the
186 OSWALT & KEMP
quickest, easiest, and most effective ways to support ventilation involves

a one-way valve facemask with oxygen inlet port (eg, Pocket-Mask [Laerdal
Medical Corporation, Gatesville, Texas] or similar device). Oxygen satura-
tions comparable to endotracheal intubation have been demonstrated in pa-
tients who require artificial ventilation by mouth-to-mask technique with
oxygen attached to the inlet port. Patients with adequate, spontaneous
respirations may breathe through the mask.
Ambubags of less than 700 mL are discouraged in adults in the absence
of an endotracheal tube, because ventilated volume will not overcome the
150 to 200 mL of anatomic dead space to provide effective tidal volumes.
Recommended tidal volume during artificial ventilation is 6 to 7 mL/kg
over 1.5 to 2 seconds. (Ambubags may be used in children if the reservoir
volume of the device is sufficient. Avoid over-inflation.) Endotracheal intu-
bation or cricothyroidotomy may be considered where appropriate and pro-
vided that clinicians are adequately trained and proficient in this procedure.
The rate of administered oxygen depends on clinical response and on the
device used. A nasal cannula will deliver an oxygen concentration of 25% to
40% with a 4 to 6L/min flow. A simple plastic face mask will deliver an ox-
ygen concentration of 50% to 60% with an 8 to 12 L/min flow. By compar-
ison, the one-way valve facemask with oxygen inlet valve permits ventilation
with up to 50% oxygen at a flow rate of 10 L/min and approaching 90% to
100% if the rescuer periodically occludes the opening of the mask with his/
her tongue during mouth-to-mask ventilation.
Persistent hypotensiondappropriate roles of volume replacement,

glucagon, and vasopressors
Special considerations for b-adrenergic blockade
Patients taking b-adrenergic blockers may be more likely to experience se-
vere anaphylactic reactions characterized by severe bronchospasm, paradox-
ical bradycardia, and profound hypotension. Use of selective b1 blockers does
not reduce the risk of anaphylaxis, because both b1 and b2 blockers may inhibit
the b-adrenergic receptor [41–43]. In such situations, intravenous glucagon
potentially may reverse hypotension and bronchospasm, because it bypasses
the b receptor and directly activates adenyl cyclase [44–46].
Fluid resuscitation
The patient whose hypotension persists despite epinephrine injections
should receive intravenous crystalloid solutions or colloid volume ex-
panders. Crystalloid volumes (eg, saline) of up to 7 L may be necessary
for the distributive shock of anaphylaxis. One to 2 L of normal saline should
be administered to adolescents and adults at a rate of 5 to 10 mL/kg in the
first 5 minutes. Children can receive 10 to 20 mL/kg boluses up to 30 mL/kg
in the first hour. Adults receiving colloid solution should receive 500 mL
ANAPHYLAXIS 187
rapidly, followed by slow infusion. Normal saline is preferred, because lac-

tated Ringers may contribute to metabolic acidosis, and dextrose is extrava-
sated rapidly from the intravascular circulation into the interstitial tissues.
Cases not responding to epinephrine injections and fluid resuscitation may
require epinephrine or dopamine infusions [22].
For intravenous volume replacement, one generally should insert the
largest catheter needle possible into the largest available peripheral vein
and use an administration set that permits rapid infusion of fluids. For ex-
ample, large bore cannula needles (14- to 16-gauge) and standard infusion
sets (10 to 15 drops/mL) are preferred in adults. Intraosseous vascular ac-
cess may be established in infants and children if urgent access is needed,
and reliable venous access cannot be achieved rapidly. The microdrop infu-
sion set (60 drops/mL) is appropriate for keep-vein-open access and infu-
sions of medications (eg, epinephrine or a vasopressor), but it does not
permit rapid volume replacement.
Vasopressors
Vasopressors, such as dopamine or norepinephrine, should be adminis-
tered if epinephrine injections, volume expansion, and H1 and H2 antihista-
mines in combination (see Table 1) fail to alleviate hypotension. The
vasopressor of choice is probably dopamine (400 mg in 500 mL of 5% dex-
trose), administered at 2 to 20 mg/kg/min and titrated to systolic blood pres-
sure. Dopamine increases the force and rate of myocardial contractions
while maintaining or enhancing renal and mesenteric blood flow. In con-
trast, norepinephrine constricts renal arteries. Vasopressors would not be
expected to work as well in those patients who have experienced maximal
vasoconstriction as their internal compensatory response to anaphylaxis.
Central venous access should be attempted to facilitate both rapid adminis-
tration of fluids and continuous assessment of intravascular volume status.
As mentioned previously, oxygen should be administered to subjects who
have protracted anaphylaxis, because patients who have prolonged hypox-
emia and/or hypotension may experience myocardial dysfunction, possibly
resulting in refractory hypotension and/or end organ damage. A critical
care specialist may need to be consulted for a patient who has intractable
hypotension.
The role of antihistamines, inhaled adrenergic agonists, and corticosteroids

H1 and H2 antihistamines are used commonly as additional agents. An-
tihistamines, however, act much slower than epinephrine, have minimal ef-
fect on blood pressure, and should not be administered alone as treatment
for anaphylaxis [22]. Inhaled b2 agonists (eg, albuterol) are helpful when
bronchospasm resists epinephrine injections alone. Systemic corticosteroids
traditionally have been used in anaphylaxis, but controlled trials have not
evaluated their effect. They might help to prevent biphasic anaphylaxis,
188 OSWALT & KEMP
Box 3. Preventive measures to reduce the risk for anaphylaxis

General measures
Obtain thorough history to diagnose life-threatening food or drug
allergy.
Identify cause of anaphylaxis and those individuals at risk for
future attacks.
Provide instruction on proper reading of food and medication
labels, where appropriate.
Avoidance of exposure to antigens and cross-reactive substances
Optimal management of asthma and coronary artery disease
Implement a waiting period of 20 to 30 minutes after injections of
drugs or other biologic agents.
Consider a waiting period of 2 hours if a patient receives an oral
medication in the office he/she has taken previously.
Specific measures for high-risk patients

Individuals at high risk for anaphylaxis should carry self-
injectable syringes of epinephrine at all times and receive
instruction in proper use with a placebo trainer
MedicAlert (MedicAlert Foundation International, Turlock,
California) (or similar warning bracelets or chains)
Substitute other agents for b-adrenergic antagonists,
angiotensin-converting enzyme inhibitors, tricyclic
antidepressants, monoamine oxidase inhibitors, and certain
tricyclic antidepressants whenever possible.
Slow, supervised administration of agents suspected of causing
anaphylaxis, orally if possible
Where appropriate, use specific preventative strategies,
including pharmacologic prophylaxis, short-term challenge
and desensitization, and long-term desensitization.
Modified from Kemp SF. Anaphylaxis: current concepts in pathophysiology,

diagnosis, and management. Immunol Allergy Clin N Am 2001;21:611–34.
but failures are documented [22]. Corticosteroids administered during ana-

phylaxis, however, might benefit patients who have asthma or other condi-
tions recently treated with corticosteroids [22].
Follow-up and observation after anaphylaxis

Observation after anaphylaxis should be individualized and based on
such factors as comorbid conditions and distance from treatment facilities,
ANAPHYLAXIS 189
particularly because there are no reliable predictors for biphasic anaphylaxis

[14,22]. For example, patients who have severe anaphylaxis should be admit-
ted, and others who experience anaphylaxis in the office setting probably
should be discharged home only if they stay for the next 72 hours where
they have adequate supervision and, if symptoms recur, they readily can se-
cure emergency medical transportation to the closest emergency
department.
Prevention of anaphylaxis
Optimizing prevention (Box 3) is crucial, because future anaphylaxis may
be fatal despite appropriate management. An allergist–immunologist can
provide comprehensive professional advice on these matters and should
be consulted if he/she is not already involved in the anaphylaxis plan of
care. All patients at risk for future anaphylaxis should carry at least one epi-
nephrine syringe and know how to administer it. An EpiPen (Dey Labora-
tories, Napa, California) is a spring-loaded, pressure-activated syringe with
a single 0.3 mg dose (1:1000 dilution) of epinephrine. An EpiPen Jr., which
delivers 0.15 mg (1:2000 dilution) epinephrine, is appropriate for children
weighing less than 30 kg. The Twinject (Verus Pharmaceuticals, San Diego,
California) is a prefilled, pen-sized, epinephrine auto-injector with two doses
of either 0.3 or 0.15 mg. Both auto-injector devices are easy to use and will
inject through clothing.
References
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;117:391–7.
[2] Kemp SF, Lockey RF. Anaphylaxis: a review of causes and mechanisms. J Allergy Clin
Immunol 2002;110:341–8.
[3] Valentine M, Frank M, Friedland L, et al. Allergic emergencies. In: Drause RM, editor.
Asthma and other allergic diseases. NIAID Task Force Report. Bethesda (MD): National
Institutes of Health; 1979. p. 467–507.
[4] Yocum MW, Butterfield JH, Klein JS, et al. Epidemiology of anaphylaxis in Olmsted
County: a population-based study. J Allergy Clin Immunol 1999;104:452–6.
[5] Neugat AI, Ghatak AT, Miller RL. Anaphylaxis in the United States: an investigation into
its epidemiology. Arch Intern Med 2001;161:15–21.
[6] Simons FE, Peterson S, Black CD. Epinephrine dispensing for the out-of-hospital treatment
of anaphylaxis in infants and children: a population-based study. Ann Allergy Asthma
Immunol 2001;86:622–6.
[7] Simons FE, Peterson S, Black CD. Epinephrine-dispensing patterns for an out-of-hospital
Immunol 2002;110:647–51.
[8] Pumphrey R. Anaphylaxis: can we tell who is at risk of a fatal reaction? Curr Opin Allergy
Clin Immunol 2004;4:285–90.
190 OSWALT & KEMP
[9] Fisher M. Clinical observations on the pathophysiology and implications for treatment. In:
Vincent JL, editor. Update in intensive care and emergency medicine. New York: Springer-
Verlag; 1989. p. 309–16.
[10] Fisher MM. Clinical observations on the pathophysiology and treatment of anaphylactic
cardiovascular collapse. Anaesth Intensive Care 1986;14:17–21.
[11] Kovanen PT, Kaartinen M, Paavonen T. Infiltrates of activated mast cells at the site of cor-
onary atheromatous erosion or rupture in myocardial infarction. Circulation 1995;92:
1084–8.
[12] Kounis NG. Kounis syndrome (allergic angina and allergic myocardial infarction): a natural
paradigm? Int J Cardiol 2006;110:7–14.
[13] Steffel J, Akhmedov A, Greutert H, et al. Histamine induces tissue factor expression: impli-
cations for acute coronary syndromes. Circulation 2005;112:341–9.
[14] Lieberman P. Biphasic anaphylactic reactions. Ann Allergy Asthma Immunol 2005;95:
217–26.
[15] Brazil E, MacNamara AF. Not so immediate hypersensitivity: the danger of biphasic ana-
phylactic reactions. J Accid Emerg Med 1998;15:252–3.
[16] Ellis AK, Day JH. Biphasic anaphylaxis: a prospective examination of 103 patients for the
incidence and characteristics of biphasic reactivity [abstract]. J Allergy Clin Immunol
2004;113:S259.
[17] Stark BJ, Sullivan TJ. Biphasic and protracted anaphylaxis. J Allergy Clin Immunol 1986;78:
76–83.
[18] Sampson HA, Mendelson L, Rosen JP. Fatal and near-fatal food anaphylaxis reactions in
children. N Engl J Med 1992;327:380–4.
[19] LaRoche D, Vergnaud M, Sillard B, et al. Biochemical markers of anaphylactoid reactions
to drugs. Comparison of plasma histamine and tryptase. Anesthesiology 1991;75:945–9.
[20] Brown SGA, Blackman KE, Stenlake V, et al. Insect sting anaphylaxis: prospective evalua-
tion of treatment with intravenous adrenaline and volume resuscitation. Emerg Med J 2004;
21:149–54.
[21] Smith PL, Kagey-Sobotka A, Bleecker ER, et al. Physiologic manifestations of human ana-
phylaxis. J Clin Invest 1980;66:1072–80.
[22] Lieberman P, Kemp SF, Oppenheimer J, et al. Joint task force on practice parameters. The
diagnosis and management of anaphylaxis: an updated practice parameter. J Allergy Clin
Immunol 2005;115:S483–523.
[23] Project Team of the Resuscitation Council (UK). Emergency medical treatment of anaphy-
lactic reactions. J Accid Emerg Med 1999;16:243–7.
[24] Cummins RO, Hazinski MR, Baskett PJF, et al, editors. Guidelines 2000 for cardiopulmo-
nary resuscitation and emergency cardiovascular care: an international consensus on science.
American Heart Association in collaboration with the International Liaison Committee on
Resuscitation (ILCOR). Part 8: advanced challenges in resuscitation. Section 3: special chal-
lenges in ECC. Anaphylaxis. Circulation 2000;102(Suppl I):I241–3.
[25] American Heart Association in collaboration with International Liaison Committee on
Resuscitation. 2005 American Heart Association guidelines for cardiopulmonary resusci-
tation and emergency cardiovascular care. Anaphylaxis. Circulation 2005;112(Suppl IV):
IV143–5.
[26] Soar J, Deakin CD, Nolan JP, et al. European Resuscitation Council guidelines for resusci-
tation 2005. Section 7. Cardiac arrest in special circumstances. Resuscitation 2005;67(Suppl
1):S135–70.
[27] Gompels LL, Bethune C, Johnston SL, et al. Proposed use of adrenaline (epinephrine) in
anaphylaxis and related conditions: a study of senior house officers starting accident and
emergency posts. Postgrad Med J 2002;78:416–8.
[28] Clark S, Bock SA, Gaeta TH, et al. Multicenter study of emergency department visits for
food allergies. J Allergy Clin Immunol 2004;113:347–52.
ANAPHYLAXIS 191
[29] Haymore BR, Carr WW, Frank WT. Anaphylaxis and epinephrine prescribing patterns in
a military hospital: underutilization of the intramuscular route. Allergy Asthma Proc 2005;
26:361–5.
[30] Board of Directors. American Academy of Allergy and Immunology. Guidelines to mini-
mize the risk from systemic reactions caused by immunotherapy with allergenic extracts
[position statement]. J Allergy Clin Immunol 1994;93:811–2.
[31] WHO Position Paper. Allergen immunotherapy. Allergen immunotherapy: therapeutic vac-
cines for allergic diseases. Allergy 1998;53:S1–42.
[32] Caroline NL. Emergency care in the streets. 2nd edition. Boston: Little, Brown; 1983. p.
57–98.
[33] Pumphrey RS. Fatal posture in anaphylactic shock. J Allergy Clin Immunol 2003;112(2):
451–2.
[34] AAAAI Board of Directors. The use of epinephrine in the treatment of anaphylaxis. J Al-
lergy Clin Immunol 1994;94:666–8.
[35] Simons FER, Roberts JR, Gu X, et al. Epinephrine absorption in children with a history of
anaphylaxis. J Allergy Clin Immunol 1998;101:33–7.
[36] Simons FER, Gu X, Simons KJ. Epinephrine absorption in adults: intramuscular versus
subcutaneous injection. J Allergy Clin Immunol 2001;108:871–3.
[37] Song TT, Nelson MR, Chang JH, et al. Adequacy of the epinephrine auto-injector needle
length in delivering epinephrine to the intramuscular tissues. Ann Allergy Asthma Immunol
2005;94:539–42.
[38] Barach EM, Nowak RM, Lee TG, et al. Epinephrine for treatment of anaphylactic shock.
JAMA 1984;251:2118–22.
[39] Lieberman P. Use of epinephrine in the treatment of anaphylaxis. Curr Opin Allergy Clin
Immunol 2003;3:313–8.
[40] Westfall TC, Westfall DP. Adrenergic agonists and antagonists. In: Brunton LL, editor.
Goodman and Gilman’s the pharmacological basis of therapeutics. 11th edition. New
York: McGraw-Hill; 2006. p. 215–68.
[41] Toogood JH. Beta blocker therapy and the risk of anaphylaxis. Can Med Assoc J 1987;136:
929–33.
[42] Lang DM. Anaphylactoid and anaphylactic reactions. Hazards of B blockers. Drug Saf
1995;12:299–304.
[43] Toogood JH. Risks of anaphylaxis in patients receiving beta blocker drugs [editorial]. J Al-
lergy Clin Immunol 1988;81:1–5.
[44] Pollack CV. Utility of glucagon in the emergency department. J Emerg Med 1993;11:
195–205.
[45] Sherman MS, Lazar EJ, Eichacker P. A bronchodilator action of glucagon. J Allergy Clin
Immunol 1988;81:908–11.
[46] Thomas M, Crawford I. Best evidence topic report. Glucagon infusion in refractory anaphy-
lactic shock in patients on beta blockers. Emerg Med J 2005;22:272–3.
27 (2007) 193–212
Food Allergy and Anaphylaxis

Corinne A. Keet, MD, MS, Robert A. Wood, MD*
Department of Pediatrics, Johns Hopkins School of Medicine, CMSC 1102,
600 North Wolfe Street, Baltimore, MD 21287, USA
Food allergy is the most common cause of anaphylaxis. Up to one-fifth of

the United States population avoids a food at some point because of con-
cern about allergy, while 4% to 8% of children and 1% to 3% of adults
have food allergy confirmable on testing [1–6]. For reasons that have not
been explained fully, the incidence of food allergy is rising rapidly, and al-
lergies may be getting more severe. Food allergy can be life-threatening
and has effects on quality of life similar to other chronic diseases [7]. Al-
though understanding of the immune system has advanced tremendously
in recent years, basic mechanisms of tolerance and allergy remain obscure.
New therapies hold hope for prevention, amelioration, and even cure.
Pathophysiology of food allergy and anaphylaxis

Tolerance
Understanding the normal and pathologic immune response to food al-
lergens is a key part of understanding anaphylactic reactions to food. Un-
fortunately, mechanisms of both tolerance and sensitization have yet to be
elucidated fully. Oral tolerance is thought to occur through various
methods, including clonal anergy and deletion, active suppressive measures,
and conversion of T helper cell 2 (Th2) responses to T helper cell 1 (Th1)
and the more recently described T helper cell 3 (Th3) responses [8]. The rel-
ative contribution of each of these mechanisms is controversial, and may de-
pend on the dose and route of administration of the foreign protein. At low
doses, suppression may be accomplished by activation of regulatory T cells
[9]. At higher doses, anergy and clonal deletion are likely the mechanisms of
tolerance. Lack of inflammatory costimulatory signals may be a key compo-
nent of these mechanisms. Antigen presenting cells (APCs), such as active
E-mail address: rwood@jhmi.edu (R.A. Wood).
194 KEET & WOOD
dendritic cells, activated macrophages, and activated B cells, present T cells

with antigen and the appropriate costimulation for an inflammatory re-
sponse; nonprofessional APCs, such as resting dendritic cells, epithelial cells,
and naı̈ve B cells are thought to induce tolerance in T cells [10]. These non-
professional APCs are found in large numbers in the gut, perhaps explaining
the long-time observance that systemic tolerance can be induced by oral ad-
ministration of allergen. Regulatory cytokines, such as interleukin (IL)-4,
IL-10, and transforming growth factor (TGF)-beta, are produced by the
tolerized T cells and are import in maintenance of tolerance [8].
The allergic immune response is characterized by Th2 polarization. IL-4
and 5, which are produced by Th2 cells, promote class switching of B cells,
and thus IgE production and eosinophilia [8]. Clinically, allergic diseases
can be subdivided into those that are IgE-mediated, such as anaphylaxis,
atopic dermatitis, and allergic asthma, and those mediated by the cellular
immune system, such as eosinophilic gastroenteritis.
The developing immune system

Many factors likely contribute to the failure of development of tolerance
in allergy, including immature gastrointestinal (GI) and immunologic sys-
tems in infancy, lack of normal infectious stimuli, specific patterns of aller-
gen exposure, and genetic factors. Infants have an immature mucosal
surface, with increased intestinal permeability and decreased gastric acid
and pancreatic enzyme production. Thus, allergenic proteins are more likely
to be absorbed intact in infants than in older children and adults [9].
In addition to the GI system, the immune system is also immature in in-
fants. The newborn’s immune system is skewed toward Th2 responsiveness.
Normally, the balance between T helper cells shifts toward a Th1-dominated
response to food proteins by age 5. In allergic disease, the Th2 response
instead is amplified [8]. It is thought that the developing immune system
requires particular stimuli for the attainment of this functional oral
tolerance. Experiments with germ-free mice show that it is difficult to induce
tolerance without intestinal microflora, and that germ free mice lack fully
developed gut-associated lymphoid tissue, which may play a role in suppres-
sion and anergy [11]. In people, observational data point to a protective ef-
fect of certain types of early childhood infections. There is now a body of
evidence that shows that having older siblings, living on a farm, and early
daycare are protective against allergic disease [12,13]. For specific infections,
the data are mixed, suggesting that certain infections are protective, while
others may increase the risk of allergic disease [14].
Manner of allergen exposure

Type, frequency, and route of exposure to allergens are factors in devel-
opment of a pathologic response to food, although the specific ways that
FOOD ALLERGY AND ANAPHYLAXIS 195
exposure affects allergy remain unclear. Some of the previous suppositions

about sensitization have been challenged recently, with implications for at-
tempts at primary prevention of food allergy. Consumption patterns cer-
tainly explain some of the geographical differences in rates of food
allergy. Peanut allergy rates are higher in countries like the United States
and United Kingdom, where rates of consumption are high. Shellfish, fish,
and sesame allergy are much higher in areas where these foods are staples
of the diet. Some have suggested that the increasing rate of peanut allergy
is caused by increased consumption of peanut by pregnant and lactating
women, and by earlier exposure to peanut in children’s diets, although
this is controversial [15]. Exposure levels themselves, however, do not ex-
plain population differences in allergy, much less why an individual will
become allergic.
Both quantity and conformation of allergic proteins can be changed by
gastric breakdown. Interruption of the normal gastric breakdown of pro-
teins by antacid administration has been shown to increase IgE levels
against dietary proteins [16]. This may be caused by degradation of allergens
by gastric acids, as for example, with parvoalbumin, the major fish allergen,
which has been shown to bind to IgE with less avidity, and to trigger hista-
mine release at much lower levels after exposure to gastric acids [17]. The
relative lack of gastric acidity in infants may be yet another reason that
they are at such high risk for food allergy.
Sensitization to food allergens is not limited to the gut. Use of peanut oil-
containing body products in infants has been associated with a higher rate
of peanut sensitization [18]. For shellfish allergy, a growing body of evidence
links dusts mite and cockroach aeroallergy to sensitization to shellfish. One
of the allergenic proteins shared by dust mite, cockroaches, and crustaceans
is tropomyosin. A study of orthodox Jews who had never consumed shell-
fish, but were sensitized to dust mite, found a high rate of skin prick sensi-
tivity to shellfish, indicating that sensitization can happen without direct
contact with shellfish [19]. This may help explain why shellfish allergy, in
contrast to most other allergy, begins at later ages. The pollendfood allergy
syndrome is perhaps the clearest example of aeroallergy causing food al-
lergy. This typically mild allergy affects about one half of pollen-allergic
adults, and consists of oral symptoms on exposure to raw fruits, vegetables,
and nuts in patients who are allergic to pollen that shares homologous
proteins with the foods [20].
The role of cross reactivity, timing of exposure, and type of allergen expo-
sure in development still are being worked out. At this time, a unified theory
explaining the role of exposure in development of allergy remains elusive.
Genetics
Genetic risk factors are also important for the development of food
allergy. Peanut allergy is more common in siblings of peanut-allergic
196 KEET & WOOD
patients than the general population [15], much more common in mono-
zygotic twins than in dizygotic twins [21], and more common in children
of atopic mothers. Atopic disease, in general, has been shown to be genet-
ically determined, at least in part [22,23]. Linkage analyses have provided
candidate areas of interest on the human genome [24], but the specific
genetic basis for allergic disease has yet to be found, and allergy is likely
polygenic.
Anaphylaxis
The pathophysiology of anaphylaxis is reviewed in more detail in the ar-
ticle by Brown elsewhere in this issue. Anaphylaxis to food is a multiorgan
system response that occurs when antigen binds to membrane-associated
IgE on mast cells and basophils, causing the release of inflammatory medi-
ators. The mediators of anaphylaxis include histamine and other products of
arachidonic acid metabolism, proteoglycans such as heparin, and neutral
proteases such as tryptase and chemo–attractants. Histamine, which can re-
produce most of the symptoms of anaphylaxis when administered intrave-
nously to laboratory animals, binds to both H1 and H2 receptors. This
causes smooth muscle spasm and vasodilatation and increases vascular per-
meability, eosinophil activation, and other effects. Tryptase and the other
neutral proteases have various effects, including further activation and de-
granulation of mast cells [25].
There is some evidence that the pathophysiology of food-induced ana-
phylaxis differs from that of other types of anaphylaxis. In contrast to fatal
venom- and drug-induced anaphylaxis, death by food-induced anaphylaxis
almost always is caused by respiratory collapse. Distributive shock is seen
infrequently, and almost never is seen in isolation. Some have suggested
that basophils, rather than mast cells, are the predominant cells involved
in severe food anaphylaxis. One piece of evidence for this is the apparent
less frequent elevation of tryptase in cases of severe food-induced anaphy-
laxis [26–28]. Tryptase is concentrated preferentially in mast cells, rather
than in basophils, whereas histamine and other mediators are found in
both cells. In a series described by Yunginger and colleagues [29], only six
of eight food-induced anaphylaxis victims had an elevation of tryptase, com-
pared with nine of nine with hymenoptera stings, and two of two fatalities
caused by diagnostic agents. Sampson and colleagues [28] reported on serial
measurements of tryptase in five cases of food-induced anaphylaxis in 1992.
In only one measurement was tryptase elevated above 2.5 ng/mL, and in
that case only slightly so. These were very small series, however, and the
data are mixed [30]. Whether these findings indicate true pathophysiological
differences in the role of basophils versus mast cells remains to be elucidated.
In the absence of further data, tryptase, which has been advocated as a diag-
nostic tool for anaphylaxis, cannot be said to be a reliable diagnostic tool
for cases of food-induced anaphylaxis.
Epidemiology
The epidemiology of anaphylaxis is discussed in more detail in the article
by Camargo and Clark elsewhere in this issue. To date, there have been no
large-scale prospective studies of the incidence of anaphylaxis. Retrospective
analysis in one county, Olmstead, Minnesota, placed the incidence at 21 per
100,000 person–years [31]. In another study of children in a large health
maintenance organization (HMO), the incidence ranged from 10.5 per
100,000 person–years (range 8.1 to 13.8 per 100,000 person–years) using the
most specific codes, to an estimated 68.4 per 100,000 person years if nonspe-
cific codes were used [32]. In the United Kingdom, analysis of Health Service
data gave a crude estimate of 8.4 per 100,000 person–years [33]. The diag-
nostic criteria for anaphylaxis remain controversial, and the diagnostic codes
for anaphylactic reactions to food have been shown to miss many true
cases of anaphylaxis, while capturing cases that are not anaphylaxis [32].
Consensus definitions of anaphylaxis will be required before a true estimate
of incidence can be made. Based on the most conservative estimate, about
25,000 cases of anaphylaxis occur each year in the United States.
Contribution of food allergy to anaphylaxis

The contribution of food allergy to anaphylaxis varies across series, rang-
ing from 15% to 57% of cases of anaphylaxis [33–38]. Nuts, fish, and
shellfish are consistently the most common food allergens triggering ana-
phylaxis, with dairy, eggs, fruits, and vegetables also common causes. As
discussed previously, the relative contribution of these foods varies by age
and geography, according to both the natural history of food allergy and
the patterns of exposure. Foods that frequently cause anaphylaxis in one
region may not be a part of the diet in another part of the world.
Incidence and prevalence of food allergy

As with anaphylaxis, determining the true incidence of food allergy is
hindered by a lack of uniform definitions, geographical and age heterogene-
ity, and lack of standardized reporting. Unlike anaphylaxis, however, there
are several prospective studies of the incidence of food allergy. In a classic
study, Bock [6] followed 480 children from birth to age 3. Adverse reactions
to foods were described by parents in 28% of children, but in only 8% were
these symptoms reproduced in open or blinded food challenges. Thirty-five
percent of 3623 children were reported to have at least one adverse reaction
to a food by age 2 in a series of surveys done by Eggesbo and colleagues [39].
These reports were not confirmed by food challenge or further testing, how-
ever. Venter and colleagues [40] followed 969 children from birth to 12
months. Overall, adverse reactions to food were reported in one quarter
of children, and were confirmed in 4% of children. Rates of self-reported
food allergy are lower in older children and adults, although, in general, still
198 KEET & WOOD
substantially higher than confirmed rates. Rates of self-reported allergy

range from 4.6% to 22% across developed countries. When confirmed by
skin testing, history and/or food challenge, the rates of food allergy are
1.5% to 3.2% in older children and adults [1–5].
To both physicians and the lay public, food allergy seems to be increasing
at an alarming rate. This anecdotal feeling is confirmed by epidemiologic
studies. Sicherer and colleagues [41] conducted telephone surveys of United
States households to assess for the rate of nut allergy. They used the same
methodology in 1997 and 2002, and found a 100% increase in the rate of
nut allergy [41,42]. Other atopic diseases, in general, also are increasing,
although it appears that this increase has been occurring over a somewhat
longer time period [43].
This rapid increase in prevalence makes it difficult to precisely define the
prevalence of nut allergy. The survey studies done by Sicherer found a rate
of 1.2% of overall nut allergy in children in 2002 [41]. Other surveys and
studies that confirmed allergy by testing have found rates of nut allergy
between 0.5% and 1.5% of the overall population of the United Stats and
United Kingdom [41,42,44].
In contrast to peanut and tree nut allergy, in which children have a rate of
allergy greater than or equal to that of adults [44], adults are more than four
times as likely as children to have a convincing history of reaction to shell-
fish. In a survey of 5529 households and 14,948 individuals, convincing
shellfish allergy was reported in 2.5% of adults and 0.5% of children,
with an overall rate of 2.0% in the population as a whole. Fish allergy,
which is immunologically distinct from shellfish allergy, was reported in
0.2% of children and 0.5% of adults in that same study [45].
Cow’s milk allergy is estimated to effect 2% to 3% of infants in the de-
veloped world [46–48], with a sharp drop off after age 1. Data from a pop-
ulation study of allergy in general placed the rate of hen’s egg allergy at
1.6% in children, but the rate of sensitivity is much higher in children
who have eczema [5,49].
Natural history
Cow’s milk
Cow’s milk is the first allergen to which infants commonly react. Both
IgE and non-IgE mediated allergic reactions are common, especially in in-
fancy. Although allergy occurs in 0.5% of breastfed infants, it is much
more common in formula-fed infants, often occurring in the first week after
introduction of cow’s milk-based formulas [48]. GI and cutaneous reactions
are most common, while respiratory symptoms develop in 20% to 30% of
patients [46,50]. In population-based studies, approximately one half of in-
fants with both IgE- and non-IgE-mediated cow-s milk protein allergy
recovered completely by 1 year of age. Sixty percent to 75% recovered by

age 2, and 85% to 90% recovered by age 3 [47,48]. For those referred to
an allergist for care, the prognosis is worse. In series from allergists’ offices,
recovery rates vary widely, with 22% to 67% of children with IgE-mediated
milk allergy and 38% to 86% of non-IgE-mediated milk allergy recovering
during follow-up [51]. As these data show, children with non-IgE-mediated
milk allergy have earlier and more complete recovery. Despite the generally
high rates of recovery from cow’s milk allergy, these patients have a high
risk of developing other allergies, with 50% developing adverse reactions
to other foods by age 3, and 50% to 80% developing inhalant allergies
[47,48].
Egg, wheat, and soy allergy

Egg allergy has been studied less than cow’s milk allergy, but it is thought
to recede by school age [39,51–53]. Egg allergy is associated strongly with
atopic dermatitis, and egg-allergic children have more severe and persistent
atopic dermatitis [54]. There is even less study devoted to wheat and soy al-
lergy. From the larger studies of allergy development and persistence in gen-
eral, it appears that these allergies frequently are lost by the age of 3
[6,55,56].
Peanuts and tree nuts

As children grow, peanut and tree-nut allergies remain among the most
important food allergies. In a registry of 5149 people who had peanut or
tree nut allergy, the median age of reaction to peanuts was 14 months,
and the median age of reaction to tree nuts was 36 months. Before the first
allergic reaction, there was no known previous exposure in 74% of peanut-
and 68% of tree nut-allergic subjects. Anaphylaxis was commonly the man-
ifestation of allergy, with more than one half of subjects reporting greater
than one organ system’s involvement [57]. It should be emphasized to clini-
cians and patients that at each subsequent reaction, a higher proportion of
patients had severe symptoms and required treatment with epinephrine
[58,59].
Until recently, it was thought that peanut and tree nut allergies were uni-
versally life-long. This thinking has been revised. It now is understood that
approximately 20% of children outgrow peanut allergy, including some who
previously had anaphylactic reactions and high initial peanut IgE. Patients
who are able to successfully strictly avoid peanuts are more likely to out-
grow their allergy, but initial reactivity, atopic disease, and other food aller-
gies have not been shown to predict consistently whether a patient will
outgrow peanut allergy [60]. Rechallenge may be appropriate when peanut
IgE falls to 5 kua/L or lower, when more than half may be expected to have
outgrown their allergy, and is even more likely to be successful at peanut
200 KEET & WOOD
IgE levels less than 2 kua/L. Eight percent of children who outgrow their
peanut allergy have a recurrence, and this risk is higher for those who con-
tinue to avoid peanut after passing a food challenge [61]. For tree nut al-
lergy, approximately 9% outgrow their allergy. Fleisher and colleagues
[62] recommend that patients 4 years or older with tree nut IgE levels less
than or equal to 5 kua/L be considered for food challenge.
Shellfish allergy
Although data directly reporting the age of onset of shellfish allergy are
not available, the natural history can be inferred from data showing that
shellfish allergy is reported in only 0.1% of children aged 0 to 5 years and
0.8% of children aged 6 to 17 years, but is reported in 2.6% and 3.3% of
18- to 40-year-olds and 41- to 60-year-olds, respectively [45]. It generally
is thought that shellfish allergy is permanent, although no studies systemat-
ically addressing this hypothesis are available.
Clinical presentation of food-induced anaphylaxis

Timing of onset
Anaphylaxis to food typically develops rapidly after exposure. In a series
of children with anaphylaxis referred to an allergist, 57% of whom had re-
acted to food, the mean latent period between ingestion and symptoms was
15.4 minutes [63]. In a series of fatal and near-fatal cases of anaphylaxis
caused by food, all had symptoms within the first 30 minutes after exposure,
most within the first 5 minutes [28]. In contrast, for allergic reactions to food
presenting to the emergency room, the latent period is longer, in general,
with a median of 2 hours [64]. The more severe the reaction, the earlier it
seems to occur after exposure [28].
Symptoms
The skin and respiratory system are the most commonly affected systems
in food-induced anaphylaxis, with symptoms in 76% and 80%, respectively,
of children in one series. Skin manifestations are not limited to urticaria,
and can include generalized flushing. The GI system is involved more often
than in other types of anaphylaxis (41% of food-induced anaphylaxis com-
pared with 3.7% of food-independent anaphylaxis in that same series) [63].
Initial cardiovascular involvement is rare, and it is atypical for a patient to
have isolated cardiovascular symptoms without respiratory arrest, even in
severe or fatal cases [28,63,65,66].
Time course of reactions

Reactions can be uniphasic, biphasic, or protracted. Limited evidence
suggests that biphasic reactions may be more common in cases of enteral
allergen exposure compared with parenteral allergen exposure [67]. Biphasic

and protracted reactions were each reported in 3 of 13 cases of near-fatal or
fatal food-induced anaphylaxis by Sampson and colleagues [28]. Biphasic re-
actions may be more common in cases of inadequate or delayed epinephrine
administration [67].
Food-induced fatalities
Fatal anaphylactic reactions to food are the most feared outcome of food
allergy, but they occur only rarely. Yunginger and colleagues [27] compiled
the first case series of fatal food-induced anaphylaxis, providing a descrip-
tion of seven patients who died within a 16-month period throughout the
United States. This was followed by series of six children and adolescents
who had fatal reactions to food and seven who nearly died identified by
Sampson and his colleagues in 1992 [28]. In 2001, Bock and colleagues
[68] reported on 32 fatal cases of anaphylaxis that were reported to the
Food Allergy and Anaphylaxis Network (FAAN) between 1994 and 1999.
Although small, and with designs that likely do not capture atypical reac-
tions or those that occurred in individuals without a history of food allergy,
these series identify several risk factors of importance for fatal food-induced
anaphylaxis.
Asthma
Most salient in these descriptions is the history of asthma in almost all
patients with fatal anaphylactic reactions. In Yunginger’s report, all four pa-
tients for whom history was available had a history of asthma [27]. All 13
patients in Sampson’s report had a history of asthma, and in Bock’s study,
only one patient for whom a history was available did not have a history of
asthma [28,68]. The importance of history of airway hyper-reactivity is un-
derscored by the fact that respiratory arrest is the mechanism of almost all
food-induced anaphylaxis fatalities [66].
Foods most commonly causing fatalities

Nuts are the cause of most fatal cases of anaphylaxis to food in the
United States and the United Kingdom, with peanuts accounting for 50%
to 62% of fatalities, and tree nuts accounting for 15% to 30% of fatalities
in several series [27,28,66,68]. Other causes of fatal reactions have been shell-
fish, fish, milk, eggs, and fruit. Nearly all patients had a known history of
allergy to the food to which they had a fatal reaction, but before reaction,
nearly all subjects did not know that the food to which they were allergic
was an ingredient in the food they were about to consume. Restaurants
and educational settings were the most common locations of fatal reactions.
202 KEET & WOOD
Baked goods and candy, Chinese food, and Mexican food were the most
common foods that contained the undisclosed ingredients [27,28,68].
Lack of timely treatment

Despite the prior history of food allergy in almost all patients, and the
history of severe reactions in many, lack of immediately available epineph-
rine was another factor that most fatalities shared. Of 32 patients in Bock’s
series, only four were known to have received epinephrine in a timely way
[68]. None of the seven patients in Yunginger’s series or the six patients in
Sampson’s series were given epinephrine immediately after symptom onset.
Many of the patients did, however, take oral antihistamines, apparently
believing that this medication would be sufficient treatment [27,28].
Diagnosis
The diagnosis of an anaphylactic episode is reviewed in detail here and in
the article by Kemp elsewhere in this issue [69]. Anaphylaxis usually is de-
fined by the involvement of two or more organ systems, and is characterized
by:
Respiratory symptoms, including wheeze and stridor
GI symptoms, including abdominal pain and vomiting
Cutaneous symptoms, such as urticaria, flushing, and angioedema
Cardiovascular symptoms, such as hypotension and shock
For individuals with a history of allergic reaction, fewer symptoms are re-
quired for definition if the individual has a suspected exposure. A high index
of suspicion for anaphylaxis should be maintained, as cases can present
atypically [69].
Determining which, or if, food caused an anaphylactic episode is not al-
ways obvious by history alone. Allergens commonly are mixed with other,
nonallergic foods, so identification of the specific allergen can be initially
challenging. The most important diagnostic aids are measurements of IgE
levels and skin tests. Food challenge is the gold standard for diagnosis of
food allergy, but is often not necessary in cases where history and diagnostic
testing are strongly suggestive of a food allergy. Attempts to use these tests
to predict severity of community reactions have been mixed.
Skin testing
Skin puncture or prick testing historically has been the mainstay of diag-
nosis for IgE-mediated food allergy. Purified allergen is introduced percuta-
neously, and the resulting size of reaction is measured. Traditionally,
a reaction of more than 3 mm has been considered positive. The sensitivity
of skin testing is high, but specificity is poor, and in many clinical
populations the positive predictive value for clinical reaction is low. At-
tempts to improve the specificity by setting higher cutoffs have been mixed,
but, in general, the larger the reaction, the more likely a patient is to have
a clinical response on food challenge [70,71]. Skin testing is not recommen-
ded in patients who have severe skin conditions that could interfere with the
test, who are pregnant, or who are taking medicines, such as antihistamines,
that can interfere with skin reactivity. Infants have smaller reactions,
reducing the sensitivity in this age group [72].
IgE levels
Whereas skin tests are a measure of bound IgE, serum tests of IgE di-
rectly measure circulating IgE. Like skin tests, IgE assays are more sensitive
than specific. Perry and colleagues [73] looked at a retrospective series of
children who had food challenge and IgE levels available. They determined
that the 50% food challenge pass level was 2 kua/L for milk, egg, and pea-
nut, while the data were less clear for wheat and soy [73]. Sampson and Ho
[74] reported on the IgE levels where 95% of subjects had a positive food
challenge and found that they were: egg (6 kua/L), milk (32 kua/L), peanut
(15 kua/L), and fish (20 kua/L) [75]. For a given patient, the positive predic-
tive value of these tests will depend on the likelihood that the patient’s
history was consistent with an allergic reaction to a specific food.
Food challenge
When the cause of an anaphylactic episode remains obscure, either
because of continued reactions despite following an elimination diet, or be-
cause of nondiagnostic history and testing, a food challenge may be appro-
priate. Food challenges can be open, single-blinded (to the patient), or
double-blinded (to both the patient and physician). For diagnosis of foods
thought to be responsible for an anaphylactic reaction, open challenges
are generally reasonable. These challenges should happen under physician
supervision, and where emergency equipment is available.
Severity index
Currently, IgE levels, skin prick tests and food challenges, are used as di-
chotomous tests, giving the patient and clinician an answer only to the ques-
tion of whether a patient is likely to react to a food in the community, but
have not been used to predict the severity of possible reactions. The search
to evaluate whether these tests have qualitative predictive value is hindered
by the lack of standardized systems for reporting severity. Hourihane and
his colleagues [76] have developed a scoring system for reactions to peanut
in the community or during low-dose double-blinded placebo-controlled
food challenge (DBPCFC); in this system the estimated dose of exposure
and the extent of systems elicited are included in the score. When they
204 KEET & WOOD
used this severity index, they did not find a significant correlation between
severity scores in the community or on DBPCFC and IgE or skin tests. Van-
der Leek and colleagues [59] did find that children who had only skin reac-
tions on exposure to peanut had significantly lower levels of IgE than those
who had more severe reactions, but overlap of IgE levels between groups ne-
gated any clinical relevance for the individual patient. Similarly, Spergel and
colleagues [77] did not find any significant relationship between size of skin
wheal and severity of reaction on food challenge. Wensing and colleagues
[78] found a relationship between threshold dose on DBPCFC and severity
of reaction in the community, but while Hourihane and his colleagues [76]
also found that the severity of reaction in the DBPCFC was related to the
severity of the most recent community reaction, this association was weak
(r ¼ 0.37, P ¼ .03). One reason for this lack of association is that the
dose of community exposure varies widely. At this time, the severity index
has found utility only for research. Clinical features such as asthma (as
outlined previously) are currently the best predictors of a severe reaction.
Treatment
Treatment of anaphylaxis is reviewed in more detail in the article by Si-
mons elsewhere in this issue and in a recent Joint Task Force on Practice
Parameters [69]. Currently, the main approaches to food-related anaphy-
laxis are avoidance of triggers, and, when that fails, timely administration
of epinephrine. Children especially, require close monitoring to ensure
that nutrition is adequate, to continue education, and to assess for remission
of allergies.
Avoidance
Patients, and when appropriate, their parents, should be educated about
the need for allergen avoidance and potential pitfalls. They should be taught
about foods that are most likely to contain hidden ingredients. For peanuts,
tree nuts and milk, those foods are baked goods, candy, and snack foods.
Eating in restaurants can be particularly challenging, and patients should
be educated about the importance of communicating with restaurant staff
about ingredients. Asian and Mexican restaurants have been common sites
of hidden nuts and should be approached with care [28,68].
Label reading is an important skill that must be imparted. New regula-
tory requirements for food labeling came into effect in 2006, with the
Food Allergen Labeling and Consumer Protection Act (FALCPA). This
act requires that sources of ingredients derived from commonly allergenic
sources be labeled using ‘‘plain English language.’’ For purposes of this
law, milk, eggs, fish, crustacean shellfish, peanuts, soybeans, wheat, and
tree nuts are identified as the most common allergenic foods. Highly refined
oils are exempted [79]. These regulations do not address accidentally in-
cluded ingredients. Although there are no regulations mandating labeling
of nonintentional ingredients, companies have adopted systems that identify
such potential exposures. In the United States, commonly used labels are
‘‘may contain,’’ ‘‘manufactured on shared equipment with,’’ and ‘‘manufac-
tured in shared facility with.’’ Patients who have had an anaphylactic reac-
tion to an allergen should avoid food that is labeled with ‘‘may contain’’ and
‘‘manufactured on shared equipment with’’ for that allergen. Whether a pa-
tient should avoid food labeled ‘‘manufactured in a shared facility with’’
depends on the particular allergen, and the patient’s individual medical
history.
Highly processed foods

