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Allergy

REVIEW ARTICLE

Anaphylaxis: past, present and future


M. Ben-Shoshan1 & A. E. Clarke2,3
1
Division of Pediatric Allergy and Clinical Immunology, Department of Pediatrics, McGill University Health Center; 2Division of Clinical
Epidemiology, Department of Medicine, McGill University Health Center; 3Division of Allergy and Clinical Immunology, Department of
Medicine, McGill University Health Center, Montreal, QC, Canada

To cite this article: Ben-Shoshan M, Clarke AE. Anaphylaxis: past, present and future. Allergy 2011; 66: 114.

Keywords Abstract
anaphylaxis; anaphylaxis prevention;
epinephrine treatment; fatality; genetics of
Anaphylaxis is a clinical emergency, and recent reports suggest increased prevalence.
anaphylaxis. A diverse set of primary genetic and environmental inuences may confer suscepti-
bility to anaphylactic reactions. Anaphylaxis presents diagnostic and therapeutic
Correspondence challenges. It often manifests with a broad array of symptoms and signs that might
Moshe Ben-Shoshan, Montreal Childrens be similar to other diseases. The management of anaphylaxis consists of emergency
Hospital, 2300 Tupper St, Montreal, QC, treatment of acute episodes as well as preventive strategies to avoid recurrences.
Canada H3H 1P3. Treatment is complicated by its rapid onset and progression, presence of concurrent
Tel.: (514) 412 22858 diseases or medications, and need for long-term allergen avoidance. Health care pro-
Fax: (514) 412 4390 fessionals must be able to recognize the signs of anaphylaxis, treat an episode
E-mail: daliamoshebs@gmail.com promptly and appropriately, and provide preventive recommendations. Recognizing
the gaps in our understanding and management of anaphylaxis may help identify
Accepted for publication 1 May 2010 promising targets for future treatment and prevention and areas that require further
study.
DOI:10.1111/j.1398-9995.2010.02422.x

Edited by: Hans-Uwe Simon

The term anaphylaxis stems from the Greek words ama ana ably combats the allergic reaction (7), it was only at the
(against) and utkaniV phylaxis (protection) and was rst beginning of this century that it was nally established that
coined by Professor Charles Robert Richet in 1902, Nobel IM epinephrine should be used as rst-line treatment for ana-
Prize Winner for Medicine and Physiology, and by Dr Por- phylaxis (8, 9).
tier to describe a set of symptoms that was the opposite of In this review, we seek to highlight current knowledge and
immunity(1). Arthus was the rst to experimentally describe concepts regarding the denition, pathophysiology, diagnosis,
anaphylaxis in rabbits, and Auer in 1911 expanded these ini- and management of anaphylaxis as well as some of the cur-
tial observations and concluded that lethal anaphylaxis in rent gaps regarding its understanding and treatment. Finally,
experimental models of rabbits is caused by heart failure we indicate potential future research directions that might
associated with impaired coagulation. He also suggested that bridge these gaps.
anaphylaxis can be diagnosed only when an exposure to a
previously tolerated substance causes severe symptoms and
Current definitions
signs on subsequent exposure and implicates that a certain
factor is responsible for these deleterious effects of the second Based on the World Health Organization (WHO) denition,
exposure (2). It took almost six decades until the crucial role anaphylaxis is a severe, life-threatening generalized or sys-
of IgE and mast cells in anaphylaxis in both animal models temic hypersensitivity reaction (10). However, this denition
(3) and man (4) was elucidated. can be problematic given that the term life-threatening may
The majority of anaphylaxis cases in humans were initially be interpreted differently by health care providers. A recent
reported to occur in those exquisitely hypersensitive to horse meeting in the US sponsored by the National Institute of
serum, penicillin (5) or insect stings (6), while food-related Allergy and Infectious Disease (NIAID) and the Food
cases were rarely reported before the last three decades. Fur- Allergy and Anaphylaxis Network (FAAN) has established a
ther, although it was well recognized that epinephrine favor- consensus denition to satisfy epidemiological, research, and

