EAACI Guideline on Allergen Immunotherapy - allergic asthma

V 4.0/04 June 2017

Short title: EAACI Guidelines on AIT for allergic asthma

Key words:
AGREE II, allergen immunotherapy, allergic diseases, atopy, asthma, asthma
control, asthma exacerbations, lung function

Abbreviations

AD = atopic dermatitis
AEs = adverse events
AGREE = Appraisal of Guidelines, Research and Evaluation
AHR = airways hyperreactivity
AIT = allergen immunotherapy
AR = allergic rhinitis
ARIA = Allergic Rhinitis and its Impact on Asthma
EAACI = European Academy of Allergy and Clinical Immunology
GINA = Global Initiative for Asthma
HCP = healthcare professional
HDM = house dust mites
ICS = inhaled corticosteroids
QoL = quality of life
RCT = randomised control trial
SLIT = sublingual AIT
SCIT = subcutaneous AIT
SMS = symptom and medication score

Abstract

Allergen immunotherapy (AIT) has been used to treat allergic disease for
more then 100 years. Despite broad evidence of clinical efficacy AIT remains
underused in allergic asthma. Achieving a wider consensus is of utmost importance
as AIT is the only treatment that can change the course of allergic disease by
inducing allergen-specific immune tolerance.
The European Academy of Allergy and Clinical Immunology has developed
clinical practice guidelines that aim to provide evidence-based recommendations for
the use of AIT for allergic asthma. These guidelines have been developed by a multi-
disciplinary expert working group using the Appraisal of Guidelines, Research and
Evaluation (AGREE) II framework. A systematic review of the current evidence has
been used to generate evidence based clinical recommendations.
The key recommendation is that AIT delivered via subcutaneous or sublingual
route is beneficial for mild and moderate allergic asthma, provided that asthma is
adequately controlled by pharmacotherapy. AIT has a significant impact on asthma
symptoms and medication, with a steroid sparing effect, improves disease specific
and generic quality of life (QoL) and specific airways hyperreactivity (AHR). The
influence on non-specific AHR and lung function is less prominent. No consistent
effects on asthma control and exacerbations have been validated yet in clinical trials.
AIT is a safe treatment for well-controlled allergic asthma in children and in adults.
AIT should be integrated in the general frame of asthma management aiming
to reduce symptoms, improve QoL and minimize future risk by decreasing
exacerbation rate, improving lung function (including AHR) and decreasing adverse
reactions to medication (steroid and beta-2 agonists sparing effect). More effective
AIT strategies including novel preparations, adjuvants and alternate routes of
administration are underway.

