Current update on anaphylaxis: anaphylaxis management in recent guidelines

© 2024 Associazione Allergologi Immunologi Italiani Territoriali e Ospedalieri - AAIITO. Published by EDRA SpA. All rights reserved
R E V I E W Eur Ann Allergy Clin Immunol Vol 56, N.2, 51-64, 2024
Current update on anaphylaxis: anaphylaxis
management in recent guidelines
Darío Antolín-Amérigo , Carmen Vidal-Albareda , David González de Olano ,
Belén de la Hoz-Caballer
Introduction
The awareness of anaphylaxis as a life-threatening medical
condition and its incidence have been increasing among dif-
ferent specialties, and so is the growth of evidence in the field.
The reported increases probably reflect a true increase in the
prevalence of allergic disease, but they are also confounded by
the cumulative incidence of anaphylaxis, better awareness and
recognition of anaphylaxis, and due to changes in anaphylaxis
coding.
Anaphylaxis is recognized as a severe, life-threatening systemic
hypersensitivity reaction, characterized by rapid onset and the
potential to endanger life through respiratory or circulatory
compromise.
In our article we aimed to cover not only what it is included in
the scientific Societies guidelines, but also other means of scor-
ing the severity of the anaphylactic episodes which is in our view
not sufficiently gathered in the literature.
Definitions
Anaphylaxis is an underrecognized acute syndrome comprising
a life-threatening generalized or systemic hypersensitivity reac-
tion characterized by a severe acute onset of symptoms, involv-
Allergy Service, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS),
Madrid, Spain
Key words
Anaphylaxis; hypersensitivity reaction; adrenaline;
epinephrine; Immunoglobulin E.
Corresponding author
Darío Antolín-Amérigo
Allergy Service
Hospital Universitario Ramón y Cajal, Instituto Ramón
y Cajal de Investigación Sanitaria (IRYCIS)
Carretera de Colmenar, Km 9,100
28034 Madrid, Spain
ORCID: 0000-0001-5699-4022
E-mail: [email protected]
Doi
10.23822/EurAnnACI.1764-1489.306
Impact statement
Currently existing definitions, scoring methods,
potential triggers of anaphylaxis and its
epidemiology, and guideline recommendations are
reviewed, proposing a novel anaphylaxis calculator.
Summary
Anaphylaxis is a potentially fatal hypersensitivity reaction but frequently un-
derrecognized. Although its incidence rates vary according to geographical
location, it seems clear that there has been a general increase in recent years,
either because of greater recognition of this entity or because it is progressing
proportionally to the presence of allergic diseases in the world. The devel-
opment of anaphylaxis management guidelines adapted to local or regional
needs seems of utmost importance. Furthermore, it is necessary to assess their
implementation and their positive effect regarding diagnosing and treating
anaphylaxis. In this review we explore the currently existing definitions of
anaphylaxis and its epidemiology, the potential triggers of anaphylaxis and
guideline recommendations in terms of diagnosis and management, propos-
ing a novel anaphylaxis calculator and reviewing the current scoring methods
for anaphylactic episodes.

52
Darío Antolín-Amérigo, Carmen Vidal-Albareda, David González de Olano, Belén de la Hoz-Caballer
ing different organ systems, generally involving airway, breath-
ing or circulatory problems and is usually, although not always,
associated with skin and mucosal changes, requiring immediate
medical intervention (figure 1) (1-4).
The mechanism of anaphylaxis may be either: 1) immunologic,
involving Immunoglubulin E (IgE), IgG or immune complexes;
or 2) non-immunological (5).
The presenting symptoms can be very varied. However, in over
90% of cases, there are associated skin and mucosal changes.
Furthermore, it usually (> 50% of cases) involves the airway
(pharyngeal or laryngeal oedema) and/or breathing (broncho-
spasm with tachypnoea) and/or circulation (hypotension and/
or tachycardia).
Epidemiology
None of the actual Academy guidelines, namely, EAACI, WAO,
AAAAI, NICE, or the Australian Society of Allergology and
Clinical Immunology, has a major focus in this area, but all in-
clude important information about epidemiology, supported by
relevant references. Therefore, focusing on anaphylaxis remains
as an unmet need, in terms of trustable data. The potential chal-
lenges could be the diverse and sometimes overlapping nomen-
clature and criteria for diagnosis of anaphylaxis. Hitherto, prev-
alence estimates of anaphylaxis vary widely, and many studies,
particularly in developed countries, suggest that the prevalence
is increasing.
There are differences in prevalence and causes throughout the
world probably due to distinct environmental factors which might
act differently to affect risk of different types of allergies accord-
ing to genetic predisposition in diverse areas of the globe and that
would account for the rise in the prevalence more rapidly than
expected (table I) (1-13).
Data from the European anaphylaxis registry revealed that over
one-quarter of cases (25%) occurred in patients under 18 years
of age (14).
Although the fatality rate attributable to anaphylaxis remains low
(15), the frequency of hospitalization for food and drug-induced
anaphylaxis has been increasing in recent years (7, 16, 17).
The main causes of fatal anaphylaxis are drugs (29%-58.5%), in-
sect stings (3.3%-54%) and food (2%-6.7%) (table II) (9, 18-25).
An important aspect are biphasic anaphylactic reactions which
account for up to 20% but other studies report a prevalence
from 1% to 7% among patients with anaphylaxis (26, 27).