Because processing can affect the level of allergenic proteins in end prod-
ucts strongly, the new labeling requirements may cause unnecessary dietary
restrictions. Current labeling may cause overavoidance of some foods. For
example, fish-allergic individuals have been shown to tolerate high levels of
fish gelatin [80]. Soy lecithin and soy oil, which are common ingredients in
various processed foods, contain only very small amounts of soy allergen
[81]. The new regulations require only that a food be labeled ‘‘contains
soy,’’ ‘‘contains fish,’’ and similar labels, which leaves the allergic patient
to guess if a food contains a significant amount of the labeled allergen. Al-
though the new requirements are an improvement over the state of labeling
previously, where allergens could go unlabeled or be lumped under the term
‘‘natural flavoring,’’ they do not ensure complete clarity regarding the
potential risks of processed foods to allergic patients [82].
Threshold doses
For both the individual food-allergic patient and the manufacturing in-
dustry, determining threshold doses of allergic proteins below which most
of the food-allergic population is unlikely to react is a way toward clarity
regarding allergen avoidance and labeling [82,83]. Although there is
a body of literature available that relates to threshold doses for some of
the major allergens, including peanut, cow’s milk and egg, a roundtable con-
ference of prominent allergists in 1999 was not able to produce a consensus
statement regarding threshold doses for even those foods. Reported series of
food challenges use different forms of allergen, generally exclude patients
who have a history of severe reactions, define positive results in different
ways, and start with different quantities of allergic foods. Many patients re-
act to the first administered dose of allergen, which likely results in systemic
overestimation of threshold doses for reaction [84]. In response to these
problems, a roundtable of prominent food allergists was convened in 2002
to establish consensus recommendations for design of studies of threshold
206 KEET & WOOD
doses. They agreed on a format for these studies and suggested ways to sys-
tematically assess threshold levels for antigens [85].
In the studies done up to the time of the consensus recommendations, re-
actions were reported during food challenges to as little as 1 mg of peanut,
1 mg of egg, 0.02 mL of milk, 5 mg of fish, and 1 mg of mustard [84].
Resources
The impact of food allergy on quality of life has been shown to be similar
to other chronic diseases [7], and patients need ongoing support. FAAN is
source of reliable information and support services. (www.foodallergy.org
or 1-800-929-4040). As patients become teenagers, they are at highest risk
for severe anaphylactic reactions, and basic avoidance techniques may
need to be revisited by their primary care physicians and allergists [27,28,
66,68].
Epinephrine
When avoidance has failed, and an anaphylactic reaction ensues, epi-
nephrine is the mainstay of treatment. Lack of timely epinephrine treatment
is a common factor in fatal anaphylactic reactions [28,29,68]. Even after the
patient is in the emergency department, epinephrine infrequently is given
during acute attacks [35,64,65]. In a recent multicenter study of anaphylaxis
treatment in emergency rooms in the United States, less than one quarter of
patients with severe anaphylaxis were given epinephrine. Physicians do an
even poorer job of prescribing self-administered epinephrine to patients
who are at risk for anaphylaxis [64]. All patients who have potential for ana-
phylactic reactions should have ready access to epinephrine wherever they
are, and prescriptions should be given at the time of emergency treatment
for food allergy. Use of self-administered intramuscular epinephrine should
be taught to patients and/or their parents, and enough should be prescribed
so that it is available at all locations where they commonly spend time. Pa-
tients should give themselves epinephrine at the first sign of a potential ana-
phylactic reaction to a food, and proceed immediately to an emergency
room. Because many patients will require more than one dose of epineph-
rine, twin or dual packs of epinephrine are being marketed; patients would
self-administer another dose of epinephrine if they still had anaphylactic
symptoms 10 minutes after the first dose. Although these packs may be help-
ful, they are not a substitute for emergency medical attention. In addition,
health care providers need to emphasize to patients that antihistamines
are not effective for sole treatment of anaphylactic reactions.
Continued monitoring
Because such a high percentage of children allergic to milk, egg, soy, and
wheat outgrow their allergies, early and frequent monitoring to assess for
remission is warranted, as described previously. Nutritional monitoring is

vital, especially in children allergic to milk or wheat. At each visit, patients
should be asked about which foods they have been avoiding, and diets
should be assessed to make sure that they adequately provide both macro-
and micronutrients. Height and weight should be compared with growth
curves, as these children are at risk for malnutrition [86].
Future directions for therapy

Recent years have seen the initial development of several promising strat-
egies for food allergy treatment. Because there is not space to discuss all of
the avenues of current research here, this article focuses on a few treatments
that have shown early successes.
One area of active interest has been the use of anti-IgE therapy for peanut
allergy. In 2003, Leung and colleagues [87] described a double-blind pla-
cebo-controlled study of TNX-901, a monoclonal antibody that binds to
IgE, preventing interaction of IgE with mast cells and basophils. TNX-901
was given subcutaneously every 4 weeks. After 4 months, oral food-challenge
threshold doses of peanut increased for all dosages of TNX-901, although
only by a significant amount in the group given the highest dose (450 mg).
In that group, the threshold for reaction to peanut increased from ap-
proximately one half peanut to almost nine peanuts [87]. Although this
experimental drug was tolerated well, it suffers from several limitations.
Monoclonal antibody pharmaceuticals are very expensive. The duration of
effect was not studied; theoretically, protection is likely to wane quickly as
antibodies degrade. Thus, patients would need regular injections indefinitely.
Moreover, although threshold doses for reaction increased, peanut allergy
was not cured, and peanuts must still be avoided.
Given the success of immunotherapy for inhaled allergens, it might be
thought that immunotherapy for food allergy would be a logical treatment
modality. Although subcutaneous immunotherapy was shown to decrease
reactivity to peanut in one trial, patients had very high rates of systemic
reactions, some severe, during treatment [88]. Sublingual immunotherapy
may be an equally effective but safer alternative. Recently, Enrique and col-
leagues [89] conducted a randomized double-blinded placebo-controlled
trial of sublingual hazelnut extract in patients with hazelnut allergy. Fifty
percent of the treated patients were able to tolerate the highest tested dose
of hazelnut (20 g), and the mean threshold dose increased fivefold. Although
localized symptoms to therapy were common, systemic reactions were very
rare.
In another attempt to create a safer kind of immunotherapy, researchers
are modifying allergenic proteins so that they stimulate T cells without
cross-linking IgE and causing mast cell and basophil degranulation. Both
peptide fragments and mutated proteins that lack affinity for IgE are being
208 KEET & WOOD
used. Mutated proteins have proven very effective in a mouse model, while
peptide fragments were effective when used in cat-allergic patients [90]. Hu-
man trials of using modified peanut protein will be starting this year.
Herbal treatments for food allergy long have been used in China, and are
another potential therapy for food allergy being evaluated in the United
States. In a mouse model of peanut allergy, an herbal formula (FAHF-1)
consisting of traditional Chinese herbs completely blocked anaphylactic re-
actions to peanut without significant adverse effects [91]. Animal studies of
the formula and its components are ongoing, and human trials hopefully
will start in the next few years.
Summary
As understanding of the physiology of tolerance and allergy advances,
prospects for prevention, treatment, and cure of food allergy improve. There
are several promising experimental treatments for food allergy in develop-
ment, and ongoing prospective studies are exploring how allergy may be
prevented. In the meantime, avoidance of allergenic foods and timely
administration of epinephrine remain the mainstays of treatment for food-
allergic patients. Monitoring for proper nutrition and remission of food
allergy, as well as continued education and support, are necessary comple-
ments to these interventions.
References
[1] Venter C, Pereira B, Grundy J, et al. Prevalence of sensitization reported and objectively as-
sessed food hypersensitivity amongst six-year-old children: a population-based study. Pe-
diatr Allergy Immunol 2006;17(5):356–63.
[2] Pereira B, Venter C, Grundy J, et al. Prevalence of sensitization to food allergens, reported
adverse reaction to foods, food avoidance, and food hypersensitivity among teenagers. J Al-
lergy Clin Immunol 2005;116(4):884–92.
[3] Woods RK, Thien F, Raven J, et al. Prevalence of food allergies in young adults and their
relationship to asthma, nasal allergies, and eczema. Ann Allergy Asthma Immunol 2002;
88(2):183–9.
[4] Woods RK, Abramson M, Bailey M, et al. International prevalences of reported food aller-
gies and intolerances. Comparisons arising from the European Community Respiratory
Health Survey (ECRHS) 1991-1994. Eur J Clin Nutr 2001;55(4):298–304.
[5] Osterballe M, Hansen TK, Mortz CG, et al. The prevalence of food hypersensitivity in an
unselected population of children and adults. Pediatr Allergy Immunol 2005;16(7):567–73.
[6] Bock SA. Prospective appraisal of complaints of adverse reactions to foods in children dur-
ing the first 3 years of life. Pediatrics 1987;79(5):683–8.
[7] Sicherer SH, Noone SA, Munoz-Furlong A. The impact of childhood food allergy on quality
of life. Ann Allergy Asthma Immunol 2001;87(6):461–4.
[8] Prescott SL, Macaubas C, Smallacombe T, et al. Development of allergen-specific T-cell
memory in atopic and normal children. Lancet 1999;353(9148):196–200.
[9] Nowak-Wegrzyn A, Sampson HA. Adverse reactions to foods. Med Clin North Am 2006;
90(1):97–127.
[10] Smith KM, Eaton AD, Finlayson LM, et al. Oral tolerance. Am J Respir Crit Care Med
2000;162(4 Pt 2):S175–8.
[11] Sudo N, Aiba Y, Oyama N, et al. Dietary nucleic acid and intestinal microbiota synergisti-
cally promote a shift in the Th1/Th2 balance toward Th1-skewed immunity. Int Arch Allergy
Immunol 2004;135(2):132–5.
[12] Strachan DP. Hay fever, hygiene, and household size. BMJ 1989;299(6710):1259–60.
[13] McKeever TM, Lewis SA, Smith C, et al. Siblings, multiple births, and the incidence of al-
lergic disease: a birth cohort study using the West Midlands general practice research data-
base. Thorax 2001;56(10):758–62.
[14] Liu AH, Leung DY. Renaissance of the hygiene hypothesis. J Allergy Clin Immunol 2006;
117(5):1063–6.
[15] Hourihane JO, Dean TP, Warner JO. Peanut allergy in relation to heredity, maternal diet,
and other atopic diseases: results of a questionnaire survey, skin prick testing, and food chal-
lenges. BMJ 1996;313(7056):518–21.
[16] Untersmayr E, Jensen-Jarolim E. Mechanisms of type I food allergy. Pharmacol Ther 2006;
112:787–98.
[17] Untersmayr E, Poulsen LK, Platzer MH, et al. The effects of gastric digestion on codfish
allergenicity. J Allergy Clin Immunol 2005;115(2):377–82.
[18] Lack G, Fox D, Northstone K, et al. Factors associated with the development of peanut
allergy in childhood. N Engl J Med 2003;348(11):977–85.
[19] Fernandes J, Reshef A, Patton L, et al. Immunoglobulin E antibody reactivity to the major
shrimp allergen, tropomyosin, in unexposed Orthodox Jews. Clin Exp Allergy 2003;33(7):
956–61.
[20] Ma S, Sicherer SH, Nowak-Wegrzyn A. A survey on the management of pollen–food allergy
syndrome in allergy practices. J Allergy Clin Immunol 2003;112(4):784–8.
[21] Sicherer SH, Furlong TJ, Maes HH, et al. Genetics of peanut allergy: a twin study. J Allergy
Clin Immunol 2000;106(1 Pt 1):53–6.
[22] Rasanen M, Laitinen T, Kaprio J, et al. Hay feverda Finnish nationwide study of adolescent
twins and their parents. Allergy 1998;53(9):885–90.
[23] Lichtenstein P, Svartengren M. Genes, environments, and sex: factors of importance in
atopic diseases in 7-9-year-old Swedish twins. Allergy 1997;52(11):1079–86.
[24] Kere J, Laitinen T. Positionally cloned susceptibility genes in allergy and asthma. Curr Opin
Immunol 2004;16(6):689–94.
[25] Lieberman P. Anaphylaxis. Med Clin North Am 2006;90(1):77–95, viii.
[26] Lin RY, Schwartz LB, Curry A, et al. Histamine and tryptase levels in patients with acute
allergic reactions: an emergency department-based study. J Allergy Clin Immunol 2000;
106(1 Pt 1):65–71.
[27] Yunginger JW, Sweeney KG, Sturner WQ, et al. Fatal food-induced anaphylaxis. JAMA
1988;260(10):1450–2.
[28] Sampson HA, Mendelson L, Rosen JP. Fatal and near-fatal anaphylactic reactions to food
in children and adolescents. N Engl J Med 1992;327(6):380–4.
[29] Yunginger JW, Squillace DL, Jones RT, et al. Fatal anaphylactic reactions induced by pea-
nuts. Allergy Proc 1989;10(4):249–53.
[30] Low I, Stables S. Anaphylactic deaths in Auckland, New Zealand: a review of coronial
autopsies from 1985 to 2005. Pathology 2006;38(4):328–32.
[31] Yocum MW, Butterfield JH, Klein JS, et al. Epidemiology of anaphylaxis in
Olmsted County: a population-based study. J Allergy Clin Immunol 1999;104(2 Pt 1):
452–6.
[32] Bohlke K, Davis RL, DeStefano F, et al. Epidemiology of anaphylaxis among children and
adolescents enrolled in a health maintenance organization. J Allergy Clin Immunol 2004;
113(3):536–42.
[33] Peng MM, Jick H. A population-based study of the incidence, cause, and severity of anaphy-
laxis in the United Kingdom. Arch Intern Med 2004;164(3):317–9.
210 KEET & WOOD
[34] Yocum MW, Khan DA. Assessment of patients who have experienced anaphylaxis: a 3-year
survey. Mayo Clin Proc 1994;69(1):16–23.
[35] Brown AF, McKinnon D, Chu K. Emergency department anaphylaxis: a review of 142 pa-
tients in a single year. J Allergy Clin Immunol 2001;108(5):861–6.
[36] Mehl A, Wahn U, Niggemann B. Anaphylactic reactions in childrenda questionnaire-based
survey in Germany. Allergy 2005;60(11):1440–5.
[37] Thong BY, Cheng YK, Leong KP, et al. Anaphylaxis in adults referred to a clinical immu-
nology/allergy centre in Singapore. Singapore Med J 2005;46(10):529–34.
[38] Pastorello EA, Rivolta F, Bianchi M, et al. Incidence of anaphylaxis in the emergency de-
partment of a general hospital in Milan. J Chromatogr B Biomed Sci Appl 2001;756(1–2):
11–7.
[39] Eggesbo M, Halvorsen R, Tambs K, et al. Prevalence of parentally perceived adverse reac-
tions to food in young children. Pediatr Allergy Immunol 1999;10(2):122–32.
[40] Venter C, Pereira B, Grundy J, et al. Incidence of parentally reported and clinically diag-
nosed food hypersensitivity in the first year of life. J Allergy Clin Immunol 2006;117(5):
1118–24.
[41] Sicherer SH, Munoz-Furlong A, Sampson HA. Prevalence of peanut and tree nut allergy in
the United States determined by means of a random-digit dial telephone survey: a 5-year
follow-up study. J Allergy Clin Immunol 2003;112(6):1203–7.
[42] Grundy J, Matthews S, Bateman B, et al. Rising prevalence of allergy to peanut in children:
data from 2 sequential cohorts. J Allergy Clin Immunol 2002;110(5):784–9.
[43] Downs SH, Marks GB, Sporik R, et al. Continued increase in the prevalence of asthma and
atopy. Arch Dis Child 2001;84(1):20–3.
[44] Emmett SE, Angus FJ, Fry JS, et al. Perceived prevalence of peanut allergy in Great Britain
and its association with other atopic conditions and with peanut allergy in other household
members. Allergy 1999;54(4):380–5.
[45] Sicherer SH, Munoz-Furlong A, Sampson HA. Prevalence of seafood allergy in the United
States determined by a random telephone survey. J Allergy Clin Immunol 2004;114(1):
159–65.
[46] Schrander JJ, van den Bogart JP, Forget PP, et al. Cow’s milk protein intolerance in in-
fants under 1 year of age: a prospective epidemiological study. Eur J Pediatr 1993;152(8):
640–4.
[47] Host A, Halken S. A prospective study of cow milk allergy in Danish infants during the first 3
years of life. Clinical course in relation to clinical and immunological type of hypersensitivity
reaction. Allergy 1990;45(8):587–96.
[48] Host A. Frequency of cow’s milk allergy in childhood. Ann Allergy Asthma Immunol 2002;
89(6 Suppl 1):33–7.
[49] Giusti F, Seidenari S. Patch testing with egg represents a useful integration to diagnosis of
egg allergy in children with atopic dermatitis. Pediatr Dermatol 2005;22(2):109–11.
[50] Martorell A, Plaza AM, Bone J, et al. Cow’s milk protein allergy. A multicentre study: clin-
ical and epidemiological aspects. Allergol Immunopathol (Madr) 2006;34(2):46–53.
[51] Wood RA. The natural history of food allergy. Pediatrics 2003;111(6 Pt 3):1631–7.
[52] Heine RG, Laske N, Hill DJ. The diagnosis and management of egg allergy. Curr Allergy
Asthma Rep 2006;6(2):145–52.
[53] Ford RP, Taylor B. Natural history of egg hypersensitivity. Arch Dis Child 1982;57(9):
649–52.
[54] Wolkerstorfer A, Wahn U, Kjellman NI, et al. Natural course of sensitization to cow’s milk
and hen’s egg in childhood atopic dermatitis: ETAC study group. Clin Exp Allergy 2002;
32(1):70–3.
[55] Sampson HA, McCaskill CC. Food hypersensitivity and atopic dermatitis: evaluation of
113 patients. J Pediatr 1985;107(5):669–75.
[56] Sampson HA, Scanlon SM. Natural history of food hypersensitivity in children with atopic
dermatitis. J Pediatr 1989;115(1):23–7.
[57] Sicherer SH, Furlong TJ, DeSimone J, et al. The US peanut and tree nut allergy registry:
characteristics of reactions in schools and day care. J Pediatr 2001;138(4):560–5.
[58] Sicherer SH, Furlong TJ, Munoz-Furlong A, et al. A voluntary registry for peanut and tree
nut allergy: characteristics of the first 5149 registrants. J Allergy Clin Immunol 2001;108(1):
128–32.
[59] Vander Leek TK, Liu AH, Stefanski K, et al. The natural history of peanut allergy in young
children and its association with serum peanut-specific IgE. J Pediatr 2000;137(6):749–55.
[60] Fleischer DM, Conover-Walker MK, Christie L, et al. The natural progression of peanut al-
lergy: resolution and the possibility of recurrence. J Allergy Clin Immunol 2003;112(1):
183–9.
[61] Fleischer DM, Conover-Walker MK, Christie L, et al. Peanut allergy: recurrence and its
management. J Allergy Clin Immunol 2004;114(5):1195–201.
[62] Fleischer DM, Conover-Walker MK, Matsui EC, et al. The natural history of tree nut
allergy. J Allergy Clin Immunol 2005;116(5):1087–93.
[63] Novembre E, Cianferoni A, Bernardini R, et al. Anaphylaxis in children: clinical and aller-
gologic features. Pediatrics 1998;101(4):E8.
[65] Cianferoni A, Novembre E, Mugnaini L, et al. Clinical features of acute anaphylaxis in pa-
tients admitted to a university hospital: an 11-year retrospective review (1985-1996). Ann Al-
lergy Asthma Immunol 2001;87(1):27–32.
[66] Pumphrey RS, Roberts IS. Postmortem findings after fatal anaphylactic reactions. J Clin
Pathol 2000;53(4):273–6.
[67] Lieberman P. Biphasic anaphylactic reactions. Ann Allergy Asthma Immunol 2005;95(3):
217–26; [quiz 226, 258].
[68] Bock SA, Munoz-Furlong A, Sampson HA. Fatalities due to anaphylactic reactions to
foods. J Allergy Clin Immunol 2001;107(1):191–3.
[69] Joint Task Force on Practice Parameters; American Academy of Allergy, Asthma and
Immunology; American College of Allergy, Asthma and Immunology; Joint Council of Al-
lergy, Asthma and Immunology. The diagnosis and management of anaphylaxis: an updated
practice parameter. J Allergy Clin Immunol 2005;115(3 Suppl 2):S483–523.
[70] Eigenmann PA, Sampson HA. Interpreting skin prick tests in the evaluation of food allergy
in children. Pediatr Allergy Immunol 1998;9(4):186–91.
[71] Sporik R, Hill DJ, Hosking CS. Specificity of allergen skin testing in predicting positive
open food challenges to milk, egg, and peanut in children. Clin Exp Allergy 2000;30(11):
1540–6.
[72] Adkinson NF. Middleton’s allergy: principles and practice. 6th edition. Philadelphia:
Mosby, Inc.; 2003.
[73] Perry TT, Matsui EC, Kay Conover-Walker M, et al. The relationship of allergen-specific
IgE levels and oral food challenge outcome. J Allergy Clin Immunol 2004;114(1):144–9.
[74] Sampson HA, Ho DG. Relationship between food-specific IgE concentrations and the risk
of positive food challenges in children and adolescents. J Allergy Clin Immunol 1997;100(4):
444–51.
[75] Sampson HA. Utility of food-specific IgE concentrations in predicting symptomatic food
[76] Hourihane JO, Grimshaw KE, Lewis SA, et al. Does severity of low-dose, double-blind, pla-
cebo-controlled food challenges reflect severity of allergic reactions to peanut in the commu-
nity? Clin Exp Allergy 2005;35(9):1227–33.
[77] Spergel JM, Beausoleil JL, Fiedler JM, et al. Correlation of initial food reactions to observed
reactions on challenges. Ann Allergy Asthma Immunol 2004;92(2):217–24.
[78] Wensing M, Penninks AH, Hefle SL, et al. The distribution of individual threshold doses
eliciting allergic reactions in a population with peanut allergy. J Allergy Clin Immunol
2002;110(6):915–20.
212 KEET & WOOD
[79] Taylor SL, Hefle SL. Food allergen labeling in the USA and Europe. Curr Opin Allergy Clin
Immunol 2006;6(3):186–90.
[80] Hansen TK, Poulsen LK, Stahl Skov P, et al. A randomized, double-blinded, placebo-
controlled oral challenge study to evaluate the allergenicity of commercial, food-grade fish
gelatin. Food Chem Toxicol 2004;42(12):2037–44.
[81] Awazuhara H, Kawai H, Baba M, et al. Antigenicity of the proteins in soy lecithin and soy oil
in soybean allergy. Clin Exp Allergy 1998;28(12):1559–64.
[82] Simons E, Weiss CC, Furlong TJ, et al. Impact of ingredient labeling practices on food-
allergic consumers. Ann Allergy Asthma Immunol 2005;95(5):426–8.
[83] Moneret-Vautrin DA, Kanny G. Update on threshold doses of food allergens: implications
for patients and the food industry. Curr Opin Allergy Clin Immunol 2004;4(3):215–9.
[84] Taylor SL, Hefle SL, Bindslev-Jensen C, et al. Factors affecting the determination of thresh-
old doses for allergenic foods: how much is too much? J Allergy Clin Immunol 2002;109(1):
24–30.
[85] Taylor SL, Hefle SL, Bindslev-Jensen C, et al. A consensus protocol for the determination of
the threshold doses for allergenic foods: how much is too much? Clin Exp Allergy 2004;34(5):
689–95.
[86] Christie L, Hine RJ, Parker JG, et al. Food allergies in children affect nutrient intake and
growth. J Am Diet Assoc 2002;102(11):1648–51.
[87] Leung DY, Sampson HA, Yunginger JW, et al. Effect of anti-IgE therapy in patients with
peanut allergy. N Engl J Med 2003;348(11):986–93.
[88] Nelson HS, Lahr J, Rule R, et al. Treatment of anaphylactic sensitivity to peanuts by immu-
notherapy with injections of aqueous peanut extract. J Allergy Clin Immunol 1997;99(6 Pt 1):
744–51.
[89] Enrique E, Pineda F, Malek T, et al. Sublingual immunotherapy for hazelnut food allergy:
a randomized, double-blind, placebo-controlled study with a standardized hazelnut extract.
[90] Pons L, Burks W. Novel treatments for food allergy. Expert Opin Investig Drugs 2005;14(7):
829–34.
[91] Srivastava KD, Kattan JD, Zou ZM, et al. The Chinese herbal medicine formula FAHF-2
completely blocks anaphylactic reactions in a murine model of peanut allergy. J Allergy Clin
Immunol 2005;115(1):171–8.
27 (2007) 213–230
Peri-anesthetic Anaphylaxis
Thomas Chacko, MDa,b,c, Dennis Ledford, MDa,b,c,*
a
University of South Florida College of Medicine,
13000 Bruce B. Downs Boulevard, VAR 111D, Tampa, FL 33612, USA
b
The James A. Haley VA Hospital, 13000 Bruce B. Downs Boulevard,
VAR 111D, Tampa, FL 33612, USA
c
The Joy McCann Culverhouse Airways Disease Research Center,
13000 Bruce B. Downs Boulevard, VAR 111D, Tampa, FL 33612, USA
Anaphylaxis is the umbrella term for an acute reaction defined as a severe,

life-threatening, generalized, or systemic hypersensitivity reaction. The imme-
diate treatment of allergic anaphylaxis (allergic anaphylaxis includes both
IgE-mediated immunologic reactions and IgG/IgM immunologic-mediated
reactions, such as occur in blood transfusion reactions) and nonallergic
anaphylaxis (previously referred to as anaphylactoid reactions) are identical,
but the subsequent evaluation, testing, and recommendations vary. IgE-
mediated anaphylaxis indicates the presence of IgE, specific for the causal
agent. A good, general example of IgE-mediated anaphylaxis is an allergic
reaction to peanut ingestion. Severe forms of allergic, non-IgE-mediated
reactions also can occur, such as with blood transfusion reactions. These
are mediated by IgG, IgM, and complement-related immune complexes. In
contrast, nonallergic anaphylaxis indicates the lack of a specific antibody or
immune response. The exact etiology for nonallergic anaphylaxis is unknown.
The potential pathogenic mechanisms of nonallergic anaphylaxis include
idiosyncratic events, nonspecific complement activation, activation of hum-
oral proteolytic systems such as the clotting cascade, and direct histamine
release (Table 1) [1–3].
In contrast to nonallergic anaphylaxis, the cause of allergic anaphylaxis
may be elucidated by specific immune testing of the suspected drug. This test-
ing may include skin testing or in vitro drug-specific testing for IgE. Nonaller-
gic anaphylaxis cannot be explained by testing for specific sensitivity.
Distinguishing allergic versus nonallergic anaphylaxis is of some clinical
* Corresponding author. 13000 Bruce B. Downs Boulevard, VAR 111D, Tampa, FL

33612.
E-mail address: dledford@hsc.usf.edu (D. Ledford).
214 CHACKO & LEDFORD
Table 1
Agents frequently implicated in peri-anesthetic anaphylaxis and probable mechanisms of
adverse reactions
IgE-mediated Direct mast
Agent mast cell activation Complement-mediated cell activation
Muscle relaxants þ þ
d-Tubocurarine
Suxamethonium
(succinylcholine)
Pancuronium
Atracurium
Vecuronium
Hypnotics–barbiturates þ þ þ
Thiopental
Methohexital
Nonbarbiturate hypnotics þ þ
Propofol
Althesin
Opioids þ
Morphine
Buprenorphine
Fentanyl
Plasma expanders þ þ
Dextran
Hydroxyethyl starch
Protamine þ þ þ
Radiocontrast media þ þ
Latex þ
importance. Allergic anaphylaxis, particularly IgE-mediated, often is more se-

vere with subsequent administration of the causal drug. The severity of non-
allergic anaphylaxis tends to be similar with repeat administration of the
causal drug. Nonallergic anaphylaxis is more likely dose-dependent (ie, lower
doses or slower rates of administration may not result in reactions). Specific
desensitization may be an option for subsequent treatment with a drug previ-
ously causing allergic anaphylaxis, but this is not usually helpful for nonaller-
gic anaphylaxis. A pretreatment regimen may be effective in nonallergic
anaphylaxis, such as results with radiocontrast media, but pretreatment is gen-
erally of limited value with allergic anaphylaxis. Some drugs, such as prot-
amine or muscle relaxants, may result in both allergic (IgE-mediated) and
nonallergic anaphylaxis.
Direct histamine release is common during anesthesia [4]. Physiologic
changes resembling anaphylaxis rarely occur following direct histamine
release, however. Several observations support this statement. Morphine,
a very potent histamine-releasing drug, rarely causes severe systemic reac-
tions. Muscle-relaxing agents that are potent direct histamine-releasing drugs
do not result in anaphylaxis more often than agents that are less potent hista-
mine releasers. Bronchospasm, a frequent clinical feature of anaphylaxis,
rarely occurs with direct histamine release or experimental histamine infusion
PERI-ANESTHETIC ANAPHYLAXIS 215
[5,6]. Similar plasma histamine levels occur transiently following exposure to

direct histamine-releasing drugs and allergen-specific, IgE-induced histamine
release, yet the physiologic effects differ [7]. Anaphylaxis is common in the lat-
ter and rare in the former, suggesting that mediators other than histamine are
essential for the syndrome of anaphylaxis.
Epidemiology
Anaphylaxis, both allergic and nonallergic, occurs in 1 out of every 3500
to 25,000 general anesthetic administrations, with a mortality rate of up to
6% [8–11]. The wide variability reflects the difficulty in determining the
denominator (or total number of anesthesia cases) and the limitations in
diagnosing anaphylaxis. The incidence of peri-anesthetic anaphylaxis is
increasing, with one Australian source reporting an increased incidence
from 1 case per 28,000 general anesthetic administrations in 1970 to 1 case
per 5000 general anesthetic administrations in 1981 [11–14]. Muscle relax-
ants are the most common agents causing anaphylaxis during anesthesia,
accounting for 60% to 70% of reactions [15,16].
Diagnosis
Signs of anaphylaxis include flushing or urticaria, hypotension, difficulty
with intubation caused by laryngeal edema, and the requirement of incre-
ased ventilatory pressure or the inability to ventilate because of broncho-
spasm. Diagnosis of peri-anesthesia anaphylaxis may be hampered by the
limited ability of the affected subject to describe symptoms of pruritus,
shortness of breath, or angioedema. Skin manifestations may be masked
by surgical drapes. The early signs often are unrecognized, and cardiovascu-
lar collapse may be the sole presentation, occurring in about 50% of cases
[17]. Anaphylaxis always should be considered if immediate hypotension
develops, with or without bronchospasm, following parenteral administra-
tion of a therapeutic agent or the induction of anesthesia [18]. Bradycardia
occurs more often with peri-anesthetic anaphylaxis compared with other
causes of anaphylaxis [19,20]. For example, 12% to 30% of anaphylaxis
cases attributed to muscle relaxants are associated with bradycardia
[14,21]. The differential diagnosis of any adverse reaction during or follow-
ing general anesthesia should include the possibility of an anaphylaxis. The
differential diagnosis of peri-anesthetic anaphylaxis includes the conditions
listed in Box 1.
Pathophysiology
Four mechanisms may result in the release of mast cell or basophil
mediators during anesthesia:
1. Specific IgE on mast cells and basophils cross-linked by allergen (drug)
Box 1. Differential diagnosis of peri-anesthetic anaphylaxis

Asthma
Arrhythmia
Hemorrhage
Hereditary angioedema
Jarish-Herxheimer reaction
Mastocytosis
Myocardial infarction
Overdose of vasoactive drug
Pericardial tamponade
Postextubation stridor
Pulmonary edema
Pulmonary embolus
Sepsis
Tension pneumothorax
Vasovagal reaction
Venous air embolism
2. Complement activation by specific IgG or IgM binding to antigen (drug)

3. Direct activation of humoral proteolytic systems such as complement
by way of the alternative pathway, the kinin pathway, or the plasmin
systems
4. Direct activation of mast cells or basophils
Examples of agents used in proximity of anesthesia and the mechanisms
most often responsible for anaphylaxis are listed in Table 1. Most causal
agents may stimulate adverse reactions by more than one mechanism, fur-
ther adding to the complexity of recognizing and diagnosing this problem.
Neuromuscular blocking agents are the most common cause of peri-
anesthetic reactions, followed by latex and antibiotics [15]. The rank order
of occurrence is based on reviews of general surgery anesthesia, but specific
surgical procedures might differ with respect to likely cause [15,16]. For
example, in cardiovascular surgery, anesthesia-induced anaphylaxis is
more likely caused by antibiotics, gelatin solutions or protamine allergy
rather than muscle relaxants [22]. Table 2 describes one study’s findings
on the causality incidence, and these causes are reviewed in detail.
Causal agents
Muscle relaxants
Sixty percent to 70% of anaphylaxis cases in the peri-anesthetic period are
secondary to muscle relaxants [23,24]. The muscle relaxants are used to facil-
itate endotracheal intubation or to optimize surgical exposure. Although
Table 2
Agents involved in perioperative anaphylaxis (N ¼ 518) between January 1, 1999, and Decem-
ber 31, 2000 in France
Cause Rate of reaction
Muscle relaxants 58.2% (n ¼ 306)
Latex 16.7% (n ¼ 88)
Antibiotics 15.1% (n ¼ 79)
Colloids 4.0% (n ¼ 21)
Hypnotics 3.4% (n ¼ 18)
Opioids 1.3% (n ¼ 7)
Other agents (chymopapain, 1.3% (n ¼ 7)
propacetamol, protamine,
methylene blue, ethylene oxide)
Data from Mertes PM, Laxenaire MC, Alla F. Groupe d’Etudes des Reactions Anaphylac-
toides Peranesthesiques. Anaphylactic and anaphylactoid reactions occurring during anesthesia
in France in 1999–2000. Anesthesiology 2003:99:536–45.
rocuronium and succinylcholine were the most frequently incriminated

muscle relaxants in a French study [15], the causation frequency of the
putative drugs varies according to the relative amount of each muscle relaxant
used in each location [24]. Succinylcholine anaphylaxis may be disproportion-
ately frequent, because the molecular flexibility of this agent facilitates cross-
linking of specific IgE bound on the surface of mast cells and basophils. Most
of the muscle relaxants cause direct release of mast cell histamine without
the requirement for specific antibody; however, life-threatening reactions
usually are IgE-mediated [25]. The tertiary or quaternary ammonium group,
common to all muscle relaxants, is likely the immunodominant determinant
recognized by the IgE [26]. The antigenicity of the shared ammonium struc-
tures may be responsible for cross-reactivity among the muscle relaxants.
Cross-reactivity occurs most consistently between pancuronium and vecuro-
nium [27]. Cross-reactions also may occur with other classes of pharma-
ceuticals, based upon in vitro inhibition of specific IgE binding to the muscle
relaxants. These drugs include:
Acetylcholine
Choline
Morphine
Neostigmine
Pentolinium
Procaine
Promethazine
Cross-inhibition suggests that previous exposure to these nonanesthetic
drugs may sensitize individuals to muscle-relaxing agents, resulting in reac-
tions among subjects without prior anesthesia [28]. Three out of four cases of
anaphylaxis to muscle relaxants occur in females, suggesting cross-reactivity
with ammonium compounds in personal care products [23]. Skin testing may
be useful to determine the safest alternative for subsequent anesthesia
following a suspected reaction, recognizing that nonimmunologic reactions

are not identified by this diagnostic method (Table 3) [29,30]. Skin testing
is not recommended for preanesthetic screening of subjects without a history
of suspected reactions [31].
Latex
Natural rubber latex sensitivity is the second most common cause of peri-
operative anaphylaxis in some series [22]. Latex allergy may develop from
multiple medical and nonmedical sources. Thus, the absence of a history
of reactions or prior anesthesia should not eliminate the suspicion of latex
causality. The prevalence of latex allergy increased in the later part of the
20th century. Latex allergy accounted for approximately 10% of anaphy-
laxis cases during surgery in 1996 [32], and by 2000, latex caused more
than 16% of perioperative anaphylaxis cases [33]. The increase in latex
hypersensitivity is probably multifactorial, partially related to the demand
for latex gloves with increased HIV awareness and increased use of latex
products in general [32,34]. Nonmedical latex exposure occurs from contact
with balloons, gloves, condoms, toys, and other domestic articles made of
latex. Although the incidence of latex allergy has increased over the last
20 years, it appears to have reached a plateau largely because of increased
awareness, a decreased use of latex products, and new label warnings about
the presence of latex in medical products [17].
Individuals at high risk for latex allergy include health care workers and
patients who have spina bifida, urogenital abnormalities, and multiple prior
surgeries (Box 2) [35]. The prevalence of latex hypersensitivity in the general
population ranges from 0.8% to 6.5% [36]. In nurses working in the operating
room, the prevalence is approximately 11%, and in patients requiring
Table 3
Skin testing concentrations for anesthetic agents
Medication Intradermal skin test concentration (mg/mL)
Alcuronium 0.005a
Methohexital 0.1b
Metocurine 0.002b
Pancuronium 0.002a,b
Succinylcholine 0.02b, 0.05a
Thioamyl 0.1b
Thiopental 0.20b
Tubocurarine 0.0003b, 0.001a
Rocuronium 0.01a
Vecuronium 0.004a
a
Data from Moscicki RA, Sockin SM, Corsello BF, et al. Anaphylaxis during induction of
general anesthesia: subsequent evaluation and management. J Allergy Clin Immunol 1990;
86:325–32.
b
Data from Rose M, Fisher M. Rocuronium. High risk for anaphylaxis? Br J Anaesth 2001;
86:678–82.
Box 2. Groups at risk for anaphylaxis to latex

Chronic bladder care
Neural tube defects
Spinal bifida
Myelomeningocele
Spina cord trauma
Urogenital malformations
Neurogenic bladder
Health care workers (greatest for operating room)
Patients with multiple surgical procedures
Atopic individuals
Data from Lieberman P. Anaphylactic reactions during surgical and medical

procedures. J Allergy Clin Immunol 2002;110:S64–9.
repeated bladder care, it is as high as 72% [37,38]. Anaphylaxis caused by latex

is more likely to be delayed or to occur later during the procedure compared
with muscle relaxants or induction agents [23]. Latex- containing articles
potentially used for anesthesia or surgery are listed in Box 3. Latex gloves
and catheters are the most common sources of significant exposure. Articles
such as diaphragms, valves, syringes, and tubing are not likely to cause
symptoms because of the limited amount of latex allergen in these products.
Skin testing with latex is the most sensitive method to detect latex allergy,
but a commercial, standardized testing reagent is not available [39]. A stan-
dardized in vitro assay is US Food and Drug Administration (FDA) approved
but has a lower sensitivity than skin testing, ranging from 73% to 93% [16,40].
Latex exposure should be limited as much as possible once sensitivity is
demonstrated. Ideally, latex-safe operative suites should be available. If
a latex-safe suite is not an option, scheduling the anesthesia or interventional
procedure as the first case of the day and avoiding latex products as much as
possible is an option [41]. None of the anesthesia or surgical team should use
latex gloves. Contact with blood pressure cuffs or tourniquets should be
limited by wrapping the arm with gauze or other protectants. Premedication
regimens, usually including corticosteroids and combination antihistamines,
may lessen the severity but not prevent latex reactions [42,43].
Antibiotics
Antibiotics frequently are administered before, during, or immediately
after anesthesia and surgery. Allergic reactions to antibiotics, particularly
anaphylaxis, may present during the peri-anesthetic period. The most com-
monly implicated antibiotics resulting in reactions are b-lactam antibiotics
and vancomycin [44].
Box 3. Latex-containing articles potentially used for anesthesia

or surgery
Adhesive tape
Airway masks
Ambu-bag
Anesthesia bags and tubing
Self- adhesive bandages
Blood pressure cuffs
Bulb syringes
Catheter leg bag straps
Catheters
Condoms
Indwelling
Straight
Elastic bandages
Electrode pads
Endotracheal tubes
Gloves, sterile and exam
Intravenous bags, ports, infusion sets
Penrose drains
Rubber pads
Stethoscope tubing
Suction catheters
Syringes
Tourniquets
Allergic reactions occur in 0.015% to 0.04% of penicillin-treated subjects,

and approximately 0.001% of subjects treated with parenteral penicillin
develop anaphylaxis [45,46]. Intravenous penicillin administration results in
the most severe forms of anaphylaxis. Lack of a prior reaction is not com-
pletely reassuring, as most serious and fatal reactions occur in individuals
without a history of penicillin allergy. Penicillin skin testing is validated by
laboratory studies, clinical science, and experience [39,47]. The sensitivity of
penicillin skin testing is approximately 97% if aqueous penicillin and penicillin
major determinant are used [47]. Major determinant is a product of in vivo
metabolism and comprises the largest component of metabolites, resulting
in the designation major determinant. Percutaneous testing followed by intra-
cutaneous testing with concentrations of up to 3 mg/mL for aqueous penicillin
and 6 105 M/L for major determinant, when available, are recommended
to exclude penicillin allergy [47–49]. In vitro testing for penicillin-specific IgE
is available, but its sensitivity and specificity are less than skin testing. The pen-
icillin major determinant Pre-Pen, previously manufactured by Hollister-Stier
Laboratories, is not available commercially. The development of a commercial
penicillin major determinant product is in progress. Besides the current lack of

major determinant, there has never been a commercially available minor
determinant. Minor determinant is a metabolic product with lower concentra-
tion than major determinant. The lack of minor determinant is an impedi-
ment, as sensitivity to minor determinant is associated with the most severe
anaphylaxis. Skin testing with penicillin derivatives or cephalosporins is not
as well studied but is used clinically. Maximum testing concentrations of
1 to 3 mg/mL have been suggested. Monobactams, such as aztreonam, do
not cross-react immunologically with penicillin and may be used in penicillin
allergic subjects. Desensitization protocols are available to facilitate use of
b-lactam antibiotics in subjects with documented or suspected allergy and
a critical need for treatment with b-lactams.
Vancomycin is a glycopeptide antibiotic selectively used for treatment of
resistant organisms and for use in individuals who have penicillin allergy.
Administration, especially rapid, may result in life-threatening non-IgE-medi-
ated anaphylaxis [50–52]. Both direct histamine release and direct myocardial
depression partially explain this phenomenon [53]. These nonimmunologic re-
actions to vancomycin can be reduced or eliminated by administering this
drug as a dilute solution, dissolved in at least 200 mL, and infused over a
2 hour period or longer. IgE-mediated anaphylaxis to vancomycin is much
less common than other reactions [54]. Skin testing with a concentration of
0.15 mg/mL or less has been reported, but the reliability of this testing is
less secure than with penicillin [54]. Skin testing may have some value in
distinguishing rate-related adverse events from anaphylaxis.
Colloid plasma expanders

Dextran and hydroxyethyl starch (HES), large molecular-weight polysac-
charides, may be used as a nonblood, high-oncotic fluid replacement during
surgery. These agents infrequently are associated with adverse reactions and
anaphylaxis, most likely caused by complement activation. Estimates of re-
action rates are 0.008% to 0.08% for dextran and 0.08% for HES [23,55].
Specific antibodies can be detected for dextran or HES, but their clinical sig-
nificance is unknown [55–57]. Confirmation of dextran or HES as the cause
of an adverse reaction is limited by the absence of accurate serologic or skin
tests. Skin test reactivity to undiluted solutions has been described but is of
unknown significance [23].
Case reports in the medical literature also describe systemic reactions to
albumin [27]. Details concerning the mechanism of the adverse effects are
not available.
Hypnotic induction agents