Allergy 66 (2011) 114 2010 John Wiley & Sons A/S 1


Anaphylaxis Ben-Shoshan and Clarke

clinical needs. According to this denition, anaphylaxis is Reports from Australia suggest that the incidence of ana-
considered likely if any one of the following three criteria is phylaxis based on ICD codes is as high as 1 per 1000 ED
satised within minutes to hours (Table 1) (9). presentations (14). Studies determining rates according to
Anaphylaxis mediated by IgE, IgG, complement, or hospital admissions suggest a much lower estimate of 10.8
immune complexes is dened as immune-mediated anaphy- per 100 000 hospital admissions in Australia (21) or 36 per
laxis vs nonallergic anaphylaxis (previously known as an million of population in the UK (22). Limitations include
anaphylactoid reaction) (10). diagnostic coding inaccuracies, inclusion of only admitted
cases (11, 21, 22) and reliance on a single hospitals database,
which might not be representative of the national data (14).
Prevalence and incidence (Table 2)
A retrospective study in Korea between 2000 and 2006 on
The American College of Allergy, Asthma and Immunology anaphylaxis, including inpatients, outpatients, and ED visi-
Working Group has concluded that data on anaphylaxis inci- tors in the Seoul National University Hospital, reports a rate
dence and prevalence are sparse, often imprecise, and may of 0.014% during the study period (23). Evaluating anaphy-
underestimate the true incidence of anaphylaxis. This is a laxis cases in allergy clinics provides mainly information
direct result of the absence of a universal consensus on the regarding triggers, associated factors, and use of epinephrine,
denition of anaphylaxis, inadequate International Classica- but is less useful in providing prevalence or incidence esti-
tion of Diseases (ICD) codes, and incorrect use of the terms mates, because of the selection bias associated with such
prevalence and incidence in reports of anaphylaxis (1114). studies (17).
Prevalence and incidence estimates may be based on data Reports on the incidence of all provider-diagnosed ana-
collected from Emergency Medical Services (EMS) systems phylaxis are extremely rare. A study on children and adoles-
(15), emergency department (ED) or hospital admissions (11, cents enrolled at a health maintenance organization in Seattle
13, 16), visits to allergists (17), all medical records obtained between 1991 and 1997 aimed at determining anaphylaxis
from residents of a specic area (18, 19), and analysis of incidence based on conrmation of data collected from auto-
epinephrine auto-injectors (EAI) prescriptions (20). Each of mated databases and chart review using the ICD-9 codes of
these has potential limitations. anaphylaxis and related diagnosis. This study estimates an
In a study on EMS-reported anaphylaxis rates in 10 US incidence of 10.5 episodes per 100 000 person-years. The
states and one Canadian city (Toronto), it was found that in authors noted that the majority of episodes were treated in
nine EMS system databases, totaling over 2.8 million runs, the ED and concluded that anaphylaxis in this population
between 0.34% and 0.82% of the runs were for allergy/ana- was frequently diagnosed as another related condition such
phylaxis, and roughly 0.5% were for allergy/anaphylaxis as allergic urticaria or angioneurotic edema (13).
complaints, with epinephrine administered in roughly one- In the US, two reports on the prevalence of anaphylaxis in
tenth of these. A signicant limitation of the manuscript was Olmsted County, Rochester, Minnesota were published. The
the lack of standardization of case denitions among sites rst, conducted by Yocum et al. in 1999, was a retrospective
(15). population-based cohort study in which the medical records
of 1255 Olmsted County residents identied by computer-
linked, medical diagnostic indices were reviewed retrospec-
Table 1 Definition of anaphylaxis
tively to identify residents whose clinical episodes met the
1. Acute onset of illness with cutaneous and/or mucosal criteria for anaphylaxis (18). The denition of anaphylaxis in
involvement AND at least one of the following: this study differed from the current proposed denition
a. Respiratory compromise (e.g. dyspnoea, bronchospasm, (Table 1) as it required one symptom of generalized mediator
stridor, hypoxia) release, such as ushing; pruritus or paresthesias of lips,
b. Cardiovascular compromise (e.g. hypotension, collapse) axilla, hands, or feet; generalized pruritus; urticaria or an-
gioedema; and conjunctivitis or chemosis. In addition, the
2. Two or more of the following occur rapidly after exposure to a
likely allergen (minutes to several hours):
authors required involvement of at least one of the following
a. Involvement of skin or mucosa (e.g. generalized hives, itch, systems: oral and gastrointestinal, respiratory, or cardiovas-
flushing, swelling) cular. The reported average annual incidence rate of anaphy-
b. Respiratory compromise laxis was 21 per 100 000 person-years (18). A more recent
c. Cardiovascular compromise retrospective 10-year report on all providers of medical care
d. Or persistent gastrointestinal symptoms (e.g. crampy abdominal to residents of Olmsted County suggests that the incidence of
pain, vomiting) anaphylaxis is as high as 49.8 per 100 000 person-years (19).
Consistent with other reports (22, 24), this group reports an
3. Hypotension after exposure to known allergen for that patient
increase in the annual anaphylaxis incidence rate from 46.9
(minutes to several hours): age-specific low blood pressure or
per 100 000 persons in 1990 to 58.9 per 100 000 persons in
greater than 30% decline from baseline (or less than
2000 (19). The denition of anaphylaxis in this study was
90 mm Hg for adults).
comparable to that of Yocum et al. and differed from the
Hypotension for children is defined as systolic blood pressure recently suggested denition (Table 1), but the authors state
<70 mm Hg from 1 month to 1 year, <(70 mm Hg+[2Xage]) from 1 that re-analyzing the data using the NIAID/FAAN criteria
to 10 year, and <90 mm Hg from 11 to 17 year. did not signicantly affect the ndings. Although this study

2 Allergy 66 (2011) 114 2010 John Wiley & Sons A/S


Ben-Shoshan and Clarke Anaphylaxis

Table 2 Anaphylaxis rates

Publication Anaphylaxis Data collection


Study Country year rate (%) method Comments References

Kane et al. US, Canada 2004 0.5 EMS Per all runs during the study (15)
follow-up period
Braganza et al. Australia 2006 0.1 ED Per ED presentations of patients (14)
under 16 years attending one
pediatric hospital in Australia over
3 years
Gupta et al. UK 2007 0.0036 ED Per population (22)
Poulos et al. Australia 2007 0.01 ED Per hospital admissions (21)
Yang et al. Korea 2008 0.014 ED, inpatients and Per all patients who visited the (23)
outpatients visitors Seoul National University Hospital
in 2006
Boros et al. Australia 2000 0.59 Parent report of anaphylaxis Per participating children (26)
in children registered in the
South Australian DETE
system and participating in
the study (2% of the total
population of children
enrolled at DETE sites)
Simons et al. Canada 2002 0.95 EAI dispensing rates Per the entire Manitoba population (20)
during a 5-year period
Kemp AS Australia 2003 0.18 EAI Jr dispensing rates in Per the entire Australian children (25)
children less than 10 years. population (younger than 10 years)
Bohlke et al. US 2004 0.01 All care-providers data Per participants of a Group Health (13)
Cooperative in Seattle between
1991 and 1997
Yocum et al. US 1999 0.021 All care-providers data Per residents of Olmsted County (18)
Decker et al. US 2008 0.049 All care-providers data Per residents of Olmsted County (19)

US, United states; EMS, Emergency Medical Services; ED, Emergency Department; UK, United Kingdom; DETE, Department of Education,
Training and Employment; EAI, epinephrine auto-injector; EAI Jr, EAI Junior.