I. Introduction

Asthma represents a major health problem, affecting 300 million people

around the globe, with increasing prevalence and an overall projected increase to
400 million within the next 30 years [1-5]. It is the main cause for hospitalization and
paediatric emergency and causes significant burden by direct and indirect costs
(72,2 billion Euro annual). The major economic impact is due to indirect costs
(absenteeism and decreased productivity at the workplace) [6-9].
Asthma is a heterogeneous condition characterized by chronic airway
inflammation. Recognisable clusters of visible properties (clinical, inflammatory,
morphologic characteristics and unique responses to treatment) are described as
asthma phenotypes. Phenotypes do not necessarily provide insight into the
underlying pathogenetic mechanisms, which define the disease endotype [10-12].
Endotyping asthma enables its individualised management, including optimised AIT.
Allergic asthma has been extensively studied. It usually starts in childhood
and is often accompanied or preceded by allergic rhinitis (AR), atopic dermatitis (AD)
and/or food allergy [13]. The proportion of asthma that is allergic varies from 30 to
79% in children [14-16] and from 30 to 60% in adults [17, 18]. Children with severe
preschool wheeze or severe asthma are usually allergic [19]. Although type 2-driven
inflammation is key in allergic asthma the pathophysiology might be complex
involving several endotypes [10, 20]. Assessing the role of atopy in asthma is an
important step in asthma evaluation since these patients might benefit from AIT in
addition to pharmacological asthma treatment (figure 1 and box 1).
Global Initiative for Asthma (GINA) 2017 guidelines recommend assessment
of two domains: symptom control and future risk of adverse outcomes including
exacerbations, poor lung function and/or fixed airflow limitation and medication side
effects [21]. Achieving control is the major goal currently proposed in asthma
management where pharmacological and non-pharmacological treatment is adjusted
in a continuous cycle that involves assessment, treatment and review [21].
The rationale for AIT is the modification of the underlying atopic disease
mechanisms triggering sustained clinical effect. Effective AIT induces multiple
immune-mediated mechanisms, which are sequentially activated leading to allergen-
specific tolerance, suppression of inflammation and multifaceted clinical improvement
[22, 23]. AIT is currently provided in allergic asthma via the subcutaneous (SCIT) or
sublingual (SLIT) route, with alternate routes being currently explored. A limited
number of studies have been specifically designed to evaluate AIT in asthma. Most
data come from indirect evidence from AIT trials that included patients with both AR
and asthma. No consensus has been achieved on the best endpoints, with lung
function or asthma exacerbations only occasionally being assessed as primary
outcomes.
According to GINA 2017 the benefit of AIT in asthma in reducing symptoms
and medication and AHR must be weighed against the risk of side effects, relative
inconvenience and its cost incurred by prolonged course of treatment (level D
evidence) [21]. GINA 2017 reports SLIT as a possible add-on option for adults with
asthma and AR sensitised to house dust mites (HDM) with exacerbations despite low
to high doses of inhaled corticosteroids (ICS) provided that their FEV1 is >70%
predicted [21]. The current Allergic Rhinitis and its Impact on Asthma (ARIA)
guidelines [24] give both SCIT and SLIT a conditional recommendation in allergic
asthma due to moderate or low quality of evidence. AIT should be integrated in the
general frame of asthma management.
Figure 1: Allergic asthma diagnosis and management. Following an accurate asthma diagnosis the investigation
of the allergic phenotype includes evidence of sensitisation to a specific allergen. The essential step is the
confirmation of the allergic sensitisation as the main driver of asthma symptoms and control

Box 1: Nomenclature and Terms

Anaphylaxis = immediate systemic reaction often occurring within minutes and occasionally as
long as an hour or longer after exposure to an allergen.
AIT = allergen immunotherapy = procedure inducing tolerance to a specific allergen by repetitive
administration of an allergen
AE = adverse event = reaction triggered by AIT administration; can be local or systemic; systemic
AE has 4 degrees of severity
Allergic asthma = typical symptoms of asthma (wheezing, cough, dyspnea, chest tightness)
induced upon exposure to an allergen together with the proof of immunological sensitization to
that allergen
AHR= airway hyperreactivity = exaggerated response of the airways to specific (allergen) and
nonspecific stimuli, which results in airway obstruction
AR = allergic rhinitis = inflammation of nasal mucosa induced upon exposure to an allergen
together with the proof of immunological sensitization to that allergen
Asthma control = evaluated in the past 4 weeks; well controlled asthma has daytime symptoms
less then 2/week, no nighttime awakenings, reliever is needed for symptoms less then 2/week
and there is no activity limitation due to asthma; 1-2 of these criteria define partially controlled
asthma and 3-4 of these criteria define uncontrolled asthma (GINA 2017)
Asthma future risk = includes risk of exacerbations, fixed airway obstruction and adverse
reactions to medications used to control asthma; lung function measurement is an important
part of the assessment of future risk
Build-up phase = period of AIT where increasing amounts of the allergen are given until a
maintenance dose is reached
CSMS = combined symptom and medication score = standardized method that balances both
symptoms and the need for anti-allergic medication in an equally weighted manner
LR = local reaction – inflammatory response confined to the contact site
Long-term AIT efficacy = Clinical benefit one year or longer after AIT cessation
QoL = quality of life = the individual’s perception of their position in life in the context of the
culture and value systems in which they live and in relation to their goals (WHO)
Monosensitised = IgE reactivity to one allergen or related allergenic molecules
Polysensitised = IgE reactivity to several non-related allergenic molecules; The discrimination
between mono- and polysensitised is optimally achieved using purified natural or recombinant
allergens
Polyallergic = situation when 2 or more sensitizing allergens are triggers of symptoms.
SCIT = Subcutaneous immunotherapy = subcutaneous, injectable route of allergen administration
Severe asthma = asthma that requires treatment with high dose inhaled corticosteroids plus
a second controller and/or systemic corticosteroids to prevent it from becoming
‘‘uncontrolled’’ or that remains ‘‘uncontrolled’’ despite this therapy (ATS/ERS consensus
statement); severe asthma status is only after correct diagnosis of asthma and after all
comorbidities and adherence to treatment are properly addressed
Short term AIT efficacy = Clinical benefit under AIT treatment
SLIT = Sublingual immunotherapy = sublingual (drops or tablets) route of allergen administration