Existing anaphylaxis guidelines therefore recommend contin-
uous follow-up for several hours after resolution of the initial
reaction after administering intramuscular injection of adren-
aline as first-line anaphylaxis treatment and glucocorticoids,
histamine-1 receptor blockers, and beta-2-adrenergic receptor
stimulants as second-line treatments (27). In a meta-analysis of
retrospective-observational studies performed in Japan of the
31,570 eligible patients, 28,145 (89.2%) were treated with glu-
cocorticoids on the day of admission. The overall percentage of
biphasic reactions within 7 days of admission was 11.2%, and
the authors stated that there were no significant differences in
rates of biphasic reactions (10.7% in the glucocorticoids group
vs 10.5% in the control group; odds ratio 1.03; 95% confidence
interval 0.85-1.24; p = 0.77) between patients with anaphylaxis
Table I - Worldwide incidence, prevalence and mortality of anaphylaxis.
European
(globally) 
U.K. U.S.A. WAO Children 
AAAAI/
ACAAI 
Spain
Incidence 1.5-7.9/100,000
person-years
1-7
cases/100,000
person-years
50-112/100,000
persons-years
1-761/100,000
person-years
42/100,000
persons-years
Prevalence 0.3% 1.6% 0.3-5.1% 1.6-5.1%
Mortality 0.47-0.69 per
10
6 
persons-years
63-99 deaths/
year (> 75%
in hospitalized
patients)
Drugs: 0.005-
0.51 per 10
6
persons-years
Food: 0.09-0.13
0.002-2.51
deaths/10
6
persons-
years
Figure 1 - Severity scoring.
*Modified from Shaker et al. (72); subjectivity of studies regarding scoring anaphylaxis.
Subjectivity
Small expert
groups
Most existing
scoring systems
were developed by
a limited number
of experts, and fit
into this category
This approach
uses data to
inform otherwise
subjective decisions
by experts as to
what symptoms
constitute what
level of severity
This approach uses
raw symptom data
and mathematical
modelling to
derive a score
independent of
expert input
(e.g. nFASS score)
Dribin et al.
Expert consensus
(e.g. Delphi) 
Data-informed Data-driven

53
Anaphylaxis management in recent guidelines
treated with and without glucocorticoids on the day of admis-
sion and the authors concluded that they would not support the
use of glucocorticoids to prevent biphasic reactions in hospital-
ized patients with severe anaphylaxis requiring adrenaline.
Therefore, the prevalence of the various causes of anaphylaxis is
age-dependent and varies between different geographical areas
(tables I and II). In general, food, drugs, and Hymenoptera
venom are the most frequent elicitor groups worldwide (10, 24-
41).
Drug-induced anaphylaxis is typically caused by antibiotics and
nonsteroidal anti-inflammatory drugs (NSAIDs) with age and
geographical variations (42-44). In terms of quality standards,
NICE guidelines are a unique document as it proposes some
criteria which are expected to contribute to improvements in
the following outcomes (45):
• Incidence of anaphylactic episodes.
• Admission rate due to anaphylactic episodes.
• Mortality from anaphylactic episodes.
NICE quality standards are centered on aspects of health and so-
cial care that are commissioned locally and comprise a brief set
of prioritized statements designed to drive measurable improve-
ments in the 3 dimensions of quality – safety, experience and
effectiveness of care, in terms of anaphylaxis (2, 45-49).
Key triggers include food, drugs, and stinging insects; in up to
20%, the elicitor is not identified. Their relative importance
varies with age and geography studied. For ED (Emergency De-
partment) presentations, drugs and foods are the most common
elicitors of anaphylaxis, with age-related differences (6, 50).
Foods are the most frequent cause of anaphylaxis in children,
with pollen allergy and asthma being important risk factors
(4, 6).
Drug- and Hymenoptera venom-triggered anaphylaxis are more
common in adults than in children (6) in general, and specifi-
cally to plant foods and NSAID. Drugs are the most frequent
cause of anaphylaxis in hospitalized patients.
Compared to males, adult females have a higher frequency of
anaphylaxis.
Cumulative incidence of anaphylaxis ranges from 26.5% to
54%, with a follow-up time of 1.5 years to 25 years (9). In
general terms, long-term management, and several structured
Table II - Principal triggers of anaphylaxis*.
Trigger Frequency in Spain Frequency in Europe Frequency in USA Frequency Worldwide
Drugs/medication 46.7-62%
NSAIDs, beta-lactams,
iodinated contrast media
Beta-lactams and
NSAIDNSAID
29%-58.5%
Antibiotics, NSAIDs,
immunomodulators, and
biological agents
Geographical variations
Foods 22.6-24.1%
Adults: fruits, nuts,
shellfish and fish
Children: egg, milk,
nuts, fish and shellfish
Central: peanut, tree nuts,
seeds like sesame, wheat,
and shellfish
Southern: LTP
Children: peanut,
hazelnut, milk, and egg
Adults: wheat, celery, and
shellfish; fruits such as
peaches are also typical
causes of food-induced
anaphylaxis in adults in
some European countries
such as Spain and Italy
2%-6.7%
Peanut and tree nuts are
dominating elicitors of
food-induced anaphylaxis
in adults in North
America and Australia
Vary locally.
Food-induced anaphylaxis
in children toto hen’s egg
(in infants and pre-school
children), cow’s milk,
wheat, and peanut.