attempts to obtain a true population-based estimate of ana- A common conclusion in the majority of studies, regard-
phylaxis incidence, it is retrospective and is limited to the less of study design or geographic area, is that the rate of
predominantly white, middle class population of Olmsted anaphylaxis has increased during the last decades. This is
County (19). reected by higher report rates for anaphylaxis in all age
Studies estimating the incidence of anaphylaxis in Canada groups in recent years (11, 21, 22). This increase may be as
based on real-time prescription information for EAI have high as 350% for food-induced anaphylaxis and 230% for
been published (20). Estimates based on EAI prescription in nonfood-induced anaphylaxis over the last decade (11).
Manitoba, Canada suggest that during a 5-year period, Given the disparities in different studies using different
0.95% of the population had an EAI dispensed for out-of- methodologies and the lack, until recently, of worldwide
hospital treatment. There were substantial variations in EAI accepted denition of anaphylaxis, future prospective studies
dispensing rates across subsets of the population, ranging based on the recent consensus denition are required to
from 1.44% for individuals younger than 17 years of age, to better estimate anaphylaxis incidence and prevalence.
0.90% for individuals 1764 years of age (inclusive), to
0.32% for those aged 65 or older (20). However, EAI may be
Triggers
an unreliable marker of anaphylaxis as exemplied by
reported disparities between EAI prescriptions and estimated The three principal immunologic triggers of anaphylaxis are
anaphylaxis rates. Studies in Australia, for example, report foods, insect stings, and drugs, although the relative contri-
a current crude rate of EpiPen provision of one per 544 bution of each of these to anaphylaxis may differ according
children (25), which is way below the estimated prevalence of to the study design, study population, or geographic area.
anaphylaxis (one in 166 children), possibly because of under- Foods are reported to be primary inciting allergens for
distribution of EAI (26). In addition, EAI may be prescribed anaphylaxis and account for 33.256% of all anaphylaxis
for food-related allergic reactions that do not necessarily cases (27). Further, food-induced anaphylaxis hospital admis-
meet the denition of anaphylaxis. sions are reported to have increased, mainly in the rst two

Allergy 66 (2011) 114 2010 John Wiley & Sons A/S 3


Anaphylaxis Ben-Shoshan and Clarke

decades of life (28). Peanut and tree nut account for the (ionic) contrast material triggers anaphylactoid reactions in
majority of severe reactions (18), but sh and shellsh are about 10% of patients receiving it and low osmolar in 1% of
also reported to cause severe reactions, especially in Asia (29) patients. Fatality is rare and comparable between high and
and parts of Europe (30). low osmolar contrast agents (8).
In studies conducted in the US, insect stings are the second There are several proposed grading systems for anaphy-
leading culprit for anaphylaxis and account for 18.5% of laxis severity. Brown developed a system based on the
anaphylactic cases, followed by medications (13.7%) (19), premise that unequivocal compromise of either the cardiovas-
mainly b-lactams (8), but more recently, biologic modiers cular or respiratory system denes a severe reaction (39).
such as iniximab, omalizumab, and cetuximab (31) have According to this grading system, it was found that in older
been implicated in anaphylaxis. However, insect stings (32) age groups, insect venom and iatrogenic causes were indepen-
or drugs (23) are reported to be the leading cause of anaphy- dent predictors of severity and that preexisting lung disease
laxis in other studies. Other less common triggers include was associated with an increased risk of hypoxia (39).
latex, immunotherapy, cleaning agents, and environmental
allergens (19).
Factors influencing the incidence of anaphylaxis
Nonimmunologic triggers include exercise, cold exposure,
radiocontrast materials, and opioids. It should be noted that Numerous factors may affect the incidence of anaphylaxis:
the 20% of anaphylaxis cases in which no trigger is identied
are considered idiopathic anaphylaxis (8).
Previous history of anaphylaxis
This is suggested to be the only known reliable predictor of
Clinical presentation
future anaphylaxis (40). However, at least 25% of adults (41)
Anaphylaxis symptoms involve several organ systems includ- and 65% of children (42) presenting with anaphylaxis do not
ing the skin, causing mainly urticaria (8090% of episodes), report a previous episode.
respiratory tract (70% of episodes), gastrointestinal tract (30
45% of episodes), cardiovascular (1045% of episodes) and
Atopy
central nervous system (1015% of episodes) (8, 32).
In 10% of anaphylaxis cases, there are no cutaneous symp- Atopy is common in subjects who experience anaphylaxis,
toms, and in 4% of cases, there is bradycardia, especially in regardless of its origin. The extracellular cytokine milieu
association with insect sting anaphylaxis (33). Cardiovascular associated with atopic diseases may contribute to the
symptoms are more common in events occurring in the oper- increased risk of an anaphylactic reaction (12). However,
ating room and are associated mainly with muscle relaxants some studies suggest that atopy does not confer an additional
and latex (8). Unusual manifestations include syncope alone risk of anaphylaxis (40).
(reported in patients with mastocytosis) and seizures (8, 31).
Prolonged episodes with hypotension can trigger dissemi-
Socioeconomic factors
nated intravascular coagulation characterized by massive acti-
vation of coagulation and brinolytic enzymes that may Studies suggest an increased number of episodes in higher
result in depletion of platelets and coagulation factors (con- socioeconomic populations (12).
sumption coagulopathy). Platelet-activating factor (PAF)
released from mast cells may play an important role in this
Gender
process (34).
Biphasic allergic reactions, dened as a second reaction In adults, anaphylaxis is more common in women potentially
occurring 172 h after initial recovery (9), were reported in because of estrogens enhancing mast cell activation and aller-
11% of children presenting with anaphylaxis to a pediatric gic sensitization as was shown in an animal model (17, 43).
ED (35). Biphasic reactions account for 25% of cases of fatal However, in studies estimating anaphylaxis incidence in
and near-fatal food reactions and 23% of drug/biologic reac- children, males predominate (12).
tions, but they occurred in only 6% of anaphylaxis of mixed
causes and are uncommon with insect stings. Biphasic reac-
Geography
tions rarely occur without initial hypotension or airway
obstruction (36). Recent studies suggest higher rates of anaphylaxis in north-
Up to 20% of those presenting with anaphylaxis have a ern vs southern areas. These are mainly based on EAI distri-
second episode, and 5% have a third event. The median time bution data (44). It has been suggested that this northsouth
of presentation with a second episode is 395 days (19). Pea- gradient might be because of differences in vitamin D status
nut/tree nut accidental ingestion is the most common trigger (44).
associated with recurrences (37). Recurrences occur mainly in
women and are not necessarily associated with a history of
Season
atopy (37).
Anaphylactoid reactions are usually less severe and can In the US, anaphylaxis peaks between July and September
thus be prevented with premedication (38). High osmolar (when the leading culprit is insect stings) (19). The Practical