II. Scope, purpose and methodology

These Guidelines have been prepared by the European Academy of Allergy

and Clinical Immunology’s (EAACI) Taskforce on AIT for Allergic Asthma and are
part of the EAACI AIT Guidelines.
The aim of these Guidelines is to provide evidence-based clinical
recommendations for indications and contraindications of AIT in allergic asthma and
to identify gaps in knowledge and/or implementation, unmet needs and future
perspectives. The primary audience is clinical allergists (specialists and
subspecialists) and all healthcare professionals e.g. doctors, nurses, and
pharmacists working across a range of primary, secondary and tertiary care settings
managing patients with allergic asthma.
The EAACI Taskforce on AIT for Allergic Asthma included a wide range of
countries, professional background (allergy, paediatrics, internal medicine, paediatric
pulmonology, basic and clinical immunology, primary care) and patient
representatives. The broad allergy community, connected specialities and
representatives of AIT vaccine manufactures were given the opportunity to review
and comment on the draft guidelines, and where appropriate revisions were made.
 These guidelines have been developed using the Appraisal of Guidelines,
Research and Evaluation (AGREE) II framework, a structured approach to guidelines
for public health [25]. Agreement was reached on the search strategy, key questions
formulating recommendations and the peer review process. A systematic review of
the current evidence conducted by the methodologist [26], complemented by the
results of other systematic reviews and by a narrative review for evidence not
covered by the systematic review, have been used to generate evidence based
clinical recommendations formulated by clinical academics. The key overarching
question: “What is the effectiveness, safety and cost-effectiveness of AIT for allergic
asthma in all populations?” was pursued through the formal review of the evidence
[27]. The primary outcomes considered were effectiveness assessed by symptom
score, medication score and symptom and medication score, both during treatment
(short-term) and post discontinuation (i.e. at least one year after stop of treatment).
Secondary outcomes were asthma control and exacerbations, QoL, lung function
(including AHR), safety and health economic analysis from the perspective of the
health system/payer (table S1).
We graded the strength and consistency of key findings from the critical
appraisal of the evidence published so far to formulate evidence-based
recommendations for clinical care using an approach that was adapted from that
proposed by the Oxford Centre for Evidence-Based Medicine (Oxford Centre for
Evidence-based Medicine) (Box 2). In brief the terms “strong, moderate and weak”
were used for recommendations.
Appropriate representation all stakeholders, peer review by invited experts
from a full range of organizations, countries, and professional backgrounds and
editorial independence were insured. Identifying gaps, barriers and facilitators were
an important part of the process. All stakeholders had an opportunity to comment on
the draft guidelines publicised on the EAACI Website for a 3-week period to allow
any omissions or errors in the evidence-base to be highlighted.
The development of AIT for Allergic Asthma was funded and supported by
EAACI. The funder did not have any influence on the guideline production process,
on its contents or on the decision to publish.
The review of these guidelines is planned for 2020, as new evidence will
probably emerge during the next 2-3 years.

