REVIEW Eur Ann Allergy Clin Immunol Vol 53, N.

1, 4-17, 2021

M. B. Bilò1, M. Martini2, C. Tontini3, A. Corsi2, L. Antonicelli3

Anaphylaxis
1
Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Allergy Unit, Department of Internal
Medicine, University Hospital, Ancona, Italy
2
Allergy Unit, Department of Internal Medicine, University Hospital of Ancona, Allergy and Clinical Immunology School,
Polytechnic University of Marche Ancona, Italy
3
Allergy Unit, Department of Internal Medicine, University Hospital of Ancona, Italy

Key words Summary

Adrenaline; anaphylaxis; Anaphylaxis is the most severe systemic hypersensitivity reaction, and it can be life-threatening
idiopathic anaphylaxis; biomarkers; or even fatal. It involves the activation of multiple immune and non immune pathways
co-factors; endotypes; beyond IgE, thus exhibiting different phenotypes. New symptoms of hypersensitivity caused
exercise-induced anaphylaxis; by chemotherapy drugs, monoclonal antibodies, and biological agents have been suggested to
management; phenotypes; be recognized as anaphylaxis phenotypes. No biomarker has been described that allows an
preventive measures; risk factors. unequivocal diagnosis of anaphylaxis. Moreover, more biomarkers for specific endotypes are
needed to stratify severity, to predict risk, and to optimaze tretament choice in the individual
patient.
Corresponding author Food, drugs and stinging insects represent the most commly identified triggers. Idiopathic ana-
Maria Beatrice Bilò phylaxis is a diagnosis of exclusion and it can hide a clonal mast cell disorder.
Department of Clinical Individual risk factors and co-factors may influence the severity of anaphylaxis or its onset,
and Molecular Sciences and they should be identified to implement the appropriate measures to prevent recurrence.
Polytechnic University of Marche Prompt recognition and treatment are critical in anaphylaxis, adrenaline being the first-line
Allergy Unit, Department of
saving therapy. Individualized anaphylaxis action plan should include avoidance measures,
Internal Medicine
University Hospital
prescription of an adrenaline autoinjector, education, optimal management of relevant comor-
Ancona, Italy bidities, venom specific immunotherapy, food oral immunotherapy, and drug desensitization,
E-mail: m.b.bilo@univpm.it when appropriate.
However, the quality of acute and long-term anaphylaxis management is variable influencing
Doi the poor outcomes experienced by many patients. Clinical practice guidelines have the potential
10.23822/EurAnnACI.1764-1489.158 to improve outcomes, but they often prove challenging to implement in routine clinical care.

Introduction patients with anaphylaxis and it is used in preference to terms

such as “anaphylactoid reaction”, or “pseudo-anaphylaxis” (1-3).
Anaphylaxis is the most severe systemic hypersensitivity reac- All Guidelines report that anaphylaxis is a “life-threatening re-
tion, it involves multiple organ systems, can be caused by a action”, even though in general mortality or morbidity do not
number of triggers and conditions, and be deadly. A number seem to have increased in recent decades (7-9), despite the vast
of slightly different definitions for anaphylaxis has been used majority of anaphylaxis reactions are not treated properly with
in different Guidelines (1-6). In these guidelines, the indepen- prompt administration of adrenaline. However, as it is not pos-
dently developed definitions of anaphylaxis for clinical use all sible to predict the severity of reaction and early adrenaline ad-
include the concepts of a serious, generalized or systemic, al- ministration may reduce the risk, the concept of “life-threaten-
lergic or hypersensitivity reaction that can be life-threatening ing” must be present in the anaphylaxis definition (10).
or fatal. Importantly, none of the definitions include the word The anaphylaxis guidelines of the World Allergy Organization
“shock” (1-3). The correct term “anaphylaxis” is preferred to (WAO) (2) and of the European Academy of Allergy and Clinical
“anaphylactic shock” because shock is not necessarily present in Immunology (EAACI) (1) have established 3 sets of clinical crite-

© 2021 Associazione Allergologi Immunologi Italiani Territoriali e Ospedalieri - AAIITO. Published by EDRA SpA. All rights reserved.
Anaphylaxis 5