Adults: nuts (U.S.A.),
shellfish (Asia),
buckwheat (Korea)
Insect stings 8.6-13.9% Wasp: Central Europe 3.3%-54% Bee: South Korea
Wasp: Central Europe
Snake Antivenom:
Australia
Physical factors 3.4-4%
Others (including latex) 7.26%
Idiopathic 3.4-5% 6.5-35%
There are regional differences in terms of culprit agents related to anaphylaxis; modified from Tanno et al. (3) and Gold et al. (49).

54
Darío Antolín-Amérigo, Carmen Vidal-Albareda, David González de Olano, Belén de la Hoz-Caballer
actions could achieve the desired prevention of recurrence [(ex-
tracted from references 8 and 34):
• Avoidance and/or allergen immunotherapy and/or desensi-
tization.
• Medical identification alert: e.g., bracelet or wallet card.
• Register in electronic or paper medical record the suspected
trigger(s).
• Anaphylaxis education and training.
• Public health measures, e.g., improved food labelling.
Methods
As this is a narrative review, evidence has been retrieved from
different sources. A literature search was performed using key-
words agreed on by the authors. The search was performed using
electronic databases (MEDLINE and PubMed), electronic li-
braries (Clinical Key, Science Direct, OVID), resources of clini-
cal guidelines (UpToDate, Allergy Societies Society Guidelines,
and Dynamed: https://www.dynamed.com/condition/anaphy-
laxis), and a database of systematic reviews (Cochrane Library).
Publications were selected from between January 2015 and De-
cember 2022. The selection took into account the keywords:
“anaphylaxis” and “guideline”. Due to the revolution in terms
of vaccines and adverse effects, we have also used the Brigh-
ton Collaboration Guideline for scoring anaphylaxis, which is
currently used worldwide for drug/vaccination regulatory issues
(available at: https://brightoncollaboration.us/anaphylaxis-case-defi-
nition-companion-guide/).
In addition, the filters used in PubMed were as follows: guide-
line, consensus development conference and consensus de-
velopment conference (NIH), practice guidelines, review,
systematic review, and meta-analysis. Guidelines, consensus
reports, systematic reviews, and meta-analysis were included;
nonsystematic reviews, comments, and other types of articles
were excluded. We also included studies examining incidence,
prevalence, natural history, clinical manifestations, pathogene-
sis, diagnosis, and treatment. All articles were reviewed by the
authors. Following this review process, 89 publications were
finally selected.
Diagnosis management ‒ scoring systems: beyond the
guidelines?
Anaphylaxis, as mentioned above, is known as a life-threatening
generalized or systemic hypersensitivity reaction involving dif-
ferent organ systems (1, 3, 34, 51).
There is a list of criteria that detail the symptoms or combi-
nation of symptoms which meet the clinical characteristics of
anaphylaxis. Traditionally, anaphylaxis was labeled when any of
the 3 proposed criteria were met (table IIIA) (52), although
recently the World Allergy Organization (WAO) has proposed a
new set of criteria (34, 52–55).
There are 2 recently proposed criteria for diagnosing anaphy-
laxis:
1. EAACI guidelines 2021 (table IIIA).
2. WAO guidelines 2020 (table IIIB).
The first one, probably is more specific, including the concept of
likely and/or known allergen in its criteria and the WAO guide-
lines specify the possibility of the absence of typical skin involve-
ment in the symptoms - WAO guidelines 2020 (table IIIB).
Classification of severity of anaphylactic episodes
Classification of severity implies a challenge, given that there
are not homogeneous definitions of subtypes of anaphylaxis (4).
In fact, there are different classifications that attempt to classify
anaphylaxis according to its severity (34, 52, 55-59). They are
divided into grades, ranging from I to V, based on the degree of
vital compromise. Not all of them cover the full range of symp-
toms that patients may present, and some of them were created
specifically for a particular trigger, such as Hymenoptera venom
(56) or food (58). This has led to the recent proposal of a classifi-
cation that attempts to unify the previous ones (59-61) or to the
creation of a new way of classifying anaphylaxis proposed by the
WAO (34) but none of them have been widely used up to now.
Given the trend on immunization, the Brighton Collaboration
(BC) was established in 2000 with the aim of developing glob-
ally accepted standardized case definitions for adverse events
following immunization (AEFI) as well as guidelines for the
collection, analysis and presentation of surveillance data (61).
It has served to improve the classification of the severity of an
anaphylactic episode following immunization. The Brighton
Collaboration Cased Definitions (BCCD), which are evidence
based, were developed by a group of experts to describe, in sim-
ple terms, all signs and symptoms used to constitute the BCCD
on anaphylaxis (62). The descriptive terms used in the case defi-
nitions could be used as a guide to develop educational and re-
cording material (63). The checklist could be used when sudden
or unexpected symptoms or signs occur post-vaccination, and
where anaphylaxis is a possibility. In contrast, checklist 2 col-
lects additional details such as demographic information as well
as vaccine data. Such checklists are more comprehensive and are
better suited to clinical trials or to the analysis of AEFI data at
a regional or national level. For example, more extensive check-
lists could be used as part of an investigation of individual cases.
If correctly completed, such checklists will aid in the assignment
of a BCCD for anaphylaxis (63, 64).
Once the symptoms and signs that may indicate anaphylaxis
have been reported on an AEFI report form and/or through
the use of a checklist, a case definition for anaphylaxis can be
assigned. It is intended that the task of assigning a case defini-
tion is performed at a regional or national level because of the
complexity of the case definition. In addition, online tools are
being developed by the BC to facilitate this process and these

55
Anaphylaxis management in recent guidelines
will be freely accessed at the Brighton Collaboration website:
http://www.brightoncollaboration.org/internet/en/index.html.