Box 2: Assigning levels of evidence and grade and strength recommendations

Level of evidence
Level I = systematic reviews, meta-analysis, randomised controlled trials
Level II = two-groups, non-randomised studies (eg cohort, case-control studies)
Level III = one group, non-randomised (eg before and after, pre test and post test)
Level IV = descriptive studies that include analysis of outcomes (single-subject design, case-
series)
Level V = case-reports and expert opinion that include narrative literature, reviews and
consensus statements
Grades of recommendation
Grade A = consistent level I studies
Grade B = consistent level II or III studies or extrapolations from level I studies
Grade C = level IV studies or extrapolations from levels II or III studies
Grade D = level V evidence or troublingly inconsistent or inconsistent studies of any level
Strength of recommendation
Strong = Evidence from studies at low risk of bias, i.e. high quality
Moderate = Evidence from studies at moderate risk of bias, i.e. moderate quality
Weak = Evidence from studies at high risk of bias, i.e. low quality
Terminology
Recommendations are phrased according to the strength of recommendation: strong: “is
recommended”; moderate: “can be recommended”; weak: “may be recommended in specific
circumstances” and negative: “cannot be recommended”

III. Current evidence for AIT effectiveness and safety in allergic asthma

The clinical outcome of AIT in allergic asthma can be assessed by a

decrease in the severity of symptoms and in the need for concomitant medication. As
a result of reciprocal interactions, symptoms and medication should not be analyzed
separately and a combined symptom and medication score (SMS) is recommended
for AIT trials [28]. SMS has been mostly validated in rhinitis AIT studies [28,29].
Several systematic reviews show a strong effect of SCIT on decreasing asthma
symptoms and medications during AIT treatment, both in children and in adults. The
evidence for SLIT is less prominent (tables S2 and S3 – supplement). A potential
steroid-sparing effect of AIT is of utmost importance to reduce potential side effects
of ICS in asthma, in line with the general accepted aim to reduce future risk of
treatment related adverse events. No SCIT or SLIT studies reported on the effect of
AIT on symptoms or medication after AIT discontinuation. In the EAACI systematic
review data pooled from 2 trials showed no evidence of reduction in short-term of
SMS [26]. Lin et al. brought moderately strong body of evidence that SLIT improved
SMS (20 of 41 studies) [30].
The moderate-to-low quality RCTs provided mixed evidence that SLIT is
effective in improving asthma control in patients with allergic asthma. One study at
low risk of bias found that SLIT did not improve asthma control [31]. In subjects with
controlled mild to moderate HDM allergic asthma one-year SLIT treatment allowed
reduction in daily ICS dose from individual baseline dose without deterioration in the
asthma control [32]. The EAACI systematic review found no evidence to assess
whether SCIT is effective in improving asthma control [26].
Several trials report on asthma exacerbations under AIT. The Wang SCIT trial
at low risk of bias failed to demonstrate evidence of a reduction in exacerbations in
AIT-treated subjects compared with placebo [33]. Two SLIT trials reported a positive
effect of AIT on asthma exacerbations, one in the context of reducing the dose of ICS
[31,32]. Another SLIT trial failed to demonstrate evidence for SLIT in reducing
asthma exacerbations [34].
Lu et al. found no significant differences in lung function (PEF, FEV1 and
FVC) between subjects receiving SCIT and the control group [35] . Twenty studies
included in SR of Abramson which included the measurement of lung function
showed only a trend towards improvement, without statistical significance [36].
EAACI meta-analysis evaluated 25 studies reporting on lung function and showed a
favourable response in the overall evaluation and a large beneficial effect on small
airways [26]. There are limited numbers of AIT studies using allergen specific
bronchial provocation test as primary or secondary endpoint. The marked reduction
in allergen-specific AHR to HDM, pollen and animal dander allergens reported by
Abramson can be considered as potentially lowering the risk of allergic asthma
exacerbations on exposure to the relevant allergen [36]. In the EAACI meta-analysis
pooled data from three SCIT studies demonstrated a large effect of AIT [26]. There is
also evidence from several high quality randomised control trials that SCIT is
effective in reducing specific AHR [37-44]. Limited, however significant reduction in
non-specific AHR are reported both by the Abramson and the EAACI systematic
reviews. [26, 36]
The EAACI systematic review showed a large treatment effect for SCIT for
improving QoL in allergic asthma [26]. For SLIT the EAACI systematic review was
unable to pool data. One SLIT trial at low risk of bias showed no significant
improvement in disease-specific QoL [31].
Recent pharmacoeconomic studies demonstrate that AIT in asthma gives
value for money, however heterogeneity in methodology limits the data interpretation,
and it is difficult to extrapolate the results from one healthcare setting to another [45-
49]. More data on cost-effectiveness of AIT in allergic asthma are presented in the
supplementary material.
The EAACI systematic review indicated that AIT was associated with a minor
increase in the risk of adverse events (AEs), these being seen both with SCIT and
SLIT. While severe systemic AEs can occur, these appeared to be uncommon and
mainly associated with SCIT. The limited safety data available included in the EAACI
SR suggests that local AEs are more common with SLIT, while Kim et al reported
that local reactions were frequent with both SCIT and SLIT [26,50]. Real-life data on
AIT safety have accumulated both in Europe and US. The survey performed by the
American Academy of Allergy, Asthma, and Immunology and American College of
Asthma, Allergy, and Immunology from 2008 to 2013 collected data from 28.9 million
injection visits and off-label SLIT. Four fatalities occurred under SCIT, systemic AEs
were reported in 1.9% patients receiving SCIT and 1.4% of patients receiving off-
label SLIT [51]. The European Survey on Adverse Systemic Reactions in Allergen
Immunotherapy (EASSI) followed 4316 patients and reported a rate of 2.1% for
systemic AE (89% with SCIT, 11% with SLIT) [52]. EASSI also recently evaluated
prospectively 1563 children (61.5% with asthma) and reported a rate of 1.53% for
systemic AEs [53]. Safety of initiation and continuation of AIT during pregnancy
analysed in 4 studies totalling 422 women demonstrated no increased incidence of
prematurity, hypertension/proteinuria, congenital malformations or perinatal deaths
for women continued or initiated on SCIT or SLIT during pregnancy. Among the 10
out of 453 pregnancies who experienced systemic AEs while receiving AIT, none
were found to have fetal complications [54].