ria for the diagnosis of anaphylaxis, confirming the proposal of the from 1.5 to 7.9 per 100,000 person-years. These data indicated
second symposium on the definition and management of anaphy- that an estimated 0.3% (95% CI 0.1-0.5) of the population
laxis summary report - Second National Institute of Allergy and experience anaphylaxis at some point in their lives, with food,
Infectious Disease/Food Allergy and Anaphylaxis Network Sym- drugs, stinging insects, and latex being the most commonly
posium (4). In short, anaphylaxis is highly likely in the case of an identified triggers. Overall, the case fatality ratio from anaphy-
acute onset of an illness (minutes to several hours) affecting at least laxis was low, estimated at under 0.0001% (17).
2 different organs (e.g. skin-mucosal tissue, airways, gastrointesti- A review by a Working Group of the American College of Al-
nal apparatus, cardiovascular system) or in the case of a a reduced lergy, Asthma, and Immunology including a number of non-
blood pressure after exposure to known allergen for that patient European studies, concluded that the overall incidence of
(minutes to several hours). Because anaphylaxis mimics common anaphylaxis was between 30-60 cases per 100,000 person-years
syndromes, such as asthma and urticaria, and it can present with- and 950 cases per 100,000 person/years, with a lifetime preva-
out hypotension, its diagnosis is often missed or delayed. lence 0.05-2.0% (18). The lower estimates by Panesar et al. may
For a number of good clinical reasons, very recently the Ana- reflect differences in diagnostic criteria for anaphylaxis between
phylaxis Committee of the WAO proposed to revisit the defi- Europe and North America.
nition and clinical criteria of anaphylaxis, in order to better Moreover, it is estimated that 1 in every 3,000 inpatients in
capture the reality of anaphylaxis, simplify diagnosis, thus in- US hospitals suffer from an anaphylactic reaction with a risk of
proving the management (10). This proposal will certainly be death around 1%, accounting for 500 to 1000 deaths annually
the subject of worldwide discussion. It will probably has to take in this country (19).
into account that there is a new understanding that atypical Based on these statistics, anaphylaxis would fit well the definition
symptoms, such as pain, chills, fever can be seen during chemo- of a rare disease, although it is not currently listed in rare diseases
therapy-induced anaphylaxis characterized by hypotension, de- registries (20). In public health terms, anaphylaxis is considered
saturation, and cardiovascular collapse, which can lead to a new to be an uncommon cause of death (2, 21-23). The case fatality
classification of anaphylaxis pathways (11). Moreover, clonal rate is difficult to ascertain with accuracy. Accurate anaphylaxis
disorders, such as monoclonal mast cell activation syndrome, mortality data are hampered by the limited recognition of this
are considered part of the wide spectrum of anaphylaxis (11). condition among health professionals, the absence of historical
A minority of patients exhibit biphasic allergic reactions indu- details from eyewitnesses, incomplete death scene investigations,
ced by a variety of causes,, in which signs and symptoms of paucity of specific pathologic findings at postmortem examina-
anaphylaxis recur hours after initial resolution of anaphyla- tion, and the under-notification of anaphylaxis, particularly in
xis without re-exposure to the trigger (12). In addition to the the International Classification of Diseases, Injuries and Cause of
biphasic reactions, patients who have IgE reactive with the oli- Death (ICD) (2, 20, 24). Although currently misclassified in the
gosaccharide galactose-alpha-1,3-galactose, which is present in ICD, anaphylaxis is now one of the principal headings in the “Al-
mammalian meat and in some therapeutic antibodies, can exhi- lergic and hypersensitivity conditions” section recently compiled
bit anaphylaxis after a delay of several hours during which no for the forthcoming 11th Revision of ICD (ICD-11). Thanks to
signs or symptoms are present (13). this inclusion, it is expected that anaphylaxis should be a public
Several classifications were proposed to assess the degree of severi- health priority and that it should therefore be formally added
ty of anaphylaxis; the most used in clinical practice is Ring’s (14). into the list of rare diseases in order to support awareness and
New proposed severity scores from Brown and EAACI guidelines quality clinical management of patients.
suggest simpler criteria, namely dividing reactions in mild, mode- As for the triggers, a pan-European registry for severe allergic re-
rate or severe, or in grades according to local (grade 1) or systemic actions collecting 3333 cases of anaphylaxis, showed that allergic
involvement (grade 2, 3), respectively (15, 16). In the latter, ho- reactions were mainly caused by food and insect venom and less
wever, such proposed grading might be confusing for Hymenop- often by drugs (25). Most reactions occurred within 30 min of
tera venom allergy, given that local reactions are referred to local exposure (80.5%); a delay of 4+ hours was mainly seen in drug
cutaneous involvement, rather than generalized urticaria. anaphylaxis (6.7%). Symptom patterns differed by elicitor, with
the skin being affected most often (84.1%). Usually previous
Epidemiology and triggers milder reaction to the same allergen was reported by 34.2% (25).
Data collected in the European Anaphylaxis Registry from 2007
There is some evidence that the incidence of anaphylaxis may be to 2015 (25), allowed to characterize anaphylaxis in children
increasing, but this may be due to changing clinical definitions and adolescents (26). Food items were the most frequent trig-
or thresholds for presentation or admission. ger (66%), followed by insect venom (19%). Cow’s milk and
A systemic review of the epidemiology of anaphylaxis in Europe hen’s egg were prevalent elicitors in the first 2 years, hazelnut
(17) found the incidence rates for all-cause anaphylaxis ranging and cashew in preschoolaged children, and peanut at all ages.
6 M. B. Bilò, M. Martini, C. Tontini, et al.