Intravenous drugs used for anesthetic induction are the third to fifth most
common cause of peri-anesthetic anaphylaxis, depending on the study.
More than 290 cases of anaphylaxis are reported in the literature from the
use of barbiturates, especially thiopental; however, the reaction rate with
barbiturates is only 1:25,000, with the reported occurrence of reactions
reflecting the common use of these compounds [25]. Women are three times
more likely to react to thiopental than men [23,31]. Most of the adverse re-
actions with barbiturates, particularly thiopental, are caused by specific IgE
antibody, although direct histamine-releasing activity also occurs [1,23,58].
The importance of immunologic cross-reactivity is unknown [29,59,60].
Skin testing may be clinically useful, but testing drug concentrations must
be less than the concentrations that result in irritation (see Table 3).
Propofol is a nonbarbiturate induction agent that is potentially useful if
sensitivity to barbiturates is a concern [61]. Specific IgE against propofol
may occur; however, most adverse reactions to propofol are nonimmuno-
logic [62–64]. Although skin testing may be positive, results do not predict
anaphylaxis. Propofol may stimulate histamine release directly, and this
effect may be greater when administered with muscle relaxants [65].
Opioids
Narcotics used in anesthesia are common causes of flushing and urticaria
following intravenous administration. The risk of anaphylaxis, in contrast,
is very rare [23,31,66,67]. Reducing the rate of opioid administration usually
limits the severity of these reactions. Dermal mast cells express opioid recep-
tors that stimulate histamine release following narcotic binding. Other
populations of mast cells do not express this receptor. Cutaneous flushing
and hives often occur after intravenous morphine, but with rare exception,
the amount of histamine release does not result in hypotension or broncho-
spasm [67]. Fentanyl does not stimulate histamine release directly by way of
the mast cell opioid receptor [1,19,68].
Reports of allergic anaphylaxis to morphine and fentanyl are in the med-
ical literature [23,69]. Skin testing, with a 1:100,000 dilution of a therapeutic
morphine concentration, has been suggested to avoid direct histamine release
resulting in a positive test [39]. This precaution would not be as great a con-
cern with fentanyl, because this agent does not result in direct histamine re-
lease [27,64]. Predictive value of skin testing with morphine has not been
validated. If morphine is needed following a previous suspected reaction,
one authority suggests test dosing or challenging with morphine, beginning
at 0.1 mg and doubling every 15 minutes until a 4 mg dose is attained [39].
Protamine
Intravenous protamine, an agent used to reverse heparin anticoagulation,
may cause allergic and nonallergic anaphylaxis. Nonallergic anaphylaxis
with protamine is characterized by increases in pulmonary blood pressure.
The potential pathophysiologic mechanisms are numerous and varied
[70–77]. A case control study (multivariate odds ratio [95% confidence
interval]) showed that previous neutral protamine Hagedorn insulin use

(8.18 [2.08, 32.2]), fish allergy (24.5 [1.24, 482.3]), and other medication al-
lergy (2.97 [1.25, 7.07]) are independent risk factors for anaphylaxis [73]. Es-
timates are that up to 39% of cardiopulmonary bypass patients have one or
more of these risk factors. Allergy to fish has not been shown conclusively to
be associated with protamine allergy [78,79]. Other literature suggests that
previous vasectomy and the rate of protamine infusion are also risk
factors, but epidemiologic confirmation is lacking [76]. Skin prick tests
and specific IgE have not been demonstrated to be clinically useful in the
diagnosis of hypersensitivity to protamine. Alternative agents may be used
for heparin reversal, but these agents are not readily available. Pretreatment
regimens with corticosteroids and antihistamines have been recommended,
but no studies confirm efficacy [75].
Benzodiazepines
Reactions to benzodiazepines are exceedingly rare; however, because of
frequent use perioperatively, one survey reported benzodiazepines were
the sixth most common cause of anaphylaxis during anesthesia [80]. No
studies are available to verify the mechanism of clinical adverse reactions.
Specific IgE has not been detected by skin tests or in vitro tests [81,82].
One in vitro study reported histamine release from lung mast cells by diaz-
epam and from basophils and mast cells by midazolam [1].
Local anesthetics
Local anesthetic agents readily induce cell-mediated immunologic reac-
tions when applied topically to the skin, but humoral immune responses
are rare [70]. Adverse effects from local anesthetics are not uncommon,
but immunologically mediated reactions following parenteral administra-
tion are very unusual. The usual cause of a local anesthetic reaction is a
vasovagal response, anxiety, toxic complications, or an idiosyncratic reac-
tion. Toxic effects usually result from inadvertent systemic, high-dose admi-
nistration of local anesthetic preparations. Systemic toxicity includes central
nervous system stimulation or suppression and cardiac suppression with
peripheral vasodilation.
Proving a pathophysiologic immune response following an adverse local
anesthetic event is often difficult or inconclusive. Both immediate, wheal-
and-flare skin testing, and delayed-type hypersensitivity patch testing have
been used for diagnosis. Positive patch tests occur more commonly with
the para-aminobenzoic ester local anesthetics compared with the amide class
(Table 4) [16]. Cross-reactions among the members of the para-aminoben-
zoic ester group occur with delayed-type hypersensitivity patch testing.
The clinical relevance of delayed hypersensitivity to the adverse effects of
injected, as opposed to topically applied, local anesthetics is unknown and
unlikely to be significant.
Table 4
Local anesthetics
Para-aminobenzoic acid esters Amides
Benzocaine Bupivicaine (Marcaine)
Butacaine (Butyn) Dibucaine (Nupercaine)
Butethamine (Monocaine) Dyclonine (Dyclone)
Chlorprocaine (Nesacaine) Lidocaine (Xylocaine)
Procaine (Novocain) Mepivicaine (Carbovocaine)
Tetracaine (Pontocaine) Oxethazaine (Oxaine)
Phenacaine (Holocaine)
Pramoxine (Tronothane)
Prilocaine (Citonest)
Data from Thong BY, Yeow-Chan. Anaphylaxis during surgical and interventional
procedures. Ann Allergy Asthma Immunol 2004;92:619–28.
Determining which local anesthetic should be used with a history of an

adverse reaction is based on details of the history and diagnostic testing.
Generally an alternative anesthetic is considered despite the knowledge
that the likely cause of a previous reaction is toxic or idiosyncratic.
The former type of reaction likely would not occur with subsequent ad-
ministration using standard techniques. An amide class anesthetic usually
would be the choice following a reaction with a para-aminobenzoic ester.
Percutaneous testing, followed by intradermal testing, usually is per-
formed with one or more local anesthetics. Dilutions of the anesthetics
may be considered for the initial testing if the history is highly suggestive
of anaphylaxis. Ideally, anesthetic agents with and without preservatives
are used to determine if preservative sensitivity, rather than anesthetic al-
lergy, is responsible for the reaction. Subcutaneous injections of increas-
ing dosages of the anesthetic agent, 0.1 to 0.5 mL, may be administered
to verify that reactions are not dose-dependent. Local anesthetics without
epinephrine are preferable if the history is suggestive of an anxiety
response.
Almost invariably, a local anesthetic can be identified as safe to permit
procedures with minimal pain. Knowledge that anaphylaxis is extraordi-
narily rare facilitates reassurance of the patient after testing and progressive
dose challenge.
Other potential causes of anaphylaxis

Various other potential causes or mimics of anaphylaxis during the
peri-anesthetic period are listed in Box 4.
Some of these causes are reviewed in other articles in this issue. Some,
such as chymopapain, are used rarely. Blood transfusion reactions may be
hemolytic reactions with complement activation or antibody specific for
IgA in nonwashed packed red blood cells or whole blood collected from
Box 4. Other potential causes or mimics of peri-anesthetic

anaphylaxis
Aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs)
Bisulfites or other medication preservatives
Blood transfusion reaction
Incompatibility
Immune reaction to IgA
Chlorhexidine
Chymopapain sensitivity (used for herniated disc surgery)
Ethylene oxide (used for sterilization)
Insulin
Hypersensitivity reaction
Isosulphan blue dye (used for sentinel lymph node biopsy)
Methylmethacrylate (bone cement)
Radiocontrast reaction
Streptokinase or urokinase
a subject with normal IgA. IgA antibodies occur in IgA-deficient subjects

and may be an IgE isotype.
Approach to patients with peri-anesthetic anaphylaxis

The management of anaphylaxis in proximity to anesthesia is similar to
anaphylaxis in other situations. The diagnosis is challenging because of
the multiple drugs administered, concurrently or sequentially, and the effects
of anesthesia itself. Serum complement assays may be valuable if comple-
ment activation is suspected. An elevated serum tryptase level 1 to 6 hours
after suspected anaphylaxis suggests mast cell degranulation and supports
the diagnosis of anaphylaxis in the presence of a typical history and clinical
findings [83–85]. Additional diagnostic testing for the agent responsible for
mast cell degranulation, usually by measuring specific IgE, would be advis-
able if the serum tryptase were elevated. A negative tryptase result, however,
does not exclude anaphylaxis.
Final testing for specific IgE to a suspected causal agent is not recommen-
ded until several weeks after the initial reaction. This recommendation is
based on the precedent of other hypersensitivities in which transient de-
creases in measurable allergen-specific IgE occur after anaphylaxis. Skin
tests may be difficult to interpret with agents used during anesthesia, because
many drugs cause direct mast cell histamine release in the absence of specific
IgE. Nonetheless, skin testing has been shown to be valuable in evaluating
anaphylaxis to barbiturates, chymopapain, streptokinase, penicillin, insulin,
and latex. Suggested concentrations of anesthetic agents for use in skin
testing are listed in Table 3 [29,30]. In vitro testing for specific IgE has been
reported for muscle relaxants, thiopental, morphine, propofol, and latex.
Latex in vitro testing is recommended because of an available standardized
assay, and there is patient risk when using nonstandardized latex skin-test-
ing reagents. Skin testing may be necessary with a strong suspicion of latex
allergy and negative in vitro results.
Prevention of peri-anesthetic anaphylaxis

The prevention of peri-anesthetic anaphylaxis is an elusive ideal because
of the rare occurrence of reactions, multiple pathophysiologic mechanisms
(many of which are undefined), the limited ability to test for sensitization,
and the limited ability to define the risk of recurrence. A careful medical
history that focuses on previous adverse reactions is most important [75].
Any previous medication reaction nonspecifically increases the possibility
of adverse reactions, and multiple previous medication reactions pose
a greater risk. Atopic individuals may be at increased risk because of either
increased occurrence of reactions or, more often, an increased severity of
reactions. Asthma therapy should stabilize optimal lung function and min-
imize bronchial hyper-reactivity, if possible, before anesthesia. b-Blocker
therapy and possibly angiotensin-converting enzyme (ACE) inhibitor
therapy are potential risk factors that ideally should be avoided or limited.
Previous anesthetic-associated reactions should be evaluated thoroughly,
with specific testing if indicated. IgA-deficient subjects should receive
washed red blood cells and not whole blood to avoid exposure to exogenous
IgA. Intraoperative antibiotics should be administered slowly with careful
hemodynamic monitoring. Drugs with histamine-releasing properties
(eg, morphine, d-tubocurarine, vancomycin, quaternary muscle relaxants)
should be administered as slowly as possible, particularly in subjects with
asthma or cardiopulmonary disease. Pretreatment regimens, as used for
radiocontrast nonallergic anaphylaxis, have not been proven to prevent
peri-anesthetic reactions, but pretreatment may reduce the severity of such
reactions if a non-IgE-mediated mechanism is suspected.
Summary
Peri-anesthetic anaphylaxis, mediated by immunologic, nonimmu-
nologic, or undefined mechanisms, is becoming more common, probably
because of more frequent use of anesthesia and the increasing complexity
of used drugs. Recognition and immediate treatment are particularly impor-
tant, because anesthetized subjects are at greater risk for adverse outcomes
caused by the physiologic effects of anesthesia. Vigilance for the signs of
anaphylaxis and consideration of risk factors, with possible modification
of the agents used, likely will reduce the morbidity and mortality associated
with these reactions.
References
[1] Genovese A, Stellato C, Marsella CV, et al. Role of mast cells, basophils, and their mediators
in adverse reactions to general anesthetics and radiocontrast media. Int Arch Allergy Immu-
nol 1996;110:13–22.
[2] Complement and contact activation. In: Levy J, editor. Anaphylactic reactions in anesthesia
and intensive care. Boston: Butterworth-Heinemann; 1992. p. 51.
[3] Tannenbaum H, Ruddy S, Schur P. Acute anaphylaxis associated with serum complement
depletion. J Allergy Clin Immunol 1975;56:226–34.
[4] Lorenz W, Doenicke A, Schöning B, et al. The role of histamine in adverse reactions to
intravenous agents. In: Thornton JA, editor. Adverse reaction of anesthetic drugs. Amster-
dam (Netherlands): Excerpts Medica/Elsevier North Holland Biomedical Press; 1981.
p. 169–239.
[5] Fisher MM. Reaginic antibodies to drugs used in anesthesia. Anesthesiology 1980;52:
318–20.
[6] Kaliner M, Sigler R, Summer R, et al. Effects of infused histamine: analysis of the effects of
H1 and H2 histamine receptor antagonists on cardiovascular and pulmonary responses.
J Allergy Clin Immunol 1981;68:365–71.
[7] Laroche D, Lefrancois C, Gerard JL, et al. Early diagnosis of anaphylactic reactions to
neuromuscular- blocking drugs. Br J Anaesth 1992;69:611–4.
[8] Baldo BA, Fisher MM. Anaphylaxis to muscle relaxant drugs: cross reactivity and molecular
basis of binding of IgE antibodies detected by radioimmunoassay. Mol Immunol 1983;20:
1393–400.
[9] Bovet D. Synthetic inhibitors of neuromuscular transmission, chemical structures and struc-
ture activity relationships. In: Cheymol J, editor. Neuromuscular blocking and stimulating
agents, vol. 1: International Encyclopedia of Pharmacology and Therapeutics. Oxford (UK):
Pergamon Press; 1972. p. 243–94.
[10] Currie M, Webb RK, Williamson JA, et al. Clinical anaphylaxis: an analysis of 2000 incident
reports. Anaesth Intensive Care 1993;21:621–5.
[11] Fisher MM, Baldo BA. The incidence and clinical features of anaphylactic reactions during
anesthesia in Australia. Ann Fr Anesth Reanim 1993;12:97–104.
[12] Laxenaire MC, Moneret-Vautrin DA, Boileaus S, et al. Adverse reactions to intravenous
agents in anaesthesia in France. Klin Wochenschr 1982;60:1006–9.
[13] Laxenaire MC, Moneret-Vautrin DA, Vervloet D. The French experience of anaphylactoid
reactions. Int Anesthesiol Clin 1985;23:145–60.
[14] Laxenaire MC, Mouton DC, Moneret-Vautrin DA, et al. Drugs and another agents involved
in anaphylactic shock during anesthesia: a French multicenter epidemiological inquiry. Ann
Fr Anesth Reanim 1993;12:91–6.
[15] Mertes PM, Laxenaire MC, Alla F. Groupe d’Etudes des Reactions Anaphylactoides
Peranesthesiques. Anaphylactic and anaphylactoid reactions occurring during anesthesia
in France in 1999–2000. Anesthesiology 2003;99:536–45.
[16] Thong BY, Yeow-Chan. Anaphylaxis during surgical and interventional procedures. Ann
Allergy Asthma Immunol 2004;92:619–28.
[17] Sampson HA, Munoz-Furlong A, Bock SA, et al. Symposium on the definition of anaphy-
laxis: summary report. J Allergy Clin Immunol 2005;115:584–91.
[18] Levy J. General approach to anaphylactic reactions. In: Levy J, editor. Anaphylactic
reactions in anesthesia and intensive care. Boston: Butterworth-Heinemann; 1992. p. 135.
[19] Hermens J, Ebertz JM, Hanifin JM, et al. Comparison of histamine release in human skin
mast cells by morphine, fentanyl, and oxymorphone. Anesthesiology 1983;62:124–9.
[20] Jacobsen J, Secher NH. Slowing of the heart during anaphylactic shock: a report of five
cases. Acta Anaesthesiol Scand 1988;32:401–3.
[21] Mautz JM, Pauli G, Meyer P, et al. [Anaphylactic shock: results of a national survey of 1074
cases]. Rev Med Int Photo Cinema Telev 1982;3:331–8 [in French].
[22] Lieberman P, Kemp S, Oppenheimer J, et al. The diagnosis and management of anaphylaxis:
an updated practice parameter. J Allergy Clin Immunol 2005;115:S483–523.
[23] Birnbaum J, Porri F, Pradal M, et al. Allergy during anaesthesia. Clin Exp Allergy 1994;24:
915–21.
[24] Laxenaire MC. Epidemiology of anesthetic anaphylactoid reactions: fourth multicenter
survey (July 1994 to December 1996). Ann Fr Anesth Reanim 1999;18:796–809.
[25] Baldo BA, Fisher MM. Mechanisms in IgE-dependent anaphylaxis to anaesthetic drugs.
Ann Fr Anesth Reanim 1993;12:131–40.
[26] Baldo BA, Fisher MM. Substituted ammonium ions as allergenic determinants in drug
allergy. Nature 1983;306:262–4.
[27] Leynadier F, Sansarricq M, Didier JM, et al. Prick tests in the diagnosis of anaphylaxis to
general anaesthetics. Br J Anaesth 1987;59:683–9.
[28] Fisher MM, Baldo BA. Immunoassays in the diagnosis of anaphylaxis to neuromuscular
blocking drugs: the value of morphine for the detection of IgE antibodies in allergic subjects.
Anaesth Intensive Care 2000;28:167–70.
[29] Moscicki RA, Sockin SM, Corsello BF, et al. Anaphylaxis during induction of general an-
esthesia: subsequent evaluation and management. J Allergy Clin Immunol 1990;86:325–32.
[30] Rose M, Fisher M. Rocuronium. High risk for anaphylaxis? Br J Anaesth 2001;86:678–82.
[31] Porri F, Lemiere C, Birnbaum J, et al. Prevalence of muscle relaxant sensitivity in a general
population: implications for a preoperative screening. Clin Exp Allergy 1999;29:72–5.
[32] Slater JE. Rubber anaphylaxis. N Engl J Med 1989;320:1126–30.
[33] Mertes PM, Laxenaire MC. Anaphylaxis during general anesthesia: prevention and manage-
ment. CNS Drugs 2000;14:115–33.
[34] Chaiear N, Foulds I, Burge PS. Prevalence and risk factors for latex allergy. Occup Environ
Med 2000;57:501.
[35] Lieberman P. Anaphylactic reactions during surgical and medical procedures. J Allergy Clin
Immunol 2002;110:S64–9.
[36] AORN latex guideline. In: Standards, recommended practices and guidelines. Denver (CO):
Association of Operating Room Nurses Inc.; 1999. p. 93–108.
[37] Ricci G, Gentili A, Di Lorenzo F, et al. Latex allergy in subjects who had undergone multiple
surgical procedures for bladder extropy: relationship with clinical intervention and atopic
disease. BJU Int 1999;84:1058–63.
[38] Lagier F. Prevalence of latex allergy in operating room nurses. J Allergy Clin Immunol 1992;
90:319–22.
[39] Patterson R. Drug allergy. In: Patterson R, Grammer LC, Greenberger PA, editors. Allergic
diseases, diagnosis, and management, 5th edition. Philadelphia: Lippincott-Raven; 1997.
p. 317–412.
[40] Yeang HY. Prevalence of latex allergy may be vastly overestimated when determined by in
vitro assays. Ann Allergy Asthma Immunol 2000;84:628–32.
[41] Senst BL, Johnson RA. Latex allergy. Am J Health Syst Pharm 1997;54:1071–5.
[42] Kelly KJ, Kurup V, Zacharisen M, et al. Skin and serologic testing in the diagnosis of latex
allergy. J Allergy Clin Immunol 1993;91:1140–5.
[43] Kwittken PL, Becker J, Oyefara B, et al. Latex hypersensitivity despite prophylaxis. Allergy
Proc 1992;13:123–7.
[44] Levy J. Common anaphylactic and anaphylactoid reactions. In: Levy J, editor. Anaphylactic
reactions in anesthesia and intensive care. Boston: Butterworth-Heinemann; 1992. p. 83.
[45] Lee CE, Zembower TR, Fotis MA, et al. The incidence of antimicrobial allergies in hospital-
ized patients: implications regarding prescribing patterns and emerging bacterial resistance.
Arch Intern Med 2000;160:2819–22.
[46] Weiss ME, Adkinson NF Jr. Immediate hypersensitivity reactions to penicillin and related
antibiotics. Clin Allergy 1988;18:515–40.
[47] Gadde J, Spence M, Wheeler B, et al. Clinical experience with penicillin skin testing in a large
inner-city STD clinic. JAMA 1993;24:2456–63.
[48] Valyasevi MA, Van Dellen RG. Frequency of systematic reactions to penicillin skin tests.
Ann Allergy Asthma Immunol 2000;85:363–5.
[49] Park M, Markus P, Matesic D, et al. Safety and effectiveness of a preoperative allergy clinic
in decreasing vancomycin use in patients with a history of penicillin allergy. Ann Allergy
Asthma Immunol 2006;97:681–7.
[50] Cook FV, Farrar WE Jr. Vancomycin revisited. Ann Intern Med 1978;88:813–8.
[51] Newfield P, Roizen MF. Hazards of rapid administration of vancomycin. Ann Intern Med
1979;91:581.
[52] Renz CL, Laroche D, Thurn JD, et al. Trypase levels are not increased during vancomycin-
induced anaphylactoid reactions. Anesthesiology 1998;89:620–5.
[53] Renz CL, Thurn JD, Finn HA, et al. Antihistamine prophylaxis permits rapid vancomycin
infusion. Crit Care Med 1999;27:1732–7.
[54] Anne S, Middleton E, Reisman RE. Vancomycin anaphylaxis and successful desensitization.
Ann Allergy 1994;73:402–4.
[55] Ring J. Anaphylactoid reactions to plasma substitutes. In: Sage DJ, editor. Anaphylactoid
reactions to anesthesia. Boston: Brown; 1985. p. 67–95.
[56] Dieterich HJ, Kraft D, Sirtl C, et al. Hydroxyethyl starch antibodies in humans: incidence
and clinical relevance. Anesth Analg 1998;86:1123–6.
[57] Kreimeier U, Christ F, Draft D, et al. Anaphylaxis due to hydroxyethyl starch-reactive
antibodies [letter to editor]. Lancet 1995;346:49–50.
[58] Hirshman CA, Edelstein RA, Ebertz JM, et al. Thiobarbiturate-induced histamine release in
human skin mast cells. Anesthesiology 1985;63:353–6.
[59] Dolovich J, Evans S, Rosenbloom D, et al. Anaphylaxis due to thiopental sodium anesthesia.
Can Med Assoc J 1980;123:292–4.
[60] Harle DG, Baldo BA, Smal MA, et al. Detection of thiopentone-reactive IgE antibodies
following anaphylactoid reactions during anaesthesia. Clin Allergy 1986;16:493–8.
[61] Williamson J. Safe induction with propofol following thiopentone anaphylaxis [letter].
Anaesth Intensive Care 1990;18:277–8.
[62] Couldwell WT, Giannotta SL, Zelman V, et al. Life-threatening reactions to propofol
[letter]. Neurosurgery 1993;33:1116–7.
[63] Laxenaire MC, Gurant JL, Bermejo E, et al. Anaphylactic shock due to propofol [letter].
Lancet 1988;8613:739–40.
[64] Pepys J, Pepys O, Baldo BA, et al. Anaphylactic/anaphylactoid reactions to anaesthetic and
associated agents. Anaesthesia 1994;49:470–5.
[65] Gueant J-L, Aimone-Gastin I, Namour F, et al. Diagnosis and pathogenesis of the anaphy-
lactic and anaphylactoid reactions to anaesthetics. Clin Exp Allergy 1998;28:65–70.
[66] Cromwell TA, Zsigmond EK. Hypersensitivity to intravenous morphine sulfate. Plast
Reconstr Surg 1974;54:224–7.
[67] Fahmy NR. Hemodynamics, plasma histamine, and catecholamine concentrations during
an anaphylactoid reaction to morphine. Anesthesiology 1981;55:329–31.
[68] Roscow CE, Moss J, Philbin DM, et al. Histamine release during morphine and fentanyl
anesthesia. Anesthesiology 1982;56:93–6.
[69] Harle DG, Baldo BA, Coroneos MJ, et al. Anaphylaxis following administration of papa-
veretum. Case report: implication of IgE antibodies that react with morphine and codeine
and identification of an allergenic determinant. Anesthesiology 1989;71:489–94.
[70] Adourian U, Shampaine EL, Hirshman CA, et al. High-titer protamine-specific IgG
antibody associated with anaphylaxis: report of a case and quantitative analysis of antibody
in vasectomized men. Anesthesiology 1993;78:368–72.
[71] Dykewicz MS, Kim HW, Orfan N, et al. Immunology analysis of anaphylaxis to protamine
component in neutral protamine Hagedorn human insulin. J Allergy Clin Immunol 1994;93:
117–25.
[72] Horrow JC, Pharo GH, Levit LS, et al. Neither skin tests nor serum enzyme-lined immuno-
sorbent tests provide specificity for protamine allergy. Anesth Analg 1996;82:386–9.
[73] Kimmel SE, Sekeres MA, Berlin JA, et al. Risk factors for clinically important adverse events
after protamine administration following cardiopulmonary bypass. J Am Coll Cardiol 1988;
32:1916–22.
[74] Kindler CH, Bircher AJ. Anaphylactoid reactions to protamine. Anesthesiology 1996;85:
1209–10.
[75] Nicklas RA, Bernstein IL, Li JT, et al. The diagnosis and management of anaphylaxis.
J Allergy Clin Immunol 1998;101(Suppl):472–8.
[76] Porsche R, Brenner ZR. Allergy to protamine sulfate. Heart Lung 1999;28:418–28.
[77] Takenoshita M, Sugiyama M, Okun Y, et al. Anaphylactoid reaction to protamine con-
firmed by plasma tryptase in a diabetic patient during open heart surgery. Anesthesiology
1996;84:233–5.
[78] Levy JH, Schwieger IM, Zaidan JR, et al. Evaluation of patients at risk for protamine reac-
tions. J Thorac Cardiovasc Surg 1989;98:200–4.
[79] Greenberger PA, Pattterson R, Tobin MC, et al. Lack of cross reactivity between IgE to
salmon and protamine sulfate. Am J Med Sci 1989;298:104–8.
[80] Leynadier F, Dry J. Anaphylaxis to muscle-relaxant drugs: study of cross-reactivity by skin
tests. Int Arch Allergy Appl Immunol 1991;94:349–53.
[81] Fujita Y, Ishikawa H, Yokota K. Anaphylactoid reaction to midazolam [letter to editor].
Anesth Analg 1994;79:811–2.
[82] Yakel DL, Whittaker SE, Elstad MR. Midazolam-induced angioedema and bronchocon-
striction. Crit Care Med 1992;20:307–8.
[83] Fisher MM, Baldo BA. Mast cell tryptase in anaesthetic anaphylactoid reactions.
Br J Anaesth 1998;80:26–9.
[84] Laroche D, Vergnaud MC, Sillard B, et al. Biochemical markers of anaphylactoid reactions
to drugs: comparison of plasma histamine and tryptase. Anesthesiology 1991;75:945–9.
[85] Matsson P, Enander I, Andersson A-S, et al. Evaluation of mast cell activation (tryptase) in
two patients suffering from drug-induced hypotensive reactions. Agents Actions 1991;33:
218–20.
27 (2007) 231–248
Anaphylaxis: Evidence-Based
Long-Term Risk Reduction
in the Community
F. Estelle R. Simons, MD, FRCPC
Department of Pediatrics & Child Health, Department of Immunology,
Canadian Institutes of Health Research National Training Program in Allergy and Asthma,
University of Manitoba, 820 Sherbrook Street,
Winnipeg, MB, R3A 1R9, Canada
Anaphylaxis, defined clinically as a serious allergic reaction that is rapid

in onset and may cause death [1], now occurs more frequently in community
settings than in health care settings [2]. As with other allergic diseases, the
rate of occurrence seems to be increasing in many countries [3]. Continued
vigilance in preventing anaphylaxis, and in assessing and treating it
promptly when it occurs, are critically important. Health care professionals
also need to focus on long-term management of those individuals who have
experienced anaphylaxis, specifically on risk assessment and risk reduction
[2]. Allergy/immunology specialists and their allied health colleagues are
uniquely trained for this task. The expertise they provide in this area is
underutilized; for example, many individuals treated in emergency depart-
ments for anaphylaxis triggered by foods or insect stings who might benefit
from the risk assessment and risk reduction measures instituted by an aller-
gist do not get referred to an allergy/immunology specialist [4,5].
The fundamental basis of long-term risk reduction in anaphylaxis is ac-
curate risk assessment, on which personalized long-term preventive mea-
sures depend [2]. The diagnosis of anaphylaxis should be confirmed by
taking or retaking a detailed history of the acute episode, all antecedent
events or exposures that occurred during the hours before the episode,
and the response to treatment. In addition, the results of any laboratory
tests, such as serum tryptase levels, that may have been obtained during
the acute episode should be reviewed [2,6]. Comorbidities and the need
E-mail address: lmcniven@hsc.mb.ca
232 SIMONS
for concurrently administered medications to control them should be eval-

uated [2].
Most individuals who have anaphylaxis have an insect venom, food, or
other allergen trigger acting through a mechanism involving allergen-specific
IgE and the high-affinity IgE receptor on mast cells and basophils [2,7].
Others have anaphylaxis triggered by non–IgE-mediated immunologic
mechanisms; for example, intravenous immunoglobulin occasionally trig-
gers anaphylaxis through immune aggregates, and the cellular elements in
transfused blood can trigger anaphylaxis through cytotoxic mechanisms
[7]. Some have anaphylaxis from nonimmune triggers, such as exercise or
cold exposure, and others have idiopathic anaphylaxis [8–10]. Trigger avoid-
ance in anaphylaxis is necessarily trigger-specific; therefore, trigger factors
suggested by the history of the episode should be confirmed by allergen
skin testing or measurement of allergen-specific IgE in serum. Positive skin
tests or elevated allergen-specific IgE levels only document sensitization to
allergens, and need to be interpreted in the context of the history in order
to determine causality of the episode [2]. Depending on the history, addi-
tional tests (eg, an exercise challenge test) may be needed [2,8,10].
The main elements of risk reduction involve prevention of future epi-
sodes, emergency preparedness, and anaphylaxis education (Box 1) [2].
Each of these areas is discussed in detail. The level of evidence for the
recommendations is graded using the following system [11]:
Grade A: based on a meta-analysis, or at least one randomized, con-
trolled trial.
Grade B: based on at least one well-designed, but not necessarily con-
trolled, study, including case control and comparative studies.
Grade C: based on expert reports or opinions.
Evidence-based medicine is extremely helpful in the management of com-
mon diseases such as asthma, in which there are many potential interven-
tions and thousands of prospective, randomized, masked, controlled
clinical trials of these interventions that are eventually summarized in evi-
dence-based reviews and national and international guidelines [12]. When
the principles of evidence-based medicine are applied to anaphylaxis, how-
ever, some limitations become apparent. For several reasons, anaphylaxis is
a disease in which it is difficult (or, for epinephrine, almost impossible) to
conduct prospective, randomized, double-masked, placebo-controlled trials.
These include unpredictability of episodes, episodes commonly occurring in
community settings rather than health care settings, and variability in symp-
toms and signs with regard to time of onset after exposure to trigger, pat-
tern, severity, and duration. In addition, it may be difficult or impossible
to obtain baseline measurements before a therapeutic intervention such as
epinephrine, because it is unethical to delay treatment in a condition that
may be acutely life-threatening. Consequently, most of the current
evidence for long-term risk reduction in anaphylaxis, as summarized in
Boxes 1 and 2, is based on consensus and opinion (Grade C), or at best
LONG-TERM RISK REDUCTION IN THE COMMUNITY 233
Box 1. Risk reduction in anaphylaxis

Risk reduction through prevention
Trigger avoidance (Gradea C)
Specific measures: immunomodulation and other approaches
(Grade Ab, C)
Management of comorbidities (Grade C)
Risk reduction through emergency preparedness

Self-injectable epinephrine (Grade B)c
Personalized Anaphylaxis Emergency Action Plan (Grade C)
Medical identification (Grade C)
Anaphylaxis education
At-risk individuals and their families (Grade C)
Health care professionals (Grade C)
General public (Grade C)
a
Grade for level of evidence.
b
Allergen-specific immunotherapy with Hymenoptera venom [15,16].
c
Epinephrine [35,36].
on well-designed studies that are not actually randomized, masked, con-

trolled trials (Grade B).
Risk reduction through prevention

Trigger avoidance
Written, personalized, specific information on trigger avoidance should
be provided, and reviewed at regular intervals with those at risk and their
caregivers [2,8,10,13–16]. Long-term avoidance is necessary for many trig-
gers. Web site resources that consistently provide credible, accurate, and
up-to-date information include the Food Allergy and Anaphylaxis Network
(www.foodallergy.org), the American Latex Allergy Association (www.
latexallergyresources.org), the American Academy of Allergy, Asthma,
and Immunology (www.aaaai.org), and the American College of Allergy,
Asthma, and Immunology (www.acaai.org).
Complete avoidance of exposure to a confirmed trigger (eg, food, stinging
or biting insect, or natural rubber latex) for prevention of anaphylaxis is eas-
ier said than done, and is easier to initiate than to maintain for years or de-
cades. Trigger avoidance can necessitate lifestyle changes that potentially
impair the quality of life for the individual who has anaphylaxis and his
or her family [17–19]. One example of this involves individuals who have
234 SIMONS
Box 2. Prevention strategies for anaphylaxis in community

settings
Allergen avoidance (trigger-specific) based on history of
exposure and confirmation of sensitization (Grade C)
Food
Insect stings and bites
Natural rubber latex
Medicationsa (eg, b-lactam antibiotics)
Biologicsa (eg, allergens, vaccines, hormones)
Spices and other food additives
Inhalants (eg, horse dander)
Seminal fluid
Occupational allergens
Novel allergensb
Avoidance of or modulation of exposure to nonimmune

triggers (Grade C):
Exercisec
Cold
Heat
Sunlight/radiation
Medications (eg, opiates)
Ethanol
Immunomodulation
Insect venoms: allergen-specific immunotherapy (Grade A)
Medications, (eg, nonsteroidal anti-inflammatory drugs):
desensitization (Grade B)
Seminal fluid: desensitization (Grade C)
Idiopathic anaphylaxisd (Grade C)

Oral glucocorticoid (eg, prednisone). H1-antihistamine
(eg, cetirizine)
a
‘‘Safe’’ medications or biologics should be substituted.
b
Save the allergen (eg, food or insect) and save serum from the individual.
c
Avoidance of relevant co-triggers, such as cold air, food, or medication is
critically important. Exercise itself should not be avoided.
d
Personalized prophylactic medication regimen for individuals who have
frequent episodes.
Data from [2,8–10,13–16].
insect sting- or bite-triggered anaphylaxis, who may avoid outdoor sports or

leisure and vacation activities in order to avoid exposure to insects. Another
example involves individuals who have food-triggered anaphylaxis who re-
quire special food substitutes, with consequent potential economic, social,
and cultural burdens [19]. For individuals who have confirmed anaphylactic
sensitivity to foods, consultation with a licensed dietician can provide rele-
vant information about the minimal daily requirements for essential nutri-
ents, the basic food groups, any food substitutes or recipe adaptations
that may be required, and food product allergen labeling interpretation
[19]. Although improved food labeling should reduce the occurrence of
anaphylaxis in at-risk individuals, it may also mean that those who have
not been avoiding foods containing traces of allergen or allergens of doubtful
relevance face additional ambiguity and unnecessary dietary restrictions [20].
Optimal management of comorbidities and wise selection

of concurrent medications
Individuals who have mastocytosis, whether or not they have any symp-
toms of this disease, are at increased risk for anaphylaxis [21]. Some atopic
individuals who have raised baseline total tryptase levels in serum may also
be at increased risk for anaphylaxis.
Other at-risk individuals have comorbidities that can interfere with recog-
nition of anaphylaxis triggers and symptoms. These include vision or hearing
impairment, neurologic disease, or psychiatric disease, including depression,
substance abuse, attention deficit hyperactivity disorder, behavior problems,
and developmental delay [2,22,23].
Comorbidities can also affect the response to anaphylaxis treatment; in-
deed, most individuals dying from food-related anaphylaxis have concurrent
asthma [24,25]. Cardiovascular disease can affect treatment in several ways,
including reluctance to use self-injectable epinephrine because of fear of po-
tential increased risk for adverse effects. Neuromuscular diseases and arthritis
potentially place individuals at increased risk if they cannot self-inject epi-
nephrine rapidly or correctly because of lack of coordination or strength.
In addition, concurrent medications used to treat comorbid diseases
can place individuals at increased risk for anaphylaxis and for fatality
from anaphylaxis. Some medications, such as first-generation sedating H1-
antihistamines, hypnotics, and other sedatives, potentially interfere with
an individual’s ability to recognize anaphylaxis triggers or symptoms, as
do ethanol and recreational drugs.
Other concurrent medications can affect an individual’s response to ana-
phylaxis treatment. a- and b-adrenergic blockers, especially nonselective
b-blockers, regardless of the route of administration, potentially decrease
epinephrine efficacy by interfering with a- and b-agonist effects at adrenergic
receptors. Angiotensin-converting enzyme inhibitors, and to a lesser extent
angiotensin II receptor blockers, potentially interfere with endogenous
236 SIMONS
compensatory responses in anaphylaxis. Although less commonly used now

than in years past, tricyclic antidepressants and monoamine oxidase inhibi-
tors potentially increase the adverse effects of epinephrine because of pre-
vention of epinephrine uptake at adrenergic receptors [2,26–28].
Some medications (eg, those used for treatment of attention deficit hyper-
activity disorder) can lead to side effects that are similar to those produced
by epinephrine; amphetamines and methylphenidate release intracellular
stores of epinephrine and also block monoamine oxidase, preventing
epinephrine uptake at adrenergic receptors [2].
Specific preventive measures

Exercise-induced anaphylaxis
Strategies for preventing exercise-induced anaphylaxis are focused on
avoiding relevant co-triggers, such as cold or dry air, food, or medication.
Foods, including common triggers (eg, seafood) and less common triggers
(eg, wheat) or medication, (eg, nonsteroidal anti-inflammatory medications)
should be avoided for 4 hours before strenuous exercise. If no specific co-
trigger can be identified, the at-risk individual should refrain from ingesting
anything at all within 4 hours of exercise. General precautions include dis-
continuing exercise at the earliest hint of development of symptoms, such as
itching, dizziness, or respiratory symptoms; never exercising alone; and
always carrying self-injectable epinephrine. Warm-up and premedication
are often recommended, although these measures seem to be less effective
in prevention of exercise-induced anaphylaxis than they are in prevention
of exercise-induced bronchospasm [8,10].
Idiopathic anaphylaxis
Idiopathic anaphylaxis, currently a diagnosis of exclusion, is more com-
mon in adults than in children and likely has an autoimmune cause. It is
a glucocorticoid-responsive disease [9]; therefore, individuals who have
frequent episodes of idiopathic anaphylaxis, defined as two episodes in
2 months or six in 12 months, benefit from prophylactic glucocorticoid
treatment (eg, prednisone 40 to 60 mg every morning, often supplemented
with an H1-antihistamine, such as cetirizine 10 mg at bedtime). After symp-
tom control is achieved, the prednisone can be given on an alternate-day
basis, then gradually tapered. H2-antihistamines or leukotriene modifiers
are also sometimes recommended for individuals who have idiopathic ana-
phylaxis [9,10]. Prophylactic medication is not recommended for individuals
who have infrequent episodes of idiopathic anaphylaxis [9].
Immunomodulatory strategies
Anaphylaxis triggered by stings of insects in the order Hymenoptera
(bees, wasps, hornets, yellow jackets, fire ants) can be almost entirely
prevented by use of allergen-specific immunotherapy initiated by an
allergy-immunology specialist [15,16], and protection is long lasting in most

individuals [16].
Desensitization strategies are effective for anaphylaxis triggered by some
medications, including b-lactam antibiotics and acetylsalicylic acid and
other nonsteroidal anti-inflammatory drugs, and for seminal fluid–induced
anaphylaxis [10].
Additional effective immunomodulatory strategies for long-term risk re-
duction in anaphylaxis are being developed [13,14,29–31]. These include al-
lergen-specific treatment, such as ‘‘engineered’’ recombinant proteins in
which substitution of a critical amino acid within the IgE-binding epitopes
reduces IgE binding and prevents IgE-mediated reactions [29], or allergen-
nonspecific treatment, such as administration of anti-CD63 antibodies [30].
Proof of principle of one allergen-nonspecific approach, regular subcuta-
neous injections of anti-IgE antibody to prevent anaphylaxis, has already
been obtained in humans who have peanut allergy [31]. In the future, this
approach might provide many at-risk individuals with an increased margin
of protection against exposure to trace amounts of various allergens to
which they are sensitized.
Risk reduction through emergency preparedness