4 Allergy 66 (2011) 114 2010 John Wiley & Sons A/S


Ben-Shoshan and Clarke Anaphylaxis

Allergy (PRACTALL) meeting held by researchers from the


Genes affecting the anatomic barrier and allowing sensitiza-
American Academy of Allergy, Asthma and Immunology
tion
and the European Academy of Allergology and Clinical
Immunology underscored the importance of relevant clinical Filaggrin
factors including age, comorbid conditions (e.g. asthma, Filaggrin gene defects increase the risk of developing allergic
mastocytosis, and ischemic heart disease), medication use, or sensitization, atopic eczema, and allergic rhinitis. Restoring
strenuous exercise as these may increase the risk of anaphy- skin barrier function in laggrin-decient people in early life
laxis and/or fatality (45). may help prevent the development of sensitization and halt
the development and progression of allergic disease (46).
Genes potentially involved in anaphylaxis (Table 3)
Innate system genes
In addition to the environmental inuences discussed earlier,
studies suggest that a complex of genes affects the anaphylac- NLRP3
tic response. Anaphylaxis is reported to be associated with Nucleotide-binding domain and Leucine-rich Repeat-contain-
several gene groups including genes affecting the anatomic ing (NLR) family pyrin domain containing 3 (NLRP3) controls
barrier, genes associated with the innate immune system in the activity of inammasomes, which leads to cleavage of
general and mast cells in particular, and genes associated the procytokines IL-1b and IL-18. Recent studies have shown
with the adaptive immune system. The function of some of associations of human NLRP3 polymorphisms with suscep-
the genes implicated in the pathogenesis of anaphylaxis is tibility to various inammatory diseases including food-
described in the following paragraphs: associated anaphylaxis. Two NLRP3 single-nucleotide

Table 3 Genes implicated in the pathogenesis of anaphylaxis

Group Name of gene Comments References

Barrier genes Filaggrin Increased risk of developing allergic sensitization and not (46)
necessarily anaphylaxis
Innate immunity genes NLRP3: SNPs (rs4612666 and Significantly associated with susceptibility to food-induced (47)
rs10754558) anaphylaxis
Innate immunity and C-KIT Mutations associated with anaphylaxis after hymenoptera (48, 49)
mast cells genes stings and may also underlie cases of idiopathic anaphylaxis
SWAP-70 Anaphylactic responses are strongly reduced in mice with (50)
mutations in this gene
PAF V279F is found in more Mutations increase the risk for various inflammatory diseases in (51, 52)
than 30% of Japanese Japanese subjects.
subjects PAF and PAF-AH activity affect severity of anaphylaxis
Sphk1 Sphingosine 1-phosphate receptors play a critical role in (53)
regulating human mast cell functions, including degranulation
and cytokine and chemokine release
Rcan Rcan1 is a novel negative regulator in FceRI-induced mast cell (54)
activation
CCRL2 Enhance tissue swelling and leukocyte infiltrates (55)
Adaptive immunity STAT-6 (13/15-GT repeat Polymorphisms higher in children in the Japanese population (56)
heterozygosity and the 15GT with allergic disease
repeat homozygosity)
IL-4 (Ile75Val variant of IL-4Ra Polymorphisms of IL-4 have been implicated in drug allergy (58, 59)
gene) especially in women
IL-10 ()819 C > T and )592 Polymorphisms of the IL-10 promoter have been associated (58, 59)
C > A variants) with b-lactam anaphylactic reactions
IL-13, 18 (promoter Latex allergy phenotype was significantly associated with (6062)
polymorphisms in IL13 -1055, polymorphism in the promoter site of these cytokines
IL18 -607 and IL18 -656)
Unknown function DOCK8 Absence of DOCK8 protein associated with severe atopy and (63)
anaphylaxis

NLRP3, NLR (Nucleotide-binding domain and Leucine-rich Repeat-containing) family pyrin domain containing 3; SNP, single-nucleotide poly-
morphism; PAF, platelet-activating factor; PAF-AH, PAF-acetylhydrolases; Sphk1, sphingosine kinase; Rcan, regulators of calcineurin; FceRI,
Fc epsilon receptor I; CCRL2, chemokine (CC motif) receptor-like 2; STAT-6, signal transducers and activators of transcription 6; IL, interleu-
kin; IL-4Ra, IL4 receptor alpha; DOCK8, dedicator of cytokinesis 8.