There was a continuous shift from food- to insect venom- and and AT-2 did not (32). Indeed, it was recently shown that be-
drug-induced anaphylaxis up to age 10 years. Vomiting and ta-blockers (BBs) and the ACE inhibitor (ACEI) ramipril can
cough were prevalent symptoms in the first decade of life, and directly promote mast cell activation and are associated with in-
subjective symptoms (nausea, throat tightness, and dizziness) creased odds for severe anaphylaxis (33).
were prevalent later in life. Most incidents occurred in private In contrast, a systematic review and metaanalysis of studies that
homes (46%) and outdoors (19%). One third of the patients assessed the influence of BBs and ACEIs on anaphylaxis showed
had experienced anaphylaxis previously (26). low quality of evidence that the use of BBs and ACEI increases
Looking at epidemiological data from from intensive care units the severity of anaphylaxis, due to differences in the control of
pediatric anaphylaxis admissions, 1989 patients were reported confounders arising from the concomitant presence of cardio-
from 2010 to 2015 in the United States and Canada, the most vascular diseases (34).
common identified trigger being food (mainly peanuts) (27). In a large observational cohort study performed in the United
One percent of patients died because of critical anaphylaxis, and States from 2005 to 2014, age of 65 years or older, medication as
identified triggers for fatal cases were food (peanuts and milk) a trigger, and presence of comorbid conditions (specifically car-
and blood products (27). diac and lung disease) were associated with significantly higher
Comparing European patients aged > 65 (elderly: 1, 123) with odds of severe anaphylaxis (35). On the other hand, evidence
adults (18-64 years: 5.768) regarding elicitors, symptoms, co- showing that respiratory disease increases the severity of anaphy-
morbidities, and treatment measures, insect venoms were the laxis according to a recent a systematic review and metaanalysis
most frequent elicitor in the group (p < 0.001), followed by is low to moderate, although studies do not usually assess the
drugs like analgesics and antibiotics (28). Food allergens elicited importance of severity of asthma (36).
less frequently anaphylaxis (p < 0.001). Skin symptoms occurred A genetic diversity should be also included among the host
less frequently in elderly patients (77%, p < 0.001). The clinical factors influencing anaphylaxis in some cases of food and drug
symptoms were more severe in the elderly (51% experiencing allergy (37, 38). Polymorphisms affecting metabolism of me-
grade III/IV reactions), in particular when skin symptoms (p diators of anaphylaxis also can influence anaphylaxis severity,
< 0.001) were absent. Most strikingly, a loss of consciousness since PAF-AH activity levels inversely correlated with severity
(33%, p < 0.001) and preexisting cardiovascular comorbidity of anaphylaxis (39, 40), and subjects with variants in angiotensi-
(59%, p < 0.001) were more prevalent in the elderly (28). nogen were reported to have increased rates of Hymenoptera ve-
nom allergy (41). D816V mutations are found in some patients
Risk factors and co-factors with mast cell disorders and recurrent anaphylaxis to Hymenop-
tera stings (42, 43).
The risk to develop severe reactions like anaphylaxis, may de- It is of note that variations in metabolism of mediators, can
pend on several factors, including the allergens an individual influence not only the manifestations of anaphylaxis, but the-
patient is sensitized to, the degree of sensitization, the quality oretically also the ability to recover from these manifestations
of binding allergens, probably also the relative proportions of in patients who have experienced anaphylaxis and survived the
antigen-specific immunoglobulin subtypes, the route of aller- episod even though not treated (44).
gen application, and finally, the presence and ‘amount’ of risk Risk factors for severe anaphylaxis may be different also accord-
factors and cofactors (29). According to some authors, ‘risk ing to the trigger, as demonstrated in the case of HV allergy.
factor’ is a general term covering any factor, which may lead Mastocytosis and monoclonal mast cell activation syndrome
to more severe allergic reactions, including augmenting factors (MMAS) are well known risk factor for severe and even fatal
(also called aggravating factors), concomitant diseases and co- anaphylaxis due to Hymenoptera stings, while this association is
factors (30), while others distinguish between risk factors and less clear for drug hypersensitivity (45).
co-factors (2, 31). Also risk factors for fatal anaphylaxis vary according to cause.
Very recently, processing the data from the European Anaphy- For fatal drug anaphylaxis, previous cardiovascular morbidity
laxis Registry (122 centers in 11 European countries) higher age and older age are risk factors, with beta-lactam antibiotics, gene-
(not related to concomitant cardiovascular or other diseases) ral anesthetic agents, and radiocontrast injections the commo-
and concomitant mastocytosis have been identified as the most nest triggers (46). For fatal food anaphylaxis, delayed adrenaline
important predictors for an increased risk of severe anaphylax- administration is a risk factor; common triggers are nuts, sea-
is (32). Vigorous physical exercise, male sex, and psychological food, and in children, milk. For fatal venom anaphylaxis, risk
burden were more often associated with severe reactions. More- factors include middle age, male sex, white race, cardiovascular
over, intake of beta-blockers and ACE inhibitor (ACE-I) in tem- disease, and possibly mastocytosis; insect triggers vary by region.
poral proximity to allergen increased the risk to develop severe Upright posture was reported a a feature of fatal anaphylaxis to
anaphylaxis exposition in logistic regression analysis, while ASA both food and venom (46).
Anaphylaxis 7

The so-called co-factors may explain why an allergen can either Type-I-like reactions
be tolerated or trigger a mild reaction or, in the same patients, These reactions represent the vast majority and include im-
induce a severe anaphylaxis. They may have two different ef- mune-mediated and non-immune-mediated pathogenesis.
fects: lowering the threshold, so that severe allergic reactions Antibody dependent anaphylaxis includes IgE-mediated and
may be observed at much lower doses of allergen; increasing the IgG-mediated reactions. In IgE-mediated reactions, anaphy-
severity, meaning that more severe reactions are elicited by the laxis initiated by an allergen interacting with allergen-specific
same dose of food or anaphylaxis is observed for the first time. IgE (sIgE) bound to its high-affinity receptor (Fce RI) expressed
Co-factors play a role in 30% of all anaphylactic reactions in on effector cells, mainly mast cell and basophils (44). Mast cell
adults and in 18% of children. The most frequent co-factors mediators responsable for allergic symptoms are represented by
are exercise, non-steroidal anti-inflammatory drugs (NSAID), preformed mediators stored in the cytoplasmic granules released
alchool, but menstruation, infections, medications other than by degranulation such as histamine, the proteases tryptase and
NSAID (e.g. antiacids), extreme air temperature, cannabis use, chymase, carboxypeptidase A and proteoglycans (with heparin
stress and disruption of routine have been also reported (47). as the major component); newly generated proinflammatory li-
The vast majority (90%) of excercise-induced anaphylaxis are pid mediators (i.e. prostaglandins, leukotrienes and PAF); and
related to food ingestion (FDEIA) (29, 48). Most of the data for newly synthesized growth factors, cytokines and chemokines.
FDEIA focusses on wheat triggers, being ω-5 gliadin the culprit Mast cell, IgE and Fce RI depletion in animal models suppresses
proteins in most cases (49), even though in Mediterranea area anaphylaxis (53-55), indicating that this pathway is crucial. In
lipid transfer proteins (LTPs) seem to be the most frequent sen- human anaphylaxis, the use of anti-IgE antibody, omalizumab,
sitizer (50). In other studies (31) NSAID were the most frequent as an adjuvant treatment in food and venom immunotherapy
co-factor enhanced food allergy, followed by exercise, with LTP reduces the risk (56, 57) and it prevents anaphylaxis in patients
allergens being again the allergen most frequently involved. with systemic mastocytosis (58, 59). However, the presence of
The underlying mechanisms in FDEIA are still unclear and sev- antigen-specific IgE antibodies does not indicate that the person
eral hypotheses have been proposed, like exercise increasing gas- necessarily will exhibit any, let alone severe, clinical reactivity to
trointestinal permeability, increasing activity of tissue transglu- the recognized antigens. On the other hand, severe anaphylaxis
taminase in the gut mucosa, inducing blood flow redistribution, can occur despite low levels or undetectable specific-IgE (sIgE)
and finally, exercise increasing histamine release from basophils (44), suggesting the existence of IgE-independent mechanisms.
because of an increase of plasma osmolarity (51). Not definitive evidence of IgG-mediated anaphylaxis in hu-
The frequent implication of cofactors in anaphylaxis highlights man subjects is present to date. It has been suggested that IgG-
the importance of recognizing and including them into diag- mediated anaphylaxis in humans requires considerably more
nostic workup (52). antigen than IgE-mediated anaphylaxis, such as in reactions to
infused drugs such as contrast media and antivenoms, due to
Phenotypes and endotypes the lower affinity of IgG binding by Fcg RIII than of IgE bin-
ding by Fce RI (60). Indeed, cases of anaphylaxis were reported
Anaphylaxis involves the activation of multiple pathways (table after treatment with therapeutic monoclonal antibodies (mAbs)
I). Its endotypes can be divided according to the underlying without detectable levels of anti-drug IgE (61, 62).
mechanism and/or the effector cells involved in the reaction. A Basophils have been shown to be dispensable for IgE-mediated
recent classification of anaphylaxis phenotypes has been propo- anaphylaxis but play a crucial role in IgG-mediated anaphylaxis
sed: type-I-like reactions, cytokine storm-like reactions, mixed in murine models, through their release of PAF and their ability
reactions and complement-mediated reactions (1). Endotypes, to bind immune complexes via the low-affinity IgG receptor Fcg
underlying these phenotypes, are based on biological and mole- RIII (63). Recently, an emergency department study recruiting
cular mediators supported by biomarkers. Type-I-like reactions 31 patients with acute anaphylaxis, predominantly to Hyme-
are characterized by classical allergic symptoms (e.g. urticaria, noptera venom, showed that human anaphylaxis involves a sub-
pruritus, shortness of breath, throat tightness, nausea, vomiting, stantial reduction in numbers of circulating basophils, which
diarrhea, cardiovascular collapse), frequently (but not always) inversely correlate with serum CCL2 levels, a major basophil
IgE-dependent, due to foods, drugs, Hymenoptera venoms, and chemotactic factor, thus implying an important and specific role
environmental allergens. Cytokine storm-like reactions, as well for basophils in the pathophysiology of human anaphylaxis (64).
as mixed reactions, are usually elicited by chemotherapy or bio- Several drugs can induce direct nonimmunologic type-1-like
logical agents and additionally induce some atypical symptoms activation of mast cells/basophils by basic secretagogues, in-
such as chills, fever or pain. Finally, reactions mediated by com- cluding vancomycin, NSAIDS, opiates, fluoroquinolones and
plement can be induced by contrast dyes or dialysis membranes, neuromuscular blocking agents. For example, opiates induce hi-
among others, and provoke hypotension and desaturation. stamine release presumably through a mechanism that involves
8 M. B. Bilò, M. Martini, C. Tontini, et al.