Self-injectable epinephrine: medication of choice in anaphylaxis
Despite long-term preventive measures to reduce risk, anaphylaxis trig-
gers can be accidentally encountered, and anaphylaxis can recur. Symptoms
may be more severe than those noted during previous episodes [32,33]. In
community settings, when no health care professionals are available to rec-
ognize and treat anaphylaxis, individuals and their caregivers must be pre-
pared to recognize and treat it. Physicians should ensure that all at-risk
individuals or their caregivers have self-injectable epinephrine and know
how to use it in the context of a personalized Anaphylaxis Emergency
Action Plan [2,10,34,35].
Epinephrine is the medication of choice in the first-aid treatment of
anaphylaxis in the community [35,36]. Acting through cyclic adenosine
monophosphate, it has broad pharmacologic effects, the most important
of which are: vasoconstriction with consequent increase in systolic blood
pressure and decrease in laryngeal edema, decreased release of mediators
of inflammation from mast cells and basophils, and bronchodilation [35].
Albuterol and other selective b2-adrenergic bronchodilators cannot replace
epinephrine, although they may be given as ancillary medications to relieve
wheeze, cough, and shortness of breath. Likewise, H1-antihistamines cannot
replace epinephrine, although they may be given as ancillary medications to
relieve itch, hives, and nasal symptoms (Table 1) [2,35,37,38].
Death can occur within a few minutes in anaphylaxis [24,25], and there-
fore epinephrine should be injected promptly, preferably intramuscularly in
238 SIMONS
Table 1
Rationale for epinephrine as the first-aid treatment of choice for anaphylaxis in the community
Medications and Epinephrine b2-adrenergic agonists H1-antihistamines
routes of (injection) (inhalation) (oral)
administration
Grade for level of B (adults and C in anaphylaxis; C in anaphylaxis
evidence older A for asthma treatment, B-C
children) symptom relief and in anaphylaxis
C (infants) for prevention of prevention, A in
exercise-induced allergic rhinitis,
bronchospasm A in urticaria
Pharmacologic At a1-receptor At b2-receptor At H1-receptor
effects [ vasoconstriction [ bronchodilation Y itch (skin, mucus
[ peripheral vascular membranes)
resistance Y flush
[ blood pressure Y hives
Y mucosal edema Y sneezing
(eg, in larynx); Y rhinorrhea
At b1-receptor
[ heart rate
[ force of cardiac
contraction,
At b2-receptor
Y mediator release
[ bronchodilation
[ vasodilation
Potential adverse Anxiety, pallor, Tremor, tachycardia, First-generation
effects when given tremor, dizziness, jitteriness H1-antihistamines
in usual doses by the palpitations, cause sedation
routes stated above headache and impaired
cognitive/
psychomotor
function; also dry
mouth, urinary
retention, and other
antimuscarinic effects
Current Treatment of Asthmatics should use Not life-saving;
recommendations first choice their albuterol or ancillary treatment
other bronchodilator for symptom relief in
inhaler in addition to addition to
epinephrine epinephrine
In community settings, where health care professionals are not available, individuals (or for
children, their caregivers) are on their own regarding recognition and first-aid treatment of ana-
phylaxis. Treatment of anaphylaxis in community settings therefore differs from treatment in
health care settings, such as emergency departments, where continuous monitoring of vital signs
and frequent reassessment of symptoms and signs is performed, and where treatment can be
modified rapidly if needed. Glucocorticoids (evidence grade for use ¼ C) and other
medications are not included in the table because they are not recommended for the first-aid
treatment of anaphylaxis in community settings.
Data from [2,35–38].
the anterolateral thigh to achieve peak concentrations rapidly in plasma and

tissues [39,40]. If epinephrine is injected into subcutaneous tissue, which has
poor vascularity in comparison to skeletal muscle, complete absorption oc-
curs eventually but is slow in many individuals. The pharmacokinetic elim-
ination half-life of epinephrine is 43 minutes in children and slightly longer
in adults [39]. The pharmacodynamic half-life has never been established;
however, based on retrospective studies, more than one epinephrine injec-
tion may be needed in up to 35% of individuals [41]. Although the optimal
interval between injections is not known, 5 to 15 minutes is commonly rec-
ommended [10]. Many of the individuals at risk for anaphylaxis in the com-
munity are infants and children [42]. The limited range of premeasured fixed
epinephrine doses, 0.15 mg and 0.3 mg, currently available in auto-injectors
presents a quandary for physicians wishing to prescribe an optimal epineph-
rine dose for infants and many young children [34,35,43] or for large teens
and adults. Lack of availability of auto-injectors with a needle length ade-
quate to achieve intramuscular injection in overweight and obese individuals
is also a concern [44].
Currently, two types of epinephrine auto-injectors are available in North
America. The advantages and disadvantages of each have been recently
reviewed [45]. One Twinject provides two epinephrine doses less expensively
than two EpiPens do and is more than 50% lighter and smaller. The Twin-
ject auto-injector needle is 25-gauge in contrast to the EpiPen auto-
injector needle, which is 22-gauge. The second epinephrine dose from
a Twinject is not an auto-injector dose; rather, it requires manipulation of
the needle and syringe.
In many countries life-saving epinephrine auto-injectors are either not
available, or, if available, are not affordable for at-risk individuals who
need them [46]. Existing alternatives cannot be depended on to produce
high concentrations of epinephrine rapidly in tissues; these include la-
ypersons’ use of a needle and syringe to draw up and measure an epineph-
rine dose from an ampule [47] or use of an epinephrine metered-dose
inhaler [48]. Sublingual dosage formulations of epinephrine are being
developed specifically for use as noninvasive first-aid treatment in the
community [49].
Rarely, an individual seems to be unresponsive to epinephrine. This un-
responsiveness may be due to an extremely rapid progression of the anaphy-
laxis episode, or failure to administer epinephrine in a timely manner. Even
if epinephrine is injected promptly, the dose may be inadequate or it may be
given through a suboptimal route of injection or site of injection, or by
a suboptimal injection technique, such as withdrawing the auto-injector
too quickly. As described previously, some individuals may be refractory
to epinephrine because they are concurrently taking a medication, such as
a nonselective b-blocker, that prevents optimal epinephrine effect. In rare in-
stances, an individual may be allergic to sodium metabisulfite, an antioxi-
dant in epinephrine solutions [35]. Moreover, epinephrine in solution is
240 SIMONS
notoriously prone to degradation. If the expiry date printed on the label has
passed or if the auto-injector has been exposed to high ambient tempera-
tures, the dose of epinephrine actually injected may be significantly lower
than the dose stated on the label [50].
Epinephrine is underused in anaphylaxis for various reasons, including
lack of recognition of the episode, spontaneous recovery from a previous
anaphylaxis episode in which epinephrine was not injected, or fear of nee-
dles. In addition, an epinephrine auto- injector may not be readily available
or may never have been prescribed or dispensed [35].
Occasionally, epinephrine is not injected because of fear of adverse
effects. Individuals at risk for anaphylaxis, or their caregivers, should be
advised that the transient anxiety, pallor, tremor, and palpitations that
commonly occur after epinephrine injection correlate with the beneficial
pharmacologic effects of epinephrine and should not be a cause for concern
(see Table 1) [35]. Serious adverse effects, such as myocardial ischemia,
arrhythmias, and pulmonary edema, are seldom attributable to use of
epinephrine auto-injectors by individuals in the community. More com-
monly they are attributable to overdose of epinephrine in health care
settings, such as intravenous administration of inappropriately high concen-
trations or an overly rapid rate of infusion. Moreover, there is increasing
awareness that the heart, like the skin, airways, gastrointestinal tract, and
vasculature, can be a target organ in anaphylaxis and that coronary artery
spasm, myocardial injury, and cardiac arrhythmias can occur in individuals
who have anaphylaxis episodes before they receive any epinephrine
treatment [51].
Personalized Anaphylaxis Emergency Action Plan

Epinephrine should always be prescribed in the context of broader edu-
cational interventions, including a written, personalized Anaphylaxis Emer-
gency Action Plan [2,52,53]. Such plans should list the most common
symptoms and signs of anaphylaxis, emphasize prompt epinephrine injec-
tion, and state clearly that asthma puffers and oral antihistamines cannot
be depended on in anaphylaxis [2,34,35].
Action plans should also make it clear that after epinephrine injection,
the individual should be transported to the nearest hospital emergency de-
partment [2], preferably in the supine position [54], for additional monitor-
ing of the episode and further treatment if necessary. Although more than
80% of anaphylaxis episodes are uniphasic, some episodes are biphasic or
prolonged and involve recurrent or persistent symptoms without any addi-
tional exposure to the trigger. Factors associated with increased risk for
such reactions are: history of a previous biphasic response, severity of the
episode being treated, brief time elapsed from trigger exposure to onset of
primary symptoms, presence of hypotension or laryngeal edema during
the primary response, and administering too little epinephrine too late
[55]. In reality, there is no certain way to predict the occurrence of biphasic

or prolonged anaphylaxis.
Medical identification
Individuals known to be at risk for anaphylaxis should be equipped with
accurate medical identification, such as a wallet card (available at
www.aaaai.org) or a medical identification bracelet or other jewelry, listing
their confirmed trigger factors and their relevant comorbidities and concur-
rent medications [2,56]. Options with regard to medical identification
jewelry include Medic Alert, Bodyguard, American Medical ID, E-health-
KEY, Stay Stat, and Medi-Guard ID. These vary with regard to range of
different items available, durability, initial purchase cost, annual fee, pres-
ence or absence of an embedded medical record, and reliability of worldwide
confidential 24-hour access 365 days per year to the at-risk individual’s
medical record.
Anaphylaxis education
At-risk individuals and their families
Education sessions should provide basic information about anaphylaxis,
prevention of anaphylaxis, and emergency preparedness for anaphylaxis
recurrence. Education of individuals at risk for anaphylaxis and their families
helps to reduce stress and instill confidence in ability to cope, not only by
avoiding relevant triggers for anaphylaxis and preventing episodes but also by
recognizing and treating episodes promptly if they occur.
To provide a framework for discussion, educators may find it helpful to use
commonly asked, basic questions, such as: Who is at risk? When can it hap-
pen? How do we recognize it? Where can it happen? What should we do?
Why is follow-up needed? [2]. In addition, anaphylaxis education may involve
broaching some difficult topics. For example, at-risk individuals and their
families may find it helpful to discuss the balance between maintenance of vig-
ilance and preparedness versus overprotection and withdrawal from daily life.
Educators may encounter individuals who deny the possibility that an ana-
phylaxis episode might recur, and the possibility that a subsequent anaphy-
laxis episode may be more severe than a previous episode. At the opposite
end of the spectrum, some individuals who have anaphylaxis are coming to
the attention of psychologists and psychiatrists because of high anxiety levels
that restrict their lives beyond what is medically necessary [57].
Supervised practice with an epinephrine auto-injector trainer until tech-
nique is perfected, and review of the Anaphylaxis Emergency Action Plan,
should take place at yearly intervals, or more often if needed (eg, if an ana-
phylaxis episode has inadvertently occurred despite preventive measures).
Supervised practice with an actual epinephrine auto-injector has been rec-
ommended [58].
242 SIMONS
Anaphylaxis education may be more complex and time-consuming than

asthma education is, and for the many individuals at risk for anaphylaxis
who have concurrent asthma, both types of education need to be provided
(Table 2).
Health care professionals

Health care professionals, including nurses, emergency medical service
technicians, first responders, and pharmacists, need regular anaphylaxis ed-
ucation updates. Pharmacists are an underutilized resource for providing
Table 2
Management of anaphylaxis compared with management of asthma
Anaphylaxis Asthma
Treatment options Limited number Many well-studied options
Self-treatment in Medication of choice: Medication of choice: inhalation
community settings epinephrine injection; of albuterol or other
implement action plan bronchodilator (reliever);
adjust dose of controller
or add another controller;
implement action plan
Trigger avoidance Difficult; constant vigilance Easier to institute for allergens
required (eg, for peanut such as house dust mites and
avoidance) indoor molds than for
household pets, outdoor
molds, or pollen; difficult to
maintain
Immunomodulation: Where relevant, insect venom Specific immunotherapy with
allergen-specific immunotherapy provides airborne allergens may be
highly effective, long-lasting helpful in selected patients
protection in selected patients
Immunomodulation: Proof of concept exists for use Anti-IgE antibody is helpful in
allergen-nonspecific of an anti-IgE antibody, but moderate–severe asthma
further studies are needed
Quality of the evidence Not optimal; the only Excellent: the level of evidence for
base for interventions intervention graded A is venom many interventions is graded A
immunotherapy; few are
graded B; most are graded C
Guidelines for No widely accepted national or Well-accepted international and
management international guidelines national guidelines that are
regularly updated
Education programsa Not formalized or validated yet Formalized, validated education
programs and certified
educators are widely available
and have already reached many
individuals in the community
a
Anaphylaxis education is a relatively new concept [2]. Many at-risk individuals require
both anaphylaxis education (level of evidence grade C) and asthma education (level of evidence
grade A).
anaphylaxis education in the community at the time prescriptions for epi-

nephrine auto-injectors are filled or refilled [59].
All physicians, including primary care physicians and emergency medi-
cine specialists, need to be aware of the new definition of anaphylaxis and
the criteria for diagnosis [1]. One of the key aspects of this definition is rec-
ognition that many individuals who die of anaphylaxis die of respiratory
failure rather than cardiovascular system failure and shock; therefore, it is
unwise to delay aggressive management until hypotension develops. More-
over, all physicians should also be aware of the need for prompt treatment
and for implementation of long-term preventive strategies. Ideally, ad-
vanced cardiac life support instruction should introduce the concepts of pre-
scribing self-injectable epinephrine for individuals who are treated for
anaphylaxis occurring in community settings, and of referring such individ-
uals to appropriate specialist physicians for long-term risk assessment and
risk reduction. Allergy/immunology specialists need to make themselves
available in their communities as providers of risk assessments and long-
term risk-reduction strategies in anaphylaxis.
General public
The first episode of anaphylaxis can be fatal [24,25]. It is therefore impor-
tant to increase widespread awareness of anaphylaxis as a killer allergy, es-
pecially among educators, coaches, camp directors, childcare providers,
food industry workers, restaurant workers, and transportation industry
workers; to provide clear aids to recognition of early symptoms and signs;
and to promulgate prompt use of self-injectable epinephrine. Optimally, epi-
nephrine auto-injectors should be available in all public places because ana-
phylaxis can occur anywhere in the community.
All educators, whether at the childcare, preschool, school, or college
level, need to be aware that children, teens, and young adults who seem
to be in robust good health can be at increased risk for anaphylaxis and
that fatal anaphylaxis can occur in the educational setting [24].
The childcare system presents unique challenges regarding anaphylaxis
education. Infants and preschool children are vulnerable to accidental
allergen exposure because of age-related inability to recognize and avoid
triggers, and in addition, anaphylaxis is more difficult to recognize in the
very young because of their inability to describe symptoms [2,60]. Moreover,
in many jurisdictions, childcare centers and preschools are not as well
regulated by government agencies as school systems are, and may not
have policies in place to facilitate prompt recognition and treatment of
anaphylaxis.
Allergy/immunology specialists and their allied health colleagues have
been instrumental in developing anaphylaxis programs for schools. There
are ongoing attempts to ensure that children and adolescents can carry
or access self-injectable epinephrine in the school environment. The need
244 SIMONS
Box 3. Anaphylaxis in schools

Student’s responsibilitiesa
Avoid his/her trigger (eg, if food-allergic: do not trade food
with others, do not eat anything containing unknown
ingredients)
Notify an adult immediately if inadvertently exposed to trigger or
if symptoms develop
Wear medical identification jewelry and/or carry wallet card
Carry self-injectable epinephrine if age-appropriate and if
permitted by local regulations
Family’s responsibilitiesa
Notify the school in writing of the student’s risk for anaphylaxis
and his/her triggers
Educate student about trigger avoidance
Provide medical documentation from the student’s physician,
including an Anaphylaxis Emergency Action Plan
Provide a properly labeled epinephrine auto-injector
Replace epinephrine auto-injector after use or if past expiry
date
Provide emergency contact information for parents or
guardians
Work with the school to further develop a personalized action
plan for the student
Physician’s responsibilitiesa
Provide accurate risk assessment
Recommend risk reduction measures (eg, allergen avoidance,
venom immunotherapy, if relevant)
Prescribe self-injectable epinephrine
Recommend medical identification jewelry and/or wallet card
Provide Anaphylaxis Emergency Action Plan
Provide medical information to student and parents
Provide medical documentation to the school
If the student has concurrent asthma, achieve optimal symptom
control
School’s responsibilitiesa
Review health records of at-risk students
Identify a team (eg, teachers, school nurse, principal) to prevent,
recognize, and treat anaphylaxis
Designate school personnel who are trained to administer
epinephrine injections
Rehearse the response to an anaphylaxis episode:

Give epinephrine promptly
Contact 911 or emergency medical services
Contact parents
a
All information should be updated annually before the start of the school
year and at additional intervals as needed (eg, if an episode of anaphylaxis occurs
or if a student’s allergen triggers change) ([61] and the Food Allergy and Anaphy-
laxis Network, 2007, www.foodallergy.com).
to address the significant racial and socioeconomic differences identified in

providing self-injectable epinephrine for schoolchildren has been recognized.
Students, families, physicians, and schools all bear responsibility for ana-
phylaxis risk reduction in the educational environment (Box 3). Efforts to
streamline communication between parents, physicians, and schools need
to be adopted; currently, numerous different forms are needed for different
schools [61–64].
Many teens and young adults are at increased risk for anaphylaxis.
Individuals in this age group have been reported to have a high level of
risk-taking and coping behaviors and to be at increased risk for fatal
food-induced anaphylaxis on college campuses and elsewhere [24,25,65].
Colleges and universities therefore offer unique opportunities for anaphy-
laxis education of at-risk individuals and their peers. Policies with regard
to supporting these individuals vary from one institution to another, and
this, too, presents unique opportunities for dialog and education.
In recent years, legislators in many countries have been receptive toward
changing public policy and improving medical services for individuals who
have anaphylaxis. Two examples of important legislation being imple-
mented in the United States include: the National Food Allergy Labeling
Consumer Protection Act, which mandates clear food labeling, and
HR23, a bill mandating that children and teens in schools should have ac-
cess to life-saving epinephrine auto-injectors. In many Canadian schools,
an Act to Protect Anaphylactic Pupils (Sabrina’s Law) is being imple-
mented. This law mandates the establishment of minimum standards for ed-
ucation of all school personnel with regard to recognition and management
of anaphylaxis in the school setting.
In summary, all time and effort spent on anaphylaxis education of at-risk
individuals and their families, health care professionals, and the general
public is immensely rewarding and potentially life-saving.
References
246 SIMONS
[2] Simons FER. Anaphylaxis, killer allergy: long-term management in the community.
[3] Lieberman P, Camargo C Jr, Bohlke K, et al. Epidemiology of anaphylaxis: incidence and
prevalence. Findings of the ACAAI Anaphylaxis Study Group. Ann Allergy Asthma Immu-
nol 2006;97:596–602.
[5] Clark S, Long AA, Gaeta TJ, et al. Multicenter study of emergency department visits for in-
sect sting allergies. J Allergy Clin Immunol 2005;116(3):643–9.
allergic reactions: an emergency department-based study. J Allergy Clin Immunol 2000;
106(1):65–71.
Immunol 2002;110(3):341–8.
[8] Beaudouin E, Renaudin JM, Morisset M, et al. Food-dependent exercise-induced anaphy-
laxisdupdate and current data. Allerg Immunol (Paris) 2006;38(2):45–51.
[9] Lenchner K, Grammer LC. A current review of idiopathic anaphylaxis. Curr Opin Allergy
Clin Immunol 2003;3(4):305–11.
[10] Joint Task Force on Practice Parameters; American Academy of Allergy Asthma and Immu-
nology, American College of Allergy Asthma and Immunology. The diagnosis and
management of anaphylaxis: an updated practice parameter. J Allergy Clin Immunol 2005;
115(3):S483–523.
[11] Levels of evidence and grades of recommendation. Oxford (UK): Centre for Evidence-Based
Medicine. Available at: http://www.cebm.net/levels_of_evidence.asp. Accessed October 5,
2006.
[12] National Asthma Education and Prevention Program Expert Panel (NAEPP) Report. Long-
term management of asthma in children: effectiveness of inhaled corticosteroids compared to
other medications. J Allergy Clin Immunol 2002;110(Suppl 5 Pt 2):S147–60.
[13] Sampson HA. Update on food allergy. J Allergy Clin Immunol 2004;113(5):805–19.
[14] Sampson HA. Clinical practice. Peanut allergy. N Engl J Med 2002;346(17):1294–9.
[15] Freeman TM. Clinical practice. Hypersensitivity to Hymenoptera stings. N Engl J Med
2004;351(19):1978–84.
[16] Golden DBK, Kagey-Sobotka A, Norman PS, et al. Outcomes of allergy to insect stings in
children, with and without venom immunotherapy. N Engl J Med 2004;351(7):668–74.
[17] Cohen BL, Noone S, Munoz-Furlong A, et al. Development of a questionnaire to measure
quality of life in families with a child with food allergy. J Allergy Clin Immunol 2004;114(5):
1159–63.
[18] Oude Elberink JNG, de Monchy JGR, Golden DB, et al. Development and validation of
a health-related quality-of-life questionnaire in patients with yellow jacket allergy. J Allergy
Clin Immunol 2002;109(1):162–70.
[19] Munoz-Furlong A. Daily coping strategies for patients and their families. Pediatrics 2003;
111(6):1654–61.
[20] Simons E, Weiss CC, Furlong TJ, et al. Impact of ingredient labeling practices on food
allergic consumers. Ann Allergy Asthma Immunol 2005;95(5):426–8.
[21] Akin C, Metcalfe DD. Occult bone marrow mastocytosis presenting as recurrent systemic
anaphylaxis. J Allergy Clin Immunol 2003;111:S206.
[22] Mullins RJ. Anaphylaxis: risk factors for recurrence. Clin Exp Allergy 2003;33(8):1033–40.
[23] Ring J, Brockow K, Behrendt H. History and classification of anaphylaxis. Novartis Found
Symp 2004;257:6–16.
[24] Bock SA, Munoz-Furlong A, Sampson HA. Fatalities due to anaphylactic reactions to
foods. J Allergy Clin Immunol 2001;107(1):191–3.
[25] Pumphrey R. Anaphylaxis: can we tell who is at risk of a fatal reaction? Curr Opin Allergy
Clin Immunol 2004;4(4):285–90.
[26] TenBrook JA Jr, Wolf MP, Hoffman SN, et al. Should beta-blockers be given to patients
with heart disease and peanut-induced anaphylaxis? A decision analysis. J Allergy Clin
Immunol 2004;113(5):977–82.
[27] Muller UR, Haeberli G. Use of beta-blockers during immunotherapy for Hymenoptera
venom allergy. J Allergy Clin Immunol 2005;115(3):606–10.
[28] Kemp SF, Lieberman P. Inhibitors of angiotensin II: potential hazards for patients at risk for
anaphylaxis? Ann Allergy Asthma Immunol 1997;78(6):527–9.
[29] Li X-M, Srivastava K, Grishin A, et al. Persistent protective effect of heat-killed Escherichia
coli producing ‘‘engineered,’’ recombinant peanut proteins in a murine model of peanut
[30] Kraft S, Fleming T, Billingsley JM, et al. Anti-CD63 antibodies suppress IgE-dependent
allergic reactions in vitro and in vivo. J Exp Med 2005;201(3):385–96.
[31] Leung DYM, Sampson HA, Yunginger JW, et al. Effect of anti-IgE therapy in patients with
peanut allergy. N Engl J Med 2003;348(11):986–93.
[32] Vander Leek TK, Liu AH, Stefanski K, et al. The natural history of peanut allergy in
young children and its association with serum peanut-specific IgE. J Pediatr 2000;137(6):
749–55.
[33] Sicherer SH, Furlong TJ, Munoz-Furlong A, et al. A voluntary registry for peanut and tree
nut allergy: characteristics of the first 5149 registrants. J Allergy Clin Immunol 2001;108(1):
128–32.
[34] Sicherer SH, Simons FER. Quandaries in prescribing an emergency action plan and self-
injectable epinephrine for first-aid management of anaphylaxis in the community. J Allergy
Clin Immunol 2005;115(3):575–83.
[35] Simons FER. First-aid treatment of anaphylaxis to food: focus on epinephrine. J Allergy
Clin Immunol 2004;113(5):837–44.
[36] McLean-Tooke APC, Bethune CA, Fay AC, et al. Adrenaline in the treatment of anaphy-
laxis: what is the evidence? Br Med J 2003;327(7427):1332–5.
[37] Simons FER. Advances in H1-antihistamines. N Engl J Med 2004;351(21):2203–17.
[38] Sheikh A, Ten Broek V, Simons SGA, et al. H1-antihistamines for anaphylaxis: systematic
review. Cochrane Database Syst Rev 2007;1:CD006160.
[39] Simons FER, Roberts JR, Gu X, et al. Epinephrine absorption in children with a history of
anaphylaxis. J Allergy Clin Immunol 1998;101(1):33–7.
[40] Simons FER, Gu X, Simons KJ. Epinephrine absorption in adults: intramuscular versus
subcutaneous injection. J Allergy Clin Immunol 2001;108(5):871–3.
[41] Korenblat P, Lundie MJ, Dankner RE, et al. A retrospective study of epinephrine admin-
istration for anaphylaxis: how many doses are needed? Allergy Asthma Proc 1999;20(6):
383–6.
[42] Simons FER, Peterson S, Black CD. Epinephrine dispensing patterns for an out-of-hospital
Immunol 2002;110(5):647–51.
[43] Simons FER, Peterson S, Black CD. Epinephrine dispensing for the out-of-hospital treat-
ment of anaphylaxis in infants and children: a population-based study. Ann Allergy Asthma
Immunol 2001;86(6):622–6.
[44] Song TT, Nelson MR, Chang JH, et al. Adequacy of the epinephrine autoinjector needle
length in delivering epinephrine to the intramuscular tissues. Ann Allergy Asthma Immunol
2005;94(5):539–42.
[45] Kelso JM. A second dose of epinephrine for anaphylaxis: how often needed and how to
carry. J Allergy Clin Immunol 2006;117(2):464–5.
[46] Simons FER. Lack of worldwide availability of epinephrine autoinjectors for outpatients at
risk of anaphylaxis. Ann Allergy Asthma Immunol 2005;94(5):534–8.
[47] Simons FER, Chan ES, Gu X, et al. Epinephrine for the out-of-hospital (first aid) treatment
of anaphylaxis in infants: is the ampule/syringe/needle method practical? J Allergy Clin
Immunol 2001;108(6):1040–4.
248 SIMONS
[48] Simons FER, Gu X, Johnston L, et al. Can epinephrine inhalations be substituted for epi-
nephrine injection in children at risk for systemic anaphylaxis? Pediatrics 2000;106(5):
1040–4.
[49] Rawas-Qalaji MM, Simons FER, Simons KJ. Sublingual epinephrine tablets versus intra-
muscular injection of epinephrine: dose-equivalence for potential treatment of anaphylaxis.
[50] Simons FER, Gu X, Simons KJ. Outdated EpiPen and EpiPen Jr auto-injectors: past their
prime? J Allergy Clin Immunol 2000;105(5):1025–30.
[51] Marone G, Bova M, Detoraki A, et al. The human heart as a shock organ in anaphylaxis.
Novartis Found Symp 2004;257:133–49.
[52] Ewan PW, Clark AT. Efficacy of a management plan based on severity assessment in longi-
tudinal and case-controlled studies of 747 children with nut allergy: proposal for good prac-
tice. Clin Exp Allergy 2005;35(6):751–6.
[53] American Academy of Allergy Asthma and Immunology Board of Directors. Anaphylaxis in
schools and other child-care settings. J Allergy Clin Immunol 1998;102(2):173–6.
[54] Pumphrey RSH. Fatal posture in anaphylactic shock. J Allergy Clin Immunol 2003;112(2):
451–2.
[55] Lieberman P. Biphasic anaphylactic reactions. Ann Allergy Asthma Immunol 2005;95:
217–26.
[56] Gillespie CA, Ernst F, Goritz SS, et al. Anticipatory anaphylaxis management in a children’s
hospital allergy clinic: a quality assurance audit of physician and nurse recommendations
and teaching. J Allergy Clin Immunol 2004;113:S240.
[57] Monga S, Manassis K. Treating anxiety in children with life-threatening anaphylactic
conditions. J Am Acad Child Adolesc Psychiatry 2006;45(8):1007–10.
[58] Rosen JP. Empowering patients with a history of anaphylaxis to use an epinephrine autoin-
jector without fear. Ann Allergy Asthma Immunol 2006;97(3):418.
[59] Barnett CW. Need for community pharmacist-provided food-allergy education and auto-
injectable epinephrine training. J Am Pharm Assoc (Wash DC) 2005;45(4):479–85.
[60] Bansal PJ, Marsh R, Patel B, et al. Recognition, evaluation, and treatment of anaphylaxis in
the child care setting. Ann Allergy Asthma Immunol 2005;94(1):55–9.
[61] Munoz-Furlong A. Food allergy in schools: concerns for allergists, pediatricians, parents,
and school staff. Ann Allergy Asthma Immunol 2004;93(5):S47–50.
[62] McIntyre CL, Sheetz AH, Carroll CR, et al. Administration of epinephrine for life-threaten-
ing allergic reactions in school settings. Pediatrics 2005;116(5):1134–40.
[63] Murphy KR, Hopp RJ, Kittelson EB, et al. Life-threatening asthma and anaphylaxis in
schools: a treatment model for school-based programs. Ann Allergy Asthma Immunol 2006;
96(3):398–405.
[64] Hannaway PJ, Connelly ME, Cobbett RM, et al. Differences in race, ethnicity, and socioeco-
nomic status in schoolchildren dispensed injectable epinephrine in 3 Massachusetts school
districts. Ann Allergy Asthma Immunol 2005;95(2):143–8.
[65] Sampson MA, Munoz-Furlong A, Sicherer SH. Risk-taking and coping strategies of adoles-
cents and young adults with food allergy. J Allergy Clin Immunol 2006;117(6):1440–5.
27 (2007) 249–260
Mediators of Anaphylaxis
Yoshiko Ogawa, MD*, J. Andrew Grant, MD,
FAAAAI, DFACAAI
Division of Allergy, Pulmonary, Immunology, Critical Care, and Sleep [APICS],
University of Texas Medical Branch, Medical Research Building 8.104,
Galveston, TX 77555-1083, USA
Anaphylaxis is a systemic, immediate hypersensitivity reaction that re-

sults from IgE-mediated release of vasoactive and inflammatory mediators
from mast cells and basophils. The classic form, described in 1902 [1], in-
volves prior sensitization to an allergen with later re-exposure, producing
symptoms by means of an IgE-mediated immunologic mechanism. Clinical
features in anaphylaxis are induced by the mediators released mainly by the
high-affinity IgE receptor (Fc3RI) cross-linking on mast cells and basophils
previously sensitized by antigen (Fig. 1). Experimentally, mediators can be
released by responding not only antigens, but also by anti-IgE, calcium ion-
ophore A23187, compound 48/80, morphine sulfate, formyl-met-leu-phe
(fMLP) peptide, substance P, anaphylatoxins, chemokines, complement
fragments, and stimulation of toll-like receptors [2] (Fig. 2). The effects of
IgE and Fc3RI potentially can be reversed by IgG combining with the
FcgRIIb receptor on basophils and mast cells [3]. Patients develop urticaria,
angioedema, bronchospasm, hypotension, and gastrointestinal (GI) symp-
toms typically within an hour after mast cell activation.
In the early days, histamine was considered to be the principal mediator
of anaphylaxis; however, it now is known that various mediators are
involved. Preformed granule mediators are released by exocytosis within
minutes. Synthesis of arachidonic acid (AA) metabolites including prosta-
glandins (PGs) and leukotrienes (LTs) also occurs within minutes, while
activation of the synthesis of inflammatory cytokines and chemokines may
take hours [2]. Typically, additional cells are recruited and activated during
the late phase of allergic reactions, and these include basophils, eosinophils,
and Th2 cells. A new approach to demonstrating basophil activation during
E-mail address: yoogawa@utmb.edu (Y. Ogawa).
250 OGAWA & GRANT
Fig. 1. Fc3RI-mediated signaling pathways in mast cells. (Adapted from Siraganian RP. Mast cell
signal transduction from the high-affinity IgE receptor. Curr Opin Immunol 2003;15:639–46; with
permission.)
Fig. 2. Degranulation of mast cell. (Adapted from Grant JA, Hassan S, Leonard PA. Mast cell
and basophil-derived mediators. Atlas of Allergic Diseases. 2nd edition. New York: Current
Medicine Group; 2005. p. 1–10; with permission.)
MEDIATORS OF ANAPHYLAXIS 251
anaphylactic reactions is use of flow cytometry and identification of surface

markers of activation including CD63 and CD203c [4].
Approximately 84,000 cases of anaphylaxis occur in the United Sates
every year, which affect 1.2 to 15% of the population. Among these cases,
500 to 1000 are fatal [5]. Therefore it is important to characterize the medi-
ators of anaphylaxis in understanding the pathophysiology and treatment of
anaphylaxis. This article reviews these mediators, first granule-associated
preformed mediators, followed by membrane-derived lipid mediators, and
then chemokines/cytokines.
Mediators from mast cells and basophils

Granule-associated preformed mediators
Histamine
Histamine is a critical mediator of the most rapidly occurring anaphylac-
tic symptoms. Histamine is a diamine produced by decarboxylation of
amino acid histidine in the Golgi apparatus of mast cell and basophils.
Once in the extracellular environment, histamine is metabolized rapidly
(half-life of 30 minutes) by histamine methyl transferase [6], which limits
its use as a marker for mast cell and basophil activation. In an anaphylactic
patient, plasma histamine begins to rise in 5 minutes and remains elevated
only for 30 to 60 minutes. Urinary histamine metabolites, including methyl-
histamine, may be found for up to 24 hours after onset of anaphylaxis. The
effects of histamine are mediated through H1, H2, H3, and H4 receptors, all
of which are G protein-coupled receptors. This type of receptor is a heptahel-
ical transmembrane molecule that can transduce extracellular signals by way
of G proteins to intracellular second messenger systems. H1 receptors, fol-
lowed by H2 receptors, are responsible for most anaphylactic reactions [7].
The physiologic phenomena that both H1 and H2 receptors exert with
histamine stimulation are vasodilatation, increased vascular permeability,
increased heart rate, increased cardiac contraction, and increased glandular
secretion. Increased vascular permeability leads to urticaria and angioe-
dema. Urticaria and angioedema are the most common clinical symptoms
in anaphylaxis and are seen in 88% of cases [8]. Although platelet-activating
factor (PAF) and arachidonic acid metabolites (prostaglandin D2, leukotri-
enes C and D) also contribute to urticaria and angioedema formation, his-
tamine appears to be the major mediator.
Cardiac effects from histamine, such as enhanced inotropy and chrono-
tropy, mainly are mediated by H2 receptors and also some effects from
H1 receptors. H1 receptor stimulation increases the heart rate by shortening
of sinoartrial node diastolic phase. H1 receptor simulation also may cause
coronary artery vasospasm and lead to myocardial infarction even in a
patient who has normal coronary arteries [9].
252 OGAWA & GRANT
When the H1 receptor is stimulated, it will lead to contraction of smooth

muscles in the bronchial tree and GI tract. Wheezing and dyspnea are
caused by H1 receptor stimulation and seen 55% to 60% of the time. GI
symptoms such as nausea, vomiting, diarrhea, and cramping pain are seen
in 25% to 30% of cases [10]. Increased mucous secretion is the result of in-
creased mucous viscosity by H1 receptor stimulation and increased produc-
tion by H2 receptor stimulation. It is seen as rhinorrhea and bronchorrhea.
H1 receptors on endothelial cells will stimulate the production of nitric
oxide (NO), which indirectly will cause vasodilatation [10]. NO is produced
from L-arginine by NO synthetase (NOS), and its actions are mediated by
cyclic guanosine monophosphate (cGMP). There are three forms of the
enzyme NOS; neuronal NOS (nNOS) is cloned from neurons, eNOS originally
characterized in endothelial cells, and inducible NOS (iNOS), whose produc-
tion appears to be inflammation-related and pathologic. Inducible NOS
(iNOS) appears to be produced as an offshoot of the inflammatory response,
by the stimulatory effects of tumor necrosis factor (TNF) and other cytokines.
It results in massive production of NO, causing widespread vasodilatation
(caused by loss of vasomotor tone) and hypotension. NO has these detrimen-
tal effects and beneficial effects, but studies are supporting the concept that NO
inhibition will lead to better outcome in a shock state [11,12].
H2 receptors exert their effect directly on the vascular smooth muscle and
cause vasodilatation. In anaphylactic shock, it has been shown that block-
ade of both H1 and H2 receptors is superior to H1 blockage alone
[13,14]. Flushing, headache, increased pulse pressure, and increased diastolic
pressure are controlled better with both H1 and H2 blockage.
There are recent studies showing that pruritus may be related the stimu-
lation of the H3 receptors located in a brain [15]. Chrusch and colleagues
[16] observed that a specific H3 receptor blocker thioperamide was effective
in improving cardiac function in a dog model of anaphylaxis. H4 receptors,
the newest member of the histamine receptor family, may play a role in
inflammatory processes. A selective H4 receptor blocker was found to
have anti-inflammatory effects in mice by blocking histamine-induced che-
motaxis and calcium influx in mouse bone marrow-derived mast cells, and
the histamine-induced migration of tracheal mast cells from the connective
tissue toward the epithelium [17].
Neutral proteases
Tryptase
Tryptase is a serine esterase protein with a molecular weight of 110-130
kDa. Tryptase binds to heparin or other proteoglycans through its cationic
groove. Heparin-stabilized tetramers of tryptase are stored mainly in mast
cell secretory granules [18]. Small amounts of tryptase are found in baso-
phils also. When tryptase is released, it is secreted as an active proteoglycan
complex with a large size (200 to 250 kDa) that limits diffusion away from
mast cell activation sites. Therefore, circulating tryptase levels increase only
after the massive mast cell activation seen in anaphylactic shock or masto-
cytosis. Tryptase can spread the degranulation signal from mast cell to mast
cell [19]. Serum tryptase peaks 60 to 90 minutes after the onset of anaphy-
laxis and remains elevated for up to 5 hours [20], making this an effective
laboratory marker for anaphylaxis. There are a, b, and g tryptases, and
only minor differences in amino acid sequences are seen between a and b.
a-tryptase is thought to be released constitutively from mast cells in an
inactive form and the stored forms of tryptase which are released during
degranulation thought to be b-tryptase [21]. The study by Schwartz and col-
leagues [22], however, suggests that pro-a and b tryptases, unprocessed tryp-
tases before propeptide removal, are secreted constitutively rather than
stored granules with mature tryptases. Mature b-tryptase level is elevated
only after severe anaphylaxis, and it is shown in Fig. 3 [23]. The ratio of
total tryptase to b-tryptase is helpful in differentiating anaphylaxis from
mastocytosis (Table 1). A ratio of 10 or less is indicative of anaphylaxis
not associated with systemic mastocytosis, and a ratio of 20 or greater indi-
cates systemic mastocytosis [23,24]. This is helpful, especially when anaphy-
laxis occurs in a systemic mastocytosis patient who has a high baseline total
tryptase level [25]. Increased level of total tryptase often correlates with an
increased histamine level, but imperfect correlation may be seen, because b-
tryptase diffuses through tissue more slowly than histamine with its associ-
ation with the protease/proteoglycan complex [23] and also probably
Fig. 3. Hypothetic time course for the appearance of mature tryptase in serum or plasma dur-
ing systemic anaphylaxis. The maximal level is set at 100% in the figure; however, in reality, it
varies depending at least in part on the clinical severity and nature of the anaphylactic stimulus,
which, in turn, affects how long mature tryptase is in a detectable range. Abbreviation: t1/2, half-
life. (From Shwartz LB. Diagnostic value of tryptase in anaphylaxis and mastocytosis. Immunol
Allergy Clin N Am 2006;26:451–63; with permission.)
254 OGAWA & GRANT
Table 1
Mature and total tryptase levels
Tryptase levels (ng/mL)
Tryptase ratio
Clinical condition Total Mature (total/mature)
Normal 1–15 !1 Not applicable
Systemic anaphylaxis Greater than O1a !10
(acute) baseline
Systemic mastocytosis O20b !1 to small O20
(nonacute) elevations
a
Level related to clinical severity (hypotension), timing of sample collection in relation to
onset of signs and symptoms, and nature of the anaphylactic stimulus.
b
Speculated to reflect primarily the total body burden of mast cells.
Data from Shwartz LB. Diagnostic value of tryptase in anaphylaxis and mastocytosis.
Immunol Allergy Clin N Am 2006;26:451–63.
because of difference in time course. Tryptase level is more likely to elevate

in severe anaphylaxis, and a normal tryptase level does not rule out
anaphylaxis.
As seen in Box 1 [10], multiple inflammatory cascades (contact system, clot-
ting system, and complement system) are involved in anaphylactic events.
Along with tryptase, mast cell kininogenase and basophil kallikrein activate
these systems. Tryptase can activate the contact (kallikrein-kinin) system,
which leads to decreased high molecular weight kininogen and formation of
activation complexes, followed by bradykinin production, causing angioe-
dema. Tryptase also can inactivate procoagulant proteins [26] and promote fi-
brin clot lysis [27], which may lead to disseminated intravascular coagulation.
Box 1. Multimediator recruitment occurring during anaphylaxis

and anaphylactic events (pathway activated)
Coagulation pathway
Decreased factor V
Decreased factor VIII
Decreased fibrinogen
Complement cascade
Decreased C4
Decreased C3
Formation of C3a
Contact system (kinin formation)
Decreased high-molecular-weight kininogen
Formation of kallikrein-C1-inhibitor complexes and factor
XIIa-C1-inhibitor complexes
Chymase
As seen with tryptase, chymase also is bound to proteoglycans and stored
in mast cell granules [2]. Chymase is a monomer and present only in MCTC
mast cells. Chymase can activate the angiotensin system, with conversion of
angiotensin I to angiotensin II to compensate intravascular volume loss sec-
ondary to increased vascular permeability [10]. It has been suggested by
Hermann and colleagues [28,29] that baseline angiotensin II levels and I
are lower in hymenoptera-sensitive patients than normal patients, and the
severity of the anaphylaxis correlates with lower levels. Hence, intake of an-
giotensin-converting enzyme (ACE) inhibitors may predispose anaphylaxis
because of blockage of this compensatory effect, and it is beneficial to con-
sider avoiding ACE inhibitors in the setting of chronic anaphylaxis or im-
munotherapy. Chymase also cleaves neuropeptides, such as vasoactive
intestinal peptide, and acts on substance P and bradykinin.
Proteoglycansdheparin
As discussed previously, human mast cells contain heparin and chondroi-
tin sulfate proteoglycans to stabilize secretory granule proteases [2]. When
mast cells are activated, heparin is released from mast cell granules with pro-
teases and histamine. Heparin can work as anticoagulation by binding to
antithrombin III, so that clotting cascade will not progress. Heparin also
is known to bind phospholipase A2 and inhibit the arachidonic acid cas-
cade, which yields factors that are chemoattractants for eosinophils. Hepa-
rin also inhibits cytokine function, activation of kinin pathway, and the
complement cascade.
Membrane-derived lipid mediators

Mast cells generate and release eicosanoids lipid mediators such as pros-
taglandins and leukotrienes through multiple enzymatic steps from nuclear
membrane phospholipids. Arachidonic acid (AA) is cleaved from membrane
phospholipids by means of cytosolic phospholipase A2, and subsequently
metabolized by several routes, including the cyclooxygenase pathway and
5-lipoxygenase pathway. These pathways are illustrated in Fig. 4. After
Fc3RI activates bone marrow mast cells, two phases of eicosanoid lipid me-
diator generation are seen [2]. An acute phase takes place within 10 minutes,
and leukotriene C (LTC)4 and prostaglandin D (PGD)2 are generated de-
pendent on constitutively expressed cyclooxygenase (COX)-1. During a de-
layed phase (2 to 10 hours after activation), PGD2 alone is synthesized by
induced COX-2.
Prostaglandins
COX-1 and COX-2 are enzymes that catalyze conversion of arachidonic
acid to prostaglandins (PGs) [2]. The major COX product is PGD2 in mast
cells. Basophils do not produce PG2, making this a distinguishing feature
256 OGAWA & GRANT
Fig. 4. Arachidonic acid cascade. (Courtesy of Sigma-Aldrich Co., St. Louis, MO; with permis-
sion. Ó 2005 Sigma-Aldrich Co.)
from mast cells. After synthesis in mast cells, PGD2 is excreted by means of
a prostaglandin transporter protein and binds to two receptors DP1 and
DP2. DP2 receptors are found in most tissues. PGD2 produces bronchocon-
striction, peripheral vasodilation, and coronary and pulmonary artery vaso-
constriction. Operating through the DP2 receptor, PGD2 is chemotactic for
basophils, eosinophils, dendritic cells, and Th2 cells, and it is an enhancer of
histamine release from basophils. Skin mast cells mainly produce PGD2,
whereas mast cells at the lung, heart, and GI tract secrete predominately
PGD2 and LTC4.
PGF2 is also a bronchoconstrictor, peripheral vasodilator, coronary va-
soconstrictor, and platelet aggregation inhibitor. PGE2 is mainly a broncho-
dilator, but the rest of the PGs are bronchoconstrictors. Thromboxane A2
causes vasoconstriction, platelet aggregation, and bronchoconstriction.
Leukotrienes
Cysteinyl leukotrienes (cysLTs) are a class of structurally related lipid
molecules, originally described as slow-reacting substance of anaphylaxis,
with a myriad of biologic functions [2,30,31]. CysLTs are synthesized by
mast cells, basophils, and eosinophils. LTC4 if formed when LTC4 synthase
conjugates glutathione to leukotriene A (LTA)4. After cellular export,
LTC4 is metabolized to LTD4 and LTE4 by sequential removal of glutamic
acid and glycine. The biological activities of the cysLTs include producing
smooth muscle contraction and mucus secretion, recruiting allergic inflam-
matory cells, modulating cytokine production, influencing neural transmis-
sion, and altering structural changes in the airway. CysLTs potently can
stimulate smooth muscle contraction independent of histamine. On inhala-
tion, LTC4 and LTD4 induce bronchoconstriction in normal subjects with
a 1000-fold greater potency than histamine, and LTE4 is 10-fold more po-
tent [32]. CysLTs also cause increased vascular permeability, which can in-
duce wheal-and-flare responses in skin, and cause arteriolar constriction.
Denzlinger and colleagues [33] investigated cysteinyl leukotriene production
in anaphylactic reactions and found that the concentrations of urinary leu-
kotriene E4 plus N-acetyl leukotriene E4 were enhanced strongly in urine
samples during or shortly after the anaphylactic reaction. Correlation be-
tween leukotrienes and anaphylaxis is suggested especially in exercise-
induced anaphylaxis in animal models [34]. LTB4 is a chemotactic agent
and thus theoretically might contribute to the late phase of anaphylaxis
and to protracted reactions [35].
There are two receptors for the CysLTs, CysLT1 and CysLT2. Both are
G protein coupled transmembrane receptors. CysLT1 is expressed highly on
lung smooth muscle cells, peripheral blood leukocytes including eosinophils
and monocytes, and on mast cells. CysLT1 antagonists, including montelu-
kast, are effective in attenuating early and late responses of allergen expo-
sures, chronic bronchial asthma, and exercise challenges, but no clinical
studies have shown the effect of any antileukotrienes to modify the course
of anaphylaxis.
Platelet-activating factor
Platelet-activating factor (PAF) is synthesized from membrane phospho-
lipids by means of a different pathway from arachidonic acid. It is produced
by acetylation at the SN-2 position after PLA2 cleavage of AA in the mem-
brane, and binds to a G protein-coupled 7 transmembrane receptor. PAF
aggregates platelets (that is how PAF originally was named), and it is also
a very potent mediator in allergic reactions and stimulates a broad range
of cell types. PAF causes bronchoconstriction with the potency of 1000
times greater than histamine, but also increases vascular permeability, che-
motaxis, and degranulation of eosinophils and neutrophils.
Cauwels and colleagues [36] recently showed a surprising finding that hy-
peracute PAF shock depends entirely on NO, produced by constitutive
eNOS, instead of iNOS. In this murine model, PAF was administered to
wild-type, iNOS knockout, and eNOS knockout mice. Only eNOS knock-
out mice survived. One plausible explanation is that anaphylaxis overstim-
ulates eNOS and thereby excessively relaxes vascular smooth muscle,
leading to hypotension and death. eNOS is phosphorylated rapidly and ac-
tivated by means of the PI3 K pathway in endothelial cells, which might lead
to excessive NO synthesis.
258 OGAWA & GRANT
Cytokines and chemokines