Allergy 66 (2011) 114 2010 John Wiley & Sons A/S 5


Anaphylaxis Ben-Shoshan and Clarke

polymorphisms (rs4612666 and rs10754558) were signicantly both IL-4- and IL-13-mediated biologic responses. It was
associated with susceptibility to food-induced anaphylaxis (47). found that the dinucleotide repeat polymorphism of the
STAT6 exon 1 (13/15-GT repeat heterozygosity and the
Mast cells genes 15GT repeat homozygosity) was higher in children in the
Japanese population with allergic diseases (bronchial asthma,
C-KIT. The concomitant presence of systemic reactions (espe- atopic dermatitis, and/or food-related anaphylaxis) compared
cially anaphylaxis) after hymenoptera stings and increased to controls (56).
tryptase levels are reported to be associated with a clonal
mast cell disease characterized by a C-KIT mutation, usually Interleukin-4 (IL-4)
involving exon 17, with the imatinib-resistant type D816V IL-4 is an essential cytokine for isotype switch of B cells to
being most frequent (48). C-KIT mutations may also underlie IgE. In mice and human beings, IL-4 has been associated
cases of idiopathic anaphylaxis (49). with drug allergy in a small number of genetic studies of pen-
icillin allergy (57). Polymorphisms of IL-4 have been impli-
cated in drug allergy especially in women with the Ile75Val
SWAP-70. Mast cells express the unusual phosphatidylinosi-
variant of IL-4Ra gene (58, 59).
tol 3-kinase (PI3K)-dependent, Rac-binding protein SWAP-
70. It was shown that IgE-mediated passive cutaneous and
IL-10
systemic anaphylactic responses are strongly reduced in mice
IL-10, produced by TH2 cells and macrophages, is thought to
with mutations in the SWAP-70 gene although no similar
inhibit TH1 cytokine production and to promote B-cell sur-
studies are reported in humans (50).
vival, proliferation, and differentiation. Polymorphisms of
the IL-10 promoter have been associated with b-lactam ana-
PAF. Platelet-activating factor is a phospholipid that acts phylactic reactions especially the )819 C > T and )592
as a mediator of inammation, and rapid degradation of C > A variants in some studies, but not consistently (58,
PAF by intracellular and extracellular PAF-acetylhydrolases 59).
(PAF-AH) is one of the mechanisms regulating the level of
PAF. The most common loss-of-function mutation in PAF- IL-13 and IL-18
AH, V279F, is found in more than 30% of Japanese subjects A signicant positive association was also reported between
and is thought to be a risk factor in various inammatory atopic disease and the IL-13 promoter -1055 TT genotype, a
diseases (51). Further, studies reveal that serum PAF levels polymorphism that results in an increase in IL-13 protein
were directly correlated, and serum PAF-AH activity was production through putative dysregulation of IL-13 transcrip-
inversely correlated with the severity of anaphylaxis (52). tion (60). IL-18 is a proinammatory cytokine, which
strongly induces IFN-gamma production. IL-18 has been
implicated in atopic dermatitis, and IL-18 -137 and -607 pro-
Sphingosine kinase (Sphk1). It was also reported that suscep- moter polymorphisms have been associated with altered cyto-
tibility to in vivo anaphylaxis is determined both by sphingo- kine expression (61). In line with this, the latex allergy
sine-1-phosphate (S1P) within the mast cell compartment and phenotype was signicantly associated with promoter poly-
by circulating S1P generated by mammalian Sphk1 predomi- morphisms in IL-13 -1055, IL-18 -607, and IL-18 -656 (62).
nantly from a nonmast cell source(s) (53).

Genes with unknown function


RCan. A new family of regulators of calcineurin (Rcans) has
been shown to modulate calcineurin activity. Rcan1 was Novel homozygous or compound heterozygous deletions and
identied as an endogenous negative regulator in FceRI-med- point mutations in the gene encoding the dedicator of cytoki-
iated signaling and mast cell degranulation. Accordingly, nesis eight protein (DOCK8) led to the absence of DOCK8
Rcan1 deciency was shown to result in increased passive protein in lymphocytes. Most patients had severe atopy with
cutaneous anaphylaxis in vivo in mice (54). anaphylaxis (63).

CCRL2. Chemokine (CC motif) receptor-like 2 (CCRL2) is Pathophysiology (Fig. 1)


an orphan receptor with homology to other CC chemokine
receptors. It was shown that the mast cell-expressed orphan Mast cell activation through either IgE-mediated mechanisms
serpentine receptor mCCRL2 can enhance tissue swelling and or through non-IgE-mediated mechanisms results in the
leukocyte inltration in mice (55). release of preformed mediators such as histamine, heparin,
tryptase, chymase, carboxypeptidase A3, tumor necrosis fac-
tor a (TNFa), and cathepsin G, and newly formed mediators
Genes affecting the adaptive system and IgE production such as PAF, PGD2, leukotriene C4, cytokines such as IL-5,
STAT-6 IL-6, IL-8, IL-13, TNFa, and GM-CSF and chemokines such
The signal transducers and activators of transcription 6 as MIP-1a, MIP-1b, and MCP-1 (64) and possibility also
(STAT-6) protein is a key transcription factor involved in activated kallikrein (65).

6 Allergy 66 (2011) 114 2010 John Wiley & Sons A/S


Ben-Shoshan and Clarke Anaphylaxis

Histamine receptors

Mast cell
Complement Histamine

IgE
Anaphylatoxins Tryptase IgE
mediated

Bradykinin
Kallikrein

Contact
Non-IgE
mediated
Fibrinolysis
Complement
Clotting

PAF
Clotting
Myocardial
depression
NO

Figure 1 Anaphylaxis pathogenesis. Because of space limitation not all mast cell mediators and their effects are depicted in the figure.

Histamine actions are mediated through the H1H4 recep- local sympathetic nerve endings potentially leading to car-
tors leading to coronary vasoconstriction and cardiac depres- diac arrhythmias (71, 72).
sion (H1-receptor), systemic vasodilatation and tachycardia
(H2-receptor), inhibition of norepinephrine release (H3-recep-
Diagnosis
tors) and possibly chemotaxis and mediator release by
inammatory cells (H4-receptors) (66). Heparin (67) and pos- Anaphylaxis remains a clinical diagnosis; identication of
sibly tryptase activate prekallikrein (68) and the contact sys- specic triggers relies on a careful history supplemented by
tem (69) with subsequent release of bradykinin and activation conrmatory testing including prick skin tests, allergen-
of the clotting and complement systems. Tryptase also acti- specic IgE, and if necessary, allergen challenges. However,
vates the complement system directly (64). Of the newly this review will focus on laboratory tests that might help estab-
formed mediators, PAF has been suggested to play a major lish the diagnosis of anaphylaxis itself, including the following:
role in anaphylaxis. Platelet-activating factor decreases coro-
nary blood ow and myocardial contractility, increases acti-
Tryptase and histamine levels
vation and recruitment of neutrophils and eosinophils, and
induces local and systemic platelet aggregation as well as Currently, total tryptase and histamine are the only ana-
peripheral vasodilatation and severe hypotension possibility phylaxis markers measured in clinical laboratories. The com-
through the induction of NO (70). mercially available uorescence immunoassay measures both
Because of the physiologic changes induced by an ana- a- and b-tryptase. The baseline serum level in the absence of
phylactic reaction, compensatory mechanisms are activated an allergic or anaphylactic reaction is considered an indicator
including increased secretion of neuroepinephrine as well as of the whole body mast cell load and, if elevated, may indi-
activation of the reninangiotensinaldosterone system. cate the presence of systemic mastocytosis (normal threshold
These compensatory mediators may also have negative levels are up to 10 ng/ml). An increase in serum tryptase level
effects. Activated cardiac mast cells contain and release within 15 h after the rst symptoms of a suspected systemic
renin that results in local activation of the reninangiotensin hypersensitivity reaction characterizes IgE-mediated anaphy-
system. Mast cell chymase as well as plasma kallikrein also laxis (8).
contribute to the production of renin (71). The angiotensin In contrast, histamine levels are less useful for anaphylaxis
II that is produced induces norepinphrine secretion from assessment as elevated levels last only 1 h after the onset of