opioid receptors in mast cell (65). Vancomycin is able to directly Cytokine storm-like reactions
activate mast cell leading to histamine release in the ‘red man Cytokine storm-like reactions are caused by release of proin-
syndrome’ through a calcium-dependent mechanism that invol- flammatory mediators, such as TNF-a, IL-1B, and IL-6, and
ves activation of phospholipase C and phospholipase A2 (66). the target cells include monocytes, macrophages, mast cells, and
An alternative mechanism, based on non IgE-mediated mast other immune cells with FcgR (11, 71). Triggers for these reac-
cells activation by means of the G-protein-coupled receptor X2 tions include chimeric, humanized, and human mAbs and che-
(MRGPRX2) has been identified. The receptor MRGPRX2, motherapy, including oxaliplatin. Reactions are characterized by
which is expressed on mast cells and other cells, has been shown chills, fever, generalized malaise followed by hypotension, desa-
to be activated by quinolone antibiotics, such as ciprofloxacin turation, and cardiovascular collapse.
and levofloxacin; general anesthetics, such as atracuronium and Similar to infusion-related reactions, cytokine-release reactions
rocuronium; icatibant; and other drugs with Tetrahydroisoqui- to mAbs can occur at first infusion, even though they have also
noline (THIQ) motifs (67), even though its partecipation has been seen after several exposures. The difference between the
not been confirmed in human subjects. two reactions is the self-limiting nature of infusion-related reac-
Contact and coagulation system can be activated in anaphylaxis tions on repeat exposure and the response to premedication (72-
through immunological and nonimmunological mechanisms 74). Premedication with anti-inflammatory COX-1 inhibitors
(table I). The latter was related with oversulfated condroitin- and corticosteroids can decrease the intensity of cytokine release
contaminated heparin causing severe anaphylaxis through direct reactions but does not protect from severe reactions.
activation of factor XII (FXII) of the contact system and release
Mixed reactions
of bradykinin (68). During the acute phase of human anaphy-
Mixed reactions with features of type I – and cytokine storm –
laxis, a strong consumption of contact system factors has been
like reactions can be seen with chemotherapy and mAbs in which
observed, associated with mast cell degranulation and increased
pruritus, hives, and swelling are associated with chills, fever,
plasma heparin levels, being heparin a potent FXII activator
hypotension, and desaturation (11, 72).
(69).
Finally, an activating mutation in c-KIT D816V promotes mast Complement-mediated reactions
cell proliferation in patients with clonal mast cell disorders, Complement-mediated anaphylaxis may also occurr through im-
including mastocytosis, in whom type-I-like anaphylaxis may munological and nonimmunological mechanisms (table I). The
occur with or without known triggers, with or without specific anaphylatoxins C3a and C5a are potent inflammatory mediators
IgE sensitization (70). generated upon activation of the complement cascade. Mast cell, ba-

Table I - Immunologic and nonimmunologic pathways in anaphylaxis.