A potential limitation to collecting exhaustive adverse event re-
ports is that health care providers are unlikely to spontaneous-
ly report enough symptoms and signs to allow application of
BCCD. A checklist, based on the terms used in the case defini-
tion, could be developed and incorporated in an AEFI report-
ing form to remind vaccine providers to note whether specific
features of anaphylaxis were present. Another limitation of the
anaphylaxis case definition is the hypothetical inconsistencies in
the reporter’s use of the terms used to describe possible anaphy-
laxis. This would be addressed by the development of a glossary
to describe those terms used in the anaphylaxis case definition.
With these barriers in mind, Stafford et al. have created a clini-
cal checklist for the application of the BCCD and a glossary of
terms to harmonize the use of reporting terms (65).
As Stafford et al. stated recently, having a standardized, inter-
nationally agreed on quantitative measure of severity might be
useful in facilitating risk communication, both with patients
and with industry/regulators. Consistency and translatability in
recording results are essential and currently constitute unmet
needs in the field of anaphylaxis. However, any severity score
must be fit for purpose, be informed by patient and clinician
experience, and ideally be data driven to minimize the impact of
subjectivity and provide objective validation (figure 1 modified
from Dribin et al.) (66).
In the meantime, the severity score proposed by Dribin et al.
highlights the inconsistencies and limitations of the NIAID cri-
teria for anaphylaxis (66).
Developing our acquaintance of the relationship between the
definition of anaphylaxis (and indications for epinephrine treat-
ment) and severity grading of symptoms is essential for further
progress in this area. We need to achieve a global consensus on
updated anaphylaxis criteria to improve anaphylaxis recognition
and thus patient care ‒ it is what patients deserve.
Calculator of anaphylaxis
For the diagnosis of anaphylaxis in an acute context, the 2020
EAACI Task Force on anaphylaxis, has suggested using clinical
criteria, including rapid onset of multiple symptoms, measuring
serum tryptase half to two hours after the start of the reaction,
and baseline tryptase at least 24 hours after complete resolution
of symptoms, to support diagnosing anaphylaxis retrospectively.
A number of studies have assessed the diagnostic accuracy of
Table III - (A) Clinical criteria for diagnosing anaphylaxis (EAACI guidelines 2021) (4); (B) WAO anaphylaxis guidelines 2020 (36).
A 
B
1. Acute onset of an illness (minutes to several hours) with
involvement of the skin, mucosal tissue or both (e.g., generalized
hives, pruritus or flushing, swollen lips-tongue- uvula and at least
one of the following: a. respiratory compromise (e.g., dyspnea,
wheeze-bronchospasm, stridor, reduced PEF and hypoxemia); b.
reduced BP or associated symptoms of end-organ dysfunction (e.g.,
hypotonia [collapse], syncope, incontinence).
1. Acute onset of an illness (minutes to several hours) with simultaneous
involvement of the skin, mucosal tissue, or both (e.g., generalized hives,
pruritus or flushing, swollen lips–tongue-uvula) and at least one of the
following: a. respiratory compromise (e.g., dyspnea, wheeze–bronchospasm,
stridor, reduced PEF, hypoxemia); b. reduced BP or associated symptoms of
end-organ dysfunction (e.g., hypotonia (collapse), syncope, incontinence);
c. severe gastrointestinal symptoms (e.g., severe crampy abdominal pain,
repetitive vomiting), especially after exposure to non-food allergens.
2. Two or more of the following that occur rapidly after exposure to a likely
allergen for that patient (minutes to several hours): a. involvement of the
skin–mucosal tissue (e.g., generalized hives, itch-flush, swollen lips-tongue-
uvula; b. respiratory compromise (e.g., dyspnea, wheeze-bronchospasm,
stridor, reduced PEF, hypoxemia); c. reduced BP or associated symptoms
(e.g., hypotonia [collapse], syncope, incontinence); d. persistent
gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting).
2. Acute onset of hypotension or bronchospasm or laryngeal
involvement after exposure to a known or highly probable allergen for
that patient (minutes to several hours), even in the absence of typical
skin involvement.
3. Reduced BP after exposure to known allergens for that patient
(minutes to several hours): a. infants and children: low systolic BP (age
specific) or > 30% decrease in systolic BP*; b. adult: systolic BP of <
90 mmHg or > 30% decrease from that person’s baseline PEF, peak
expiratory flow; BP, blood pressure. *Low systolic blood pressure for
children is defined as < 70 mmHg:
- from 1 month to 1 year, less than (70 mmHg + [2 × age])
- from 1 to 10 years and < 90 mmHg from 11 to 17 years.
(A) Anaphylaxis is highly likely when any one of the three criteria is fulfilled; (B) Anaphylaxis is highly likely when any one of the two criteria is fulfilled.

56
Darío Antolín-Amérigo, Carmen Vidal-Albareda, David González de Olano, Belén de la Hoz-Caballer
serum tryptase measurements for anaphylaxis, but the evidence
is of very low certainty, derived from consecutive case series or
case control studies (55, 67, 68).
In terms of practical management, taking the blood sample
should not delay treating a patient with adrenaline where nec-
essary. A sample taken later than 2 hours after the reaction may
still demonstrate a raised tryptase level.
An event-related transient elevation of the serum tryptase level
by at least 20% over the individual baseline plus 2 ng/mL ab-
solute (20%+2) within a 2-4 h window after reaction supports
a diagnosis of anaphylaxis (tryptase peak rising level ≥ (20% ×
baseline tryptase) + 2 μg/L) (69, 70).