Allergy 66 (2011) 114 2010 John Wiley & Sons A/S 7


Anaphylaxis Ben-Shoshan and Clarke

symptoms, and special handling of the blood sample is measures (Table 4) to a known allergen and prompt adminis-
required. However, histamine metabolites in the urine can tration of intramuscular epinephrine (8).
last up to 24 h and may serve as a useful anaphylactic mar- Primary anaphylaxis prevention is based on allergen desen-
ker (31). sitization through immunotherapy. In the case of food aller-
In regard to food-induced anaphylaxis, tryptase measure- gies, desensitization remains experimental and is not yet used
ment may be less useful as mucosal tissue mast cells contain in routine clinical practice. There are currently no known
less tryptase compared to connective tissue mast cells and guidelines describing the optimal candidate for desensitization
consequently when an antigen is ingested and binds to muco- or the safest and most effective dosing schedule. Food aller-
sal mast cells, usually less tryptase is released (31). gen immunotherapy through the oral or sublingual routes
might be less risky than subcutaneous (78). Signicantly
increased thresholds to food-induced allergic reactions after
Basophil activation tests
oral immunotherapy was described in 100% of those with
Newer tests for anaphylaxis evaluation include determining milk (7981) and egg allergy (82) and more than 90% of
CD63 and CD203 expression in active basophils (73) those with peanut allergy (83). A recently described desensiti-
(through ow cytometry) and PGD2 levels (74). zation protocol to milk consisted of administration of
Assessing PGF2 and carboxypeptidase levels could help increasing amounts of milk at weekly intervals at the clinic
establish the diagnosis in cases of mastocytosis given that these under medical supervision. The starting dose was one drop of
mediators are selectively localized in mast cell granules (31). milk, doubled every week to achieve a total intake of 200 ml
in approximately 4 months (79). Encouraging results have
also been described with hazel-nut (84), milk (80), and peach
Differential diagnosis of anaphylaxis
(85) sublingual immunotherapy. It is likely that the nature of
Several clinical conditions may present with clinical features this increased threshold is transient and reects desensitiza-
suggesting anaphylaxis including vasovagal reactions, ushing tion rather than true tolerance given that avoidance of these
syndromes, respiratory or cardiovascular diseases, poisoning, foods was shown to increase sensitization as well as to lower
mast cell clonal disorders, and psychogenic conditions. the threshold of subsequent reactivity (81, 83). The efcacy
Vasovagal reactions are probably the most common condi- of the immunotherapy, extent of desensitization vs tolerance,
tion masquerading as anaphylaxis. These reactions usually and the quantity/frequency of allergen consumption required
are not associated with urticaria and dyspnea, the skin is typ- to maintain this effect are currently unknown.
ically cool and pale, and the heart rate is low. However, as Secondary prevention measures for food-associated ana-
noted previously, bradycardia following an initial tachycardia phylactic reactions include patient/caregiver education on
may occur in anaphylaxis as well, mainly in association with strict allergen avoidance and the need for Medic-Alert brace-
venom allergy (75). Patients with comorbid conduction lets and EAI. It was recently shown that among food-allergic
defects or using sympatholytic medications may present with individuals who experienced an accidental exposure, almost
bradycardia rather than tachycardia during an anaphylactic 47.0% attributed at least one such event to inappropriate
reaction. food labeling for allergens, 28.6% to failure to read a food
Flushing syndromes should be considered in the differen- label, and 8.3% to ignoring a precautionary statement (86).
tial diagnosis of anaphylaxis. These may be either wet, i.e. These results are consistent with other studies suggesting that
associated with sweating (e.g. postmenopausal state or spicy a signicant proportion of accidental exposures are because
foods) or dry ushing syndromes (e.g. metastatic carcinoid). of both manufacturer and consumer error (87). Improved
The alcohol ushing response, (76) sometimes as an indica- product labeling must be combined with enhanced consumer
tor of underlying malignancy, may present with ushing, education on the constant necessity to scrutinize food labels
nausea, and tachycardia after drinking alcohol. Up to 36% for allergens.
of East Asians may experience this response, predominantly The development of rapid desensitization for the treatment
because of an inherited deciency in the enzyme aldehyde of drug hypersensitivities is aimed at providing essential med-
dehydrogenase 2 (76). ications while protecting patients from IgE and non-IgE
Pulmonary embolism, asthma and paradoxical vocal cord hypersensitivity reactions. Desensitization for type I hyper-
motion, foreign body aspiration, acute poisoning, hypoglyce- sensitivity reactions in penicillin-allergic patients was rst
mia, and seizure disorders may also present with features developed more than 50 years ago (88). Other empiric proto-
similar to an anaphylactic reaction. Mastocytosis, hereditary cols were developed to treat hypersensitivity reactions to
angioedema, and psychiatric disorders such as acute anxiety essential drugs that could not be substituted, such as antibi-
can also contribute to diagnostic confusion (8). In addition, otics (89102), allopurinol (103), aspirin (104) and clopidogrel
anaphylaxis has been described in association with the acute (105), insulin (106), chemotherapy agents (107, 108), and
coronary syndrome, Kounis Syndrome (77). biologics (109, 110). Secondary prevention relies mainly on
identication of allergic patients, avoidance of the culprit
drug and drugs that cross-react and use of a Medic-Alert
Management of anaphylaxis
bracelet (8).
The keys to the management of anaphylaxis are rapid diag- Regarding insect stinginduced anaphylaxis, immunother-
nosis, implementation of primary and secondary prevention apy is a common practice for hymenoptera stingallergic