Type of anaphylaxis pathway Mechanism Effector cell Main mediator involved

Immunologic IgE-dependent Mast cell/basophil Histamine, tryptase,
chymase, carboxipeptidase,
IgG-dependent Basophil/Macrophage/Neutrophil heparin, PAF
PAF
Complement system Mast cell/macrophage Histamine, PAF

Contact system/Coagulation system Endotelial cells Bradykinin

(Kallikrein-FXII system)
Nonimmunologic Complement system Mast cells
(physical factors, ethanol, drugs)
Mast cell/basophil activation
- Quinolones Mast cells Histamine, tryptase
- Neuromuscolar blockers Mast cells Chymase, Heparin, PAF
- NSAIDs Mast cells
- Opiates Mast cells
- Vancomicin Mast cells
- Contact Endothelial cells Bradykinin
system/Coagulation system
Anaphylaxis 9

sophils and monocytes/macrophages express receptors for C3a and tained 15-30 minutes after symptom onset. In fact, plasma his-
C5a (75), and release histamine and/or PAF in response to exposu- tamine peaks within 5-10 min of the onset of symptoms and de-
re to these complement fragments. In human and mice anaphyla- clines to baseline within 30 min as a result of rapid metabolism
xis, complement activation by peanut (76, 77) or wasp-sting acted by N -methyltransferase and diamine oxidase (2).
synergistically with IgE-dependent mast cell activation (78). Blood tests for other biomarkers, such as chymase (87), carboxy-
Activation of complement without immune complex formation peptidase A3 (88), and CCL-2 (89) remain experimental.
has been shown to induce anaphylaxis in the absence of specific Despite mast cell heparin has been reported to activate the plas-
IgG or IgE. This mechanism has been described in association ma contact system during anaphylaxis, there are no available as-
with hemodialysis, liposomal drug infusion, radiocontrast me- says to measure it directly. Anti-Xa is an indirect measure of plas-
dia, polyethylene-glycol infusion and micellar solvents contai- ma heparin, but commercial assays are not sensitive enough (69).
ning amphiphilic lipids (e.g. Cremophor EL, diluent in propo- PAF is a potent phospholipid-derived mediator implicated in
fol or paclitaxel) or liposomal doxorubicin (79-81). platelet aggregation and it is secreted by mast cells, monocytes and
fixed tissue macrophages (90). A limited number of reports have
Biomarkers assessed concentrations of PAF or platelet-activating factor acetyl-
hydrolase (PAF-AH), an enzyme responsible for the rapid degrada-
A biomarker is a “defined characteristic that is measured as an tion of PAF, after anaphylaxis in human subjects. In these reports
indicator of normal biological processes, pathogenic processes circulating PAF levels were increased, and circulating PAF-AH ac-
or responses to an exposure or intervention” (82). The ideal tivity was inversely correlated with the severity of anaphylaxis (39,
biomarker should be highly specific, sensitive, predictive, rapid 40, 91). One of the challenges with measurement of PAF and PAF
and easy to measure, cheap, stable in vivo and in vitro, and AH in a routine clinical setting is its very short half-life and special
noninvasive. Biomarkers in anaphylaxis hold the potential for sampling and transport precautions that are required thus making
improving diagnosis, stratification of severity, risk prediction, it an unattractive candidate for routine use (84).
and therapeutic management, even tough they have no role for CysLTs are potential mediators of anaphylaxis and are synthesized
the moment in acute management. from arachidonic acid by a variety of cells, including mast cells, ba-
Tryptase is considered a largely mast cell-derived product, be- sophils, and macrophages (44). Several reports show that levels of
ing present in much lower amounts also in basophils. Mature some of these products, namely LTE4, 2,3-dinor-9a,11b-PGF2,
β-tryptase is stored in mast cell granules and released on acti- and 9a,11b-PGF2, are increased during the onset of anaphylaxis
vation, such as in anaphylaxis, whereas α- and β-protryptases (92, 93). However, like histamine, they have to be measured by
are secreted constitutively by mast cells, and therefore increased 24-h urine collection, meaning that the sensitivity might be low.
blood levels might indicate increased mast cell burden rather than Finally, levels of other serum inflammatory mediators, such as
anaphylaxis (83). Tryptase is much more stable than histamine TNF-a, IL-6, and IL-1b, can be increased in patients with cyto-
and blood samples for its measurement are optimally obtained kine storm-like reactions and anaphylaxis, but their sensitivity
15 minutes to 2-3 hours after symptom onset (84). Even though or specificity has not been demonstrated. Among them, IL-6 has
commercial methods measure total serum tryptase (immature and been pointed out as a potential biomarker for identifying and
mature), this assay is still the best routine biomarker available to managing cytokine-release reactions (72).
assess mast cell activation. Increased serum tryptase levels often
support the clinical diagnosis of anaphylaxis from insect stings or Diagnosis
injected medications and in patients who are hypotensive; howev-
er, levels are often within normal limits in patients with anaphy- If the trigger is highly suspect, an accurate clinical history col-
laxis triggered by food and in those who are normotensive (85). lection togheter with conventional diagnostic tools are sufficient
Furthermore, we must bear in mind that in anaphylactic reactions to confirm the diagnosis. However, in many cases, especially in
in which the main involved effector cell is not the mast cell, trypt- polysensitised patients, other procedure may help to confirm
ase may not rise. Serial measurement of tryptase levels during an the cause, for istance component-resolved diagnosis (CRD),
anaphylactic episode, and measurement of a baseline level after and basophil activation test (BAT).
recovery are reported to be more useful than measurement at only
one point in time (85). The “20% + 2 formula” has been validat- Skin testing
ed in clinical practice and currently considered significant in clin-
ical practice as a criterion of severe systemic mast cell activation The rationale of skin testing lies in the presence of an IgE-mediat-
and mast cell activation syndrome (MCAS) (86). ed pathogenesis and mast cell involvement. If performed within
Histamine is also a marker of mast cell and basophil activation. 2 to 4 weeks after anaphylaxis, skin tests are highly specific for
Blood samples for measurement of its levels are optimally ob- type I reactions to Hymenoptera venoms (HV), foods, drugs (e.g.
10 M. B. Bilò, M. Martini, C. Tontini, et al.