It is interesting to note that a recent study quantified the ac-
tual benefit of measuring tryptase in Emergency Department
patients with anaphylaxis, which found that around 2% of the
patient cohort who did not meet diagnostic criteria for anaphy-
laxis would have elevated levels of serum-tryptase, higher than
the normal ranges of the local laboratory (> 12 μg/L) (57).
A raised serum tryptase level can be associated with a mast cell
disorder or hereditary alpha tryptasemia (71-73), so it is im-
portant to compare with a baseline level at least 24 hours after
complete resolution of a reaction. Moreover, serum tryptase is
not always elevated in anaphylaxis, especially in children and
with food triggers in all ages (74).
Apart from tryptase, a number of other MC-derived com-
pounds may serve as suitable parameters to document severe
reactions following systemic MC activation. These substances
include, among others, histamine and its metabolites, PGD2
and its metabolites, and heparin (75-77).
However, except for heparin, these mediators are less specific
for MC compared to tryptase. Methods to determine these
mediators are also much less available through widely distrib-
uted commercial assays and, moreover, none of these labora-
tory exams are validated for the diagnosis of anaphylaxis, so
far (69).
Management
The evidence base for the acute management of anaphylaxis is
weak and is established mainly by means of systematic reviews,
due to the absence of randomized controlled trials. However,
there seems to be a global consensus that intramuscular (IM)
adrenaline is the treatment of choice as the first step in the man-
agement of acute anaphylaxis (19, 34, 78).
All in all, there is room for improvement in its management
which shall be systematic (79).
Some of the unmet needs with regard to anaphylaxis are acute
management and with regards prophylactic measures (3).
There are several factors influencing the successful treatment of
an anaphylactic reaction such as specific training in anaphylax-
is management along with rapid identification and treatment,
which are critical (52, 79).
The basic principles for the treatment of anaphylaxis are com-
mon for all age groups, but it may be influenced by the context/
setting, personnel, equipment and by the available medication
(79, 80).
The necessary materials and medications to treat an anaphylac-
tic episode are (5, 6):
1. Stethoscope, pulse-oxymeter and tensiometer (including
equipment for blood pressure and cardiac continuous moni-
toring), watch or clock.
2. Tourniquets, syringes (with needles:1 mL, 10 mL, 20 mL)
and needles IV (gauge 19, 21, 23 and 25) and IM, and cath-
eter (gauges 14, 16, 18, 20 and 22).
3. Aqueous Adrenaline (1 mg/ml or 1/1,000) 0.01 mg/kg to a
maximum of 0.5 mg (adult) and 0.3 mg (child).
4. Equipment to deliver oxygen (oxygen tank, valve with
flow-meter, and extension tubing).
5. Equipment to deliver IV fluids.
6. Intubation material: ambu bag/valve/mask, self-inflating
with reservoir (volume 700-1,000 mL (adult), 100-700
(child) and disposable face masks; oropharyngeal airways: 6
cm, 7 cm, 8 cm, 9 cm, 10 cm; pocket masks and nasal can-
nula, laryngeal mask airways.
7. Antihistamines IV (chlorpheniramine 10 mg (adult), 2.5-5
mg (child) or diphenhydramine 25-50 mg (adult) (1 mg/kg,
maximum 50 mg (child)).
8. Corticosteroids IV (hydrocortisone 200 mg (adult), max-
imum 100 mg child or methylprednisolone 50-100 mg
(adult) 1 mg/kg, maximum 50 mg (child).
9. Vasopressors IV (dopamine, noradrenaline…).
10. Glucagon.
11. Defibrillator.
12. Inhaled Beta-Adrenergics: salbutamol solution 2.5 mg/3 mL
or 5 mg/3mL (adult) (2.5 mg/3 mL, child) given by nebu-
lizer and face mask.
13. Other supplies: extension tubing, T connectors, 3-way stop-
cocks, armboards, written emergency protocol for anaphy-
laxis treatment, flow chart for recording times and events,
gloves.
The emergency treatment of a patient who is suffering an ana-
phylactic reaction may differ if it occurs outside of a health-
care institution or inside a hospital/ambulatory center. Both the
available resources and the accessibility to a hospital/ambulatory
center may influence the first approach.
Management outside of a healthcare institution
The first step, regardless of the context and the severity of the
anaphylactic reaction, would be the use of adrenaline autoinjec-
tor and subsequently an immediate phone calling for emergency
support (table IV). Any healthcare professional shall be capable
of initiating the treatment of a patient who is suffering from
an anaphylactic reaction and calling for emergency support.

57
Anaphylaxis management in recent guidelines
Rescue volunteers, paramedics, lifeguards, and nurses shall be
trained, updated, and sufficiently skilled to cope with an ana-
phylactic reaction (81, 82).
Equipment and available medication (in a healthcare insti-
tution)
Every healthcare institution shall have a crash cart containing all
the necessary equipment and medication to make a complete car-
diorespiratory resuscitation and to treat a potential anaphylactic re-
action (see paragraph Management). Every health care professional
shall be familiar with the equipment and every medication shall be
reviewed periodically. Whenever a patient begins to suffer an ana-
phylactic reaction, it has to be monitored as soon as possible (79).