IV. Clinical recommendations for AIT in allergic asthma

General considerations
According to current evidence, SCIT and SLIT can be recommended in mild
and moderate allergic asthma, provided that asthma is adequately controlled by
pharmacotherapy. AIT should be integrated in the general frame of asthma
management aiming to reduce symptoms, improve quality of life and minimize future
risk by decreasing exacerbation rate, improving lung function (including AHR) and
decreasing adverse reactions to medication (steroid and beta-2 agonists sparing
effect). Before starting AIT benefits and potential harms/disadvantages should be
agreed together with the patient (table 1).
In most of the cases a significant clinical benefit on reducing asthma
symptoms and medication (with a steroid sparing effect), improvement in QoL and
specific AHR can be expected (tables 2,3,4,5). A smaller benefit is expected for
improving lung function and non-specific AHR while the impact on asthma control
and exacerbation needs further evaluation (tables 6, 7, 8, 9, 10).
AIT may be stopped if there is no impact after a year of therapy (IV D, weak
recommendation based on the number, size, or quality of individual studies). The
decision depends on the frequency and duration of exposure to the allergen.
Table 1 - Benefits and potential harms/disadvantages of AIT in allergic asthma
Population Benefits Potential harms/disadvantages
Children with mild/moderate Decreased symptoms Daily intake of tablets/drops
asthma and medication score (SLIT/oral) or regular injections
with a steroid sparing (SCIT) for 3 years
effect Frequency of visits in the clinic
Improvement in QoL (SCIT)
Improvement of specific Risk for adverse events
AHR Costs
Possible effect on small
airways and non-specific
AHR
Possible effect on
asthma exacerbations
and control
Adults with mild/moderate asthma Decreased symptoms Daily intake of tablets/drops
and medication score (SLIT/oral) or regular injections
with a steroid sparing (SCIT) for 3 years
effect Frequency of visits in the clinic
Improvement in QoL (SCIT)
Improvement of specific Risk for adverse events
AHR Costs
Possible effect on small
airways and non-specific
AHR
Possible effect on
asthma exacerbations
and control
Asthma and rhinitis Simultaneous tolerance Daily intake of tablets/drops
induction for the one (SLIT/oral) or regular injections
airways disease (SCIT) for 3 years
Frequency of visits in the clinic
(SCIT)
Risk for adverse events
Costs
Asthma and atopic dermatitis Possible beneficial effect Daily intake of tablets/drops
for adults sensitised to (SLIT/oral) or regular injections
HDM (SCIT) for 3 years
Frequency of visits in the clinic
(SCIT)
Risk for adverse events
Costs