beta-lactams, general anesthetics, platins). Unlike HV and drug SsIgE determination in BL allergic reactions has to be per-
allergies where both prick and intradermal test should be per- formed togheter to skin testing since cases with immediate
formed, only skin prick test (SPT) are indicated for food allergy hypersensitivity reactions to BL with negative ST and positive
diagnosis. Associations between SPT wheal size and severity of ssIgE have been reported (103). As for ST, also the sensitivity
reaction on food challenge have been observed in a few studies, of ssIgE decreases with time, thus suggesting to be performed
but these findings have not been consistent among studies (94). as soon as possible after the reaction (104). In patient with BL
In HV allergy, the sensitivity of the prick test is lower than the anaphylaxis, clearly positive ssIgE can be useful for avoiding
one of the intradermal test; intradermal tests should be per- both ST and drug provocation test (DPT) (105).
formed even in case of positive prick test to identify correctly SsIgE quantification can be used for a limited number of drugs
the cutaneous end-point which will be useful in VIT follow-up; in the perioperative setting. The reported sensitivity and spec-
in case of negative tests in subjects with a suggestive history, tests ificity are very good for sIgE for latex and chlorhexidine, but
should be repeated after 1-2 months (95). show great variation for NMBAs and morfines (99).
As for immediate hypersensitivity reactions to beta-lactams In general, ssIgE determination cannot be used for the eval-
(BL), skin tests are more sensitive than in vitro test (96); even uation of the majority of drugs able to induce IgE-mediated
tought they become negative with time (93), they should be reactions (104).
performed with great caution in case of anaphylaxis (97). It is
important to enphasize that skin testing to penicillins requires Component Resolved Diagnosis (CRD)
major and minor determinants (93), the latter being available
only in some European countries (98). CRD, using single molecules or panels of allergens, is a new tool
Skin testing in perioperative anaphylaxis are useful and all which has revolutionized allergy diagnosis in recent years, help-
drugs/agents used before the reaction should be tested. An IgE- ing to improve diagnostic accuracy, and in some cases providing
mediated mechanism has not been demonstrated for all drugs/ information on risk assessment and consequently on manage-
agents, and a validation of skin testing is lacking. Testing and ment (106). Nevertheless, we must note that is only able to as-
subsequent interpretation should be performed by experienced sess sensitization and not clinical reactivity.
personnel using standardised concentrations as several drug As for food allergy, CRD may be helpful in complicated, poly-
groups, especially NMBAs and opioids, can cause irritant skin sensitized patients, mixed food intake, as well as in cofactor-en-
reactions (99). hanced food allergy (ω-5-gliadin, and nonspecific lipid transfer
For antibiotis other than beta-lactams as well as many other proteins (nsLTP) (31, 50, 107) and in red meat delayed anaphy-
drugs, skin testing lacks well-defined predictive values. Positi- laxis (α-Gal) (108).
ve skin tests with nonirritant concentrations are suggestive of Anaphylaxis has been associated with certain components, such
drug-specific IgE; however, negative skin tests are less helpful as seed storage proteins (2S albumins, 7S vicilins, and 11S le-
due to unclear negative predictive values (100). gumines) or nonspecific lipid transfer proteins (nsLTPs) (109),
Finally, patients with cytokine storm-like reactions and com- even tough severity risk attributed to specific molecules may vary
plement activation are likely to have negative skin test results, according to other factors such as geographic variations, degree
indicating the lack of IgE participation, but patients with mixed of allergen exposure, cosensitizations, and cofactors (110).
reactions can have positive skin test results (71). In the field of HV allergy, CRD may discriminate between pri-
mary sensitization and cross-reactivity in patients with double/
Serum specific IgE multiple positivity in diagnostic tests with whole extracts (es-
pecially in case of bee and yellow jacket double sensitization),
Together with clinical history and SPTs, serum specific IgE allowing the specialist to choose the most suitable venom for
(ssIgE) determination is commonly used for diagnosis of food specific immunotherapy (VIT), avoiding unnecessary VIT and
allergy, thus reducing the need for food challenge (101). How- reducing the risk of side effects (111). CRD may be useful in
ever, the clinical utility of sIgE for assessing risk of severe reac- patients with negative allergy tests and a proven history of a
tions has not been yet established (94). previous systemic reaction, including those with mast cell disor-
The sensitivity of serological tests using HV whole extracts is ders, who could benefit from VIT. In honeybee venom allergy,
generally lower than that of skin tests, and for Vespula spp. it is different sensitization profiles have been identified, which could
lower than the one for bee venom. In general, in vitro tests for the be associated with a greater risk of VIT failure or treatment side
search of specific IgE toward the whole extract of venom can be effects (112, 113).
negative in up to 20% of patients with positive skin tests, wher Latex allergy may be an important cause of anaphylaxis, even
eas approximately 10% of patients with negative skin test are though its incidence has decreased in the last 10 years. In this re-
positive at in vitro test, suggesting to perform both tests (102). gard, monosensitization to Hev b 8 (profilin) suggests cross-re-
Anaphylaxis 11

active and asymptomatic sensitization, whereas markers of gen- other provocation tests in that incremental allergen exposure is
uine allergy like Hev b 1, Hev b 3, Hev b 5, and Hev b 6, may not possible and insect biology and several other factors may
potentially induce severe reactions, thus making it necessary to influence the test result. Even if it may have an indication du-
apply avoidance measures (114). ring VIT to verify its efficacy, it is contraindicated in untreated
A diagnosis of idiophatic anaphylaxis (IA) is based on exclusion of patients and after stopping the treatment (124).
known triggers of anaphylaxis, as well as conditions that can ma- Drug provocation test (DPT) is a part of drug allergy workup.
squerade as anaphylaxis (115). The diagnostic utility of an allergen The majority of the studies were perfomed with BL. The Euro-
microarray (ImmunoCAP ISAC) in the detection of possible aller- pean guidelines and the U.S. practice parameter give different
genic triggers in patients with unexplained anaphylaxis has been indications to the DPT with BL, and a significant heterogene-
evaluated, showing evidence of sensitization to newly identified ity in European current practice has been recently demonstrat-
allergens (mainly wheat, shrimp and peanut) that had not been ed (105). However, in the case of anaphylaxis DPT should be
detected during routine allergy workup, even tough an allergen avoided regardless of the type of drug involved.
challenge procedure to confirm the diagnosis was not performed
(116). Finally, CRD has no application in the field of drug allergy. Idiopathic anaphylaxis and mastcell diseases