Minimal approach requirements for a potential anaphylactic
episode
1. Stratifying patient’s severity (figure 2).
2. Early emergency support request.
3. Initial treatment based on ABCDE approach.
4. Adrenaline (when indicated).
5. Preferential study and follow-up by an allergist: essential.
Patient position (extensible for inside and outside a healthcare in-
stitution)
Whenever a patient is being treated or has suffered from an ana-
phylactic episode, it should be placed in a comfortable position,
laid down and with raised legs to gain venous return. This posi-
tion shall be avoided when vomiting or any kind of respiratory
failure. Postural changes shall be made with caution as they may
cause the worsening of a hemodynamic compromise. Uncon-
scious patients shall be placed in a lateral position. Pregnant
women shall be placed in the left lateral position to avoid cava
vein compression (83). Airways permeability shall be warranted
at all times (79). In case of respiratory failure, semi-recumbent
position can be considered. Anyhow, the UK Resuscitation
Council 2021 Guidelines comprise further details on patient
positioning in anaphylaxis (71).
Table IV - Indications for prescribing adrenaline autoinjectors, regardless of the context and the severity of the anaphylactic reaction.
A B
Previous (severe or near fatal)* anaphylaxis triggered
by foods, medication, aeroallergens, exercise- induced,
latex or idiopathic
Arguments for 2 autoinjectors 
Arguments for 1
autoinjector
Coexistent unstable or moderate-severe/severe asthma
and food allergy*
European Medicines Agency recommends 2
autoinjectors
Only needing to carry
one device may improve
adherence
Venom allergy in untreated patients and risk of re-
exposure
About 10% patients required a 2
nd 
dose of adrenaline
due to insufficient response to the 1
st 
dose
Most autoinjectors are
not used and have to
be replaced after 12-18
months
Underlying systemic mastocytosis in adults with any
previous systemic reaction. Children with very severe
skin involvement (>50% body surface) and increased
basal serum tryptase levels (>20 ng/ml) and with
blistering in the first three years of life*
Rarely, injection in the wrong place
Most patients respond to
1 dose and 2nd doses are
usually administered by
emergency services
Previous mild-moderate reactions to food 
Likelihood of delayed medical assistance (remote
location or travel)
Remote from medical help or repeated travel abroad
with mild moderate reactions to food, medication,
insect, latex or idiopathic*
Cardiovascular disease
Oral immunotherapy for food allergy
Previous requirement of more than 1 adrenaline dose
before arriving a healthcare institution*
If available adrenaline dose is too low for body weight*
(A) *At least 1 adrenaline autoinjector. Notwithstanding, consider prescribing 2 adrenaline autoinjectors; Modified from (4); (B) reasons for prescribing one or two
adrenaline autoinjectors (modified from references 4, 6, 79, 87).

58
Darío Antolín-Amérigo, Carmen Vidal-Albareda, David González de Olano, Belén de la Hoz-Caballer
In patients with a history of prior anaphylaxis, acute manage-
ment consists of two steps:
1. Self-management of the patient using an emergency proto-
col, in which it is important to emphasize the key role of
intramuscular adrenaline, encouraging the possibility of
self-administration of adrenaline using auto-injector devices,
no matter the severity of the anaphylactic reaction (table IV).
2. Additional interventions given by healthcare professionals
once medical help has arrived, which must include further
adrenaline if symptoms of anaphylaxis ongoing.
It is of note that the most effective and evidence-based treat-
ment for anaphylaxis is adrenaline, based on observational stud-
ies, extrapolation from retrospective case reports, and scarce
clinical trials (3, 32).
Airway protection
As patients with anaphylaxis can rapidly develop critical airway
compromise, it is crucial to protect the airway while other treat-
ments are administered (27).
Intubation should be considered early, as patients can decom-
pensate rapidly, which can make endotracheal intubation more
difficult or impossible and necessitate the placement of a surgi-
cal airway. If the patient shows intense laryngeal edema, non-
invasive positive pressure ventilation or supraglottic airways
Figure 2 - Treatment scheme of an anaphylactic episode.
Anaphylaxis
Airway, breathing, circulation, disability, exposure
Adrenaline i.m.
Children: 0.01 mL × Kg until 0.3 mg
Adults: 0.01 mL × Kg until 0.5 mg
• Call for help, remove potential trigger
• Optimize posture depending on presentation:
o Mainly respiratory- sit up with elevated legs
o Mainly cardiovascular-lie patient falt and elevate legs
High flow oxygen at 10 liters/minute with a reservoir bag:
• If circulatory/severe respiratory symptoms → i.v. fluid-crystalloid-bolus: adults/children > 30 kg:
500 ml i.v. bolus (repeat as needed)
• If stridor → nebulized adrenaline as supplement to i.m. adrenaline: 1 mg with 4 ml 0.9% NaCl
(repeat as needed)
• If wheeze → beta-agonist nebulized or Metered Dose Inhaler (MDI) + spacer (e.g., salbutamol):
o Adults and school children: nebulized 5 mg, MDI 600 mcg (repeat as needed)
If no improvement in 5-10 minutes: repeat i.m. adrenaline and give i.v. fluids
Consider giving a 2
nd 
dose by needle and syringe in case of autoinjector failure or using 0.5 mg for adolescents or adults
Circulatory or respiratory compromise despite i.m. adrenaline x 2 and i.v. fluids:
• Call emergency team including critical care expertise to provide advanced
treatment including adrenaline infusion
• Cardiac arrest: follow guidelines
When a patient is stabilized:
• Measure serum tryptase ½ to 2 hours after reaction onset
• Make decision about level and length of observation
• Consider additional treatment: antihistamines, corticosteroids
Monitor:
• Cerebral status
• Pulse oximetry
• Blood pressure
• ECG
Adrenaline i.m.