Mast cells release chemokines and cytokines, as well as previously men-
tioned mediators, and contribute to anaphylactic reactions. Chemokines
and cytokines mainly contribute to the late phase of biphasic anaphylactic
reaction, seen several hours after the first symptoms subside. TNF-a is the
major mast cell inflammatory cytokine. After IgE-, IgG-, and toll-like recep-
tor–mediated activation of mast cells, preformed TNF-a is released, and it
activates neutrophils, increases monocyte chemotaxis, and enhances produc-
tion of other cytokines by T cells. Anti-TNF treatment theoretically im-
proves anaphylaxis, but no clinical trials or animal studies have been
reported.
After mast cells are activated by means of Fc3RI, expression of nuclear
factor (NF)-kB related genes, CCL-7, CCL-1, and Th2 cytokine genes (in-
terleukin [IL]-5, IL-13) are enhanced. Other cytokines released include
granulocyte (G) colony-stimulating factor (CSF), macrophage (M)-CSF,
GM-CSF, IL-1 beta, IL-3, IL-4, IL-6, IL-8, IL-10, IL-16, IL-18, IL-22,
and TNF-a [2]. Basophils are a major source of IL-4, IL-13, and chemokines
[37]. In anaphylaxis, when Fc3RI-mediated activation takes place in the gut,
lung, and skin, a chemokine receptor CCR3 is expressed predominantly on
MCTC. After CCR3 is translocated to the surface membrane, the mast cell
becomes susceptible to its ligand CCL11 (eotaxin), and CCL 11 binds to
CCR3, leading to increased secretion of IL-13.
IL-4 stimulates and maintains Th2 cell proliferation and switches B cells
to IgE synthesis. IL-4 and IL-13 increase IgE production, Fc3RI expression,
and target cell responsiveness to various vasoactive mediators. IL-4/IL-13
activation of the transcription factor signal transducer and activator of tran-
scription 6 plays a key role by means of IL-4 receptor a chain [38]. There-
fore, IL-4 Ra antagonists might be an effective treatment for anaphylaxis,
particularly as a prophylactic therapy. Although long-term exposure to
IL-4 stimulates mastocytosis and can enhance mediator release, the most
dramatic and rapid effect of IL-4 on anaphylaxis is a three- to sixfold
enhancement of responsiveness of targeted cells to vasoactive mediators,
including histamine, serotonin, PAF, and cysteinyl leukotrienes (Strait
RT, Morris SC, Smiley K, Urban JF Jr, Finkelman FD, unpublished
data, 2005). These effects were blocked by IFN-g, a cytokine that inhibits
many effects of TH2 cytokines [39–41].
References
[1] Portier P, Richet C. De l’action anaphylactique de certains venins. C Roy Soc Biol (Paris)
1902;54:170–2.
[2] Castells M. Mast cell mediators in allergic inflammation and mastocytosis. Immunol Allergy
Clin North Am 2006;26:465–85.
[3] Saxon A, Zhu D, Zhang K, et al. Genetically engineered negative signaling molecules in the
immunomodulation of allergic diseases. Curr Opin Allergy Clin Immunol 2004;4(6):563–8.
[4] Valent P, Hauswirth AW, Natter S, et al. Assays for measuring in vitro basophil activation
induced by recombinant allergens. Methods (Duluth) 2004;32(3):265–70.
[5] Neugut AI, Ghatak AT, Miller RL. Anaphylaxis in the United States: an investigation into
its epidemiology. Arch Intern Med 2001;161(1):15–21.
[6] Friedman BS, Steinburg SC, Meggs WJ. Analysis of plasma histamine levels in patients with
mast cell disorders. Am J Med 1989;87(6):649–54.
[7] Simons EFR. Advances in H1-antihistamines. N Engl J Med 2004;351:2203–17.
[8] Green E, Lieberman P. Anaphylaxis: a review of 593 cases. J Allergy Clin Immunol 2004;
113(2):S240.
[9] Zavras GM, Papadaki PJ, Kokkinis CE. Kounis syndrome secondary to allergic reaction fol-
lowing shellfish ingestion. Int J Clin Pract 2003;57:622–4.
[10] Lieberman P. Anaphylaxis and anaphylactoid reactions. In: Middleton E, editor. Allergy:
principles and practice. vol. 2. 6th edition. Philadelphia: Mosby; 2003. p. 1497–522.
[11] Osada S, Ichiki H, Oku H. Participation of nitric oxide in mouse anaphylactic hypotention.
Eur J Pharmacol 1994;252:347–50.
[12] Cotter C, Kaluski E, Blatt A. L-NMMA (a nitric oxide synthase inhibitor) is effective in the
treatment of cardiogenic shock. Circulation 2000;28:1358–61.
[13] Lin RY, Curry A, Pesola G. Improved outcomes in patients with acute allergic syndromes
who are treated with combined H1 and H2 antagonists. Ann Emerg Med 2000;36:462–8.
[14] Kaliner M, Shelhamer JH, Ottesen EA. Effects of infused histamine: correlation of plasma
histamine levels and symptoms. J Allergy Clin Immunol 1982;70(2):82–7.
[15] Sugimoto Y, Iba Y, Nakamura Y, et al. Pruritus-associated response mediated by cutaneous
histamine H3 receptors. Clin Exp Allergy 2004;34:456–9.
[16] Chrusch C, Sharma S, Unruh H, et al. Histamine H3 receptor blockade improves cardiac
function in canine anaphylaxis. Am J Respir Crit Care Med 1999;160(4):1142–9.
[17] Thurmond RL, Desai PJ, Dunford PJ, et al. A potent and selective histamine H4 receptor
antagonist with anti-inflammatory properties. J Pharmacol Exp Ther 2004;309:404–13.
[18] Pereira PJ, Bergner A, Macedo-Ribeiro S, et al. Human beta tryptase is a ring-like tetramer
with active sites facing a central pore. Nature 1998;392(6673):306–11.
[19] Molinari JF, Scuri M, Moore WR, et al. Inhaled tryptase causes bronchoconstriction in
sheep via histamine release. Am J Respir Crit Care Med 1996;154(3 Pt 1):649–53.
[20] Laroche D, Vergnaud MC, Sillard B, et al. Biochemical markers of anaphylactoid reactions
to drugs. Comparison of plasma histamine and tryptase. Anesthesiology 1991;75(6):945–9.
[21] Sakai K, Ren S, Schwartz LB. A novel heparin-dependent processing pathway for human
tryptase. Autocatalysis followed by activation with dipeptidyl peptidase I. J Clin Invest
1996;97(4):988–95.
[22] Schwartz LB, Min HK, Ren S, et al. Tryptase precursors are preferentially and spontane-
ously released, whereas mature tryptase is retained by HMC-1 cells, Mono-Mac-6 cells,
and human skin-derived mast cells. J Immunol 2003;170(11):5667–73.
[23] Shwartz LB. Diagnostic value of tryptase in anaphylaxis and mastocytosis. Immunol Allergy
Clin North Am 2006;26:451–63.
[24] Schwartz LB, Irani AM. Serum tryptase and the laboratory diagnosis of systemic mastocy-
tosis. Hematol Oncol Clin North Am 2000;14(3):641–57.
[25] Florian S, Krauth MT, Simonitsch-Klupp I, et al. Indolent systemic mastocytosis with ele-
vated serum tryptase, absence of skin lesions, and recurrent severe anaphylactoid episodes.
Int Arch Allergy Immunol 2005;136(3):273–80.
[26] Thomas VA, Wheeless CJ, Stack MS, et al. Human mast cell tryptase fibrinogenolysis: kinetics,
anticoagulation mechanism, and cell adhesion disruption. Biochemistry 1998;37(8):2291–8.
[27] Stack MS, Johnson DA. Human mast cell tryptase activates single-chain urinary-type plas-
minogen activator (pro-urokinase). J Biol Chem 1994;269(13):9416–9.
[28] Hermann K, Rittweger R, Ring J. Urinary excretion of angiotensin I, II, arginine vasopres-
sin, and oxytocin in patients with anaphylactoid reactions. Clin Exp Allergy 1992;22(9):
845–53.
260 OGAWA & GRANT
[29] Hermann K, von Tschirschnitz M, Ebner von Eschenbach C, et al. Histamine, tryptase, nor-
epinephrine, angiotensinogen, angiotensin-converting enzyme, angiotensin I and II in
plasma of patients with hymenoptera venom anaphylaxis. Int Arch Allergy Immunol
1994;104(4):379–84.
[30] Murphy RC, Hammarstrom S, Samuelsson B, et al. A slow-reacting substance from murine
mastocytoma cells. Proc Natl Acad Sci U S A 1979;76:4275–9.
[31] Ogawa Y, Calhoun WJ. The role of leukotrienes in airway inflammation. J Allergy Clin
Immunol 2006;118(4):789–98.
[32] Lee TH, O’Hickey SP, Jacques C, et al. Sulphidopeptide leukotrienes in asthma. Adv Pros-
taglandin Thromboxane Leukot Res 1991;21A:415–9.
[33] Denzlinger C, Habrel C, Wilmanns W. Cysteinyl leukotriene production in anaphylactic
reactions. Int Arch Allergy Immunol 1995;108(2):158–64.
[34] Manning PJ, Watson RM, Margolskee DJ, et al. Inhibition of exercise-induced bronchocon-
striction by MK-571, a potent leukotriene D4-receptor antagonist. N Engl J Med 1990;323:
1736–9.
Immunol 2002;110(3):341–8.
[36] Cauwels A, Janssen B, Buys E, et al. Anaphylactic shock depends on PI3K and eNOS-
derived NO. J Clin Invest 2006;116(8):2244–51.
[37] Prussin C, Metcalfe DD. IgE, mast cells, basophils, and eosinophils. J Allergy Clin Immunol
2006;117:S450–6.
[38] Finkelman FD, Rothenberg ME, Brandt EB, et al. Molecular mechanisms of anaphylaxis:
lessons from studies with murine models. J Allergy Clin Immunol 2005;115:449–57.
[39] Strait RT, Morris SC, Smiley K, et al. IL-4 exacerbates anaphylaxis. J Immunol 2003;170:
3835–42.
[40] Siraganian RP. Mast cell signal transduction from the high-affinity IgE receptor. Curr Opin
Immunol 2003;15:639–46.
[41] Grant JA, Hassan S, Leonard PA. Mast cell and basophil-derived mediators. Atlas of Aller-
gic Diseases. 2nd edition. Philadelphia: Current Medicine Group. p. 1–10.
27 (2007) 261–272
Insect Sting Anaphylaxis

David B.K. Golden, MDa,b,*
a
Johns Hopkins University, 733 North Broadway, Baltimore, MD 21205, USA
b
Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle,
Baltimore, MD 21224, USA
Stinging insects of the order Hymenoptera can cause systemic allergic

reactions including anaphylaxis, but such reactions are rare with biting
insects. This article describes the clinical patterns and treatment of sting
reactions, including how they may resemble or differ from other causes of
anaphylaxis.
Clinical features
Transient pain, itching, and swelling are normal responses to stings, but al-
lergic reactions can cause more severe local reactions or generalized systemic
reactions. Large local sting reactions cause delayed and prolonged local in-
flammation increasing over 24 to 48 hours and resolving in 3 to 10 days. These
reactions resemble late-phase reactions, which are IgE dependent. Most pa-
tients who have large local reactions have detectable venom-specific IgE [1].
Systemic (generalized) reactions may cause any one or more of the signs
and symptoms of anaphylaxis. Although the definition of anaphylaxis
would seem to exclude reactions involving only cutaneous manifestations
(urticaria, angioedema, pruritus, flush), these are included here, because
they must be considered in diagnosis and treatment of insect allergy as
potential precursors of more severe anaphylactic reactions [2]. There are
also reports of chronic urticaria and cold urticaria developing after insect
stings, usually without any immediate hypersensitivity reaction, and with
uncertain risk of anaphylaxis to a future sting [3]. Unusual patterns of
reaction also have been reported, including nephropathy, central and
Supported by NIH Grant AI08270 and NIH GCRC Grant 5MO1-RR02719.

* Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore,
MD 21224.
E-mail address: dgolden1@jhmi.edu
262 GOLDEN
peripheral neurologic syndromes, idiopathic thrombocytopenic purpura,

and rhabdomyolysis, but most of these are not IgE-related [4,5].
Systemic (generalized) allergic sting reactions result in cutaneous, vascu-
lar or respiratory symptoms and signs, either singly or in any combination,
with possible involvement of other less common target tissues. Cardiac
anaphylaxis also can cause bradycardia, arrhythmias, angina, or myocardial
infarction. Abdominal cramps are not uncommon, and spontaneous abor-
tion can occur as a result of sting anaphylaxis. There may be a greater
chance of systemic reaction if there are multiple stings at one time, or if there
are repeated stings in the same summer. In contrast to food anaphylaxis, the
slower the onset of the sting reaction, the less likely it is to be life-threatening
[6,7].
Whether anaphylaxis differs clinically between children and adults is
unclear for most causes, but is known for insect sting allergy. Cutaneous
symptoms are most common overall, affecting 80%; they are the sole man-
ifestation in 15% of adults but in more than 60% of affected children [8].
Almost 50% of reactions in both children and adults include respiratory
complaints. Symptoms and signs of hypotension are uncommon in children
but occur in over 60% of adults, with half experiencing loss of consciousness
(rare in children) [7,9]. The clinical presentation can be vague and uncertain
both during the reaction and in the history. To aid proper diagnosis and
treatment, objective documentation should be made whenever possible,
including description of cutaneous findings, vital signs, pulse oximetry, and
air flow measurements.
Treatment of insect sting anaphylaxis is no different from other causes of
anaphylaxis [10,11]. Biphasic anaphylaxis and protracted anaphylaxis have
been reported with insect stings, so medical observation should extend for 3
to 6 hours depending on severity. Some individuals are resistant to epineph-
rine, especially those on beta-blocker medication. Nevertheless, the risk of
stopping beta blockers in patients who have cardiac disease may exceed
the risk of continuing the drugs [12]. Patients discharged from emergency
care of anaphylaxis should receive instruction about the need for an
epinephrine kit, an allergy consultation, and preventative treatment, and
should understand that using the kit is not a substitute for emergency
medical attention [13].
Etiology
Stinging insects of the order Hymenoptera are the main cause of insect-
related anaphylaxis. There are three families of Hymenoptera with clinical
importance: the bees (honeybees, bumblebees), vespids (yellow jackets,
hornets, wasps), and stinging ants (genus Solenopsis and others). Exposure
to these insects is affected by environmental and ecological factors. The
Africanized honeybee (killer bee) is an aggressive hybrid resulting from an
experiment intended to enhance honey production. The danger from the
INSECT STING ANAPHYLAXIS 263
Africanized honeybee stems from the numbers of stings because of swarm-

and-attack behavior. Their venom is actually no different than that of other
honeybees. Imported fire ants arrived almost 100 years ago in Mobile,
Alabama, and they have become an increasing public health hazard in the
south and southeast parts of the United States [14,15]. There have been
increasing reports of anaphylaxis caused by other species of stinging ants
in Asia and Australia [16].
The immunochemical characteristics and immunogenetic relationships
of the Hymenoptera venoms have been studied thoroughly [17,18]. Venoms
contain multiple protein allergens, most having enzymatic activity.
Honeybee venom is immunochemically distinct from the other Hymenop-
tera, but vespid venoms have a high degree of cross reactivity with each
other and contain essentially the same allergens. Skin tests are positive to
all three of the common vespid skin test preparations (yellow jacket, yellow
hornet, white-faced hornet) in most vespid-allergic patients. Polistes wasps
are not as closely related to the other vespids, and only 50% of yellow
jacket-allergic patients have positive tests to wasp venom. Fire ant venoms
are different in that they contain very little protein, in a suspension of alka-
loid toxins that causes the characteristic vesicular eruption. The proteins in
fire ant venoms are antigenically unique except for one that shows limited
cross reactivity with a vespid allergen. The diagnostic and therapeutic
materials currently supplied by commercial laboratories are fire ant whole-
body extracts, which, unlike the other insect whole-body extracts, do show
reasonable allergenic activity for diagnostic skin testing and for preventative
immunotherapy [19].
Epidemiology/natural history
Knowledge of the epidemiology and natural history of Hymenoptera
venom sensitivity is crucial in clinical decision-making. It was the lack of
this information that prolonged the mistaken conclusion that whole-body
extract therapy was effective for preventing anaphylaxis [20]. The studies
of whole-body extract were not placebo-controlled, and included children,
large local reactors, mild systemic reactors, and individuals who had nega-
tive venom skin tests, all of whom now are known to have very low risk of
anaphylaxis to stings.
Insect sting allergy can occur at any age, often following numerous
uneventful stings, and is more common than previously thought. Systemic
allergic reactions are reported by up to 3% of adults, and almost 1% of
children have a medical history of severe sting reactions [21,22]. The
frequency of large local reactions is uncertain, but is estimated at 10% in
adults. At least 50 fatal sting reactions occur each year in the United States
[6]. Half of all fatal reactions occur with no history of previous sting reac-
tions. Many sting fatalities may be unrecognized. It is possible to document
in some postmortem blood samples, the presence of both venom-specific IgE
264 GOLDEN
antibodies and elevated serum tryptase, suggesting a possible fatal sting

reaction in some cases of unexplained sudden death [23,24]. The presence
of IgE antibodies to Hymenoptera venom is not, in itself, however, unusual.
Over 30% of adults stung in the previous 3 months showed venom-specific
IgE by skin test or radioallergosorbent test (RAST), and over 20% of all
adults tested positive to yellow jacket or honeybee venom, even though
most had no history of allergic sting reactions [21]. Venom sensitivity in
asymptomatic adults is often transient, disappearing more rapidly than it
does in patients who have a history of anaphylaxis. Of the subjects who
had initial positive skin tests, 30% to 60% became negative after 3 to
6 years. Those who remained positive showed a 17% frequency of a systemic
reaction to a sting [25].
Systemic reactions can become progressively more severe with each sting
in some cases, but this seems to be the exception rather than the rule. In
prospective sting challenge studies, less than 1% of the patients had reac-
tions more severe than their past reactions [26,27]. In two retrospective
surveys, there were a larger number of subjects who described worsening
of the reaction with subsequent stings [7,28]. Allergic reactions to stings
usually follow a predictable and individual pattern in each patient. Anaphy-
lactic reactions to stings can occur even decades apart, with or without
intervening stings.
Diagnosis
History
The history is paramount in diagnosis and must be elicited with insight
and attention to detail. Patients usually fail to admit sting reactions without
specific inquiry; they often do not seek medical attention, and believe the re-
action was a chance occurrence that could not happen again [21]. The his-
tory should include all previous stings, the time course of the reactions,
and all associated symptoms and treatments. The reaction to any given sting
can be variable, even in sting-allergic individuals. Even without intervening
stings, sensitization can persist for decades and result in subsequent anaphy-
lactic reactions to stings. If intervening stings have occurred without sys-
temic reaction, there could be less risk of subsequent severe reaction, but
the possibility of future anaphylaxis cannot be excluded when diagnostic
tests reveal venom-specific IgE antibodies [26].
The significance of the sting reaction can be over- or underestimated.
Symptoms sometimes are exaggerated by fear, panic, exercise, heat, alcohol,
or underlying cardio–respiratory disease. For this reason, objective docu-
mentation of the physical findings during the reaction should be sought
(measurements of blood pressure or reduced air flow, observed urticaria).
The throat or chest discomfort, dyspnea, lightheadedness, nausea, and other
constitutional symptoms can be caused by anxiety/panic disorder or simple
fear. Insect sting challenge studies often have elicited subjective symptoms
that mimic anaphylaxis, but with no objective evidence of reaction.
Diagnostic tests
Diagnostic tests are indicated in patients who have had systemic reactions
to stings [11,29]. If the risk of future anaphylaxis is judged to be low (less
than 10%), diagnostic testing (and venom immunotherapy) is not required.
This is the case in patients who have had only large local reactions to stings,
and in children who have had only cutaneous systemic reactions. There are
also patients who request venom testing because of fear of the reactions
experienced by family members or others. Testing is not advised in such
cases because of the frequent occurrence of positive venom tests in individ-
uals who have been previously stung without abnormal reaction.
Unfortunately, skin tests are not a useful screening test and are not
recommended in those with no history of systemic allergic reaction to a sting.
A screening test for insect allergy would be desirable to prevent the morbidity
and mortality of the initial anaphylactic episode. In fact, half of all fatal
reactions occur without prior reactions to stings. Venom immunotherapy
is indicated only in patients who have a history of previous systemic reac-
tion, because venom skin tests can be positive in many adults who have
had previous stings and will have no reaction to a future sting. It should
not be possible to have positive tests for venom-specific IgE antibodies in
individuals who have never been stung. Although such cases have been de-
scribed, the author found that all those who could be traced through fam-
ily members were found to have had stings in early childhood that they
could not recall [21]. Other possible explanations include cross reactivity
with plant allergens (airborne or food-related) or with carbohydrate deter-
minants [30,31].
The preferred diagnostic method is venom skin testing because of its high
degree of sensitivity and proven safety [32]. In vitro methods can be useful
but are not as sensitive and therefore can yield false-negative results. The
standard method of skin testing is with the intradermal technique using
the five Hymenoptera venom protein extracts (or whole-body extracts of
imported fire ants). For Hymenoptera venom testing, intradermal tests are
performed with venom concentrations in the range of 0.001 to 1.0 mg/mL
to find the minimum concentration giving a positive result. Puncture tests
at no more than 1 mg/mL concentration may be used initially for patients
with a history of very severe reactions. Sensitization may have occurred to
multiple venoms even when there has only been a reaction to a single insect.
Therefore, skin testing should be performed with a complete set of five
Hymenoptera venoms, a negative diluent (human serum albumin-saline) con-
trol, and a positive histamine control.
Skin test results are clearly positive in 65% to 85% of patients who have
a convincing history. Negative skin tests in a history-positive patient can be
266 GOLDEN
caused by loss of sensitivity after a remote sting reaction. Negative skin tests
after recent sting anaphylaxis can occur during the refractory period of
anergy for several weeks after a sting reaction; therefore, they should be
repeated after 1 to 6 months [33]. Venom skin tests also show unexplained
variability over time such that tests can be negative on one occasion and
positive on another [34]. It may be best to perform venom skin tests on
two separate occasions before making the final therapeutic selection of
venoms. Some cases of sting anaphylaxis appear to be non-IgE-mediated
and may be related to subclinical mastocytosis or simply toxic mast cell me-
diator release. The venom causing the strongest skin test reaction is usually
the insect that caused the most recent sting. Most importantly, the degree of
skin test sensitivity does not correlate reliably with the degree of sting reac-
tion. The strongest skin tests often occur in patients who have had only large
local reactions and have a very low risk of anaphylaxis, whereas some
patients who have had abrupt and near-fatal anaphylactic shock show
only weak skin test (or RAST) sensitivity. In fact, about 25% of patients
presenting for systemic allergic reactions to stings are skin test positive
only at the 1.0 mg/mL concentration. Once again, it is the history that is
most predictive.
The detection of allergen-specific IgE antibodies in serum (typically by
RAST) is less sensitive than skin testing but is useful when skin tests cannot
be done (patients with a severe skin condition or unavoidable medications
than suppress skin tests) [32,35]. Another use of the RAST is to resolve
the discordance when skin tests are negative in a patient who has a history
of severe reaction to a sting. It is not clear whether there is any difference in
prognostic value of skin tests and RAST. Patients who have negative skin
tests and positive RAST have been reported to have systemic reactions to
subsequent stings, although the frequency may be lower than in patients
who have positive venom skin tests [26].
Other diagnostic techniques are of limited value. Some investigators have
suggested that sting challenge is the most specific diagnostic test, but others
find this unethical and impractical [27,36,37]. Furthermore, a single negative
challenge sting does not preclude anaphylaxis to a subsequent sting [26,38].
Prevention
Precautions
Individuals susceptible to allergic reactions to stings should avoid related
exposures, particularly outdoor foods and drinks that attract or harbor
stinging insects. Excessive fear impairs quality of life, however, and can
be considered among the indications for venom immunotherapy [39].
When to carry or use an epinephrine injector depends on the clinical setting.
Although having an emergency injector is reassuring to some individuals, it
is frightening to others and conveys a concern about possible dangerous
reactions to stings [40]. Many experts suggest that an injector is not neces-
sary when the chance of a systemic reaction is only 5% to 10% such as in
large local reactors, children with cutaneous systemic reactions, and patients
on venom immunotherapy. On the other hand, some feel that even a 2%
chance of anaphylaxis warrants carrying epinephrine, even if it does not
warrant venom immunotherapy. Most insect-allergic patients can be advised
to keep an epinephrine injector at the ready when stung, but may not need
to use it if the reaction does not occur or remains limited to mild symptoms.
Some patients have had rapid onset of severe reactions and (until immu-
nized) should potentially use epinephrine immediately after being stung.
Venom immunotherapy
Treatment for prevention of anaphylactic reactions is not always avail-
able; immunotherapy is currently possible only for Hymenoptera venom.
Therapy with whole- insect body extracts was proved to be no better than
placebo, whereas venom immunotherapy was 95% effective [41,42]. The in-
dications for venom immunotherapy require a history of previous systemic
allergic reaction to a sting and a positive diagnostic test for venom-specific
IgE. Those with a recent history of anaphylaxis and a positive skin test have
a 30% to 70% chance of systemic reaction to a subsequent sting [27,41,43].
A low risk (!10%) has been found in children and adults who have a history
of large local reactions, and in children who have systemic reactions limited
to cutaneous signs and symptoms (with no respiratory or circulatory
manifestations) [44–47]. Venom immunotherapy is not required in these
low-risk cases, but some patients still will request treatment because of their
fear of reaction and the impact on their quality of life. Children who have
moderate or severe systemic reactions have up to 30% chance of reaction
to a sting even decades later [44]. Unfortunately, there is no test that predicts
which patients will progress to more severe reactions. Even intervening
stings without reaction do not eliminate the risk of anaphylaxis to a later
sting.
Initial venom immunotherapy can follow any of several recommended
schedules. The common modified rush regimen is more rapid than
traditional regimens, achieving the 100 mg maintenance dose with eight
weekly injections, instead of taking 4 to 6 months [48]. With these regimens,
adverse reactions are no more common than in traditional regimens of
inhalant allergen therapy, and both regimens are equally effective. Even
1- to 3-day rush regimens are not associated with a higher frequency of ad-
verse reactions to venom injections [49–51]. Treatment usually is recommen-
ded with each of the venoms giving a positive skin test. Therapy is 98%
effective in completely preventing systemic allergic reactions to stings
when treatment includes mixed vespid venoms (300 mg total dose), but com-
plete protection is achieved in only 75% to 85% of patients using 100 mg of
any single venom (eg, honeybee, yellow jacket or Polistes wasp). Fire ant
268 GOLDEN
immunotherapy using whole-body extracts has been reported to be reason-

ably safe and effective, and should be employed in cases of significant
systemic reaction, although there have been no controlled trials [52]. Fire
ant venoms are not available for diagnosis or treatment, but there has been
a very successful controlled trial of Jack Jumper ant venom immunotherapy
in Australia [53].
Adverse reactions to venom immunotherapy occur no more frequently
than with inhalant allergen immunotherapy [54,55]. Systemic symptoms
occur in 10% to 15% of patients during the initial weeks of treatment,
regardless of the regimen used. Most reactions are mild, and fewer than
half require epinephrine injection. Virtually all patients can achieve the
full dose even after initial systemic reactions. In the unusual case of recur-
rent systemic reactions to injections, therapy may be streamlined to a single
venom and given in divided doses, 30 minutes apart. Large local reactions to
injections are common, occurring in up to 50% of patients. Unlike standard
inhalant immunotherapy, the uniform target dose in venom immunotherapy
may make it necessary to advance the dose in the face of large local
reactions, beyond what might otherwise be considered the maximum tolerated
dose.
Immunologic mechanisms of venom immunotherapy gradually have been
elucidated, but remain sketchy. Venom IgE rises initially with treatment,
then declines steadily over time toward very low levels after 5 to 10 years.
Venom IgG levels generally increase with treatment, and have been corre-
lated with clinical protection [56]. Lymphocyte subsets and cytokine
responses show a moderation of Th2 responses with increased IL-10 initially
and increased osteopontin more slowly during treatment [57–59].
Maintenance doses of venom immunotherapy are administered every
4 weeks for at least a year. Most experts agree that the maintenance interval
then may be increased gradually to every 6 to 8 weeks over several years.
Venom skin tests or RASTs are repeated periodically, usually every 2 to
3 years, to determine when there has been a significant decline in venom
IgE [11]. Skin tests generally remain unchanged in the first 2 to 3 years,
but show a significant decline after 4 to 6 years. Less than 20% of patients
are skin test negative after 5 years, but 50% to 60% become negative after 7
to 10 years (although most remain positive by RAST) [60,61].
The duration of venom immunotherapy is indefinite according to the rec-
ommendation in the product package insert. Initial efforts to stop treatment
when the RAST became negative were successful, but only a few patients
become RAST-negative within 5 years of treatment [62–65]. Extended study
of a large number of adults has shown that when venom immunotherapy is
stopped after 5 years, the chance of a systemic reaction will remain 10% for
each sting even more than 10 years after stopping treatment and even if skin
tests become negative [61,66]. When sting reactions occur after stopping
venom immunotherapy, most are quite mild and almost always are less
severe than the pretreatment reaction. A higher frequency of relapse occurs
in patients who had very severe (near-fatal) sting reactions before therapy,
those who had a systemic reaction during therapy (to a sting or a venom
injection), those with honeybee allergy, and those who had less than 5 years
of therapy [61,67–69]. Patients with any of these four high-risk characteris-
tics may need to be treated indefinitely, but there are no data on the
outcome after more than 15 years of treatment. Some patients will prefer
to continue venom treatment for security and improved quality of life.
Children who have had 3 to 5 years of venom immunotherapy have
a very low chance of systemic reaction even 10 to 20 years after stopping
treatment [44].
Summary
Anaphylaxis to insect stings has occurred in 3% of adults and can be fatal
even on the first reaction. Large local reactions are more frequent but rarely
dangerous. The chance of a systemic reaction to a sting is low (5% to 10%)
in large local reactors and in children with mild (cutaneous) systemic
reactions, and risk varies between 25% and 70% in adults depending on
the severity of previous sting reactions. Venom skin tests are most accurate
for diagnosis, but the RAST is an important complementary test. The
degree of sensitivity on skin test or RAST does not predict the severity of
a sting reaction reliably. Venom sensitization can be detected in 25% of
adults, so the history is most important. Venom immunotherapy is 75%
to 98% effective in preventing sting anaphylaxis. Most patients can discon-
tinue treatment after 5 years, with very low residual risk of a severe sting
reaction.
Anaphylaxis to insect stings is unique in some ways, especially its mode
of antigen exposure, its well-described natural history, its milder relatives
(large local and cutaneous reactions), and its remarkable response to immu-
notherapy. Familiarity with these features permits better recognition and
prevention of insect sting anaphylaxis. There is a need for improved accu-
racy in diagnostic tests for insect sting allergy, which may be achieved
with dialyzed venoms, recombinant venoms allergens, basophil activation
tests, or other in vitro procedures.
There remains a need to determine the best predictive factors that distin-
guish those who would react to stings from those who are sensitized but do
not have anaphylaxis. Such a test would identify those individuals who are
at risk before their first reaction occurs, those who are immunized but have
incomplete protection, and those who will have increased risk of reaction if
they discontinue venom immunotherapy. Therapy then could be targeted to
those most likely to benefit, and those who are sensitized but are not really
in danger could be spared. Such insight may come from studying large local
reactors (who are highly sensitized but have the lowest risk of anaphylaxis),
untreated patients who do not react to a challenge sting, and patients who
relapse after stopping venom immunotherapy.
270 GOLDEN
References
[1] Green A, Reisman R, Arbesman C. Clinical and immunologic studies of patients with large
local reactions following insect stings. J Allergy Clin Immunol 1980;66:186–9.
[2] Sampson H, Munoz-Furlong A, Campbell RL, 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;117:391–7.
[3] Hogendijk S, Hauser C. Wasp sting-associated cold urticaria. Allergy 1997;52:1145–6.
[4] Light WC, Reisman RE, Shimizu M, et al. Unusual reactions following insect stings.
[5] Reisman RE, Livingston A. Late-onset allergic reactions, including serum sickness, after in-
sect stings. J Allergy Clin Immunol 1989;84:331–7.
[6] Barnard JH. Studies of 400 Hymenoptera sting deaths in the United States. J Allergy Clin
Immunol 1973;52:259–64.
[7] Lockey RF, Turkeltaub PC, Baird-Warren IA, et al. The Hymenoptera venom study.
I. 1979–1982: demographic and history-sting data. J Allergy Clin Immunol 1988;82:370–81.
[8] Schuberth KC, Lichtenstein LM, Kagey-Sobotka A, et al. An epidemiologic study of insect
allergy in children. I. Characteristics of the disease. J Pediatr 1982;100:546–51.
[9] American Academy of Allergy, Insect Allergy Committee. Insect sting allergy, cooperative
study. JAMA 1965;193:115–20.
[10] Lieberman P, Kemp SF, Oppenheimer J, et al. The diagnosis and management of anaphy-
laxis: an updated practice parameter. J Allergy Clin Immunol 2005;115:S483–523.
[11] Moffitt JE, Golden DBK, Reisman RE, et al. Stinging insect hypersensitivity: a practice
parameter update. J Allergy Clin Immunol 2004;114:869–86.
[12] Tenbrook J, Wolf MP, Hoffman SN, et al. Should beta blockers be given to patients with
heart disease and peanut-induced anaphylaxis? A decision analysis. J Allergy Clin Immunol
2004;113:977–82.
[13] Clark S, Long AA, Gaeta TJ, et al. Multicenter study of emergency department visits for
insect sting allergies. J Allergy Clin Immunol 2005;116:643–9.
[14] Kemp SF, deShazo RD, Moffitt JE, et al. Expanding habitat of the imported fire ant: a public
health concern. J Allergy Clin Immunol 2000;105:683–91.
[15] Tracy JM, Demain JG, Quinn JM, et al. The natural history of exposure to the imported fire
ant. J Allergy Clin Immunol 1995;95:824–8.
[16] Shek LP, Ngiam NS, Lee BW. Ant allergy in Asia and Australia. Curr Opin Allergy Clin
Immunol 2004;4:325–8.
[17] Hoffman DR. Hymenoptera venoms: composition, standardization, stability. In: Levine
MI, Lockey RF, editors. Monograph on insect allergy. 4th edition. Milwaukee (WI): Amer-
ican Academy of Allergy Asthma and Immunology; 2004. p. 37–53.
[18] King TP, Spangfort MD. Structure and biology of stinging insect venom allergens. Int Arch
Allergy Immunol 2000;123:99–106.
[19] Hoffman DR, Jacobson RS, Schmidt M, et al. Allergens in Hymenoptera venoms. XXIII.
Venom content of imported fire ant whole body extracts. Ann Allergy 1991;66:29–31.
[20] Golden DB. Insect sting allergy and venom immunotherapy: a model and a mystery.
[21] Golden DBK, Marsh DG, Kagey-Sobotka A, et al. Epidemiology of insect venom sensitivity.
JAMA 1989;262:240–4.
[22] Settipane GA, Newstead GJ, Boyd GK. Frequency of Hymenoptera allergy in an atopic and
normal population. J Allergy 1972;50:146–50.
[23] Hoffman DR. Fatal reactions to Hymenoptera stings. Allergy Asthma Proc 2003;24:123–7.
[24] Schwartz HJ, Sutheimer C, Gauerke B, et al. Venom-specific IgE antibodies in post-
mortem sera from victims of sudden unexpected death. J Allergy Clin Immunol 1984;
73:189.
[25] Golden DBK, Marsh DG, Freidhoff LR, et al. Natural history of Hymenoptera venom
sensitivity in adults. J Allergy Clin Immunol 1997;100:760–6.
[26] Golden DBK, Breisch NL, Hamilton RG, et al. Clinical and entomological factors influence
the outcome of sting challenge studies. J Allergy Clin Immunol 2006;117:670–5.
[27] vanderLinden PG, Hack CE, Struyvenberg A, et al. Insect sting challenge in 324 subjects
with a previous anaphylactic reaction: current criteria for insect venom hypersensitivity do
not predict the occurrence and the severity of anaphylaxis. J Allergy Clin Immunol 1994;
94:151–9.
[28] Golden DBK, Langlois J, Valentine MD. Treatment failures with whole-body extract
therapy of insect sting allergy. JAMA 1981;246:2460–3.
[29] Bilo BM, Rueff F, Mosbech H, et al, EAACI. Diagnosis of Hymenoptera venom allergy.
Allergy 2005;60:1339–49.
[30] Aalberse RC, Koshte V, Clemens JGJ. Immunoglobulin E antibodies that cross-react
with vegetable foods, pollen, and Hymenoptera venom. J Allergy Clin Immunol 1981;68:
356–64.
[31] Hemmer W, Frocke M, Kolarich K, et al. Antibody binding to venom carbohydrates is
a frequent cause for double positivity to honeybee and yellow jacket venom in patients
with stinging insect allergy. J Allergy Clin Immunol 2001;108:1045–52.
[32] Hamilton RG. Diagnostic methods for insect sting allergy. Curr Opin Allergy Clin Immunol
2004;4:297–306.
[33] Goldberg A, Confino-Cohen R. Timing of venom skin tests and IgE determinations after
insect sting anaphylaxis. J Allergy Clin Immunol 1997;100:183–4.
[34] Graif Y, Confino-Cohen R, Goldberg A. Reproducibility of skin testing and serum venom-
specific IgE in Hymenoptera venom allergy. Ann Allergy 2006;96:24–9.
[35] Hamilton RG. Responsibility for quality IgE antibody results rests ultimately with the
referring physician. Ann Allergy Asthma Immunol 2001;86:353–4.
[36] Reisman RE. Intentional diagnostic insect sting challenges: a medical and ethical issue.
J Allergy Clin Immunol 1993;91:1100.
[37] Rueff F, Przybilla B, Muller U, et al. The sting challenge test in Hymenoptera venom allergy.
Allergy 1996;51:216–25.
[38] Franken HH, Dubois AEJ, Minkema HJ, et al. Lack of reproducibility of a single negative
sting challenge response in the assessment of anaphylactic risk in patients with suspected
yellow jacket hypersensitivity. J Allergy Clin Immunol 1994;93:431–6.
[39] Oude-Elberink JNG, deMonchy JGR, Golden DBK, et al. Quality of life in yellow jacket-
allergic patients I. Development and validation of a health-related quality-of-life question-
naire in yellow jacket- allergic patients. J Allergy Clin Immunol 2002;109:162–7.
[40] Oude-Elberink JNG, deMonchy JGR, vanderHeide S, et al. Venom immunotherapy im-
proves health-related quality of life in yellow jacket-allergic patients. J Allergy Clin Immunol
2002;110:174–82.
[41] Hunt KJ, Valentine MD, Sobotka AK, et al. A controlled trial of immunotherapy in insect
hypersensitivity. N Engl J Med 1978;299:157–61.
[42] Muller U, Thurnheer U, Patrizzi R, et al. Immunotherapy in bee sting hypersensitivity: bee
venom versus whole-body extract. Allergy 1979;34:369–78.
[43] Reisman RE. Natural history of insect sting allergy: relationship of severity of symptoms of
initial sting anaphylaxis to re-sting reactions. J Allergy Clin Immunol 1992;90:335–9.
[44] Golden DBK, Kagey-Sobotka A, Norman PS, et al. Outcomes of allergy to insect stings in
children with and without venom immunotherapy. N Engl J Med 2004;351:668–74.
[45] Graft DF, Schuberth KC, Kagey-Sobotka A, et al. A prospective study of the natural history
of large local reactions following Hymenoptera stings in children. J Pediatr 1984;104:664–8.
[46] Mauriello PM, Barde SH, Georgitis JW, et al. Natural history of large local reactions from
stinging insects. J Allergy Clin Immunol 1984;74:494–8.
[47] Valentine MD, Schuberth KC, Kagey-Sobotka A, et al. The value of immunotherapy with
venom in children with allergy to insect stings. N Engl J Med 1990;323:1601–3.
272 GOLDEN
[48] Golden DBK, Valentine MD, Kagey-Sobotka A, et al. Regimens of Hymenoptera venom
immunotherapy. Ann Intern Med 1980;92:620–4.
[49] Bernstein JA, Kagan SL, Bernstein DI, et al. Rapid venom immunotherapy is safe for
routine use in the treatment of patients with Hymenoptera anaphylaxis. Ann Allergy 1994;
73:423–8.
[50] Birnbaum J, Charpin D, Vervloet D. Rapid Hymenoptera venom immunotherapy: compar-
ative safety of three protocols. Clin Exp Allergy 1993;23:226–30.
[51] Tankersley MS, Walker RL, Butler WK, et al. Safety and efficacy of an imported fire ant rush
immunotherapy protocol with and without prophylactic treatment. J Allergy Clin Immunol
2002;109:556–62.
[52] Freeman TM, Hyghlander R, Ortiz A, et al. Imported fire ant immunotherapy: effectiveness
of whole body extracts. J Allergy Clin Immunol 1992;90:210–5.
[53] Brown SG, Wiese MD, Blackman KE, et al. Ant venom immunotherapy: a double-blind pla-
cebo-controlled crossover trial. Lancet 2003;361:1001–6.
[54] Lockey RF, Turkeltaub PC, Olive ES, et al. The Hymenoptera venom study III: safety of
venom immunotherapy. J Allergy Clin Immunol 1990;86:775–80.
[55] Mosbech H, Muller U. Side effects of insect venom immunotherapy: results from an EAACI
study. Allergy 2000;55:1005–10.
[56] Golden DBK, Lawrence ID, Kagey-Sobotka A, et al. Clinical correlation of the venom-
specific IgG antibody level during maintenance venom immunotherapy. J Allergy Clin
Immunol 1992;90:386–93.
[57] Akdis CA, Blesken T, Akdis M, et al. Role of interleukin 10 in specific immunotherapy.
J Clin Invest 1998;102:98–106.
[58] Konno S, Golden DBK, Schroeder J, et al. Level of osteopontin is increased after bee venom
immunotherapy. J Allergy Clin Immunol 2005;115:1317–8.
[59] Larche M, Akdis C, Valenta R. Immunological mechanisms of allergen-specific immuno-
therapy. Nat Rev Immunol 2006;6:761–71.
[60] Golden DBK, Kwiterovich KA, Kagey-Sobotka A, et al. Discontinuing venom immuno-
therapy: outcome after five years. J Allergy Clin Immunol 1996;97:579–87.
[61] Golden DBK, Kwiterovich KA, Addison BA, et al. Discontinuing venom immunotherapy:
extended observations. J Allergy Clin Immunol 1998;101:298–305.
[62] Muller U, Berchtold E, Helbling A. Honeybee venom allergy: results of a sting challenge
1 year after stopping venom immunotherapy in 86 patients. J Allergy Clin Immunol 1991;
87:702–9.
[63] Randolph CC, Reisman RE. Evaluation of decline in serum venom-specific IgE as a criterion
for stopping venom immunotherapy. J Allergy Clin Immunol 1986;77:823–7.
[64] Reisman RE, Lantner R. Further observations of stopping venom immunotherapy: compar-
ison of patients stopped because of a fall in serum venom-specific IgE to insignificant levels
with patients stopped prematurely by self-choice. J Allergy Clin Immunol 1989;83:1049–54.
[65] Urbanek R, Forster J, Kuhn W. Discontinuation of bee venom immunotherapy in children
and adolescents. J Pediatr 1985;107:367–71.
[66] Golden DBK, Kagey-Sobotka A, Lichtenstein LM. Survey of patients after discontinuing
venom immunotherapy. J Allergy Clin Immunol 2000;105:385–90.
[67] Lerch E, Muller U. Long-term protection after stopping venom immunotherapy. J Allergy
Clin Immunol 1998;101:606–12.
[68] Muller U, Helbling A, Berchtold E. Immunotherapy with honeybee venom and yellow jacket
venom is different regarding efficacy and safety. J Allergy Clin Immunol 1992;89:529–35.
[69] Reisman RE. Duration of venom immunotherapy: relationship to the severity of symptoms
of initial insect sting anaphylaxis. J Allergy Clin Immunol 1993;92:831–6.
27 (2007) 273–293
Idiopathic Anaphylaxis
Paul A. Greenberger, MD
Division of Allergy-Immunology, Department of Medicine, Northwestern University,
Feinberg School of Medicine, Suite 14018, 676 North St. Clair Street,
Chicago, IL 60611, USA
The designation idiopathic anaphylaxis refers to unexplained anaphylaxis

that implies a risk for death whether by shock or upper or lower airway ob-
struction. Idiopathic anaphylaxis initially was described in 1978 [1]. From
a series of 21 patients who had experienced episodes of severe anaphylaxis,
11 patients were considered to have idiopathic anaphylaxis [1]. The admin-
istration of prednisone and hydroxyzine was associated with a reduction in
the severity and frequency of episodes. Although this observation was not
controlled, it did demonstrate that the response to empiric prednisone and
hydroxyzine treatment was supportive of the diagnosis of idiopathic ana-
phylaxis. Subsequent case reports [2] and series [3,4] demonstrated that pa-
tients who had idiopathic anaphylaxis were responsive to prednisone (and
hydroxyzine with or without ephedrine). Some physicians believe that all
cases of anaphylaxis must have an identifiable cause, and this belief leads
to the mistaken notion that idiopathic anaphylaxis implies that an external
trigger has not been found. The mechanistic cause of idiopathic anaphylaxis
remains uncertain, although the elevated concentrations of urinary hista-
mine [5,6], its metabolite, methylimidazole acetic acid [7], plasma histamine
[8], and serum tryptase [7,9] are consistent with mast cell activation.
Definitions
As stated, anaphylaxis implies a potential for death, although most epi-
sodes of anaphylaxis are not fatal. Simons [10] has suggested that anaphylaxis
be considered as either immunologic (IgE or Fce RI mediated), nonimmuno-
logic, or idiopathic. The National Institute of Allergy and Infectious
Diseases/Food Allergy and Anaphylaxis Network defines anaphylaxis as
Supported by the Ernest S. Bazley Grant to Northwestern Memorial Hospital and