Basophil Activation Test (BAT) Idiopathic anaphylaxis is a diagnosis of exclusion and manda-
tes careful consideration of all recognizable and rare causes of
Among blood-cell based tests, BAT is the most widely used in anaphylaxis (115, 125, 126). The clinical manifestations and
Europe for diagnostic purposes, in selected situations, and in management of acute episodes are the same as for other forms
highly specialized laboratories. of anaphylaxis. A good clinical history is paramount to direct
The BAT has shown to be more accurate than IgE sensitization further investigations. Idiopathic anaphylaxis represents an op-
tests and able to distinguish individuals that were clinically al- portunity for identification of previously unrecognized novel
lergic from those who were tolerant to some food like peanut, triggers and also for identification of mastocytosis or clonal
showing a high specificity, thus dispensing from doing food mast cell disorders. Particular attention should be paid to “hid-
provocation test (117). den allergens,” cofactors (i.e. wheat-dependent exercise-induced
The BAT can identify approximately two thirds of HV allergic anaphylaxis), galactose alpha-1,3 galactose (a carbohydrate con-
patients with positive history and negative skin and serological tained in red meat) allergy, pigeon tick bite (Argax reflexus), and
tests (118). It is also recommended in patients with double pos- Anisakis simplex allergy (115). Out of the 30 cases of IA with
itive results and inconclusive results of in vivo or in vitro tests no signs of cutaneous mastocytosis, 47% were found to have an
with recombinant allergens (119). The role of BAT as a diag- aberrant MC population and were subsequently diagnosed with
nostic tool in patients with mastcell disorders and negative ven- clonal mastcell (MC) disorder (127). Similarly, the presence of
om-specific IgE and skin test results is still controversial (95). a clonal mast cell population with a diagnosis of IA was repor-
Taking into account the diagnostic difficulties specific to drug ted, in whom there were no features of urticaria pigmentosa or
allergy and risks related to provocation test in the case of ana- histological evidence for systemic mastocytosis on bone marrow
phylaxis, the BAT should theoretically represent a safer oppor- (BM) biopsy (128). These findings demonstrate a need for ro-
tunity to be improved. Several studies over the last 15 years have bust criteria for BM examination in cases of suspected clonal
reported the diagnostic accuracy of BAT for allergy to a range MC disorders in the context of IA. The only available validated
of drugs including betalactams, quinolones, platins, and neuro- tool is the Spanish Network on Mastocytosis (Red Española de
muscular blocking agents (NMBAs) (120). Mastocitosis - REMA) scoring system, based on a combined cli-
nical (i.e. gender and clinical symptoms) and laboratory (baseli-
Provocation test ne tryptase value with “cut-off ” of 15-25 ng/mL) parameters, to
predict underlying MC clonality in patients presenting with sy-
The food allergen provocation test (FAPT) provides a gold stan- stemic MC activation symptoms, including anaphylaxis (129).
dard diagnostic for food-related adverse reactions leading to ap- Other differential diagnoses include “allergy-mimics” such as
propriate food avoidance (101). However, a severe anaphylactic asthma masquerading as anaphylaxis, undifferentiated soma-
reaction to a given food with highly positive IgE tests, and a hi- toform disorder, panic attacks, globus hystericus, vocal cord
story of several reactions to the same food, will in most cases not dysfunction, scombroid poisoning, vasoactive amine intoleran-
need a FAPT (121). The use of CRD in some cases may help ce, carcinoid syndrome and phaeochromocytoma (115). Dia-
to grading the risk of a positive reaction to FAPT (122, 123). gnosis must be revisited in cases with recurrent episodes, where
The sting challenge has a low predictive value as a patient with there is paucity of clinical signs and/or in the context paucity of
a negative test might still react on a field sting. It differs from refractoriness to corticosteroid therapy.
12 M. B. Bilò, M. Martini, C. Tontini, et al.

Treatment and management ce, France, and Spain (maximum 66.7%). Nevertheless, over the
last decade adrenaline administration from a health professional
Patients with a history of anaphylaxis have an increased risk of se- almost doubled to reach 30.6% in 2015-2017, probably reflec-
vere reactions in the future, thus indicating that secondary preven- ting improved guideline distribution and awareness (130).
tion measures are of paramount important, as suggested by differ- All patients with a history of anaphylactic reaction should be pro-
ent international guidelines (1, 2). The most important preventive vided with adrenaline autoinjectors to be injected into the vastus
measures include the identification, and consequent avoidance of lateralis muscle (1-6). There are six absolute indications for a pre-
triggers and co-factors, the recognition by the patient of the first scription of an adrenaline auto-injector (1): previous anaphylaxis
symptoms indicative of anaphylaxis, the availability of an (AAI) with food, latex, aeroallergens such as animals or other unavoid-
and management training, optimal management of relevant co- able triggers; previous exercise-induced anaphylaxis; previous IA;
morbidities, venom specific immunotherapy, food oral immuno- co-existent unstable or moderate to severe, persistent asthma with
therapy, and drug desensitization, when indicated (figure 1). food allergy; venom allergy in adults with previous systemic reac-
tions (unless receiving maintenance VIT) and children with more
Acute treatment: adrenaline than systemic cutaneous reactions; and underlying mast cell disor-
der and any previous systemic reaction. European Guidelines (1)
The acute management and treatment of anaphylaxis depend on suggest also to consider prescribing at least one adrenaline auto-in-
early recognition and prompt use of adrenaline, as it is the first- jector with any of the following additional factors (especially if
line treatment of anaphylaxis and it is life-saving (1-6). Treatment more than one is present): previous mild-to-moderate allergic reac-
of anaphylactic reactions in the hospital setting should adhere as tion to peanut and/or tree nut; teenager or young adult with a food
closely as possible to guidelines. Indeed, only 27.1% of Euro- allergy; emote from medical help and previous mild-to-moderate
pean patients with anaphylaxis treated by a health professional allergic reaction to a food, venom, latex, or aeroallergens; previous
received adrenaline and, in total, 10.5% received a second dose mild-to-moderate allergic reaction to traces of food. Indications
(130). Interestingly, successful administration was less frequent for prescription of a second adrenaline auto-injector have been also
in German-speaking countries (minimum 19.6%) than in Gree- suggested (1). Of note, the European Medicines Agency (EMA),

Figure 1 - Algorithm for the management of anaphylaxis in clinical practice.