Children: 0/5 year old: 0.15 mg
Children: 6/12 year: 0.30 mg
Adolescents: 0.50 mg
Suspect anaphylaxis if:
- Acute onset
- Life-threatening A, B or C problems
- With skin/mucosa and/or severe
gastrointestinal (GI) symptoms 
(not always
present)
Symptoms (signs)
- Airway or breathing: dysphagia, hoarseness,
stridor, dyspnea, tachypnea, wheeze, cyanosis
- Circulation: tachycardia, hypotension,
dizziness, fainting, confusion
- Skin/mucosa/GI: generalized pruritus,
flushing, urticaria, angioedema, vomiting,
abdominal pain
Modified from references 4, 79, 84. *Adrenaline preferably shall be adjusted by weight.

59
Anaphylaxis management in recent guidelines
should be used with caution, as they may not be effective. En-
dotracheal intubation with direct or video laryngoscopy should
be attempted first by an experienced clinician if the oral edema
is judged to be navigable.
Supplemental oxygen should be administered to maintain oxy-
gen saturation > 90% (27).
Medication
Delayed epinephrine administration is associated with biphasic
reactions (78). It is a matter of debate whether glucocorticoids
would prevent biphasic reactions in patients with anaphylaxis as
they inhibit inflammatory responses by suppressing the function
of mast cells (78). Recent retrospective cohort studies have failed
to show any preventive effects of glucocorticoids on biphasic re-
actions.
Moreover, antihistamines have no role in the primary manage-
ment of life-threatening signs and symptoms of anaphylaxis, in-
cluding upper airway edema and shock. The rationale for their
use arises from the effectiveness in other allergic diseases, but
there are no specific data that suggest benefit in anaphylaxis (80).
Healthcare institution discharge after anaphylaxis
If the diagnosis of anaphylaxis (or suspicion) has been reached,
patients shall remain for 6-8 hours after complete resolution
of symptoms and up to 12-24 hours whenever a patient shows
refractory symptoms, or in the event of very severe reactions
or having a history of biphasic reactions. Other patients, who
would also need to stay longer, would be the following: 1) pa-
tients with difficult access to a healthcare institution, 2) severe
idiopathic anaphylaxis with slow progression; 3) severe asthma
or severe respiratory symptoms; 4) reactions in which the al-
lergen could be present if the patient is discharged; 5) severe
condition of the patient (cardiocirculatory compromise) (79).
It is mandatory to have a complete medical record indicating
all received medications and the evolution of the patient.
Recommendations after healthcare institution discharge be-
cause of anaphylaxis:
• Emergency department visit: if symptoms reappear.
• Antihistamines, corticosteroids, and prescription of adrena-
line autoinjector(s) (independently of the severity of the ana-
phylactic reaction) (table IV).
• Avoidance of potential culprit agents (foods, medications,
insects, etc.).
• Continued follow-up plan for general practitioners.
• Personalized plans, including referral to psychological sup-
port and patients’ organizations (4).
• Allergen immunotherapy and desensitization: allergen im-
munotherapy (AIT) is potentially a curative therapy. AIT
may increase the amount of food that the patient can tol-
erate, preventing allergic symptoms and reducing the risk of
potentially life-threatening allergic reactions (77).
Venom immunotherapy (VIT) is the model of immunotherapy
with regards the studies, its efficacy and the knowledge of the
physiologic modifications of induction of immune tolerance
produced (78). Moreover, it has been shown to improve the
quality of life of venom-allergic patients when compared with
patients who do not receive immunotherapy but carry adrena-
line (79).
Food Allergy-OIT is recommended for persistent Cow’s Milk,
Hen Egg, or peanut allergy for children from around 4 to 5
years of age on the basis of its ability to increase the threshold
for clinical reactions while on OIT (Grade A). At present, there
are insufficient data to be able to recommend AIT for other
foods and for adults outside clinical trials (77).
Personalized plans
Every patient should receive a written record with instructions
such as: avoidance measures and when and how to use the
adrenaline autoinjector (table IV). All patients shall be referred
to an Allergy Department to investigate the potential culprit
agent and to minimize present and future risks. New guidelines
point out the importance of prescribing personalized plans to
achieve the best approach in terms of continued follow-up of
patients who have suffered an anaphylactic reaction (4, 6, 52,
79, 85-87).
Education and training for health care professionals (HCP)
and patients at risk of anaphylaxis
The EAACI Task Force on anaphylaxis, along with other guide-
lines, recommends providing structured, comprehensive train-
ing to improve the knowledge and use of adrenaline autoinjec-
tors in people at risk of anaphylaxis. This is in addition to basic
instructions about autoinjector use (4).
Although it is unclear what types of training and support are
most effective, education is essential if patients at risk of ana-
phylaxis are to successfully recognize and manage future epi-
sodes. Diverse approaches are available, including the use of
adrenaline, autoinjector training devices, and online approach-
es. Training HCP using anaphylaxis simulators will improve its
management (4).
Other potential educational interventions
Some studies have also found that supporting patients to practice
using an adrenaline autoinjector or needle and syringe containing
0.9% saline can reduce anxiety or improve quality of life.
In the case of anaphylaxis during an in-hospital-based food/
drug challenge, patients and caregivers may be encouraged to
administer their own adrenaline autoinjector to improve their
confidence in this procedure. It is also important for allergists to
follow a patient’s anaphylaxis management plan during a prov-
ocation challenge (e.g., giving in adrenaline at the first sign of
anaphylaxis) to reinforce this self-management approach (88).