8 Allergy 66 (2011) 114 2010 John Wiley & Sons A/S


Ben-Shoshan and Clarke Anaphylaxis

Table 4 Primary and secondary prevention measures for main anaphylaxis triggers

Route of
Trigger Primary prevention desensitization References Secondary prevention References

Foods Milk PO, SL (7981) Avoidance of allergenic food; education of (86, 87)
Egg PO (81, 82) allergic individuals and their care givers on
Peanut PO (83) importance of avoidance, improved labeling
Tree nut SL (84) of pre-packaged foods for allergens, wearing
Peach SL (85) of Medic-Alert bracelet stating specific food
allergy
Drugs b-lactams (penicillin, cephalosporin) PO, IV, (8892) Avoidance of the culprit drug and drugs that (8)
Carbapenem IV (93, 94) cross-react, Medic-Alert bracelet
Macrolides PO (95)
Vancomycin IV (96)
Anti-tuberculosis drugs PO (97)
(isoniazid, rifampin, and
ethambutol)
Fluoroquinolones. IV, PO (98, 99)
Clindamycin PO (100)
Sulfamethoxazole PO (101, 102)
Allopurinol PO (103)
Aspirin PO (104)
Clopidogrel PO (105)
Insulin SC (106)
Chemotherapy IV, IP (107, 108)
Biologic modifiers IV, SC (109, 110)
(e.g. rituximab, infliximab,
trastuzumab, and interferon)
Insects Bee/wasps/mixed vespid SC, SL (111113) Avoidance of bright clothing and perfume and (116119)
Fire ant SC (115) sites where wasps are likely to congregate.
Bee venom + omalizumab SC (114) Removal of stinger in the case of
honeybees. Use of bait insecticides or
growth regulators or conventional
insecticides for fire ant control and wearing
socks

PO, per os; SL, sublingual; SC, subcutaneous; IV, intravenous; IP, intraperitoneal.
Only the most common foods, drugs, and insect desensitization approaches are mentioned.

patients and may be used according to a conventional, cluster guidelines, particularly the recommended dose and route of
(111), rush (112), or ultrarush (113) schedule. Protocols have administration of epinephrine (120).
been developed, which incorporate omalizumab to attenuate Because delay in administration of epinephrine is associ-
adverse effects (114). Recently, a successful 1-day immuno- ated with poor outcome in anaphylaxis and because the bene-
therapy protocol for re ant was reported in three cases less ts of epinephrine administration far outweigh the risks in
than 3 years of age (115). Secondary prevention measures otherwise healthy individuals (14), EAIs such as Epipen,
include avoiding bright clothing and perfume and sites where Epipen Jr., and Twinject should always be prescribed for
wasps are likely to congregate such as picnic grounds. It is those diagnosed with a known anaphylactic trigger and must
also suggested that the allergic individual be extremely careful be self-carried at all times (8, 9, 117). However, studies indi-
to avoid bees and wasps in the immediate vicinity (e.g. not cate that the rate of EAI prescription is low across different
walking with exposed feet, not drinking directly out of cans, settings: pediatric and military hospitals (121, 122), general
covering food) (116, 117). Fire ants can be controlled by bait community practices (hospital or ofce-based) (123), and
or conventional insecticides (118). In addition, wearing socks EDs (124). Among those identied with anaphylaxis in the
was reported to provide protection from re ant stings (119). ED, 3397% are discharged home (124126). On dismissal,
Although epinephrine is the only effective rst-aid treat- only 1633.6% (124, 126) are prescribed an EAI, and rates of
ment of anaphylaxis, studies of fatal food-induced anaphy- referral to an allergist vary between 0% and almost 80% (18,
laxis have documented that epinephrine is not usually given 126). Epinephrine administration in the ED and insect sting
soon after the onset of symptoms or after exposure to an as the inciting allergen were signicantly associated with EAI
offending trigger (14). Further, studies suggest that most prescription, while being less than 18 years was associated
physicians are not clear about current anaphylaxis treatment with referral to an allergist (126). Another study found that