Northwestern University.
E-mail address: p-greenberger@northwestern.edu
274 GREENBERGER
‘‘a severe, potentially fatal, systemic allergic reaction that occurs suddenly
after contact with an allergy-causing substance’’ [11]. The Joint Task Force
on Practice Parameters, representing the American Academy of Allergy,
Asthma and Immunology, the American College of Asthma, Allergy and Im-
munology, and the Joint Council of Asthma and Immunology, described ana-
phylaxis as ‘‘a condition caused by an IgE-mediated reaction. Anaphylactoid
reactions are defined as those reactions that produce the same clinical picture
as anaphylaxis but are not IgE-mediated’’ [12]. Idiopathic anaphylaxis is
anaphylaxis not explained by a proved or presumptive cause or stimulus. It
becomes a diagnosis of exclusion after other causes have been considered,
such as foods, medications, exercise, food and exercise, insect stings or bites,
mastocytosis, and C1esterase inhibitor deficiency/dysfunction.
Classification of anaphylactic episodes

Idiopathic anaphylaxis has been classified into two categories [3,13]. Idi-
opathic anaphylaxisdgeneralized (IA-G) is present when there is a sudden
episode that includes urticaria or angioedema associated with acute bron-
choconstriction, voice change or stridor, syncope or proven hypotension,
with or without abdominal pain and diarrhea [3]. Alternatively, idiopathic
anaphylaxisdangioedema (IA-A) refers to anaphylaxis that is characterized
by marked upper airway obstruction attributable to massive tongue enlarge-
ment or a severely edematous larynx or pharynx [3]. Patients can have
generalized urticaria in association with the severe pharyngeal, laryngeal,
or tongue swelling. Patients who have IA-A do not have decreased concen-
trations of C4 or laboratory evidence of C1 esterase deficiency/dysfunction.
Depending on the frequency of episodes, idiopathic anaphylaxis is either fre-
quent (two episodes in the past 2 months or six episodes in the past year)
or infrequent (!6 episodes in the past year) [13].
Idiopathic anaphylaxis thus can be characterized either by acute severe
bronchoconstriction or shock in association with urticaria and diarrhea or
abdominal pain, or by severe tongue, pharyngeal, or laryngeal angioedema
with or without urticaria. The categories of IA-G and IA-A condense the
listing of clinical signs and symptoms of anaphylaxis suggested by a National
Institute of Allergy and Infectious Diseases/Food Allergy and Anaphylaxis
Network symposium of 12 organizations [14]. Based on a review of medical
records from 1149 emergency department visits for anaphylaxis, Brown [15]
proposed that ‘‘generalized hypersensitivity reactions’’ could be graded as
follows:
Mild (cutaneous and subcutaneous tissues only) implying angioedema,
such as periorbital angioedema and generalized erythema, urticaria
Moderate (respiratory, cardiovascular, or gastrointestinal involvement)
with symptoms such as dyspnea, stridor, wheeze, dizziness, and so
forth)
IDIOPATHIC ANAPHYLAXIS 275
Severe (hypoxia, hypotension, or neurologic compromise), such as pulse

oximetry of less than 93%, confusion, or collapse
Some 25% of the cases were from unidentified causes [15]. This grading
system is useful, although it does not necessarily list severe pharyngeal or
laryngeal angioedema or massive tongue enlargement as severe unless pulse
oximetry is found to be low. Nevertheless, symptoms such as confusion, col-
lapse, incontinence, stridor, wheeze, nausea, and vomiting were associated
with hypoxia and hypotension [15] as occurs in idiopathic anaphylaxis.
Incidence of idiopathic anaphylaxis

In 1995, the prevalence of idiopathic anaphylaxis in the United States was
estimated to be 33,000 cases [16]. In series of patients being assessed in emer-
gency departments for anaphylaxis, the incidence of idiopathic anaphylaxis
may be estimated by subtracting the number of cases in which identifiable
causes are listed from the total number of visits. For example, 6 of 97
(6.1%) patients in New York City had ‘‘unclear or undetermined’’ causes
[17] compared with as many as 38 of 142 (27%) patients in Australia who
were labeled as ‘‘no causes were apparent or temporally related’’ [18]. This lat-
ter estimate is similar to the 291 of 1149 (25%) patients in Australia based on
data from 1990 to 1999 [15]. In the pediatric population, in a series of 57 chil-
dren who had anaphylaxis obtained from a group that also included 526 other
children with ‘‘generalized allergic reactions,’’ no cause was identified in
31.6% of patients [19]. Some inaccuracies likely exist because patients could
report to the emergency department physicians that foods were blamed
when in fact subsequent allergy evaluations may not have confirmed the
presence of anti-food IgE antibodies. From a group of 113 hospitalizations
for anaphylaxis from 1985 to 1996 at a university hospital in Italy, 6 (6%) cases
were idiopathic anaphylaxis [20]. Clearly, idiopathic anaphylaxis is not rare in
the emergency department or in patients hospitalized for anaphylaxis.
How frequent is the diagnosis of idiopathic anaphylaxis made in the out-
patient setting? After excluding patients who had Hymenoptera- and immu-
notherapy-related anaphylaxis, some 356 of 601 (59%) patients were
considered to have idiopathic anaphylaxis in a private practice, university-
affiliated office in Memphis [21]. Foods were confirmed as a cause in 131
(22%), medications in 69 (11%), and systemic mastocytosis in 3 (0.5%)
[21]. For comparison, after excluding patients who had Hymenoptera-
induced anaphylaxis, the apparent prevalence of idiopathic anaphylaxis
was 33.2% in 45 patients in Singapore [22] and 31.5% in 108 patients seen
in Rochester, Minnesota [23].
Nearly fatal and fatal idiopathic anaphylaxis

There are three reported fatalities from idiopathic anaphylaxis [24,25]. One
43-year-old patient who had asthma had a 12-year history of anaphylaxis with
276 GREENBERGER
apparently more than 100 emergency department visits over that time period
[24]. The patient’s episodes often consisted of acute onset of dyspnea and ab-
dominal pain that were associated at times with fecal incontinence and loss
of consciousness [24]. The patient would self-inject epinephrine every 1 to
2 months [24]. His food skin tests were negative although he was positive
for pollens, molds, dust mites, and Aspergillus. After being evaluated at the
Northwestern University Allergy-Immunology service, he was being treated
aggressively with prednisone 60 to 80 mg daily for 2 weeks followed by 80
mg on alternate days for 2 weeks along with hydroxyzine 25 mg and albuterol
2 mg orally three times daily. At the time of the fatal attack, he was receiving
prednisone 60 mg on alternate days [24]. Five days later, however, he was re-
ported to have eaten a barbecue dinner and consumed a half bottle of wine
[24]. He experienced acute dyspnea and fecal incontinence and did self-inject
epinephrine. In the emergency department his blood pressure was 157/70
with pulse of 117 beats/min. He was ‘‘cyanotic, nonresponsive and apneic’’
[24]. Intubation was unsuccessful because of pharyngeal edema. A tracheos-
tomy was performed but the patient ‘‘still could not be ventilated’’ [24]. No au-
topsy was performed. The patient’s close friend noted that the deceased may
not have been compliant with the medications prescribed. Two other fatalities
were reported [25]. A 51-year-old man had had four previous episodes of
abdominal pain, flushing, hypotension, and loss of consciousness during
a 13-year period [25]. One month after the previous attack, the patient experi-
enced anaphylaxis again with loss of consciousness. He was nonresponsive
when arriving in the emergency department. An autopsy revealed severe cor-
onary arteriosclerosis but the death was attributed to anaphylaxis. The third
fatality was in a 25-year-old woman who had been experiencing anaphylactic
episodes for 15 years [25]. The episodes occurred two to three times yearly in
the previous year. Her reactions consisted of diarrhea, facial edema, urticaria,
and severe bronchoconstriction [25]. As in the previous patients, allergy-
immunology evaluations could not find an explanation and skin tests for foods
were negative. The description of the fatal attack was as follows: ‘‘The fatal
episode occurred after eating a frozen pizza which she had had many times pre-
viously with no adverse reaction’’ [25]. She developed urticaria, severe respira-
tory distress, and abdominal cramping [25]. Epinephrine was administered but
the patient lost consciousness and resuscitation was not successful. In a series
of fatalities from anaphylaxis over a 20-year period in Auckland, New
Zealand, 2 of 18 (11%) deaths were from undetermined causes raising the
possibility of fatal idiopathic anaphylaxis [26]. Nearly fatal idiopathic ana-
phylaxis cases have been reported [2,25,27,28] with examples of syncope and
shock with systolic blood pressure of 50 mmHg during anaphylaxis. These
examples emphasize that anaphylaxis implies a risk for death even if most
episodes of idiopathic anaphylaxis (in the same patient or in series of patients)
are not fatal. Alternatively, as in the above case of the 51-year-old patient who
had four previous episodes of idiopathic anaphylaxis over 13 years, the fifth
attack was fatal [25].
Pathogenesis of idiopathic anaphylaxis

Mast cell activation associated with anaphylactic reactions has been
supported by detection of urinary histamine [5,6], urinary methylimidazole
acetic acid [7], plasma histamine [8], and serum tryptase [7,9] In the absence
of acute anaphylaxis, there should be normal values. A patient who had
anaphylaxis for 10 years, considered to be idiopathic, had an elevated serum
b tryptase concentration of 110 ng/mL (normal !1 ng/mL) 26 hours after
the onset of an episode, at which time a few urticarial lesions were present
[7]. Subsequent concentrations were less than 1 ng/mL. This example
suggests that the mast cells are being activated for hours after the initial
anaphylactic episode as manifested by the elevated b tryptase and urticarial
lesions.
The number of mast cells in skin is increased in patients who have pre-
sumed idiopathic anaphylaxis compared with normal subjects but is less
than that occurring in patients who have urticaria pigmentosa or systemic
mastocytosis [29]. Skin biopsies were obtained from patients who had ‘‘un-
explained anaphylaxis/unexplained flushing’’ and compared with patients
who had urticaria pigmentosa (normal bone scans or bone marrow exami-
nations) and systemic mastocytosis (bone marrow examination positive)
[29]. The mean number of mast cells (toluidine blue þ)/mm2 were as follows:
normal subjects 38; unexplained anaphylaxis/flushing 72; urticaria pigmen-
tosa, non-lesional skin 168; urticaria pigmentosa, lesional skin 597; masto-
cytosis, non-lesional skin 174; mastocytosis, lesional skin 679 [29]. The
number of mast cells in patients who had presumed idiopathic anaphylaxis
was increased compared with normal subjects but clearly less than even in
non-lesional skin of patients who had urticaria pigmentosa or systemic mas-
tocytosis. The investigators noted that four of nine patients who had unex-
plained anaphylaxis/flushing had mast cell counts similar to normal
subjects, suggesting that the other five patients had mast cell counts closer
to the urticaria pigmentosa/mastocytosis patients [29].
Lymphocyte activation has been demonstrated in idiopathic anaphylaxis
patients whose blood was obtained within 24 hours of an episode as com-
pared with patients who had not had episodes for at least a month [30].
The numbers of CD3þ HLA-DRþ T cells were increased in peripheral
blood samples obtained from acute (10.2%) compared with quiescent
(4.5%) patients [30]. None of these patients had received corticosteroids be-
fore the samples were obtained. Comparison data from patients who had
acute urticaria were similar to quiescent idiopathic anaphylaxis (4.7%)
and elevated compared with normal subjects (0.8%) [30]. Although there
were not differences in the total lymphocyte counts, CD4/CD8 ratio,
CD2, CD14, or NK cells, the percentages of CD19þ (B cells) were increased
in blood from patients who had acute episodes of idiopathic anaphylaxis
compared with controls or patients who had quiescent idiopathic anaphy-
laxis [30]. The CD19þ lymphocytes were activated (CD23þ) in patients
278 GREENBERGER
who had idiopathic anaphylaxis (and acute urticaria) compared with nor-
mal subjects [30]. These data are consistent with the notion that there are
activated T lymphocytes during acute episodes of idiopathic anaphylaxis
compared with quiescent patients and patients who have acute urticaria.
Furthermore, there are greater numbers of activated B cells also in patients
who have idiopathic anaphylaxis (and acute urticaria) compared with nor-
mal subjects. The mechanistic explanations remain to be clarified, such as T
lymphocyte–derived mast cell activation.
In vitro basophil histamine release induced by anti-IgE was not different
from non-atopic subjects [31] and end-point skin testing for cutaneous vas-
cular reactivity to histamine, leukotriene D4, and platelet-activating factor
did not differ between patients who had idiopathic anaphylaxis and chronic
idiopathic urticaria [32]. These data do not suggest that there is cutaneous
vascular hypersensitivity, hyperreactivity, or hyporeactivity in idiopathic
anaphylaxis at least to these three agonists compared with chronic idio-
pathic urticaria. In another study, there were no differences in responses
to intradermal injections of histamine or morphine in patients who had ‘‘un-
explained anaphylaxis’’ compared with normal subjects or patients who had
mastocytosis [33].
One patient had been reported whose episodes seemed related to upper
respiratory infections [34]. During one episode, the blood pressure was 80/0
in association with lightheadedness, emesis, abdominal pain, and urticaria
[34]. The onset of the anaphylaxis was 5 days into an upper respiratory in-
fection. The patient had another similar episode in that the anaphylaxis be-
gan 5 days after the onset of upper respiratory tract symptoms. The patient
had begun prednisone 40 mg daily, but she developed acute urticarial le-
sions. Hydroxyzine, albuterol, and acyclovir were started, but then she de-
veloped acute dyspnea requiring self-administration of epinephrine. There
were IgG antibodies present to Mycoplasma pneumoniae [34]. This patient
thus had two serious episodes of idiopathic anaphylaxis in the setting of up-
per respiratory tract infections. Perhaps there are lymphocyte-derived cyto-
kines that occur in the setting of viral infections that activate mast cells. This
patient seems to be a rarity.
That empiric treatment with prednisone along with hydroxyzine with or
without albuterol or ephedrine reduces the severity of and frequency of
episodes suggests that idiopathic anaphylaxis is corticosteroid responsive
[2–4]. Possible mechanisms of corticosteroid-induced reductions in anaphy-
laxis include multiple yet unproved possibilities, such as suppressed cytokine
activation of mast cells or neuropeptide-stimulated mast cell mediator re-
lease, increased numbers of beta receptors and cAMP that would reduce
the likelihood of mast cell activation, and modification of antibodies to
the Fce RI or to IgE as examples. Previously mentioned was the increased
number of CD19þ CD23þ B cells in patients who had idiopathic anaphy-
laxis [30]. Although B cells and antibody production are poorly responsive
to or suppressible by corticosteroids, T cells also were found to be activated
[30]. Their suppression by corticosteroids (especially CD4þ) is established

and could blunt effects of lymphocyte-derived histamine-releasing cytokines,
for example.
The mechanistic processes in idiopathic anaphylaxis need to reflect the
different patterns that patients experience. For example, some patients
only experience acute episodes of either idiopathic anaphylaxis with urti-
caria and syncope, whereas others experience severe upper airway obstruc-
tion. Urinary histamine has been found to be elevated in both forms of
idiopathic anaphylaxis [6]. No intercurrent urticaria or life-threatening or
-endangering angioedema occurs. Alternatively, some patients experience
sporadic or chronic idiopathic urticaria and occasional episodes of anaphy-
laxis. In those patients and perhaps all patients, there seems to be a spectrum
of mast cell activation that includes sporadic urticaria and chronic urticaria
to episodes of idiopathic anaphylaxis. For other patients, mast cell activa-
tion occurs only as acute anaphylaxis. Are the triggering mechanisms the
same for such different phenotypes? Furthermore, some patients have exer-
cise-induced anaphylaxis, chronic idiopathic urticaria, and episodes of idio-
pathic anaphylaxis. Although the pathogenesis of idiopathic anaphylaxis
remains unclear, the observation that some patients are corticosteroid re-
sponsive and others improve without treatment suggest that in contrast to
persistent asthma, idiopathic anaphylaxis does not necessarily persist indef-
initely [3,4].
Clinical presentation and demographics of idiopathic anaphylaxis

From a series of 335 patients, all had experienced either urticaria or an-
gioedema [3]. Upper airway obstruction occurred in 210 (63%) and acute
bronchoconstriction was reported in 132 (39%) [3]. Hypotension or syncope
was present in 78 (23%) and gastrointestinal symptoms were described in 75
(22%) [3]. Urticaria or angioedema that was pre-existing had occurred in 78
(23%) and exercise-induced anaphylaxis was diagnosed in 38 (11%) [3].
Forty eight percent of patients were atopic, which included the following
findings:
Allergic rhinitis alone 19%
Asthma alone 13%
Allergic rhinitis and asthma 11%
Food-induced anaphylaxis 5%
Atopic dermatitis 1.5%
Seventy eight of 272 patients who were skin tested to foods were positive
to at least one food [3]; however, clinical correlation was not present in most
patients. Just 17 (5%) had consistent histories of exposure and anaphylaxis
[3]. The skin test–positive but noncorrelating results were the pattern. Epi-
sodes of idiopathic anaphylaxis can be nocturnal or in patients who have
280 GREENBERGER
not eaten any food for more than 6 hours. The patients who had idiopathic
anaphylaxis reported medication allergies as follows:
Penicillin 19%
Sulfonamides 8%
Nonsteroidal anti-inflammatory drugs 5%
Radiocontrast material 4%
Opiates 3%
These reported allergies were not confirmed, but all prevalences are
greater that what occurs in the general population.
Most patients who have idiopathic anaphylaxis evaluated at Northwest-
ern University Allergy-Immunology service have been at least 20 years of
age, including 3% of patients being over 70 years of age [3]. Similarly, in a se-
ries of 81 patients from Spain, the mean age was 30 years with a range from
5 to 73 years [35]. Gender is important in that 68% of the Spanish patients
and 65% of the Northwestern patients were female [3,35]. Furthermore, in
the 81 patients from Spain, chronic idiopathic urticaria or acute urticarial
episodes separate from episodes of idiopathic anaphylaxis were noted in
58% of patients [35].
Idiopathic anaphylaxis has been described in the pediatric population
[3,19,35–38]. Severity can be as severe as in adults, such as with shock (sys-
tolic blood pressure of 50/20), loss of consciousness and unobtainable blood
pressure, and two episodes of loss of consciousness that characterized three
separate patients aged 15, 19, and 12 years, respectively [37].
Classification of idiopathic anaphylaxis

Idiopathic anaphylaxis has been classified based on whether there is a
generalized reaction (IA-G) with hypotension, syncope, or severe broncho-
constriction, or if upper airway obstruction is prominent (IA-A) for angioe-
dema of the tongue, pharynx, or larynx [13]. If episodes are occurring twice
in 2 months or six or more per year, then the designation frequent is added
(IA-G-F or IA-A-F) [13]. Alternatively, if episodes are less frequent, then
the designation is (IA-G-I or IA-A-I) for infrequent [13].
When the episodes of idiopathic anaphylaxis are especially difficult to
control and it is not possible to reduce the severity or frequency of episodes
without prednisone, the designation of corticosteroid-dependent idiopathic
anaphylaxis is made [13,39]. Most of these patients do not require indefinite
prednisone in addition to antihistamines and albuterol, for example. Some
respond to ketotifen 2 mg twice or three times daily [39,40]. Conversely, a small
number of patients require prednisone 20 mg each morning or 60 mg on alter-
nate days; otherwise, episodes of anaphylaxis continue to occur [27,41].
Undifferentiated somatoform idiopathic anaphylaxis (USIA) is a nonor-
ganic condition that mimics idiopathic anaphylaxis [42]. Patients do not
have objective evidence of anaphylaxis although they report syncope (in
which the blood pressure is not reduced) and massive tongue enlargement or
throat constriction (during which there is no objective evidence of airway
obstruction or angioedema) [42]. Similarly, objective evidence of acute, se-
vere bronchoconstriction is not obtained despite the patient reporting con-
vincingly, ‘‘I can’t breathe, doctor; please help me.’’ Some patients have had
tracheostomies placed during episodes of USIA because they emit loud and
frightening stridulous sounds. The lack of improvement or even increased
number of episodes during empiric treatment with prednisone and cetirizine
or hydroxyzine should raise the possibility of noncompliance with medica-
tions or USIA [42]. Some patients do indeed have objective evidence for
mast cell mediator release because dermatographism or acute urticaria
may accompany the additional reported, but not objectively confirmed,
symptoms.
The various types of idiopathic anaphylaxis are presented in Table 1. In
the work-up and treatment of patients who have anaphylaxis, it may be-
come apparent that there is no documented evidence for hypotension, severe
upper airway obstruction, or acute severe bronchoconstriction. One may use
the diagnosis of idiopathic anaphylaxisdquestionable [13] until evidence of
the lack of it becomes clear.
Differential diagnosis of idiopathic anaphylaxis

The differential diagnosis of idiopathic anaphylaxis includes organic and
nonorganic conditions [41,43]. A summary of these causes is presented in
Box 1. The list is not all-inclusive of causes of anaphylaxis. The diagnosis
of idiopathic anaphylaxis is one of exclusion of other causes with reasonable
certainty. Some areas for consideration are presented in this section.
Foods
The most severe cases of food-associated anaphylaxis occur within
minutes and in fatal cases the onset of symptoms often has been within
the first 30 minutes [44–47]. Food allergies may explain some but not all
of the episodes in patients who have idiopathic anaphylaxis [3]. Some
Table 1
Classification of idiopathic anaphylaxis
Objective evidence
Terminology for anaphylaxis
Idiopathic anaphylaxisdgeneralized Yes
Idiopathic anaphylaxisdangioedema Yes
Corticosteroid-dependent idiopathic anaphylaxis Yes
Malignant idiopathic anaphylaxis Yes
Undifferentiated somatoform idiopathic anaphylaxis Noa
a
The patient may have limited or generalized urticaria and flushing or evidence for
dermatographism.
282 GREENBERGER
Box 1. A differential diagnosis of idiopathic anaphylaxis

Identifiable causes of immediate reactions
IgE mediated
Foods (within 3 hours of ingestion)
Food supplements/additives (within 3 hours of ingestion)
Bee pollen
Psyllium
Carmine dye
Papain
Medications
Penicillin/cephalosporin
Food and exercise-induced anaphylaxis
Non–IgE mediated
Medications
Aspirin
Nonsteroidal anti-inflammatory drugs (nonselective)
Angiotensin-converting enzyme inhibitors
Angiotensin receptor blockers
Opioids
Diagnostic agents
Radiocontrast material
Gadolinium chelates
Classical forms
C1 inhibitor deficiency
Dysfunctional C1 inhibitor
Acquired forms
B cell lymphoproliferative condition (consumption of C1
inhibitor)
Autoantibodies to C1 inhibitor
Estrogen-associated angioedema
Mastocytosis conditions
Systemic mastocytosis
Urticaria pigmentosa with Hymenoptera sting anaphylaxis
IgE antibodies to Hymenoptera species
Absent IgE antibodies to Hymenoptera species
Acute severe asthma
Undifferentiated somatoform idiopathic anaphylaxis
Munchausen stridor (nonorganic stridor produced
by the patient)
Munchausen anaphylaxis (true anaphylaxis produced by the

patient)
Medications
Foods
Miscellaneous conditions
Panic attacks
Globus hystericus
Carcinoid syndrome
Pheochromocytoma (epinephrine secreting)
Histamine contamination of food
From Greenberger PA. Differential diagnosis of idiopathic anaphylaxis. In:

Patterson R, editor. Idiopathic anaphylaxis. Providence (RI): Oceanside Publica-
tions; 1997; with permission.
food-induced reactions occur when the food might be considered hidden,

such as in salad dressings or in egg rolls [48]. Furthermore, the threshold
reactive dose of peanut can be as low as 100 mg in extremely allergic subjects
[49].
Food additives
Food additives are infrequently identified as an explanation for a food-
associated case of anaphylaxis. One example is carmine powder used as
a dye in yogurt, liquors, and imitation crab meat [50]. Bee pollen [51] and
psyllium [52] are other examples. Alternatively, this author has never been
able to confirm a case of anaphylaxis from sodium metabisulfite in patients
who incriminated treated foods [53] or from monosodium glutamate [54].
Misidentified medications
Although it is obvious in retrospect, a patient, caregiver, or pharmacist
may err with the resultant anaphylactic reaction in a susceptible patient. In
a classic manuscript it is described how ‘‘ascorbic acid’’ was in fact penicillin
[55]. Nonsteroidal anti-inflammatory drugs (mostly nonselective agents but
there are case reports of immediate reactions to cyclooxygenase-2 antago-
nists) should not be overlooked as causes of anaphylaxis or urticaria.
Patients may experience idiopathic anaphylaxis but also have episodes as-
sociated with either exercise or foods plus exercise [56,57]. Patients who have
the latter condition likely have eaten a food within 5 to 6 hours of exercise,
which can consist of as little as brisk walking. The prior food ingestion can
be any food (with nonreactive skin tests) or specific foods with demonstrable
284 GREENBERGER
anti-IgE antibodies. A patient who has exercise-induced anaphylaxis should

not be confused with patients who have idiopathic anaphylaxis because there
is a temporal association between the exercise and the onset of the anaphylaxis
in the first 10 minutes. For patients who jog, it has been reported that 90% of
patients experienced anaphylaxis in the first 30 minutes of beginning [56].
Hereditary angioedema may mimic IA-A because of the massive tongue
or oropharyngeal angioedema. In idiopathic anaphylaxis, complement
determinations are not abnormal during episodes. In hereditary angioe-
dema, the C4 is reduced even in quiescent periods, typically being less
than 10 mg/dL compared with the normal range of 14 to 43 mg/dL. The
C4 concentration may be less than 2 mg/dL in some patients. The C3 con-
centration is in the normal range, although the CH50 is reduced. Often, the
laboratory performs a quantitative determination of the C1 esterase inhibi-
tor, with normal being greater than 11 mg/dL. The quantitative value is re-
duced in the classic (C1 inhibitor reduced antigenic and function) and
dysfunctional (C1 inhibitor normal antigenic but reduced function) pheno-
types [58]. For a patient who has reduced C4 and quantitative C1 inhibitor
concentrations, the next test to obtain is the C1q protein. The concentration
of C1q protein is in the normal range of 11 to 48 mg/dL, somewhat para-
doxically, in hereditary angioedema but is markedly reduced in patients
who have acquired C1 esterase inhibitor deficiency. In acquired C1 esterase
inhibitor deficiency, patients may have consumption of the C1inhibitor in
conditions in which complement is activated and the inhibitor is depleted.
An example is in lymphoproliferative conditions, such as a low-grade lym-
phoma. There may be autoantibodies to the C1 esterase inhibitor as another
mechanism for acquired C1 inhibitor deficiency [58]. Examination of the
abdomen for hepatosplenomegaly is advisable along with monitoring for
lymphadenopathy in such patients.
Systemic mastocytosis
Systemic mastocytosis may present in different forms, but in the setting of
episodes of anaphylaxis or recurrent flushing the patient may have cutane-
ous lesions of urticaria pigmentosa. The lesions are macules that are red
to light brown (salmon) in color. On light stroking of the macules there is
urticaria or at least erythema that develops. These lesions can be biopsied
and stained for mast cells, such as with toluidine blue or Giemsa stains.
Some patients have no cutaneous lesions but are positive on bone marrow
examination with special stains for mast cells. There are clusters of mast
cells [59]. The serum tryptase concentration for total tryptase is elevated
even when the there are no anaphylactic symptoms. The concentration is
greater than 20 ng/mL (normal range is 1–15 ng/mL) [59]. The 24-hour urine
collection for n-methylhistamine has an elevated concentration.
Patients who have idiopathic anaphylaxis have normal bone marrow biop-
sies and bone scans. It is not known if patients who have idiopathic anaphy-
laxis have the mast cell c-kit mutation at codon 816 or other genetic
predispositions that have been identified in systemic mastocytosis [59].
Acute severe asthma

Acute severe asthma episodes may mimic anaphylaxis because of the
abrupt onset and severity of respiratory distress with need for intubation.
There may be stridor or loud wheezing or indeed extreme dyspnea with little
wheezing on examination. In some patients who have acute severe asthma
there is facial erythema or apparent swelling. Some episodes of acute severe
asthma are in fact triggered by aspirin or nonselective nonsteroidal anti-
inflammatory drugs or foods. A college student presented with acute respi-
ratory failure requiring intubation with pH of less than 7.1, which was
believed to be anaphylaxis or acute severe asthma. A terrified friend admit-
ted that the patient, who later denied being peanut allergic, had eaten two
peanuts in a bar after a dare.
Munchausen syndrome
Munchausen stridor is nonorganic but loud, purposeful stridulous respi-
rations. These sounds can frighten medical personnel because of the differ-
ential diagnosis that includes anaphylaxis, angiotensin-converting enzyme
inhibitor angioedema, infectious epiglottitis, and hereditary angioedema.
There may be abuse of the emergency department, hospital, and emergency
phone services, and unnecessary self-administration of epinephrine.
Munchausen anaphylaxis is true anaphylaxis that the patient induces.
Examples include deliberate aspirin administration in a patient who has
aspirin-intolerant asthma or anaphylaxis, or walnut ingestion in a sensitized
patient. The patient lies about the ingestion.
Undifferentiated somatoform idiopathic anaphylaxis

Patients who have undifferentiated somatoform idiopathic anaphylaxis
believe that their symptoms of breathlessness, dyspnea, throat closure,
and syncope are real, but there is no objective evidence for upper or lower
airway obstruction or hypotension [42]. Most patients do not accept the no-
tion of anxiety or stress as being present and refuse the idea of psychologic
or psychiatric consultation. It is important to stop the oral corticosteroid
medications that may have been administered for presumptive idiopathic
anaphylaxisdfrequent.
Miscellaneous conditions
Carcinoid tumors may produce histamine-induced flushing with pruritic
wheals that mimic anaphylaxis. Some other mediators involved include
286 GREENBERGER
serotonin, substance P, kallikrein, and prostaglandins [60]. Typical symptoms

include transient flushing, tachycardia, wheezing, diarrhea, and right-
sided valvular cardiac disease [60]. Gastric carcinoid tumors, distinctively,
can produce histamine and other mediators [60,61]. Increases in histamine
are associated with flushing and hypotension [61]. The urine should be col-
lected for 5-hydroxyindoleacetic acid with elevated concentrations greater
than 25 mg/24 hours [62].
Pheochromocytoma does not produce urticarial lesions or angioedema but
may cause confusion because of flushing, dyspnea, tachycardia, and a sense of
doom. Typically the blood pressure is elevated, but if epinephrine, as opposed
to norepinephrine, is secreted, then hypotension and shock can occur [63,64].
It has been reported that less than 10% of pheochromocytomas produce
epinephrine exclusively [63]. Urine collections for catecholamines, metanephr-
ines, and possibly vanillylmandelic acid should be obtained in those patients.
If available, plasma epinephrine can be ordered and will be elevated. CT and
MRI of the abdomen and adrenals can be helpful.
Other endocrine tumors can cause flushing, such as medullary carcinoma
of the thyroid (elevated calcitonin concentration), and watery diarrhea,
vomiting, and abdominal pain in pancreatic cell tumors (elevated plasma va-
soactive intestinal peptide) [62]. These tumors do not produce urticaria and
angioedema, however.
Histamine ingestion in fish, in which histidine has been converted to his-
tamine, produces tingling sensations of the mouth, headache, sweating, and
flushing, abdominal pain, vomiting, diarrhea, and throat tightness [65]. Al-
though prototype cases have been labeled as scombroid poisoning because
of ingestion of spoiled tuna or mackerel, many other fish have been incrim-
inated [65]. An outbreak was associated with tuna that was frozen and
thawed on several occasions before serving [65]. Bacteria that harbor histi-
dine were able to survive.
Management and treatment of idiopathic anaphylaxis

Acute management
At the onset of urticaria, abdominal pain, generalized pruritus, or other
symptoms consistent with anaphylaxis, patients should self-inject epineph-
rine 0.3 mg intramuscularly and take prednisone 50 mg and an H1 antago-
nist, such as cetirizine 10 mg. Other H1 antagonists are acceptable. The
patient should contact a physician for advice, call 911, or go to an emer-
gency department depending on the circumstances of the case. Additional
intensive therapy may be needed in the emergency department. There re-
main no data to support the administration of corticosteroids for treatment
of acute anaphylaxis; however, in that idiopathic anaphylaxis is a corticoste-
roid-responsive condition, it is recommended that patients take the triple
therapy above. Some patients refuse or delay self-injecting epinephrine
because they have been informed that ‘‘If you use your epinephrine, you
must go to the emergency department.’’ This well-meaning sentence has
led some patients to withhold epinephrine so as to avoid the issues and ex-
pense of emergency department care. The educational effort should include
that epinephrine is the drug of choice for anaphylaxis [10,12] and that anti-
histamines clearly can be inadequate for treatment of episodes of idiopathic
anaphylaxis. After the patient has improved, it is advisable to review a diary
of medications, activities, and foods for the last 6 hours or anything else to
confirm that other causes of anaphylaxis are not present.
The patient should be referred to an allergist-immunologist to confirm
the diagnosis. If the patient is receiving therapy with b-adrenergic antago-
nists or angiotensin-converting enzyme inhibitors, efforts should be made
to discontinue these medications. It is necessary to identify alternative
pharmacotherapy. Angiotensin receptor blockers are usually tolerated
uneventfully in patients who have experienced angiotensin-converting en-
zyme inhibitor tongue enlargement or pharyngeal or laryngeal edema.
Specific data from patients who have idiopathic anaphylaxis and concurrent
angiotensin-converting enzyme inhibitor angioedema are limited. In any
event, such patients who have a presumed diagnosis of idiopathic anaphy-
laxis likely have medication-induced anaphylaxis and not idiopathic
anaphylaxis.
Long-term management
For patients who have infrequent episodes, such as fewer than five per
year or fewer than two in 2 months, one approach is to have expectant man-
agement with the above triple therapy should an episode occur. Patients
should use an H1 antagonist daily and have their epinephrine and predni-
sone available at all times. For patients who have frequent episodes of ana-
phylaxis, meaning six per year or two or more episodes in the past 2 months,
empiric treatment has been helpful in reducing the frequency and severity of
anaphylactic episodes [2–4]. Adults are treated with prednisone 60 to 100 mg
each morning for 7 days and then administered 60 mg on alternate mornings
[4]. Cetirizine 10 mg daily (or equivalent H1 antagonist) is administered. It is
optional to administer albuterol 2 mg twice or three times daily. Most
patients stop having urticarial lesions and anaphylactic episodes after 1
week of daily prednisone. Prednisone is then continued for 2 weeks at this
dose and then it is reduced by 5 to 10 mg every 2 weeks assuming there
are no episodes of anaphylaxis or urticaria/angioedema. If the patient has
received this empiric therapy for 2 to 3 months without any evidence of
mast cell activation, then prednisone can be discontinued, but the cetirizine
or H1 antagonist therapy is continued. When patients compare the year be-
fore this approach with the year of treatment, there is a significant reduction
in the severity and frequency of episodes [2,4]. For example, in a series of
patients who had frequent episodes of idiopathic anaphylaxis [4], the
288 GREENBERGER
number of episodes and emergency department visits per year were as shown
in Table 2.
The rate of remission (no episodes for 1 year and no prednisone) was
48% in patients who had IA-G and 40% in patients who had IA-A [4]. Al-
ternatively, 20% of patients required longer-term prednisone and H1 antag-
onists with or without albuterol. Seven of 11 patients in this group were
corticosteroid dependent with minimal controlling doses of 15 to 85 mg
prednisone on alternate days [4]. The remaining patients receive expectant
therapy for acute episodes and use H1 antagonists daily.
Although the empiric therapy with prednisone helps to reduce the sever-
ity and frequency of episodes, not all patients are able to discontinue
prednisone. Case reports of successful use of ketotifen 2 mg two or three
times daily have been published [39,40]. Oral cromolyn concentrate
(100 mg/5 mL per ampoule) can be tried as two ampoules pre-meals and
at bedtime simulating treatment of systemic mastocytosis along with H1
and H2 antagonists. Although it is possible that leukotriene antagonists
might be of benefit, proof is lacking.
If empiric treatment is not successful and episodes continue, then it is ad-
visable to reconsider the differential diagnosis of idiopathic anaphylaxis, in-
cluding undifferentiated somatoform idiopathic anaphylaxis. (see Box 1) In
that situation, the patient may have more attacks in the first 2 to 3 weeks of
intensive treatment with prednisone. Alternatively, panic disorder and pred-
nisone noncompliance should be considered. A review of tests and proce-
dures should be considered again to exclude other causes for the patient’s
condition (Box 2).
Surgical procedures per se have not been associated with episodes of id-
iopathic anaphylaxis although it is advisable to make sure that patients are
not having frequent episodes of anaphylaxis or urticaria/angioedema in the
preoperative time period. Similarly, patients should not be traveling if their
idiopathic anaphylaxis is not stable. Some patients have experienced ana-
phylaxis with hypotension in major airports or on interstate highways. A
week of prednisone 50 to 60 mg daily along with continued antihistamine
therapy should be initiated if anaphylaxis is not controlled and travel is
absolutely mandatory. Otherwise, the travel should be delayed.
Remissions do occur, and some investigators have described patients who
do not receive empiric prednisone-antihistamine treatment who improve
[8,23]. In contrast to persistent asthma, some, but not all, patients who
have idiopathic anaphylaxis may enter remission after having frequent
Table 2
Episodes and emergency department visits (per year)
Type Episodes pre/post Emergency department pre/post
Generalized 7.3/3.6 1.9/0.2
Angioedema 14.9/2.6 0.8/0.1
Box 2. Useful tests and procedures in the evaluation and

management of a patient who has suspected idiopathic
anaphylaxis
Urine histamine or metabolites, plasma histamine, serum
tryptase
Comment: confirms mast cell activation but consistently elevated
values suggest systemic mastocytosis
Complement (C4) determination
Comment: normal in idiopathic anaphylaxis
Skin testing for foods
Comment: some episodes of idiopathic anaphylaxis occur after
eating
Skin testing for spices
Comment: might identify an unrecognized food ingredient
Skin testing for penicillin minor determinants
Comment: help exclude penicillins as a cause of anaphylaxis; in
the absence of the major determinant, the negative value of
testing would be increased if a challenge is tolerated to exclude
the presence of penicillin allergy
Skin testing for latex
Comment: latex anaphylaxis has masqueraded as idiopathic
anaphylaxis
Aspirin/nonsteroidal anti-inflammatory drug challenge
Comment: to rule in the cause of recurrent anaphylaxis in certain
cases and exclude the diagnosis of idiopathic anaphylaxis
Bone marrow biopsy, skin biopsy, bone scan
Comment: part of the evaluation for systemic mastocytosis
Discontinuing angiotensin-converting enzyme inhibitors and
b-adrenergic antagonists
Comment: use substitute pharmacotherapy
Prednisone, H1 antagonist empiric therapy for 3 months
Comment: effective treatment for idiopathic
anaphylaxisdfrequent; an increase in episodes after starting
empiric therapy suggests other diagnoses
290 GREENBERGER
Reassessment of medications, circumstances of episodes,

response to treatment
Comment: patients who have idiopathic anaphylaxis have
complicated courses and can have coexisting food, exercise, or
medication-induced anaphylaxis
From Greenberger PA. Differential diagnosis of idiopathic anaphylaxis. In:

Patterson R, editor. Idiopathic anaphylaxis. Providence (RI): Oceanside Publica-
tions; 1997; with permission.
episodes for 2 to 3 years. The prognostic factors for remission or prednisone

responsiveness remain uncertain. Nevertheless, depending on the severity
and number of episodes, this author favors empiric treatment for the
3-month period for idiopathic anaphylaxisdfrequent and even some cases
of very severe single episodes of idiopathic anaphylaxis.
Summary
Idiopathic anaphylaxis is a diagnosis of reasonable exclusion in which
referral to an allergist-immunologist is advisable. For frequent episodes, it
is recommended that a 3-month empiric course of prednisone and H1 antag-
onist, with or without albuterol, be used to reduce the number and severity
of episodes. For infrequent episodes, expectant management with the triple
therapy of epinephrine, prednisone, and H1 antagonist be used. Some
patients who have idiopathic anaphylaxis can be expected to have coexistent
anaphylaxis from exercise, foods, or medications. The normal complement
concentration of C4 differentiates IA-A from hereditary angioedema or
C1 esterase inhibitor deficiency.
References
[1] Bacal E, Patterson R, Zeiss CR. Evaluation of severe (anaphylactic) reactions. Clin Allergy
1978;8:295–304.
[2] Boxer MB, Greenberger PA, Patterson R. The impact of prednisone in life threatening
idiopathic anaphylaxis: reduction in acute episodes and medical costs. Ann Allergy 1989;
62(3):201–4.
[3] Ditto AM, Harris KE, Krasnick J, et al. Idiopathic anaphylaxis: a series of 335 cases. Ann
Allergy Asthma Immunol 1996;77(10):285–91.
[4] Wong S, Yarnold PR, Yango C, et al. Outcome of prophylactic therapy for idiopathic
anaphylaxis. Ann Intern Med 1991;114(2):133–6.
[5] Myers G, Donlon M, Kaliner M. Measurement of urinary histamine: development of
methodology and normal values. J Allergy Clin Immunol 1981;67(4):305–11.
[6] Greenberger PA, Miller MM. Urine histamine during episodes of anaphylaxis. J Allergy Clin
Immunol 1994;93:302 [abstract].
[7] Shanmugam G, Schwartz LB, Khan DA. Prolonged elevation of serum tryptase in
idiopathic anaphylaxis. J Allergy Clin Immunol 2006;117(4):950–1.
[8] Lieberman P, Taylor WW Jr. Recurrent idiopathic anaphylaxis. Arch Intern Med 1979;139:
1032–4.
[9] Tanus R, Mines D, Atkins PC, et al. Serum tryptase in idiopathic anaphylaxis: a case report
and review of the literature. Ann Emerg Med 1994;24(7):104–7.
[10] Simons FER. Anaphylaxis, killer allergy: long-term management in the community.
and management of anaphylaxis: summary reportdSecond National Institute of Allergy
and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy
Clin Immunol 2006;117(2):391–7.
[12] Lieberman P, Kemp SF, Oppenheimer J, et al. The diagnosis and management of anaphy-
laxis: an updated practice parameter. J Allergy Clin Immunol 2005;115(3):S483–523.
[13] Patterson R, Stoloff RS, Greenberger PA, et al. Algorithms for the diagnosis and manage-
ment of idiopathic anaphylaxis. Ann Allergy 1993;71(1):40–4.
[15] Brown SGO. Clinical features and severity grading of anaphylaxis. J Allergy Clin Immunol
2004;114(2):371–6.
[16] Patterson R, Hogan MB, Yarnold PR, et al. Idiopathic anaphylaxis: an attempt to estimate
the incidence in the United States. Arch Intern Med 1995;155:869–71.
allergic reactions: an emergency department-based study. J Allergy Clin Immunol 2000;106:
65–71.
[18] Brown AFT, McKinnon D, Chu K. Emergency department anaphylaxis: a review of 142
patients in a single year. J Allergy Clin Immunol 2001;108:861–6.
[19] Braganza SC, Acworth JP, McKinnon DR, et al. Paediatric emergency department anaphy-
laxis: different patterns from adults. Arch Dis Child 2006;91(2):159–63.
[20] Cianferoni A, Novembre E, Mugnaini L, et al. Clinical features of acute anaphylaxis in
patients admitted to a university hospital: an 11-year retrospective review (1985–1996).
Ann Allergy Asthma Immunol 2001;87(1):27–32.
[21] Webb LM, Lieberman P. Anaphylaxis: a review of 601 cases. Ann Allergy Asthma Immunol
2006;97(1):39–43.
[22] Thong BY, Cheng YK, Leong KP, et al. Anaphylaxis in adults referred to a clinical immu-
nology/allergy centre in Singapore. Singapore Med J 2005;46(10):529–34.
[23] Khan DA, Yocum MW. Clinical course of idiopathic anaphylaxis. Ann Allergy 1994;73:
370–4.
[24] Krasnick J, Patterson R, Meyers GL. A fatality from idiopathic anaphylaxis. Ann Allergy
Asthma Immunol 1996;76(4):376–8.
[25] Patterson R, Clayton DE, Booth BH, et al. Fatal and near fatal idiopathic anaphylaxis. All
Asthma Proc 1995;16(3):103–8.
[26] Low I, Stables S. Anaphylactic deaths in Auckland, New Zealand: a review of coronial
autopsies from 1985 to 2005. Pathology 2006;38(4):328–32.
[27] Stoloff RS, Orfan N, Greenberger PA, et al. Malignant idiopathic anaphylaxis: three addi-
tional cases and extended evaluation. Ann Allergy 1992;69(1):37–42.
[28] Krasnick J, Ditto AM, Patterson R. Idiopathic anaphylaxis in children manifested as upper
airway obstruction. Pediatric Allergy, Asthma & Immunology 1996;10(1):29–33.
[29] Garriga MM, Friedman MM, Metcalfe DD. A survey of the number and distribution of mast
cells in the skin of patients with mast cell disorders. J Allergy Clin Immunol 1988;82:425–32.
[30] Grammer LC, Shaughnessy MA, Harris KE, et al. Lymphocyte subsets and activation
markers in patients with acute episodes of idiopathic anaphylaxis. Ann Allergy Asthma
Immunol 2000;85(5):368–71.
[31] Sonin L, Patterson R. Idiopathic anaphylaxis and exercise-induced ‘‘anaphylaxis’’: PAR,
pseudo-allergic reactions. Involvement of Drugs and Chemicals 1985;4:47–58.
292 GREENBERGER
[32] Greenberger PA, Boxer MB, Roberts M, et al. Cutaneous vascular reactions to leukotriene
D4, platelet activating factor and histamine in patients with idiopathic anaphylaxis and
chronic urticaria. Clin Res 1986;34:409A.
[33] Keffer JM, Bressler RB, Wright R, et al. Analysis of wheal-and-flare reactions that follow the
intradermal injections of histamine and morphine in adults with recurrent, unexplained
anaphylaxis and systemic mastocytosis. J Allergy Clin Immunol 1989;83:595–601.
[34] Mazur N, Patterson R, Perlman D. A case of idiopathic anaphylaxis associated with respi-
ratory infections. Ann Allergy Asthma Immunol 1997;79(6):546–8.
[35] Tejedor Alonso MA, Sastre Dominguez J, Sanchez-Hernandez JJ, et al. Idiopathic
anaphylaxis: a descriptive study of 81 patients in Spain. Ann Allergy Asthma Immunol
2002;88(3):313–8.
[36] Ditto AM, Krasnick J, Greenberger PA, et al. Pediatric idiopathic anaphylaxis: experience
with 22 patients. J Allergy Clin Immunol 1997;100:320–6.
[37] Hogan MB, Kelly MA, Wilson NW. Idiopathic anaphylaxis in children. Ann Allergy
Asthma Immunol 1998;81(2):140–2.
[38] Dykewicz MS, Blaser M, Evans R, et al. Pediatric idiopathic anaphylaxis: a report of three
cases with recommendation for evaluation and management. Pediatric Asthma, Allergy &
Immunology 1990;4:217–23.
[39] Dykewicz MS, Wong S, Patterson R, et al. Evaluation of ketotifen in corticosteroid
dependent idiopathic anaphylaxis. Ann Allergy 1990;65:406–10.
[40] Wong S, Patterson R, Harris KE, et al. Efficacy of ketotifen in corticosteroid-dependent
idiopathic anaphylaxis. Ann Allergy 1991;67:359–64.
[41] Patterson R, Greenberger PA. Problems in the management of idiopathic anaphylaxis.
Allergy Asthma Proc 2001;22(5):295–6.
[42] Choy AC, Patterson R, Patterson DR, et al. Undifferentiated somatoform idiopathic ana-
phylaxis: nonorganic symptoms mimicking idiopathic anaphylaxis. J Allergy Clin Immunol
1995;96:893–900.
[43] Greenberger PA. Differential diagnosis of idiopathic anaphylaxis. In: Patterson R, editor.
Idiopathic anaphylaxis. Providence (RI): Oceanside Publications; 1997. p. 7–17.
[44] Sampson HA, Mendelson L, Rosen FP. Fatal and near-fatal anaphylactic reactions to food
in children and adolescents. N Engl J Med 1992;327(6):380–4.
[45] Yunginger JW, Sweeney KG, Sturner WQ, et al. Fatal food-induced anaphylaxis. JAMA
1988;260(10):1450–2.
[46] Pumphrey RSH. Lessons for management of anaphylaxis from a study of fatal reactions.
Clin Exp Allergy 2000;30:1144–50.
[47] Greenberger PA, Rotskoff BD, Lifschultz B. Fatal anaphylaxis: autopsy findings and asso-
ciated co-morbid diseases. Ann Allergy Asthma Immunol 2007;98(3):252–7.
[48] Furlong TJ, DeSimone J, Sicherer SH. Peanut and tree nut allergic reactions in restaurants
and other food establishments. J Allergy Clin Immunol 2001;108(5):867–70.
[49] Wensing J, Penninks AH, Hefle SL, et al. The distribution of individual threshold doses
eliciting allergic reactions in a population with peanut allergy. J Allergy Clin Immunol
2002;110(6):915–20.
[50] DiCello MC, Myc A, Baker JR Jr, et al. Anaphylaxis after ingestion of carmine colored foods:
two case reports and a review of the literature. Allergy Asthma Proc 1999;20(6):377–82.
[51] Greenberger PA, Flais MJ. Bee pollen-induced anaphylactic reaction in an unknowingly
sensitized subject. Ann Allergy Asthma Immunol 2001;86(2):239–42.
[52] Khalil B, Bardana EJ Jr, Yunginger JW. Psyllium-associated anaphylaxis and death: a case
report and review of the literature. Ann Allergy Asthma Immunol 2003;91(6):579–84.
[53] Sonin L, Patterson R. Metabisulfite challenge in patients with idiopathic anaphylaxis.
[54] Geha RS, Beiser A, Ren C, et al. Multicenter, double-blind, placebo-controlled, multiple-
challenge evaluation of reported reactions to monosodium glutamate. J Allergy Clin Immu-
nol 2000;106(5):973–80.
[55] Golbert TM, Patterson R, Pruzansky JJ. Systemic allergic reactions to ingested antigens.
J Allergy 1969;44:96–107.
[56] Shadick NA, Liang MH, Partiridge AJ, et al. The natural history of exercise-induced ana-
phylaxis: survey results from a 10-year follow-up study. J Allergy Clin Immunol 1999;
104(1):123–7.
[57] Perkins DN, Keith PK. Food-and exercise-induced anaphylaxis: importance of history
in diagnosis. Ann Allergy Asthma Immunol 2002;89(1):15–23.
[58] Agostoni A, Bork K, Fischer B, et al. HAE: types I and II. J Allergy Clin Immunol 2004;
114(3):S61–5.
[59] Valent P, Akin C, Sperr WR, et al. Mastocytosis: pathology, genetics, and current options
for therapy. Leuk Lymphoma 2005;46(1):35–48.
[60] Kulke MH, Mayer RJ. Carcinoid tumors. N Engl J Med 1999;340(11):858–68.
[61] Roberts LJ, Bloomgarden ZT, Marney SR Jr, et al. Histamine release from a gastric carci-
noid: Provocation by pentagastrin and inhibition by somatostatin. Gastroenterology 1983;
84(2):272–5.
[62] Izikson L, English JC III, Zirwas MJ. The flushing patient: differential diagnosis, workup,
and treatment. J Am Acad Dermatol 2006;55(2):193–208.
[63] Erem C, Kocak M, Onder Ersoz H, et al. Epinephrine-secreting cystic pheochromocytoma
presenting with an incidental adrenal mass: a case report and a review of the literature.
Endocrine 2005;28(2):225–30.
[64] Ueda T, Oka N, Matsumoto A, et al. Pheochromocytoma presenting as recurrent hypoten-
sion and syncope. Intern Med 2005;44(3):222–7.
[65] Becker K, Southwick K, Reardon J, et al. Histamine poisoning associated with eating tuna
burgers. JAMA 2001;285(10):1327–30.
27 (2007) 295–307
Anaphylactic Reactions During

Immunotherapy
Maziar Rezvani, MD, David I. Bernstein, MD*
Division of Allergy/Immunology, University of Cincinnati College of Medicine,
231 Albert Sabin Way, Cincinnati, OH 45267–0563, USA
In the past 4 decades, the incidence of atopic disorders has expanded in

developed countries [1,2]. Subcutaneous immunotherapy (IT) with aeroal-
lergen extracts has been a venerable treatment modality for nearly 100 years
[3,4]. Controlled clinical studies have confirmed the efficacy of IT in reduc-
ing symptoms and medication requirements in patients with allergic rhinitis
(AR) caused by seasonal pollens and standardized house dust mite extract
(HDM) [5,6]. Placebo-controlled trials have also established the efficacy of
subcutaneous IT in treating allergic asthma associated with exposure to
grass pollen, cat, and house dust mite allergen [7]. The unequivocal effective-
ness of subcutaneous IT with purified venoms in prevention of insect sting
anaphylaxis has been demonstrated in patients with anaphylactic sensitivity
to Hymenoptera venoms [8–10].
As with any treatment, anticipated benefits attributed to IT must be
weighed against its potential risks. It is clear that the major risk associated
with IT with commercial aeroallergen extracts is the uncommon occurrence
of severe near-fatal or fatal anaphylaxis after injections.
The major objectives of this article are to (1) review the reported inci-
dences of severe anaphylaxis (near-fatal reactions [NFRs] and fatal reac-
tions [FRs]), (2) define factors contributing to these events, and (3)
identify preventive measures that are likely to reduce or eliminate future fa-
tal and near-fatal anaphylactic events.
Historical background
In 1910, Noon was the first to develop IT in England with pollen extracts
administered subcutaneously [3]. In 1916, Cooke and Vander Veer [11]
E-mail address: david.i.bernstein@uc.edu (D.I. Bernstein).
296 REZVANI & BERNSTEIN
reported their experience in treating 621 patients, and they identified a 3.5%
overall incidence of systemic reactions to subcutaneous grass pollen injec-
tions. Six years later, Cooke [12] reported the first known death of a
3-year-old asthmatic child during intracutaneous skin testing. In 1919,
Boughton [13] reported fatal anaphylaxis in a 29-year-old asthmatic patient
during attempted intravenous desensitization with horse serum. The two lat-
ter cases were cited in Lamson’s 1924 account [14] of another fatality imme-
diately after application of multiple intracutaneous skin tests with oat, milk,
rice, and egg in a 5-month-old child with eczema. Aggressive resuscitative
measures, including epinephrine and atropine, were of no avail. In a 1932
report of 9 patients who succumbed to fatal anaphylactic shock from vari-
ous agents, 1 was a 40-year-old ‘‘hay fever’’ patient who died from anaphy-
laxis after receiving a subcutaneous ragweed extract injection, failing to
respond to epinephrine [15].
In 1957, Van Arsdel and Sherman [16] published a larger 20-year survey
of systemic allergic reactions (1933–1953) associated with intracutaneous
testing and IT in 8706 allergy clinic patients treated at Roosevelt Hospital
in New York City. They reported the occurrence of one (0.1%) constitu-
tional reaction per 700 injections in 663 patients (7% incidence). It was note-
worthy that only 114 (0.01%) injections resulted in systemic reactions of
sufficient severity to warrant epinephrine administration and that only six
(0.0005%) reactions led to shock. No fatal events occurred. In a review of
systemic anaphylaxis published in 1964, James and Austen [17] reported
a delayed FR in a 56-year-old man undergoing ‘‘hayfever desensitization’’
manifested initially by dyspnea 45 minutes after an injection.
In 1986, the Committee on the Safety of Medicines (CSM) in the United
Kingdom reported details of 26 IT-related deaths that had occurred between
1957 and 1986 resulting from anaphylaxis or bronchospasm after adminis-
tration of allergen injections. All fatal reactors were receiving IT for allergic
asthma, and it seemed that asthmatic patients were at greatest risk for FRs
[18]. This initial report resulted in a mandated 2-hour postinjection waiting
period for patients receiving IT, which practically eliminated the use of this
modality in the United Kingdom for years until a 1-hour standard was
adopted [19].
Incidence of systemic, fatal, and near-fatal immunotherapy reactions

Because of manufacturing differences in allergen extracts, it is difficult to
compare incidence data in Europe and North America with regard to IT-re-
lated anaphylactic reactions. Currently, nearly all products used in Europe
are aluminum absorbed or modified, whereas pure aqueous extracts are used
exclusively in the United States. Severe and potentially life-threatening reac-
tions represent a small percentage of all injection-related systemic allergic re-
actions. One clinic in the United Kingdom reported that 0.2% of 919
ANAPHYLACTIC REACTIONS DURING IMMUNOTHERAPY 297
injections with alum-absorbed grass pollen extract resulted in severe sys-

temic reactions compared with 2% that led to mild systemic reactions (hives,
rhinitis, and mild wheeze) [20]. In the United States, Greenberg and col-
leagues [21] reported systemic reactions in 7% of patients receiving IT
with mixed allergen extracts and an injection reaction rate of 0.25%.
Ewan and colleagues [22] evaluated systemic reactions in patients receiving
injections with aqueous Dermatophagoides pteronyssinus in a clinical trial us-
ing a rapid build-up protocol and reported an injection reaction rate of
23%, although only 8% of these reactions were serious and required epi-
nephrine. Bousquet and colleagues [23] assessed systemic reactions in a pro-
spective study of 125 patients receiving IT with house dust mite extract
(D pteronyssinus). Systemic reactions were reported in 47 (38%) of patients
during the rush protocol, of whom 4 experienced mild urticaria, 35 had
asthma exacerbations, and 8 experienced anaphylactic shock. No reactions
occurred later than 45 minutes after the last injection. Based on the afore-
mentioned studies, rush or cluster dosing regimens seem to be associated
with increased systemic reaction rates compared with conventional and
slower induction protocols [24].
FRs associated with IT injections have appropriately received much at-
tention and scrutiny. During the past 20 years, the Immunotherapy
Committee of the American Academy of Allergy, Asthma, and Clinical
Immunology (AAAAI) has sponsored a series of retrospective surveys of fa-
talities associated with allergen injections and skin testing. In the first survey
reported in 1987, Lockey and colleagues [25] summarized information
obtained from responses to long questionnaires provided voluntarily by
physicians who had experienced IT and skin test FRs in their clinics or
were aware of others in their region. These investigators estimated that 1
FR occurred in every 2.8 million injections based on an estimated 47 million
annual doses of IT administered in the United States. In a follow-up survey
of fatal events between 1985 and 1989, Reid and colleagues [26] identified
a similar rate of 1 FR per 2 million injections based on 33 million adminis-
tered doses, or an incidence of four cases per year. In the most recent
AAAAI physician survey of FRs of events from 1990 through 2001, Bern-
stein and colleagues [27] identified 41 confirmed FRs, which translated to
an annual case incidence of 3.4 deaths per year and 1 fatal event in
2.5 million injections. The methods used in the latest survey differed from
those of the two former studies in that a brief survey was initially sent to
all physician members of the AAAAI, resulting in 646 respondents, or
27% of 2404 physicians contacted [27]. Physicians were queried about
NFRs and FRs in their clinic or other practices in their geographic regions
and were asked to estimate annual allergen injections administered based on
billing codes during the preceding 1 and 3 years. These data allowed direct
estimation of FR and NFR rates relative to the number of injections admin-
istered. Despite the fact that the initial two AAAAI surveys used a different
data source to estimate injection numbers, actual estimated fatal injection
reaction rates in all AAAAI surveys seem to remain consistent over time
(approximately 1 case in 2,000,000) [25–27].
NFRs were evaluated in the most recent AAAAI survey spanning 1990
through 2001. NFRs were defined as anaphylactic events involving signs
of cardiovascular collapse or severe bronchospasm necessitating epinephrine
administration [28], equivalent to grade IV anaphylactic events [29]. The in-
jection reaction rate was estimated at 1.0 event per 1 million injections on
the basis of confirmed NFRs (68 cases) [28], and this rate was approximately
2.5 times greater than that for confirmed FRs. Based on all 273 confirmed
and unconfirmed events reported by 646 respondents in the brief survey,
however, 5.4 near-fatal events were estimated per every 1 million injections.
The average incidence of confirmed NFRs was 4.7 events per year and 23
cases per year for all reported NFRs (confirmed and unconfirmed). In a sep-
arate prospective survey conducted in North America, 20 grade IV anaphy-
lactic events manifested by hypotension and respiratory symptoms occurred
in every 1 million aqueous IT injections administered in a large allergy clinic
population [30]. In an Italian survey of AR and asthmatic patients on stan-
dardized HDM, tree and grass pollen IT with alum-absorbed extracts,
a grade IV anaphylactic reaction rate of 82 per 1 million injections was
documented [31]. Thus, in this study, use of alum-absorbed extracts did
not seem to diminish the risk of severe IT-related anaphylaxis.
Clinical manifestations
Severe anaphylaxis is characterized by bronchospasm, respiratory failure,
or hemodynamic compromise manifested by profound hypotension and car-
diovascular shock. In the most recent AAAAI surveys of fatal (2004) and
near-fatal IT reactions (2006), hypotension was reported by 81% and
88% of respondents, respectively [27,28]. In the initial AAAAI survey
(Lockey and colleagues [25]) shock, syncope, or cardiac dysrhythmia was re-
ported in 69% of 17 reported fatal events.
In a recent AAAAI study, Amin and colleagues [28] evaluated data com-
paring clinical manifestations of near-fatal and fatal anaphylactic reactions
in detail (Fig. 1). Cutaneous manifestations, including urticaria, angioe-
dema, and pruritus, were reported at much greater frequency with NFRs
(70%) versus FRs (29%). The absence of cutaneous signs in most fatal re-
actors was noteworthy and would suggest that the absence of cutaneous
signs may have delayed prompt recognition and treatment of fatal anaphy-
laxis in some cases.
Although upper airway obstruction and bronchospasm were reported
with similar frequencies in fatal and near-fatal reactors, acute respiratory
failure was identified in 94% of FRs compared with 10% of NFRs. All fatal
and near-fatal reactors who developed respiratory failure and required intu-
bation had been previously diagnosed with asthma. It was noteworthy that
Fig. 1. Clinical manifestations reported by treating physicians during FRs and NFRs to IT in-
jections. (From Amin HS, Liss GM, Bernstein DI. Evaluation of near-fatal reactions to allergen
immunotherapy injections. J Allergy Clin Immunol 2006;117:172; with permission.)
four (57%) of seven patients with NFRs requiring intubation had pretreat-
ment forced expiratory volume in 1 second (FEV1) values of less than 70%
predicted [28].
Factors associated with severe anaphylaxis

Patient characteristics
Fatal anaphylaxis attributable to various causes has been consistently re-
ported to occur with greater frequency among patients with severe or poorly
controlled asthma [25,26,32]. As already mentioned, patients with severe or
uncontrolled asthma are at greater risk for FRs after IT injections [27]. In
the aforementioned recent AAAAI survey, asthma was present in 15
(88%) of 17 fatal reactors compared with 46% in near-fatal reactors [27].
As shown in Fig. 2, asthma was not optimally controlled before death in
most asthmatic patients who went on to have fatal IT reactions but was
poorly controlled in only 10% of asthmatics experiencing NFRs [28]. Fatal
reactors were more likely to have labile asthma and prior emergency depart-
ment visits (54% versus 9%, odds ratio [OR] ¼ 12.1, 95% confidence interval
[CI]: 2.6–61.1) and hospitalizations for asthma (61.5% versus 4%, OR ¼ 34.7,
95% CI: 5.7–251) relative to near-fatal reactors who survived severe
anaphylaxis (see Fig. 2) [28].
Fig. 2. Comparison of prior indicators of asthma severity in fatal and near-fatal reactors re-
ported by treating physicians. (From Amin HS, Liss GM, Bernstein DI. Evaluation of near-fatal
reactions to allergen immunotherapy injections. J Allergy Clin Immunol 2006;117:173; with
permission.)
The association of IT fatalities with poorly controlled asthma is consis-

tent with the findings of the 1986 British CSM report [18]. In a 1990 pro-
spective study of rush IT with a standardized D pteronyssinus extract,
more than 60% of patients with FEV1 values of less than 70% experienced
bronchospasm after IT injections, suggesting that patients with severe air-
way obstruction are at much greater risk [24]. Bernstein and colleagues
[27] reported that FEV1 values less than 70% predicted were reported in
50% of asthmatics who had FRs in whom spirometry data were available.
Practice guidelines have stated that concomitant medical conditions other
than asthma and medications could compromise the ability of patients to
tolerate IT-induced anaphylaxis and that these should be considered as
relative contraindications for administration of IT [4]. Although 5 of 17
patients with FRs reported by Lockey and colleagues had underlying car-
diovascular disease, subsequent surveys have not confirmed this association
[25–27]. There is little evidence to suggest that use of beta-blockers increases
the incidence of systemic reactions to IT [33,34]. Nevertheless, experimental
evidence has been published showing that beta-blockers may enhance hypo-
tensive responses during anaphylaxis and may reduce beneficial adrenergic
responses to emergency epinephrine [10,35]. Lockey and colleagues [25]
identified that 2 of 17 fatal reactors (1973–1984) were receiving beta-
blockers (propanolol and timolol), as was 1 of 17 fatal reactors in the sub-
sequent survey of Reid and colleagues [26]. In the AAAAI near-fatal survey
(1990–2001), Amin and colleagues [28] reported only 1 patient on low-dose

atenolol (25 mg qd), who had an excellent response to epinephrine during an
NFR and did not require glucagon. Concern has been raised about the the-
oretic risk of concomitant use of angiotensin-converting enzyme (ACE) in-
hibitors [36] in patients receiving IT. Eight cases of IT-related anaphylaxis
have been reported in patients receiving ACE inhibitors, but the relative
risk has not been determined [27,28,36,37].
Previous local and systemic reactions

Based on data from the previous surveys as well as the aforementioned
AAAAI surveys, large local reactions were not found to predict the subse-
quent occurrence of severe systemic reactions reliably [27,28,38,39]. Bern-
stein and colleagues [27] reported that 28.6% (4 of 14) of patients with
FRs reported prior injection-related systemic reactions, and Reid and col-
leagues [26] noted that 36% of IT fatal reactors had experienced prior sys-
temic reactions. Prior systemic reactions were identified in only 9% of those
with NFRs [28].Thus, these data suggest that patients with FRs are likely to
have experienced IT-related systemic reactions previously.
The tendency for the numbers of observed systemic IT reactions to in-
crease during peak allergen seasons was noted in 1957 by Van Arsdel and
Sherman [16]. In AAAAI surveys, 29% to 56% of physicians reported
that FRs and NFRs occurred during their patients’ peak allergy seasons
[28]. Unfortunately, uncontrolled surveys do not allow estimation of the rel-
ative risk of severe anaphylaxis during peak allergen exposure periods.
Other possible contributing factors

The clinic setting in which IT is administered may contribute to fatal ana-
phylaxis. In the first two AAAAI surveys, 47% to 48% of FRs occurred
outside of the prescribing allergist’s office [25,26], and 41% in the most re-
cent survey did so. Bernstein and colleagues [27] noted that 3 (18%) of 17
FRs occurred outside of a medical clinic or at home, whereas 63 (93%) of
68 NFRs occurred in the prescribing allergist’s facility and the remainder
occurred in supervised clinic settings [28]. Delay in onset of injection-related
anaphylaxis could delay prompt initiation of life-saving treatment with epi-
nephrine. In the most recent AAAAI survey (1990–2001), 3 of 17 FRs began
more than 30 to 45 minutes after allergen injections [27]. In previous sepa-
rate surveys, 8% to 13% of FRs to IT began 30 minutes or more after
injections. Due to similar infrequent delayed reactions observed in the
United Kingdom, a 60-minute postinjection observation period was been es-
tablished [40].
In the last AAAAI survey of FRs and NFRs, the mean number of injec-
tions administered by allergy clinics reporting NFRs was 51% greater than
that of clinics reporting no life-threatening IT reactions (P ! .02). The
reduced likelihood of severe reactions in clinics administering fewer IT injec-

tions could be related to more careful selection and exclusion of high-risk
patients (eg, poorly controlled asthmatics).
Serious allergic reactions to IT injections have been linked to errors in
dosing and administration [41]. In the aforementioned NFR survey, dosing
errors were implicated in contributing to 25% of anaphylactic reactions [28].
In a prospective French study, errors related to allergen extract vials or
doses accounted for 10% of all systemic reactions [42]. Lockey and col-
leagues [25] reported three ‘‘errors’’ of administration in 14 patients with
FRs. Reid and colleagues [26] reported one FR associated with a dosing er-
ror and another FR after intramuscular IT administration. Thus, dosing
and administrative errors seem to contribute significantly to injection-
related anaphylactic events.
In an earlier survey, life-threatening anaphylactic reactions were consid-
ered to occur more frequently during the build-up phase of IT [26]. Accord-
ing to the most recent AAAAI surveys, however, most FRs and NFRs
occurred after injections from maintenance allergen extract vials [27,28].
In a recent prospective multicenter Danish study of 1038 patients receiving
alum-absorbed pollen and indoor allergen extracts, timothy allergen was im-
plicated in all eight severe grade 4 injection-related anaphylactic reactions
[43]. This suggests that pollen extracts are more likely to cause severe ana-
phylactic reactions.
Management of severe reactions

It is recognized that FRs are unpredictable and can occur in patients
without any of the aforementioned underlying risk profiles [44]. Therefore,
prompt recognition and administration of parenteral epinephrine are critical
to successful management of severe anaphylaxis [32,45]. In the most recent
AAAAI survey of 17 patients with FRs, Bernstein and colleagues [27] re-
ported that administration of epinephrine was delayed (R10 minutes) or
not administered in 31% of cases. In those patients with NFRs, 82% of
NFRs were treated within 3 minutes of onset of reactions and 94% of pa-
tients received epinephrine within the first 20 minutes [28]. In earlier surveys,
epinephrine had been knowingly administered to only 18 (75%) of 24 and 12
(70%) of 17 patients with fatal IT reactions [25,40]. Similarly, fatal out-
comes related to severe food-induced anaphylaxis have been associated
with significant delays in administration of epinephrine [32]. It is likely
that epinephrine was administered by means of the subcutaneous route in
early surveys. Interestingly, in the most recent AAAAI survey of NFRs,
31% of patients who experienced NFRs received epinephrine by means of
the preferred and recommended intramuscular route, which achieves higher
plasma epinephrine levels more rapidly compared with the subcutaneous
route [45]. The initial epinephrine dose was adequate (R0.3 mg) in 88%
of NFRs. Antihistamines and systemic corticosteroids were administered
along with epinephrine in 63% of NFRs but were not administered to 37%
of patients, suggesting that these interventions were much less critical than
epinephrine. Optimal epinephrine treatment for NFRs was likely assured by
administration of IT injections in medically supervised clinic settings in 93%
of cases [28].
In the most recent AAAAI survey of FRs and NFRs, intubation was re-
quired for respiratory failure in 88% of FRs compared with only 9% of
NFRs [28]. Among the recently reported cases of severe anaphylaxis after
IT with fatal outcomes, intubation was attempted in 15 patients. In
6 (40%) patients, the establishment of an airway was delayed or unsuccess-
ful. This experience suggests that clinics administering IT must have proce-
dures in place that enable timely establishment of a functioning airway
during life-threatening anaphylaxis. Because many practicing allergists are
inexperienced in performing emergency endotracheal intubation, alternative
approaches, such as laryngeal mask airways (LMAs) or cricothyroidotomy,
may be required to maintain oxygenation.
Preventative measures to reduce immunotherapy-induced

life-threatening anaphylaxis
Recommendations have been proposed in the Joint Council of Allergy,
Asthma, and Immunology practice parameters (PPs) (2003) aimed at pre-
venting severe IT-related anaphylactic reactions and to ensure optimal man-
agement of such reactions [4]. These and other PP recommendations to
reduce the risk of systemic anaphylactic reactions to IT injections are listed
in Box 1. It should be emphasized that these recommendations are largely
based on expert opinion and that scientific evidence is often lacking. The
most recent PPs state that ‘‘Medical conditions that reduce the patient’s
ability to survive a systemic reaction are relative contraindications for aller-
gen immunotherapy’’ [4]. Examples include severe asthma uncontrolled by
pharmacotherapy and significant cardiovascular disease (summary state-
ment 15). This document also acknowledges that there is reasonable evi-
dence (category C) to indicate that patients with severe poorly controlled
asthma are at greater risk for systemic reactions to allergen IT injections
(summary statement 18). In patients with previous systemic reaction(s) to
an injection, the PPs state that ‘‘the dose of vaccine should be appropriately
reduced’’ (summary statement 38). Patients who previously experienced
a systemic reaction that begin more than 30 minutes after an injection
may need to be observed for longer than 30 minutes in the physician’s office
and trained on the use of self-injectable epinephrine.
According to the practice parameter on IT, allergen IT should be admin-
istered ‘‘in a setting where procedures that can reduce the risk of anaphy-
laxis are in place and where the prompt recognition and treatment of
anaphylaxis is assured.’’ The PPs recommend that the office of the physician
Box 1. Actions to reduce the risk of anaphylaxis

1. Assess a patient’s general medical condition at the time of
injection (eg, asthma exacerbation).
2. Adjust vaccine dose or injection frequency if symptoms of
anaphylaxis occur and IT is continued.
3. Use appropriately diluted initial vaccines in patients who seem
to have increased sensitivity on the basis of history or tests for
specific IgE antibodies.
4. Instruct patients to wait in the physician’s office for 20 to
30 minutes after an IT injection. Patients at greater risk of
reaction from allergen IT (eg, patients with increased
allergen sensitivity or those who have previously had
a systemic reaction) may need to wait longer.
5. Carefully evaluate any patient with a late reaction (ie, local or
systemic reaction more than 30 minutes after the IT injection).
6. Institute procedures to avoid clerical or nursing errors (eg,
careful checking of patient identification).
7. Recognize that dosage adjustments are usually necessary
with a newly prepared vaccine or a patient who has had
a significant interruption in the IT schedule.
8. Ensure that adequate equipment and medications are
immediately available to treat anaphylaxis, including (1)
a stethoscope, (2) a sphygmomanometer, (3) tourniquets,
(4) syringes, (5) hypodermic needles, (6) large-bore (14-gauge)
needles, (7) epinephrine at a ratio of 1:1000, (8) oxygen,
(9) equipment for administering intravenous fluids, (10)
equipment for establishing an airway, (11) antihistamine for
injection, (12) corticosteroid for intravenous injection, and (13)
vasopressor.
Adapted from Joint Council on Allergy, Asthma, and Immunology. Allergen

immunotherapy: a practice parameter. Ann Allergy Asthma Immunol 2003;90:
1–40; with permission.
who prepared the patient’s vaccine be the preferred location for the admin-
istration of allergen IT (summary statements 48–50), especially in patients
considered to be at high risk of systemic reactions, and that injections be ad-
ministered under the supervision of appropriately trained physicians and
personnel. The PPs further recommend that injections ‘‘not be administered
at home because of the risk of inadequate recognition and treatment of sys-
temic reactions.’’ A 20- to 30-minute observation period in the physician’s
office is recommended based on evidence that most severe anaphylactic re-
actions begin 20 to 30 minutes after injections.
The authors of the most recent AAAAI survey have suggested similar
and additional specific measures for preventing IT-related anaphylaxis
based on their review of FRs and NFRs (Table 1) [27,28]. Because asthma
represents the highest risk determinant, withholding IT injections is sug-
gested in patients with moderate or severe airway obstruction and in those
whose asthma is not optimally controlled. Patients should be assessed for
worsening asthma by evaluating symptoms and lung function (peak expira-
tory flow rate [PEFR] ) before each injection. Because there is limited benefit
and greater risk in asthmatic patients with FEV1 values less than 70%, risk
and benefit must be considered carefully in individual patients before initi-
ation of IT. Because suboptimal epinephrine dosing was a common feature
in fatal IT reactions, physicians supervising IT administration must adhere
to published anaphylaxis guidelines that recommend adequate and timely
dosing with intramuscular epinephrine (see Table 1). As already mentioned,
because of difficulties in establishing airways in fatal reactors, clinical staff in
a clinic administering IT must be prepared to establish and maintain an
Table 1
Selected findings of immunotherapy surveys with authors’ suggested recommendations for re-
ducing anaphylaxis caused by injection immunotherapy
Study findings Suggested recommendations
Asthma symptoms not optimally Consider risk versus benefit before initiating IT
controlled and pretreatment FEV1 Withhold IT if asthma is not well controlled
!70% predicted Assess asthma and PEFR before injections
FRs at home or in unsupervised Administer IT in fully equipped clinic by trained
clinics personnel and never at home
Inadequate epinephrine dosing Administer epinephrine at a ratio of 1:1000 IM at
a dose of 0.3–0.5 mg; repeat if needed
If no response to IM dosing, give 1:10,000
epinephrine IV infusion
Difficulty in establishing an airway Clinical staff must be prepared to establish and
maintain an airway when necessary
Prior systemic reactions Reduce subsequent immunotherapy doses
Dispense self-injectable emergency epinephrine to all
patients who continue IT
Consider discontinuation in high-risk patients
Patients depart prematurely from All patients should be required to wait 30 minutes in
clinic after injections a medically supervised setting after IT injections
Dosing errors were implicated in 25% Prevent dosing errors by educating clinic staff
of NFRs Give injections from patient-specific vials
Use standardized forms and protocols
Routinely check patient identity (eg, name, birth
date) before each injection
Same staff person that prepares IT injection should
administer
Allow only one patient at a time in the injection room
Abbreviations: FEV1, forced expiratory volume in 1 second; FR, fatal reaction; IM, intra-
muscular; IT, immunotherapy; IV, intravenous; NFR, nonfatal reaction.
Adapted from Refs. [27,28,41].
airway when necessary (eg, cricothyroidotomy). Finally, because of the re-

cently recognized high prevalence of dosing (errors) associated with systemic
reactions, several preventative measures are advocated, including education
of clinic staff, administration of injections from patient-specific vials, routine
checks of patient identifiers (eg, birth date) before each injection, adminis-
tration by the same staff person who prepares the injection, and allowing
only one patient at a time in the injection room [41].
References
[1] von Hertzen L, Haahtela T. Disconnection of man and the soil: reason for the asthma and
atopy epidemic? J Allergy Clin Immunol 2006;117:334–44.
[2] Linneberg A. Changes in atopy over 25 years: allergy epidemic has spread to old age. BMJ
2005;331:352.
[3] Finegold I. Immunotherapy historical perspective. Ann Allergy Asthma Immunol 2001;87:3–4.
[4] Joint Council on Allergy, Asthma, and Immunology. Allergen immunotherapy: a practice
parameter. Ann Allergy Asthma Immunol 2003;90:1–40.
[5] Dolz I, Martinez-Cocera C, Bartolome JM, et al. A double-blind, placebo-controlled study
of immunotherapy with grass-pollen extract Alutard SQ during a 3-year period with initial
rush immunotherapy. Allergy 1996;51:489–500.
[6] Ross RN, Nelson HS, Finegold I. Effectiveness of specific immunotherapy in the treatment
of allergic rhinitis: an analysis of randomized, prospective, single- or double-blind, placebo-
controlled studies. Clin Ther 2000;22:342–50.
[7] Abramson M, Puy R, Weiner J. Allergen immunotherapy for asthma. Cochrane Database
Syst Rev 2003;4:CD001186.
[8] Golden DB, Valentine MD, Kagey-Sobotka A, et al. Regimens of Hymenoptera venom
immunotherapy. Ann Intern Med 1980;92:620–4.
[9] Golden DB, Kagey-Sobotka A, Valentine MD, Lichtenstein LM. Dose dependence of
Hymenoptera venom immunotherapy. J Allergy Clin Immunol 1981;67:370–4.
[10] Moffitt JE, Golden DB, Reisman RE, et al. Stinging insect hypersensitivity: a practice
parameter update. J Allergy Clin Immunol 2004;114:869–86.
[11] Cooke R, van der Veer A. Human sensitization. J Immunol 1916;1:201–9.
[12] Cooke R. Studies in specific hypersensitiveness. III. On constitutional reactions. J Immunol
1922;7:119.
[13] Boughton T. Anaphylactic death in asthmatics. JAMA 1919;1912.
[14] Lamson RW. Sudden death associated with the injection of foreign substances. JAMA 1924;
82:1091–8.
[15] Waldbott GL. The prevention of anaphylactic shock. JAMA 1932;98:446–8.
[16] Vanarsdel PP Jr, Sherman WB. The risk of inducing constitutional reactions in allergic
patients. J Allergy 1957;28:251–61.
[17] James LP Jr, Austen KF. Fatal systemic anaphylaxis in man. N Engl J Med 1964;270:
597–603.
[18] CSM update: desensitising vaccines. Br Med J (Clin Res Ed) 1986;293:948.
[19] Frew AJ. Injection immunotherapy. British Society for Allergy and Clinical Immunology
Working Party. BMJ 1993;307:919–23.
[20] Adverse reactions to allergen immunotherapy. Clin Exp Allergy 1993;23(Suppl 3):32–5.
[21] Greenberg MA, Kaufman CR, Gonzalez GE, et al. Late and immediate systemic-allergic
reactions to inhalant allergen immunotherapy. J Allergy Clin Immunol 1986;77:865–70.
[22] Ewan PW, Alexander MM, Snape C, et al. Effective hyposensitization in allergic rhinitis us-
ing a potent partially purified extract of house dust mite. Clin Allergy 1988;18:501–8.
[23] Bousquet J, Hejjaoui A, Dhivert H, et al. Immunotherapy with a standardized Dermatopha-

goides pteronyssinus extract. Systemic reactions during the rush protocol in patients suffer-
ing from asthma. J Allergy Clin Immunol 1989;83:797–802.
[24] Hejjaoui A, Dhivert H, Michel FB, et al. Immunotherapy with a standardized Dermatopha-
goides pteronyssinus extract. IV. Systemic reactions according to the immunotherapy sched-
ule. J Allergy Clin Immunol 1990;85:473–9.
[25] Lockey RF, Benedict LM, Turkeltaub PC, et al. Fatalities from immunotherapy (IT) and
skin testing (ST). J Allergy Clin Immunol 1987;79:660–77.
[26] Reid MJ, Lockey RF, Turkeltaub PC, et al. Survey of fatalities from skin testing and immu-
notherapy 1985–1989. J Allergy Clin Immunol 1993;92:6–15.
[27] Bernstein DI, Wanner M, Borish L, et al. Twelve-year survey of fatal reactions to allergen
injections and skin testing: 1990-2001. J Allergy Clin Immunol 2004;113:1129–36.
[28] Amin HS, Liss GM, Bernstein DI. Evaluation of near-fatal reactions to allergen immuno-
therapy injections. J Allergy Clin Immunol 2006;117:169–75.
[29] Position paper: immunotherapy. (EAACI) The European Academy of Allergology and Clin-
ical Immunology. Allergy 1993;48:7–35.
[30] Tinkelman DG, Cole WQ 3rd, Tunno J. Immunotherapy: a one-year prospective study to
evaluate risk factors of systemic reactions. J Allergy Clin Immunol 1995;95:8–14.
[31] Nettis E, Giordano D, Pannofino A, et al. Safety of inhalant allergen immunotherapy with
mass units-standardized extracts. Clin Exp Allergy 2002;32:1745–9.
[32] Sampson HA, Mendelson L, Rosen JP. Fatal and near-fatal anaphylactic reactions to food
in children and adolescents. N Engl J Med 1992;327:380–4.
[33] Muller UR, Haeberli G. Use of beta-blockers during immunotherapy for Hymenoptera
venom allergy. J Allergy Clin Immunol 2005;115:606–10.
[34] Hepner MJ, Ownby DR, Anderson JA, et al. Risk of systemic reactions in patients taking
beta-blocker drugs receiving allergen immunotherapy injections. J Allergy Clin Immunol
1990;86:407–11.
[35] Forfang K, Simonsen S. Effects of atenolol and pindolol on the hypokalaemic and cardio-
vascular responses to adrenaline infusion. Eur J Clin Pharmacol 1989;37:23–7.
[36] Simons FE, Roberts JR, Gu X, et al. Epinephrine absorption in children with a history of
anaphylaxis. J Allergy Clin Immunol 1998;101:33–7.
[37] Tunon-de-Lara JM, Villanueva P, Marcos M, et al. ACE inhibitors and anaphylactoid reac-
tions during venom immunotherapy. Lancet 1992;340:908.
[38] Kelso JM. The rate of systemic reactions to immunotherapy injections is the same whether or
not the dose is reduced after a local reaction. Ann Allergy Asthma Immunol 2004;92:225–7.
[39] Tankersley MS, Butler KK, Butler WK, Goetz DW. Local reactions during allergen immu-
notherapy do not require dose adjustment. J Allergy Clin Immunol 2000;106:840–3.
[40] Committe on Safety of Medicines. CSM update. Desensitising vaccines: new advice. Current
Problems in Pharmacovigilance 1994;20:5.
[41] Aaronson DW, Gandhi TK. Incorrect allergy injections: allergists’ experiences and recom-
mendations for prevention. J Allergy Clin Immunol 2004;113:1117–21.
[42] Vervloet D, Khairallah E, Arnaud A, et al. A prospective national study of the safety of
immunotherapy. Clin Allergy 1980;10:59–64.
[43] Winther L, Arnved J, Malling HJ, et al. Side-effects of allergen-specific immunotherapy:
a prospective multi-centre study. Clin Exp Allergy 2006;36:254–60.
[44] Simons FE. Apparent lack of response to epinephrine in anaphylaxis. J Allergy Clin Immu-
nol 2005;115:640 [author reply-1].
[45] Simons FE, Gu X, Simons KJ. Epinephrine absorption in adults: intramuscular versus
subcutaneous injection. J Allergy Clin Immunol 2001;108:871–3.
27 (2007) 309–326
Biphasic Anaphylaxis: Review

of Incidence, Clinical Predictors,
and Observation Recommendations
John W. Tole, DOa,*, Phil Lieberman, MDb
a
Department of Internal Medicine, University of Tennessee Health Science Center,
842 Jefferson Avenue, Suite A601, Memphis, TN 38103, USA
b
Division of Allergy and Immunology, Departments of Medicine and Pediatrics,
University of Tennessee College of Medicine, 7205 Wolf River Boulevard,
Suite 200, Germantown, TN 38138, USA
Historical review
In 1902, Portier and Richet [1] attempted prophylaxis by means of immuni-
zation of dogs to sea anemone venom. The sensitized dogs had fatal reactions
to subsequent nonlethal doses of the venom, however. This unexpected ad-
verse outcome was termed by Portier and Richet [1] as anaphylaxis. Although
a biphasic anaphylactic reaction was described by Duke [2] in 1925 and in two
textbooks published in 1983 [3,4], it was Popa and Lerner [5] who described the
first case reports in 1984 and coined the term biphasic anaphylaxis.
In the early to mid-1970s, Dolovich and his coworkers [6,7] and Solley and
colleagues [8] illustrated that late-occurring skin reactions appearing after the
resolution of the immediate response may be associated with IgE. This chal-
lenged the prior concept that such late-occurring cutaneous reactions were at-
tributable to IgG or complement. These investigations radically influenced the
concept of immediate hypersensitivity and spurred interest in the late-phase
response, ultimately altering our approach to allergic respiratory tract disease.
Yet, not until the report by Popa and Lerner [5] did we appreciate that the
pathophysiology of anaphylaxis may be expressed as a biphasic response.
Clinical characteristics of the biphasic response