Clinical recommendation for AIT to reduce symptoms and medication in allergic

asthma
AIT significantly reduces asthma symptoms and medication during treatment,
with more evidence available for SCIT compared to SLIT and differences between
individual allergens (tables 2,3). There are not enough data to formulate
recommendations for AIT in reducing asthma symptom or medication long term (after
treatment cessation) or for the combined symptom and medication score.

Table 2: Recommendations for AIT in allergic asthma to reduce asthma symptoms during treatment
Recommendation Evidence Grade Strength of Other considerations Key
level recommendation References
AIT can be I B Moderate based on See evidence below [26, 36, 50,
recommended to results from well- for individual 55]
reduce symptoms designed, well- allergens, patient’s
alongside other conducted studies sensitisation pattern,
effective treatment included in several asthma severity and
options in children and SR with some route of
with allergic asthma inconsistency administration
between studies
HDM AIT is I A Strong based on [26, 35, 56,
recommended to consistent results 57]
reduce symptoms in from well-designed,
allergic asthma well-conducted
studies included in
several SR
Grass AIT is I A Strong based on the [26,58-60]
recommended to number, size, or
reduce symptoms in quality of individual
allergic asthma studies.
Cat AIT may be I B RCT data but weak Safety and extract [61, 62]
recommended in based on the limited quality concerns
specific circumstances number or size of might downgrade
to reduce symptoms in studies. the level of the
allergic asthma recommendation to
very weak
Dog AIT may be IV D No direct evidence, Can be considered
recommended in expert opinion in occupational
specific circumstances extrapolated from exposure
to reduce symptoms in other allergens
allergic asthma
Tree AIT may be I B RCT data but weak If seasonal [26,63]
recommended in based on the limited symptoms are
specific circumstances number or size of severe/impacting
to reduce symptoms in studies QoL the strength of
allergic asthma recommendation
can be upgraded to
moderate
There is not enough I B Weak to moderate Safety and extract [64,65]
data to recommend based on very quality concerns
mold AIT in allergic limited number or Data from RCT
asthma to reduce size of studies. available only for
symptom x Alternaria
AIT is recommended in I A Strong based on [26]
mild/moderate asthma consistent results
to reduce symptoms from well-designed,
well-conducted
studies included in
several SR
AIT can be I A Moderate based on Safety concern [26]
recommended for the number, size, or might decrease the
moderate/severe quality of individual level of
allergic asthma to studies. recommendation to
reduce symptoms weak
AIT is recommended in I A Strong based on [26]
monosensitised allergic consistent results
asthma to reduce from well-designed,
symptoms well-conducted
studies included in
several SR
AIT can be I B Moderate based on One relevant [26, 66]
recommended for the number, size, or allergen for AIT has
polysensitised quality of individual to be demonstrated
monoallergic asthma to studies. to induce relevant
reduce symptoms symptoms (history,
provocation test)
AIT may be IV D Very weak based on [67-71]
recommended in expert opinion
specific circumstances
for polysensitised
polyallergic asthma to
reduce symptoms
SCIT is recommended I A Strong based on [26, 35, 36,
in allergic asthma to consistent results 50, 55]
reduce symptoms from well-designed,
well-conducted
studies included in
 several SR
SLIT can be I B Moderate based on Patient’s preference [26, 50, 72-
recommended allergic results from well- or safety 76]
asthma to reduce the designed, well- considerations can
symptoms conducted studies upgrade the strength
included in several of recommendation
SR with between- to strong
study inconsistency