Hymenoptera Drugs
SYMPTOMS OF ANAPHYLAXIS
Foods
(+ atypical symptoms in case of
Unknown
chemiotherapy)
Environmentals

Risk factors Co-factors

DIAGNOSIS
Tryptase
Elevated
Skin tests
sIgE (+ CRD)
Normal
Provocation test
(REMA score +) (BAT) + + + -
Search for
Venom Food Drug Idiopathic
Mastcell diseases

+
TREATMENT
Management of co-morbidities

Multidisciplinary Avoidance Avoidance Avoidance

approach AAI (+ co-factors) Desensitization
VIT AAI
OFIT

VIT (venom immunotherapy); AAI (adrenaline autoinjector); OFIT (oral food immunotherapy); BAT (basophil activation test); CRD (component resolved diagnosis).
Anaphylaxis 13

after evaluation of all available data, recommended healthcare Drug desensitization to drug is a highly effective readministra-
professionals to prescribe two autoinjectors (European Medicine tion strategy for those patients who develop hypersensitivity reac-
Agency, 26 June 2015. EMA/411622/2015). tions to their needed medications, like chemotherapeutic agents,
According to the data from the Anaphylaxis Registry (131), mAbs (72, 139, 140), antibiotics (141) and many other drugs
an AAI prescription was offered to only 37% of the patients (142). Of note, it has been documented that carboplatin-desensi-
ouside specialized centers compared to 84% of the patients in tized patients had a non-statistically significant lifespan advantage
specialized allergy centers, highlighting the need of better edu- over nonallergic controls, indicating that the efficacy of carbopla-
cation for primary healthcare and emergency physicians to fol- tin was not reduced in allergic patients and that desensitization
low guidelines. In the multivariate analysis, the elicitor of the protocols are as effective as regular infusions (140). Even patients
reaction (less prescriptions in patients with food allergy than in presenting with type I and cytokine-release reactions to mAbs are
those with venom allergy), age of the patient (less prescriptions thought to be candidates for desensitization (11).
in babies and elderly patients), mastocytosis as comorbidity, se- The anti-IgE mAb Omalizumab has been shown to be a successful treat-
verity of the reaction, and reimbursement/ availability of the au- ment for reducing the number and severity of anaphylactic reactions
toinjector influence physician’s decision to prescribe one (131). in association with VIT (58) or with food oral immunotherapy (143).
An integral part of the anaphylaxis action plan is represented by ad-
vising patients to carry the device with them at all times, as well as Conclusions
instructing the patient on how to use the autoinjector through ed-
ucational material and practical training (1, 2). Nevertheless, in Eu- Anaphylaxis is the most severe allergic reaction, it involves mul-
rope few lay- or self-treated cases receive an autoinjector (14.7%), tiple organ systems, can be caused by a number of triggers and
even tough clinical severity considerably influence the likelihood of conditions, and be deadly. Although rapid advances in allergy
receiving adrenaline (130). Moreover, it is alarming that no chan- and immunology concerning the identification of new allergens,
ge in successful administration by lay emergency respondents was biomarkers and cofactors, as well as the availability of new diag-
found over the last 10 years (130), underlining the persistence of nostic tools, there are still many gaps in evidence and knowledge.
several gaps in the management of severe allergic reactions (132). There is still much to be done to identify genetic and epigenetic
Although many patients are afraid to use their AAI (133), no markers and cofactors for determining risk of anaphylaxis to spe-
significant adverse effects have been reported, with the excep- cific allergens, performing an individual risk assessment, and pre-
tion of the known onset of tachycardia, tremors, and peripheral venting future episodes by developing personalized risk reduction
vasoconstriction (134). strategies. Gaps in knowledge and anaphylaxis management have
Finally, corticosteroids and antihistamines are not lifesaving, they been observed at different levels, at the level of patients, communi-
have not been demonstrated to prevent biphasic anaphylaxis and ty as well as physicians (131). Diagnosis of anaphylaxis, evaluation
their use should never delay adrenaline administration (1, 2). of the severity of the allergic reaction, and the use of adrenaline is
insufficient for many physicians and a gap between best practice
Specific immunotherapy and desensitization and Emergency Department (ED) care has been also reported.
These findings highlight the need for an easier definition of ana-
Specific subcutaneous immunotherapy for hymenoptera venom phylaxis especially for non-allergists to improve the diagnosis and
is the only treatment able to protect patients from systemic reac- consequently the appropriate treatment with adrenaline.
tions after subsequent stings (protection against reported in 91- Further identified gaps in the management of anaphylaxis include
96% of cases, 77-84% for bee allergy) (135). Nonetheless, VIT infrequent or delayed use of AAI by the patients for acute aller-
offerslong lasting protection upon re-sting even after discontin- gic reactions, as well as inadequate AAI training, and prescription
uation of treatment, and increases dramatically the quality of life rates for patients at risk (144). A recent review of a number of
of HVA patients (95, 135). It is effective and safe even in patients English language anaphylaxis management plans underlines a
with mastcell diseases (136). As rush and ultra-rush protocols offer wide variety of content, with no plans having 100% of the rec-
rapid protection from re-sting as early as the maintenance dose is ommended material (145). Therefore, more appropriate training
achieved, they should be offered to patients with severe reactions. for patients, families and caregivers of patients are necessary.
Even though oral food immunotherapy may increase the Finally, very few studies are being designed to determine how to
amount of a tolerated dose over time (137), and enhances sus- increase adherence to existing anaphylaxis guidelines and best
tained unresponsiveness that persists after cessation of therapy practice through integrated knowledge translation strategies.
(138), there are currently no established oral immunotherapy
treatment protocols for food-induced anaphylaxis. Since signif- Conflict of interests
icant systemic side-effects can occur, currently this treatment is
not recommended in clinical practice (101). The authors declare that they have no conflict of interests.
14 M. B. Bilò, M. Martini, C. Tontini, et al.

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