There have been several biphasic anaphylactic reaction studies and case
reports [9–26]. These evaluations are summarized in Table 1.
E-mail address: jtole@utmem.edu (J.W. Tole).
310
Table 1
Biphasic anaphylaxis studies
Time (hours) to
Subjects Incidence of onset of second
with biphasic response after Original
Type of biphasic reactions in Age range Route of resolution of authors’
Reference study response study (%) (years) Gender administration primary reaction Fatalities comments Observations
Popa and 3 N/A 22–52 3 male, 0 oral, 3.5–4 0 Observe individuals The authors coined the term
Lerner, 0 female 3 parenteral with anaphylaxis biphasic anaphylaxis.
1984 [5] for 24 hours All their cases were
regardless of considered by the
therapy with authors to be mild.
corticosteroids. All their cases were IgE
mediated.
Stark and Prospective 5 20% 21–67 2 male, 3 oral, 1–8 0a The authors The presence of laryngeal
TOLE & LIEBERMAN

Sullivan, analysis of 3 female 2 parenteral observed that in edema in the early
1986 [26] emergency subjects with response may predispose
department biphasic to a late-phase response.
visits and responses, there Treatment with
hospitalizations was a relatively corticosteroids was not
delayed time of helpful in preventing
onset of the a late-phase response.
primary response One of the five subjects with
relative to antigen biphasic reactions had
exposure. They an anaphylactoid rather
therefore than an anaphylactic
questioned response. This patient
whether a 30- received radiocontrast.
minute waiting A delay of 30 minutes or
period after more after antigen
administration of exposure before onset of
antigen is the early phase seemed
sufficient.They to predispose to a late-
recommended an phase reaction. The
observation presence of severe
period ‘‘several respiratory or
hours after cardiovascular
apparent symptoms (hypotension)
recovery.’’ in the initial response
was not predictive of the
occurrence of a late-
phase reaction.
Douglas et al, Retrospective 6 5% in outpatient 7–77 4 male, 4 oral, 1–72 0 The authors The severity of the second
1994 [9] analysis of clinic, 7% 2 female 2 parenteral observed that reaction could be equal
records from hospitalized; their incidence of to, less than, or greater
the outpatient 5.8% overall biphasic reactions than the initial reaction.
immunotherapy incidence was significantly There was a suggestion that
patients and lower than that corticosteroids might be
records of previously beneficial in preventing
admissions to reported by Stark or reducing the severity
the emergency and Sullivan [26]. of the late response.
department and There was a suggestion that
hospital for the absence of
anaphylaxis hypotension during the
initial response might
indicate that a late-phase
response would be less
BIPHASIC ANAPHYLACTIC REACTIONS

likely to occur.
Brady et al, Retrospective 2 3% 19–21 1 male, 0 oral, 26–40 0 Recurrent (biphasic) Both patients with recurrent
1997 [11] analysis 1 female 2 parenteral responses were reactions had
considered rare hymenoptera stings and
and non-life falls in blood pressure as
threatening, well as angioedema.
manifested only Both were treated with
by urticaria in corticosteroids,
their patient epinephrine, and
population. antihistamines.
Brazil and Retrospective 6 18% 16–81 NG 3 oral, 4.5–29.5 0 Because of the Although there was no
MacNamara, review 3 parenteral delay of 29.5 clinical manifestation
1998 [13] hours before the that distinguished those
onset of the patients with biphasic
second response, reactions from those
the authors stated patients with a uniphasic
that all patients response, the authors
requiring found that patients
adrenaline to experiencing biphasic
control an reactions required larger
anaphylactic doses of epinephrine to
reaction should ameliorate the initial
be admitted for response.
observation for at
least 24 hours.
(continued on next page)
311
Table 1 (continued )
312
Time (hours) to
Subjects Incidence of onset of second
with biphasic response after Original
Type of biphasic reactions in Age range Route of resolution of authors’
Reference study response study (%) (years) Gender administration primary reaction Fatalities comments Observations
Lee and Retrospective 6 6% 1–11 3 male, 4 oral, 1.3–28.4 0 A delay in As opposed to the studies
Greenes, analysis of 3 female 2 parenteral administration of by Douglas and
2000 [10] admissions for epinephrine colleagues [9] and Stark
anaphylaxis might predispose and Sullivan [26], there
to a biphasic were no distinguishing
response.Two signs or symptoms that
percent of allowed one to predict
anaphylactic whether or not
episodes in their a biphasic response
study would have might occur in regard to
benefited from an the incidence or severity
observation of respiratory or
TOLE & LIEBERMAN

period of 24 cardiovascular
hours. manifestations.
Forrest-Hay Retrospective 9 9% NG NG NG 8 of 9 reactions 0 Because most The authors, unlike in the
et al, 2003 analysis within 6 hours, patients other studies, were
[14] 1 patient had experience unable to detect any
a second a biphasic difference between those
reaction response within 8 patients experiencing
occurring hours of the biphasic versus
at 35 hours resolution of the uniphasic reactions. This
initial phase, an was true for the time of
8-hour onset of treatment, the
observation treatment given, the
period was severity of the episode,
recommended. and the original clinical
manifestations.
Ellis and Day, Prospective 20 19.4% 11 months 11 male, 7 oral, 2–38 (average 0 A decrease in This incidence is almost
2004 [12] review of to 79 years 9 female 7 parenteral, time ¼ 10 epinephrine total identical to that
emergency 5 idiopathic, hours) dose (not described by Stark and
department 1 inhalation incidence of Sullivan [26].
visits and administration)
admissions was associated
with a biphasic
response. In
addition,
a decrease in total
dose and
frequency of
administration of
corticosteroids
was also
BIPHASIC ANAPHYLACTIC REACTIONS

associated with
this response.
Smit et al, Retrospective 15 5.3% 6–80 10 male, 9 oral, 1.2–22.5 0 The authors The authors observed that
2005 [15] analysis (median ¼ 5 female 1 parenteral, (mean ¼ 7.6) suggested that the mean time from
33) 3 not a ‘‘reasonable onset to presentation
documented, approach would was 3 times longer in
2 unknown be to observe biphasic than in
those who uniphasic patients.
received
epinephrine and
remain stable for
24 hours, and to
observe all other
patients for 12
hours.’’
Abbreviations: N/A, not applicable; NG, not given.

a
The authors commented that one of the patients ‘‘almost certainly would have died if he had not been under observation when his airway obstruction
reoccurred.’’
313
314 TOLE & LIEBERMAN
Popa and Lerner [5] reported three patients who developed systemic ana-
phylactic symptoms after exposure to rabies vaccine, rye grass extract im-
munotherapy, or yellow jacket sting. These patients were treated and had
improved until 3.5 to 4 hours later, when they redeveloped their anaphylac-
tic symptoms.
The first prospective evaluation of biphasic anaphylactic reactions was by
Stark and Sullivan [26], who reported anaphylactic episodes in 25 patients
presenting to an emergency department. Five (20%) of these subjects ex-
hibited a biphasic reaction, which the authors noted to be two episodes of
hypotension or laryngeal edema separated by an asymptomatic interval.
This asymptomatic interval after resolution of the initial episode until the
onset of the biphasic reaction was 1 to 8 hours. One of these five subjects
actually had a biphasic anaphylactoid reaction to radiocontrast rather
than an IgE-mediated biphasic anaphylactic reaction. Stark and Sullivan
[26] observed that recurrent or prolonged reactions were more likely to oc-
cur (2.8-fold) if the offending agent had been ingested or if the onset of the
original reaction was 30 minutes or more after exposure to the offending
agent. It was also noted that these reactions were more likely if laryngeal
edema was present during the first phase. Neither the severity of the initial
reaction nor the treatment administered seemed to correlate with the devel-
opment of a biphasic response. In their patients, as in those reported by
Popa and Lerner [5], corticosteroids did not seem to prevent or ameliorate
the biphasic reaction. Neither the presence of severe respiratory symptoms
nor that of cardiovascular manifestations, specifically hypotension, in the
initial episode was predictive of the occurrence of a late-phase reaction.
Stark and Sullivan [26] thought that the most salient points derived from
their study were that serious life-threatening manifestations could recur in
patients after successful treatment of the initial response and that these
events could develop anywhere from 1 to 8 hours after apparent remission
of the initial manifestations. They also concluded that such biphasic re-
sponses could be reasonably common, occurring in 20% of their series.
They thus made the suggestion that ‘‘until methods are developed to predict
or avoid late-phase anaphylactic reactions, all patients should be observed
for several hours after apparent recovery from acute anaphylaxis’’ [26].
The next study of biphasic anaphylactic events was by Douglas and col-
leagues [9]. The authors used two venues: an outpatient allergy clinic, where
patients received immunotherapy, and the Madigan Army Medical Center,
where patients had been admitted for anaphylaxis. The patients in the al-
lergy clinic were retrospectively analyzed between the years 1988 and
1991, and the inpatient subjects were retrospectively analyzed between
1986 and 1992. Two (5%) of the 35 patients in the allergy clinic who expe-
rienced anaphylaxis to immunotherapy developed a biphasic reaction. Four
(7%) of the 59 subjects admitted to the hospital with anaphylaxis developed
a biphasic response. Thus, there was an overall incidence of biphasic re-
sponses of approximately 5.8. All the patients admitted to the hospital
BIPHASIC ANAPHYLACTIC REACTIONS 315
had received allergen by means of the oral route (2 to b-lactam antibiotics

and 2 to shrimp). In their study, the biphasic response could be less severe,
similar to, or more severe than the original response. There were no fatali-
ties. In contrast to the study by Stark and Sullivan [26], there was a sugges-
tion that corticosteroids might be effective in minimizing the biphasic
manifestations or preventing such a response. Although there were no
clear-cut distinguishing features between those subjects with a biphasic re-
sponse and those with only a uniphasic reaction, the absence of hypotension
seemed to favor a uniphasic event. Douglas and colleagues [9] reported a sig-
nificantly lower incidence of biphasic reactions than did Stark and Sullivan
[26]. There was no clear explanation for this, but they postulated that, at
least within the inpatient group, ‘‘early intervention.with high dose corti-
costeroids may have played a role in decreasing the biphasic reaction rate’’
[9].
The first and only study to date specifically designed to evaluate the in-
cidence and nature of biphasic reactions in children was reported by Lee
and Greenes [10], who retrospectively analyzed the charts of 108 children
with anaphylaxis admitted to a children’s hospital between 1985 and
1999. Of these 108 episodes, 2 were fatal and 1 was protracted. The remain-
ing 105 cases showed resolution of the initial anaphylactic manifestations.
Six (6%) of these patients experienced biphasic reactions after an asymp-
tomatic interval ranging from 1.3 to 28.4 hours. Of the biphasic anaphylac-
tic cases, 4 were attributed to orally administered antigens (dicloxacillin,
trimethoprim-sulfamethoxazole, fish, and nuts) and 2 were caused by bee
stings. Each child experienced similar symptoms. All but 1 child had cutane-
ous manifestations, most had wheezing and shortness of breath, and some
had abdominal pain. Hypotension occurred in 1 child. As observed by the
authors, a notable finding is that a delay in epinephrine administration pre-
disposed to a biphasic response. The median time from the onset of initial
symptoms to the administration of epinephrine in those subjects experienc-
ing a biphasic reaction was 190 minutes versus only 48 minutes for those
with a uniphasic episode. There were no significant differences in the fre-
quency of epinephrine administration, corticosteroid use, or serious cardio-
vascular or respiratory symptoms between those children experiencing
biphasic versus uniphasic events. There were no fatalities. The incidence
in their report was similar to the 5.8% reported by Douglas and colleagues
[9] but lower than the 20% reported by Stark and Sullivan [26]. Further-
more, the authors noted in their series that ‘‘approximately 2% of patients
with anaphylaxis appeared to benefit substantially from a 24-hour period of
observation after symptoms had resolved’’ [10].
Brady and colleagues [11] performed a retrospective analysis of patients
seen in a university hospital emergency department between July 1991 and
December 1995. Their study differed from previous evaluations in that
they also searched for recurrences of anaphylactic symptoms after discharge
when individuals presented a second time to the same primary treatment
hospital or to any other hospital within a 75 mile radius of the primary in-
stitution within a 7-day period. Of the 67 patients with anaphylaxis who pre-
sented to their emergency department, 2 (3%) experienced a biphasic
response 26 and 40 hours after resolution of the initial reaction. Both pa-
tients initially presented with angioedema and falls in blood pressure after
exposure to hymenoptera stings and were treated with corticosteroids, epi-
nephrine, and antihistamines. The biphasic reactions were mild, limited to
urticaria. Neither patient required additional treatment or admission. The
authors concluded that ‘‘recurrent anaphylactic reactions were rare, occur-
ring in only 3% of cases and without life threat in this patient population’’
[11].
Ellis and Day [12] reported a prospective evaluation of emergency depart-
ment visits and inpatient admissions identifying 134 patients with anaphy-
laxis over a 3-year period, of whom 103 were available for follow-up.
Twenty patients (19.4%) had biphasic reactions occur from 2 to 38 hours
after resolution of the first reaction. Eight of those who experienced biphasic
anaphylaxis (40%) had their second-phase reaction occurring more than 10
hours after resolution of the initial symptoms. The symptoms of those expe-
riencing a second phase were similar to the symptoms of those who had only
a uniphasic response. The second phase could be milder than, similar to, or
more severe than the initial event. All subjects with second-phase responses
had cutaneous symptoms. This 19.4% incidence was similar to that found
by Stark and Sullivan [26]. Ellis and Day [12] found that patients with bi-
phasic reactions could be distinguished from those with uniphasic reactions
in that the mean time of resolution of the initial event was 133 minutes in the
biphasic group versus 112 minutes in the uniphasic group. Also, the authors
noted that those experiencing biphasic reactions tended to have initial reac-
tions that lasted longer, were given less epinephrine, and tended to receive
less corticosteroids.
Brazil and MacNamara [13] retrospectively analyzed 34 patients with
anaphylaxis admitted to a hospital. Six (18%) of these patients had biphasic
reactions occurring 4.5 to 29.5 hours after resolution of initial symptoms.
These investigators were unable to find any clinical features on initial pre-
sentation that distinguished these patients from those with uniphasic events.
Nevertheless, the authors observed that patients with biphasic reactions did
require more epinephrine to ameliorate the symptoms of their early re-
sponse; thus, they suggested that this increased requirement for epinephrine
might be considered a marker for patients subject to development of a bi-
phasic response. Because of the delay of 29.5 hours in 1 patient, the authors
stated that ‘‘all patients requiring adrenaline to control an anaphylactic re-
action should be admitted for observation for at least 24 hours’’ [13].
Forest-Hay and colleagues [14] reported a retrospective review of 103
anaphylactic events in 91 patients admitted to an emergency department
in the United Kingdom. There were nine biphasic reactions. Eight of these
occurred within 6 hours of resolution of the first reaction. The authors noted
that one of the biphasic reactions occurred as late as 35 hours after resolu-
tion of the first reaction, however. There were no distinguishing features be-
tween uniphasic and biphasic events in regard to presenting symptoms or
signs, treatments, or time to onset of therapy. Only 1 patient had a more se-
vere biphasic reaction than the initial reaction. The authors concluded that
most biphasic responses occur within 8 hours of resolution of the initial re-
sponse and that little was gained by a 24-hour waiting period. They sug-
gested discharge, after successful response to treatment, in 8 hours.
The most recently published retrospective review, and the largest study to
date reporting on biphasic anaphylaxis, was done by Smit and colleagues
[15], who evaluated 282 patients with anaphylaxis who presented to the
Prince of Wales Hospital Emergency Department in Hong Kong between
March 1999 and February 2003. Additionally, the authors searched for pre-
sentation of these patients to other hospitals in the Hong Kong area within
a 5-day period after discharge from the primary site. Fifteen (5.3%) of these
282 patients developed biphasic anaphylaxis. This study differed slightly
from most previous evaluations in that it recorded the duration of time
from treatment to onset of biphasic response rather than from resolution
of initial symptoms to onset of biphasic response. Nevertheless, mean
time until the development of biphasic symptoms was 7.6 hours, with a range
of 1.2 to 22.5 hours. Cutaneous manifestations were the most common ini-
tial complaint, whereas respiratory features were much less common. Over-
all, 12 of the 15 biphasic reactions were mild and had similar clinical
manifestations as the initial reaction. Of the remaining 3 patients, who
had stable vital signs on presentation, 2 developed hypotension and 1 expe-
rienced dyspnea with oxygen saturation of 92%. There were no fatalities in
this study. Of interest, one of the statistically significant features in the bi-
phasic group is that the mean time from onset to presentation was 3 hours
for biphasic patients versus 1 hour for uniphasic patients. Patients who went
on to develop biphasic reactions experienced less common and pronounced
respiratory features; specifically, 35% of biphasic patients complained of
dyspnea versus 77% of those with uniphasic anaphylaxis. The authors re-
ported that 4 of the biphasic patients had their reaction beyond 8 hours after
treatment, including the individual with decreased oxygen saturation, which
occurred 12 hours after treatment, yet all biphasic reactions occurred within
23 hours from time of treatment. Therefore, the authors concluded that ‘‘a
reasonable approach would be to observe those who received epinephrine
and remain stable for 24 hours, and to observe all other patients for 12
hours’’ [15].
Most of the articles described previously were specifically designed to as-
sess, in a retrospective or prospective manner, the incidence and clinical
characteristics of biphasic anaphylaxis. Although not designed specifically
to evaluate the biphasic response, some insight into the biphasic reaction
may be gleaned from case reports [16–20] and series of anaphylactic cases
that note biphasic reactions [21,22].
Brady and colleagues [16] reported a case of an elderly man on a b-adren-

ergic blocker who experienced the relatively benign initial anaphylactic man-
ifestations of diffuse pruritus, dizziness, dyspnea, and facial swelling
‘‘occurring after an encounter with an unidentified flying insect.’’ After
self-administering diphenhydramine (25 mg) orally, the patient placed a tele-
phone call to ‘‘911.’’ The paramedics arrived a short time later to find an
elderly man with a complaint of profuse itching, but without any obvious
distress. Vital signs revealed a blood pressure of 102 mm Hg by palpation,
pulse of 82 beats per minute, and respiratory rate of 16 breaths per minute.
The man had urticaria and facial edema. An intravenous line was placed,
diphenhydramine was administered, and the man was transported to the
emergency department. During the 45 minutes it took to arrive at the emer-
gency department, the symptoms resolved and he had no complaint. Vital
signs on presentation were a blood pressure of 110/70 mm Hg and a pulse
of 80 beats per minute. Shortly after arrival, however, he became lethargic,
with a blood pressure of 78/40 mm Hg, a pulse rate of 70 beats per minute,
and a respiratory rate of 28 breaths per minute. Urticarial lesions reap-
peared. He was treated with epinephrine, corticosteroids, and antihistamines
and then admitted to the hospital for a period of 36 hours. In contrast to
their series of anaphylaxis in predominantly younger patients without signif-
icant medical problems in which the second response was mild, Brady and
colleagues [11] attributed this patient’s more severe reaction to his previous
cardiovascular status, the use of a beta-blocker, and his age. They thus con-
cluded that the factors of previous cardiovascular disease, the use of a beta-
blocker, and advanced age might predispose one to the potential occurrence
of a severe biphasic response.
Some of these factors were also present in the report by Cortellini and
colleagues [17] of a 76-year-old atopic man with history of large local reac-
tions to insect stings, ischemic cardiomyopathy, and hypertension treated
with a calcium channel blocker. The patient experienced urticaria, erythema,
and hypotension of 90/60 mm Hg approximately 10 minutes after 15 vespid
stings. The patient was seen at his home 30 minutes later by an emergency
doctor, who found the patient with urticaria and erythema of the back and
neck. Nevertheless, the patient had unaffected respiratory function, and vital
signs were blood pressure ranging from 120/70 to 130/60 mm Hg and a heart
rate of 74 beats per minute. The patient received parenteral corticosteroid
and antihistamine and was observed for 45 minutes; at that time, his urti-
caria had incompletely subsided. Approximately 40 minutes later, the pa-
tient experienced a recurrence of urticaria and angioedema of the neck
and felt weak. Shortly thereafter, the patient died despite resuscitation at-
tempts by the doctor, who had returned. The authors raise the question
whether administration of epinephrine or a longer observation period would
have benefited this particular patient.
Novembre and colleagues [18] reported the first biphasic anaphylactic re-
action to ketorolac in the case of a 13-year-old girl. She received a second
dose of ketorolac for abdominal pain 8 hours after an initial dose; 30 min-
utes later, she developed urticaria and breathing difficulties. She was treated
in the emergency department 20 minutes later with hydrocortisone and
promethazine, and her symptoms abated within 2 hours. Sixteen hours after
discharge, however, she experienced a recurrence of the urticaria and dysp-
nea as well as abdominal pain and hypotension, with a blood pressure of 88/
46 mm Hg. She received epinephrine, steroid, and antihistamine, with reso-
lution of symptoms. The authors later performed skin prick and intradermal
testing with ketorolac, the results of which were negative. Thus, the authors
noted that in this patient, the reaction to the ketorolac did not seem to be
mediated by IgE.
Brady and Bright [19] reported a case of multiphasic anaphylaxis on
a transcontinental air flight in which the subject experienced a more severe
biphasic response than the initial reaction.
Ellis and Day [20], in addition to their series noted previously, reported
a case of a 14-year-old with a severe biphasic reaction to a hymenoptera
sting. Approximately 20 hours after resolution of the first phase, there
was a recurrence of symptoms. The second event consisted of urticaria, pru-
ritus, angioedema, and respiratory distress severe and persistent enough to
require admission to the pediatric intensive care unit, where the patient
was intensively treated and observed overnight. This case is similar to that
of Brady and Bright [19] in that the second phase was far more severe
than the initial event. It is also of interest because of the long 20-hour
asymptomatic phase between the first and second events.
Samson and colleagues [21] described a series of young subjects, ranging
in age from 2 to 17 years, who experienced near-fatal or fatal anaphylactic
events. Although seeming to improve, 3 of the 13 patients in this series ex-
perienced a biphasic episode.
In a series of 593 patients conducted over several decades, Webb and
colleagues [22] noted the incidence of biphasic reaction in these patients
to be less than 1%. The frequency of biphasic reactions in this study
was determined by patient questionnaire rather than by chart review,
however.
In a study of eight cases of idiopathic anaphylaxis in children, Hogan and
colleagues [23] reported one of these to have a biphasic reaction. This event
occurred in a 15-year-old who had wheezing, angioedema, and hypotension,
and who, as described by the authors, received an ‘‘inadequate amount of
epinephrine and experienced a more severe delayed event 8 hours after suc-
cessful treatment of the initial episode’’ [23].
Based on these studies, the extent of variability concerning biphasic reac-
tions is apparent. The incidence of biphasic anaphylaxis ranges from less
than 1% to 20% of anaphylactic episodes. The time of onset after resolution
of the initial reaction ranges from 1 hour to 78 hours. The severity of the
second response can be less severe, equal in severity, or more severe than
the original response, thus ranging from mild to fatal.
Only two investigations reported fatalities. In a report by Stark and Sul-

livan [26], there were two deaths among 25 patients. The 2 patients who died
did not experience a truly biphasic reaction but rather had protracted
events. In one instance, the patient was taking propanolol, and in the other,
the patient experienced adrenal insufficiency. One patient who died was
a 33-year-old woman who had received cefaclor and died 8 days after the
onset of symptoms. The other was a 50-year-old man who had been given
murine monoclonal anti-T3 antibody and died after 5 hours of treatment
[26]. Samson and colleagues [21] reported six deaths in children and adoles-
cents. Three of the six children and adolescents who died seemed to be im-
proving before the recurrence of terminal cardiorespiratory arrest. These
three had early oral and abdominal symptoms, followed by a relatively
symptom-free period of 1 to 2 hours, and then experienced respiratory
symptoms and a fall in blood pressure.
It would be ideal to predict the occurrence of a biphasic reaction based on
the clinical manifestations of the initial response. No data presented thus far
allow us to do so conclusively; however, we may glean information from
these studies and experiences to obtain some insight. It seems that a delay
in the administration of epinephrine, an inadequate amount of epinephrine
given for the first response, or the requirement of large doses of epinephrine
suggests that a biphasic response is more likely. There is less evidence to sug-
gest that the absence of corticosteroid administration might predispose to
a biphasic response. In some instances, failure to administer corticosteroids
seemed to predispose to such a response; however, in other reports, the ad-
ministration of corticosteroids seemed to make little difference. Although no
definitive conclusion can be made, the data suggest that corticosteroids
might have a beneficial effect in some individuals. Although no dogmatic
conclusions can be drawn from the patient’s history or physical manifesta-
tions of the first event, at least in one case report, the presence of previous
cardiovascular disease, the age of the patient, and the use of beta-blockers
might predispose to recurrence of symptoms after an initial remission. In
one study, a delay in the appearance of symptoms after exposure to antigen
suggested a biphasic response, but it should be noted clearly that biphasic
responses occur when the initial episode takes place within minutes of expo-
sure to antigen. The oral route of administration of antigen seems to be an
important predisposing factor. As noted, however, biphasic responses can
occur after the antigen is administered parenterally or even by inhalation.
Most such episodes have been anaphylactic in nature, but at least in one in-
stance, a biphasic response occurred after an anaphylactoid event. Such re-
actions can also occur in episodes that are idiopathic in nature.
Because of the wide variety of time intervals between the resolution of the
initial event and the reoccurrence of symptoms, it is not possible to establish
a strict observation period that would be practical and still allow for the re-
currence to occur while the patient is under medical observation. It seems,
however, that a 24-hour observation period would benefit only a small
number of patients and that most of the severe reactions occur within a far
shorter period. An 8-hour observation period might thus be sufficient to en-
sure that most severe recurrences would manifest while the patient was still
under medical observation.
No studies have systematically evaluated therapy for the late-phase reac-
tion. In all instances, as best can be gleaned from the literature, therapy for
the late-phase reaction has been similar to that of the first phase and dic-
tated by the manifestations and severity of the second reaction. Epinephrine,
antihistamines, and corticosteroids have been the mainstay of therapy for
the late-phase events, as they have been for the initial events. Because the
fatality rate has been low, it is inferred that standard therapy has been rea-
sonably effective. Therefore, from these observations, it would seem that
standard therapy for anaphylaxis as would be applied to the initial phase
constitutes treatment for the biphasic reaction as well.
The clinical characteristics of the biphasic responses are summarized in
Box 1.
Theories of biphasic pathogenesis

Several potential pathogenic mechanisms have been proposed as listed in
Box 2.
The biphasic response was originally thought to be attributable to a tem-
porarily ablated initial reaction, and therefore the result of insufficient treat-
ment [3–5]. It was later hypothesized that the biphasic anaphylactic
response, like that in the skin and respiratory tract, was the result of the sec-
ondary influx of cells into the site(s) of the reaction [5]. There are several
lines of evidence that mitigate against this possibility, however. Histologic
studies of patients experiencing fatal reactions after protracted events do
not reveal changes similar to those noted in the respiratory tract and skin
after biphasic reactions [24]. The only cell to accumulate in tissues after ana-
phylactic episodes is the eosinophil, and there is often no cellular infiltrate
[24]. Furthermore, the time interval between the first and second phases in
the biphasic anaphylactic reaction is inconsistent with that seen in cutaneous
and respiratory biphasic reactions, which is characteristically between 2 and
8 hours after resolution of the first reaction versus as early as 1 hour and as
late as 78 hours after resolution of the initial event for biphasic anaphylaxis.
It has been speculated that the oral administration of antigen, which
allows for continued antigen absorption, predisposes to biphasic reactions.
A review of the literature, as summarized in Table 1, clearly indicates that
biphasic responses occur not only after oral but after parenteral administra-
tion, however. The thought that oral administration predisposes to
a biphasic response is based on the fact that an offending agent, whether
food or drug, could be continually absorbed through the gastrointestinal
tract for several hours, thus accounting for a dual response. This indeed
Box 1. Biphasic anaphylaxis clinical characteristics

Reported incidence ranges from a minimum of less than 1% to
a maximum of 20%.
Onset of recurrence of symptoms after resolution of the initial
event ranges from 1 to 78 hours.
Most second responses occur within 8 hours after resolution of
the first event.
The second response may be less severe, similar to, or more
severe than the original episode.
Fatalities can occur.
Events can be anaphylactic or anaphylactoid.
There are no consistently reported risk factors, but several
possible features of the initial episode have been mentioned as
predisposing factors for a biphasic reaction. These include the
following:
Oral administration of antigen
Reaction occurring while a patient is taking a beta-blocker
Reaction occurring in an elderly individual with
cardiovascular disease
Delay in onset of more than 30 minutes between the
administration of antigen and the appearance of symptoms
of the first event
Presence of hypotension or laryngeal edema during the
initial event
There is no consensus as to whether therapeutic measures
affect the incidence of a delayed reaction, but some reports
mention treatment differences between patients with uniphasic
and biphasic events. These include the following:
Delay in administration of epinephrine given for the primary
response
Inadequate dose of epinephrine given to treat the primary
reaction
Absence of or too small a dose of corticosteroids given for
the initial event
could be the case, but in view of the fact that parenteral administration can
produce biphasic responses, other mechanisms must be involved. Such
a depo effect, accounting for the biphasic responses attributable to paren-
teral administration, is highly unlikely, because biphasic responses have oc-
curred to agents that have a relatively short half-life, such as radiocontrast.
In addition, in documented cases of prolonged exposure to food resulting in
delayed anaphylactic responses, the episodes are not actually biphasic but
Box 2. Hypotheses of biphasic anaphylaxis pathogenesis

The recurrence of symptoms is not attributable to a true
‘‘biphasic reaction’’ but represents a recurrence of
a temporarily interrupted protracted initial response
attributable to appropriate but perhaps inadequate therapy.
The biphasic response is attributable to the same mechanism
that underlies the biphasic respiratory and cutaneous
responsesdthe recruitment of cells to the site(s) of the original
response, followed by degranulation of these cells and
subsequent secondary release of mediators.
The biphasic response is related simply to the continued
presence of antigen with a ‘‘depo’’ release into the systemic
circulation (eg, as perhaps could occur with prolonged
absorption of an ingested antigen).
The biphasic response is attributable to bimodal synthesis of
late-phase mediators (eg, platelet activating factor) from mast
cells and other cells.
The response may be the result of a biphasic wave of
histamine release from mast cells as a result of the initial
exposure to antigen without subsequent exposure.
The late response is attributable to activation of secondary
inflammatory pathways (eg, complement, clotting, clot lysis)
resulting from mediators released during the initial event.
simply delayed in onset presumably because of delayed absorption, as has

been demonstrated for natto (fermented soybeans) contained in poly g-glu-
tamic acid, a water-soluble biodegradable polymer, which delays and per-
haps prolongs absorption [25].
Investigators have also hypothesized, based on animal models, that bi-
phasic reactions might be attributable to mediators that are synthesized
and released late or recruited after the initial event. For example, in a murine
model [27] of penicillin-induced anaphylaxis, it was found that a late-occur-
ring synthesis of platelet-activating factor was responsible for the late-phase
reaction and that mast cells were not required for this late-phase response.
Of interest, in this model, tumor necrosis factor-a (TNFa) inhibition re-
sulted in ablation of the late-phase response as well as the late increase in
platelet-activating factor. In the investigation by Samson and colleagues
[21] of fatal anaphylactic events, however, there was no elevation of
TNFa in two patients who had experienced food-induced anaphylaxis se-
vere enough to be admitted to the intensive care unit with bronchospasm
and hypotension.
A second murine model [28] has resulted in another postulation as to the

cause of the biphasic response. In this instance, mast cells in the gut under-
went a biphasic degranulation response after a single oral exposure to anti-
gen. Peak periods of mediator release occurred at 30 minutes and 72 hours
after oral challenge. In addition, mast cell degranulation was followed by
the appearance of an inflammatory infiltrate. These observations suggest
that it is possible, when antigen is given orally, for there to be a biphasic
mast cell degranulation response as well as the characteristic inflammatory
response noted in the skin and the respiratory tract, as discussed previously.
In this instance, however, the two-phase mast cell degranulation is some-
what different than in the human respiratory model, in which the second
wave of mediated release is basophil rather than mast cell generated. In ad-
dition, the prolonged time between the first and second waves of degranula-
tion would not account for most biphasic responses, which occur within the
first 8 hours.
It is known that mast cell degranulation can result in the activation of
other inflammatory cascades, such as the complement system and the clot-
ting and clot lysis pathways [24]. During severe anaphylactic episodes in hu-
man patients, falls in complement and evidence for activation of clotting
and clot lysis have been noted [24,29]. Thus, it is plausible that mediator re-
cruitment might account for some episodes, especially those characterized
by severe hypotension and shock.
Potential clinical impact

The most important clinical impact of the observations discussed previ-
ously relates to the suggested waiting period after successful treatment of
an anaphylactic episode. Unfortunately, no definitive conclusion can be
drawn from these data. Several authors have suggested a 24-hour waiting
period, although this would not be necessary for most patients. Ideally, it
would be desirable for there to be definitive clinical criteria identifying those
patients who are at risk for a biphasic response, and would therefore benefit
from a prolonged period of observation. Yet, none of the investigations
have clearly delineated such clinical criteria. It is evident that biphasic reac-
tions can range from mild events not requiring further therapy to fatal
events despite therapy. Thus, at this time, the authors cannot definitively
recommend a standard observation period after resolution of an initial reac-
tion. Some clues gleaned from the literature do suggest a prolonged period
of observation. These include the severity of the first episode, the length of
time between the onset of symptoms and the initiation of therapy, the pro-
vocative agent being ingested, and a previous history of a biphasic response.
These predisposing features have been described inconsistently, however,
and are in no way mandates of a prolonged 24-hour observation period.
Thus, in the absence of any clear-cut criterion for prolonged observation,
it becomes even more desirable to establish a therapy that would
consistently prevent the biphasic reaction. Again, the literature gives us no

solace in this regard, although there are some features related to therapy
that seem to distinguish those who experience biphasic versus uniphasic re-
actions. These include the rapidity of administration of epinephrine after the
initial manifestations appear, the adequacy of the dose of epinephrine at the
time of administration, and the early use of corticosteroids. None of these
has consistently been demonstrated to ablate the second reaction, however.
Although we have made some progress in understanding the biphasic
anaphylactic response since Popa and Lerner’s original article [5], we are
not yet close to being able to predict those who are going to develop a bi-
phasic reaction nor are we close to preventing it. The solutions to these clin-
ical problems await further knowledge of the underlying pathogenesis of the
biphasic anaphylactic response.
References
[1] Portier P, Richet C. De l’action anaphylactique de certains venins. C Roy Soy Biol (Paris)
1902;54:170.
[2] Duke WW. Allergy, asthma, hayfever, and urticaria. New York: CV Mosby; 1925. p. 163.
[3] Bleecker ER, Lichtenstein LM. Systemic anaphylaxis. In: Lichtenstein LM, Fauci AS, edi-
tors. Current therapy in allergy and immunology. Philadelphia: BC Decker Inc.; 1983.
p. 78–83.
[4] Beall GN. Anaphylaxis. In: Beall GN, editor. Allergy and clinical immunology. New York:
Wiley and Sons; 1983. p. 125–43.
[5] Popa VT, Lerner SA. Biphasic systemic anaphylactic reactions: three illustrative cases. Ann
Allergy 1984;53:151–5.
[6] Dolovich J, Little DC. Correlates of skin test reactions to bacillus subtilis enzyme prepara-
tions. J Allergy Clin Immunol 1972;49:43–53.
[7] Dolovich J, Hargrave FE, Chalmers R, et al. Late cutaneous allergic responses in isolated
IgE-dependent reactions. J Allergy Clin Immunol 1973;52:38–46.
[8] Solley GO, Gleich GJ, Jordon RE, et al. The late phase of the immediate wheal and flare skin
reaction. J Clin Invest 1976;58:408–20.
[9] Douglas DM, Sukenick E, Andrade WP, et al. Biphasic systemic anaphylaxis: an inpatient
and outpatient study. J Allergy Clin Immunol 1994;93:977–85.
[10] Lee JM, Greenes DS. Biphasic anaphylactic reactions in pediatrics. Pediatrics 2000;106:
762–6.
[11] Brady WJ Jr, Luber S, Carter CT, et al. Multiphasic anaphylaxis: an uncommon event in the
emergency department. Acad Emerg Med 1997;4(3):193–7.
[12] Ellis AK, Day JH. Incidence and characteristics of biphasic anaphylaxis: a prospective eval-
uation of 103 patients. Ann Allergy Asthma Immunol 2007;98(1):64–9.
[13] Brazil E, MacNamara AF. ‘‘Not so immediate’’ hypersensitivity: the danger of biphasic ana-
phylactic reactions. J Accid Emerg Med 1998;15:252–3.
[14] Forrest-Hay A, Taylor C, Tolchard S. Biphasic anaphylaxis in a UK emergency department.
Presented at Open Paper Presentations of the 2003 Scientific Symposium of the Resuscita-
tion Council of the United Kingdom (abstract).
[15] Smit DV, Cameron PA, Rainer TH. Anaphylaxis presentations to an emergency department
in Hong Kong: incidence and predictors of biphasic reactions. J Emerg Med 2005;28(4):
381–8.
[16] Brady WJ, Luber S, Joyce T. Multiphasic anaphylaxis: report of a case with pre-hospital and
emergency department considerations. J Emerg Med 1997;15:477–81.
[17] Cortellini G, Corvetta A, Campi P, et al. A case of fatal biphasic anaphylaxis secondary to
multiple stings: adrenalin and/or a longer observation time could have saved the patient?
European Annals of Allergy and Clinical Immunology (Paris) 2005;37(9):343–4.
[18] Novembre E, Calogero C, Mori F, et al. Biphasic anaphylactic reaction to ketorolac
tromethamine. Int J Immunopathol Pharmacol 2006;19(2):449–50.
[19] Brady WJ, Bright HL. Occurrence of multiphasic anaphylaxis during a transcontinental air
flight. Am J Emerg Med 1999;17:695–6.
[20] Ellis AK, Day JH. Biphasic anaphylaxis with an unusually late onset second phase: a case
report. Canadian Journal of Allergy and Clinical Immunology 1997;2:106–9.
[21] Samson HA, Mendelson L, Rosen J. Fatal and near fatal anaphylactic reactions to food in
children and adolescents. N Engl J Med 1992;327:380–4.
[22] Webb L, Lieberman P. Anaphylaxis: a review of 601 cases. Ann Allergy Asthma Immunol
2006;97(1):39–43.
[23] Hogan MB, Kelly MA, Wilson N. Idiopathic anaphylaxis in children. Ann Allergy Asthma
Immunol 1998;81:140–2.
[24] Lieberman P. Anaphylaxis and anaphylactoid reactions. In: Middleton E, Adkinson NF,
Yunginger JW, et al, editors. Allergy: principles and practice. 6th edition. St. Louis (MO):
Mosby-Year Book, Inc.; 2003;2:1497–522.
[25] Inomata N, Osuna H, Ikezawa Z. Late onset anaphylaxis to Bacillus nattodfermented
soybeans. J Allergy Clin Immunol 2004;115(5):998–1000.
[26] Stark BJ, Sullivan TJ. Biphasic and protracted anaphylaxis. J Allergy Clin Immunol 1986;78:
76–83.
[27] Choi IW, Kim YS, Kim DK, et al. Platelet-activating factor-mediated NF-kB dependency of
a late anaphylactic reaction. J Exp Med 2003;198:145–51.
[28] Yang PC, Berin MC, Yu L, et al. Mucosal pathophysiology and inflammatory changes in the
late phase of the intestinal allergic reaction in the rat. Am J Pathol 2001;158:681–90.
[29] De Souza RL, Short T, Warman GR, et al. Anaphylaxis with associated fibrinolysis, reversed
with tranexamic acid and demonstrated by thrombelastography. Anaesth Intensive Care
2004;32:580–7.

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Immunol Allergy Clin N Am

Rafeul Alam, MD, PhD

Rafeul Alam, MD, PhD

It could be argued that the ﬁrst description of anaphylaxis spawned the

anesthesiologists who deal with reactions during the perioperative period,

* Corresponding author. EMNet Coordinating Center, Department of Emergency

Box 1. Clinical criteria for diagnosing anaphylaxis

Abbreviation(s): BP, blood pressure; PEF, peak expiratory flow.

measures, the epidemiologic terminology frequently is misused. For exam-

cases. Using a deﬁnition of anaphylaxis of 1 organ system (mucocutaneous,

Network and reported all cases of severe anaphylaxis they treated, 84

participating households (67.3%), representing a total of 14,948 individuals,

Insect sting-induced reactions

Incorvaia and colleagues [31] surveyed factory workers and foresters in

Medication and vaccine-induced reactions

Lenler-Petersen and colleagues [34] performed a retrospective study to

Emergency medical services

Emergency department visits

accurately identifying reactions. Applying the NIAID/FAAN clinical crite-

burden of anaphylaxis. If cases of anaphylaxis occurring in the hospital set-

more likely to categorize even multisystem complaints as either acute aller-

The Pathophysiology of Shock

In one large study of deaths due to anaphylaxis, circulatory shock was

E-mail address: simon.brown@uwa.edu.au

Box 1. Determinants of blood pressure and cardiac output

SVR is determined by the tone of the precapillary arterioles

2: COfHeart Rate Stroke volume

Preload = myocardial fiber length before contraction

capillary ﬂuid leak [4–6], distributive shock caused by vasodilation [4,7–9],

Animal models and the concept of anaphylactic shock organs

Human cardiovascular collapse

Is the human heart a target organ during anaphylaxis?

obvious diﬃculty in determining the contribution of cardiac dysfunction to

Relative bradycardia during anaphylaxis

tachycardia and peripheral arteriolar constriction, followed by a second

the near-impossibility of establishing causal relationships, but also because

Platelet-activating factor, nitric oxide, and tumor

Box 2. Key pathophysiologic mechanisms of human

as metaraminol and vasopressin [7–9]. Presumably these work primarily by

Anaphylaxis: Oﬃce Management

Anaphylaxis, an acute and potentially lethal multisystem allergic reac-

Clinical manifestations of anaphylaxis

For practical purposes, delaying the diagnosis until end-organ features of

Biphasic and protracted anaphylaxis

anaphylaxis conclusively without directly challenging the patient with the

Diﬀerential diagnosis of anaphylaxis

syndromes (eg, metastatic carcinoid), and psychiatric disorders that can

the maintenance of adequate oxygenation and eﬀective circulatory volume

Box 2. Physician-supervised management of anaphylaxis

Possibly appropriate, subsequent measures depending on

Specific measures to consider after epinephrine injections,

Interventions for cardiopulmonary arrest occurring during

associated with assumption of an upright or sitting posture and postmortem

result from delayed or inadequate administration of epinephrine and from se-

Oxygen and airway adjuncts

quickest, easiest, and most eﬀective ways to support ventilation involves

Persistent hypotensiondappropriate roles of volume replacement,

rapidly, followed by slow infusion. Normal saline is preferred, because lac-

The role of antihistamines, inhaled adrenergic agonists, and corticosteroids

Box 3. Preventive measures to reduce the risk for anaphylaxis

Specific measures for high-risk patients

Modified from Kemp SF. Anaphylaxis: current concepts in pathophysiology,