60
Darío Antolín-Amérigo, Carmen Vidal-Albareda, David González de Olano, Belén de la Hoz-Caballer
Approaches to prevent anaphylaxis in schools
School policies should reflect anaphylaxis guidelines, but more
research is needed to understand how guidelines and legislation
in schools are best implemented. Anaphylaxis due to food aller-
gy, occurs in schools more than in any other community loca-
tion (6).
Therefore, it may be helpful to target secondary schools and
community settings with educational support to help raise gen-
eral awareness, empower adolescents to confident self-manage
food allergy, and enable schools to develop protocols to mini-
mize any adverse events if they occur.
Other approaches investigated to improve the management of
anaphylaxis included nurses checking whether students were car-
rying autoinjectors and availability of a 24-hour helpline (89).
Knowledge gaps
In our opinion, there are three main areas of work that we con-
sider should be a priority to improve the management of ana-
phylaxis as described in the guidelines, which are those related
to the diagnosis of the disease, its classification and its manage-
ment (66, 88-91).
The difficulty in diagnosing anaphylaxis is that there is no
pathognomonic set of signs or symptoms, especially when no
cutaneous manifestations are present and there is not an im-
mediate history of drug administration or allergen exposure.
What is typical is the rapid progression in severity or intensity
of symptoms. For this reason, it would be advisable to unify
the diagnostic criteria and disseminate them, especially among
specialties that handle clinical emergencies.
Although the most important aspect is to recognize the entity
and initiate appropriate treatment (88, 89), it is also necessary
to use the same tools to classify the severity of a reaction. It
would be advisable to find a consensus and try to find a single
and suitable classification of anaphylaxis.
It would also be important to improve knowledge and tools
for the treatment of anaphylaxis (87). Turner et al. undertook a
thorough literature search about the pharmacokinetics (PK) of
adrenaline autoinjectors (66, 92, 93).
In community settings, adrenaline can be provided for emer-
gency use as an adrenaline autoinjector (AAI) device (table IV),
although these are not available in many countries (88, 89). Be-
sides, there is a barrier in the use of AAI and is the price. Allergy
societies and Patients’ Organizations in Spain are joining forces
to achieve a symbolic price, which is for many patients high,
given the expiration date of the AAI, so as to assure that every
patient at risk would carry AAI.
Given the currently available data, it takes at least 5-10 min to
achieve early peak plasma concentration for most devices and
the authors state that the specific autoinjector device seems to be
the most important determinant of pharmacokinetics, with dif-
ferent devices giving rise to different plasma adrenaline profiles.
Needle length does not seem to be the most important factor;
rather, the force and speed of injection (which varies from one
device to another) is likely to be of greater importance. In gen-
eral, peak plasma adrenaline concentration is lower and time-
to-peak concentration is longer with increased skin-to-muscle
depth. However, it is difficult to draw conclusions with the cur-
rent available data, due to a lack of head-to-head comparisons,
small numbers of study participants, and the failure to acknowl-
edge the biphasic nature of intramuscular adrenaline absorption
for analysis purposes.
Several studies tried to assess the impact of body mass index,
using the parameter of skin-to- muscle depth (STMD), assessed
by ultrasound. Notwithstanding, the numbers in each subgroup
would not allow to detect any small differences between groups.
Other studies found significant differences in terms of lower
SMTD and faster and greater increase in plasma adrenaline in
the normal weight men and vice versa (66, 78, 88, 89).
Although PK data are available, the most helpful study com-
paring three different devices is unpublished. According to all
international guidelines, the recommended dose of IM adren-
aline in adults is 0.5 mg; thus, a dose of 0.3 mg given by AAI
may be inadequate and should be repeated after 5-10 min in the
absence of resolution of symptoms (66).
Conclusions
Anaphylaxis is a potentially fatal hypersensitivity reaction. Al-
though its incidence rates vary according to geographical lo-
cation, it seems clear that there has been a general increase in
recent years, either because of greater recognition of this entity
or because it is progressing proportionally to the presence of
allergic diseases in the world. On many occasions, episodes of
anaphylaxis are treated by physicians working in Emergency
departments and are not directly evaluated by an allergist. It
is necessary to establish common and consensual guidelines to
help professionals and patients to know how to recognize ana-
phylaxis, as well as to be able to classify it, treat it correctly and
make future recommendations after the acute episode.
Studies comprising the epidemiology of anaphylaxis, as well as
the importance of biphasic reactions seem crucial to exactly de-
fine priorities in terms of research and resources.
Preventive measures, including personalized action plans may
circumvent the burden of anaphylaxis for patients, relatives, and
caregivers.
The development of anaphylaxis management guidelines adapt-
ed to local or regional needs seems of utmost importance, but
it is necessary to assess their implementation and their positive
effect regarding diagnosing and treating anaphylaxis.
There is a clear need for establishing multinational, large data-
bases/registries to collect high-quality epidemiologic risk factor

61
Anaphylaxis management in recent guidelines
data and diagnosis or treatment outcomes for improving the
management of patients with anaphylaxis.
Fundings
None.
Contributions
DA-A: conceptualization, formal analysis, methodology, proj-
ect administration, writing - original draft, writing - review &
editing. CV-A, DGdO, BDlH-C: conceptualization, writing -
original draft, writing - review & editing.
Conflict of interests
The authors declare that they have no conflict of interests.
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