Allergy 66 (2011) 114 2010 John Wiley & Sons A/S 9


Anaphylaxis Ben-Shoshan and Clarke

medical residents were signicantly less likely to prescribe an The use of b-blockers might complicate the treatment of
EAI compared to more senior staff (122). Among those pre- anaphylaxis (133). In cases of anaphylaxis occurring in
scribed an EAI, mainly those older than 55 years and those patients using b-blockers and when epinephrine is ineffective
seen at an outpatient clinic compared to those seen in the in the management of hypotension, IV glucagon should be
ED ll the prescription (127). It is also worth noting that given (9). Other drugs reported to be associated with
even in those prescribed EAI and lling the prescription, it is increased severity of anaphylactic reactions include angioten-
not always self-carried. Our group has recently reported that sin-converting enzyme inhibitors (134), angiotensin II recep-
among children with peanut allergy living in Quebec, less tor blockers (135), and drugs with a-adrenergic receptor-
than 50% self-carry the EAI while at school (128). Lack of blocking activity (thioridazine and amitriptyline), which
anaphylaxis management plans in schools is another factor antagonize the action of epinephrine in anaphylactic collapse
contributing to poor management (129). (136). An equally effective substitute less associated with
There are no contraindications to epinephrine administra- severe anaphylaxis should be used when possible (133). There
tion for an anaphylactic reaction, and it is prudent to admin- are also concerns regarding epinephrine use in patients trea-
ister epinephrine in uncertain situations when someone may ted with monoamine oxidase inhibitors because of potentially
not yet meet the diagnostic criteria for anaphylaxis but was increased stimulation of the sympathetic system (137).
exposed to a known trigger. Adverse effects because of unin- Idiopathic anaphylaxis is a corticosteroid-responsive condi-
tentional injections are considered rare, but nonetheless tion, and patients are advised to use an H1 antagonist daily
occur. In a recent study based on databases of the American and have an EAI and prednisone available at all times.
Association of Poison Control Centers and the Food and Frequent idiopathic episodes (6 per year/2 in the last
Drug Administrations Safety Information and Adverse 2 months) are treated prophylactically with prednisone and
Event Report System, it was shown that between 1994 and H1 antagonists (138).
2007, 60% of 15 190 unintentional EAI injections occurred
between 2003 and 2007. The median age was 14 years, and
Fatal outcome
85% were injected in a home or other private residences.
Injuries resulting in permanent sequelae were rarely reported, In the UK, severe anaphylaxis is fatal in 0.652% of cases
and currently there is no consensus regarding treatment of (139), resulting in 13 deaths per million people annually.
these cases (130). Improving EAI design and developing bet- Death usually occurred within the rst hour after develop-
ter training programs and guidelines for monitoring the capa- ment of anaphylaxis (139). Fatality rate estimates in Austra-
bility of those prescribed an EAI to correctly use it are lia are 0.64 deaths per million population per year (11). The
clearly required. annual death rate for anaphylaxis in Florida based on ICD
Following administration of epinephrine, all patients codes on death certicates was 5.02/10 000 000. Death from
should be transported to a medical facility, given the poten- anaphylaxis in Florida was more likely to occur in older indi-
tial for a biphasic reaction and the attendant requirement for viduals (above 65 years), in an ED, and during March and
additional treatment (8). Airway, breathing, and circulation April and July and August (140). The main causes of fatal
should be continuously monitored with continuous pulse rate anaphylaxis in Australia, Turkey, Korea, and Shanghai are
oximetry and potentially arterial blood gas measurements. drugs (23, 141, 142), while in the UK and the US, the main
Any patient with respiratory distress or hypoxia should be factor is reported to be food allergy (mainly nuts) (142). The
placed on supplemental oxygen. An inhaled [b]2-agonist may differences may be because of varying ecologic and/or dietary
benet the patient in respiratory distress. In severe or refrac- exposures and differences in data retrieval methodologies.
tory reactions, intubation and mechanical ventilation may be Temporal trends in anaphylaxis deaths in Australia reveal
required. Patients with poor circulatory status, hypotension, low or decreased mortality rates from food- and insect sting
or anaphylactic shock should receive aggressive uid resusci- induced anaphylaxis, respectively, and increased mortality
tation. H1 and H2 antagonists are considered second-line rates from drug-induced anaphylaxis (11).
treatment of anaphylaxis (9). Potent vasopressors, such as Risk factors for food-induced anaphylaxis fatalities include
norepinephrine, vasopressin, or metaraminol, could be used age 1035 years, active asthma, peanut allergy, ingestion of
in cases of hypotension refractory to epinephrine and uid food prepared outside of the subjects residence, and delayed
resuscitation (9). Corticosteroids have never been shown in administration of epinephrine. Risk factors for drug-induced
placebo-controlled trials to affect the course of anaphylaxis anaphylaxis fatalities include age 5585 years, presence of
or prevent biphasic reactions (131), but may treat related respiratory or cardiovascular comorbidities, and use of anti-
diseases such as asthma and allergic rhinitis, and have biotics or anesthetic agents. Risk factors for insect sting
been incorporated into algorithms of anaphylaxis manage- induced anaphylaxis deaths include age 3584 years and male
ment (8, 9). sex (11). Upright posture has been found to be associated
Methylene blue was suggested to be benecial in cases of with anaphylaxis death in general (33).
severe refractory anaphylactic shock potentially because it
reduced NO production and subsequent vasodilatation (132).
Gaps and future directions in anaphylaxis research
Methylene blue treatment may be particularly useful in cases
of anaphylactic shock characterized by high PAF levels in Anaphylaxis is a life-threatening condition, and although
which NO is thought to play a major role (70). there have been important advances, signicant gaps regard-

10 Allergy 66 (2011) 114 2010 John Wiley & Sons A/S


Ben-Shoshan and Clarke Anaphylaxis

ing its epidemiology, pathogenesis, diagnosis, and treatment aromatica (144). Future directions should include initiation
still remain. Data regarding the epidemiology of anaphylaxis of randomized, placebo-controlled studies comparing new
including prevalence rates are sparse, mainly retrospective, methods of desensitization to existing strategies. These
and do not use a consensus denition. include modication of allergen dose or extract (145), addi-
Studies on the pathogenesis of anaphylaxis elucidated tion of biologic modiers to reduce side-effects (146), and
important mechanisms, regarding in particular the emerging exploring new routes of delivery (147). Finally, given the dis-
role of mediators such as PAF, DOCK8, and S1P. parities in anaphylaxis management at the level of physicians,
Although it is still unclear from these advances how genetic patients and the community, new laws, guidelines and educa-
and environmental factors interact, they may contribute to tional programs addressing these gaps, and ensuring appro-
new diagnostic and therapeutic strategies. Genetic analysis priate treatment of anaphylaxis should be developed and
of NLRP3, PAF, S1P, SWAP70, and Rcan1 polymorphisms disseminated among all potential care givers. Studies explor-
may emerge as laboratory markers of those at risk for ing and monitoring the efcacy of such approaches are
severe anaphylaxis and provide new venues for anaphylaxis needed.
management.
Preventive measures that have recently shown promise
Funding
include allergen nonspecic and allergen-specic immunother-
apy. Allergen nonspecic measures include a traditional Chi- Allergy, Genes, and Environment (AllerGen) Network of
nese medicine, Guo Min Kang, that was shown in mice Centres of Excellence, Health Canada. Dr Ben-Shoshan was
models to suppress type I hypersensitivity reactions (143), partially supported by the Ross Fellowship from the
and the use of nonspecic functional foods aimed at normal- Research Institute of the Montreal Childrens Hospital. Dr
izing the Th1/Th2 imbalance and decreasing IgE antibody Clarke is a National Scholar of the Fonds de la recherche en
production. The latter include substances such as Curcuma sante du Quebec.

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