Table 3 Recommendations for AIT in allergic asthma to reduce asthma medication during treatment
Recommendation Evidence Grade Strength of Other considerations Key
level recommendation References
AIT can be I B Moderate based on See evidence below for [26, 36, 50, 55]
recommended results from well- individual allergens,
alongside other designed, well- patient’s sensitisation
effective conducted studies pattern, asthma severity
treatment options included in several and route of
in children with SR with some administration
allergic asthma to inconsistency
reduce between studies
medication
AIT may be I B Weak based on the [26, 36,50,55]
recommended inconsistency
under specific between studies.
circumstances in
adults with
allergic asthma to
reduce
medication
HDM AIT is I A Strong based on [26, 35, 56, 57]
recommended in consistent results
allergic asthma to from well-designed,
reduce well-conducted
medication studies included in
several SR
Grass and trees I B Weak based on the [26, 58-60,63]
AIT may be limited number or
recommended size of studies.
under specific
circumstances in
allergic asthma to
reduce
medication
Molds AIT may I B Weak based on the Safety and extract quality [26]
be recommended limited number or concerns might
in allergic asthma size of studies downgrade the level of
to reduce the recommendation to
medication very weak
Cat and dog AIT IV D Very weak based Can be considered in
may be on expert opinion occupational exposure
recommended in
specific
circumstances in
allergic asthma to
reduce
medication
AIT is I A Strong based on [26]
recommended in consistent results
mild/moderate from well-designed,
allergic asthma to well-conducted
reduce studies included in
medication several SR
AIT can be I B Moderate based on Safety concern might [26]
recommended in the number, size, decrease the level of
moderate/severe or quality of recommendation to weak
allergic asthma to individual studies.
reduce in
medication score
AIT can be I B Moderate based on [26]
recommended in the number, size,
monosensitised or quality of
allergic asthma to individual studies.
reduce
medication
AIT can be I B Moderate based on One relevant allergen for [26, 66]
recommended for the number, size, AIT has to be
polysensitised or quality of demonstrated to induce
monoallergic individual studies. relevant symptoms
asthma to reduce (history, provocation test)
medication
AIT might be IV D Very weak based [67-71]
considered for on expert opinion
polysensitised
polyallergic
asthma to reduce
medication
SCIT is I A Strong based on [26, 35, 36, 50,
recommended in consistent results 55]
allergic asthma to from well-designed,
reduce well-conducted
medication studies included in
several SR
SLIT can be I B Moderate based on Patient’s preference or [26, 50, 72-76]
recommended in results from well- safety considerations can
allergic asthma to designed, well- upgrade the strength of
reduce the conducted studies recommendation to
 medication included in several strong
SR with some
inconsistency
between studies

Clinical recommendation for AIT in allergic asthma to improve asthma control and
reduce long-term risk
There are no consistent effects of AIT on asthma control and exacerbations
thus no recommendation can be made for SCIT. There is weak evidence for HDM
SLIT for achieving asthma control and moderate evidence for decreasing
exacerbations (tables 4,5). Assessing asthma control and exacerbations in addition
to symptom and medications score as primary end-point was identified as a
significant gap in AIT trials (table 14).

Table 4. Recommendations for AIT in allergic asthma to improve asthma control

Recommendation Evidence Grade Strength of Other Key References
level recommendation considerations
No recommendation IV D Weak, inconsistent [77]
can be made for or evidence
against using SCIT to
improve asthma control
SLIT may be I B Weak based on the [31-34, 78-79]
recommended in limited number or
specific circumstances size of studies or
in allergic asthma to heterogeneity in
improve asthma control evaluation of
for: asthma control*
 Children and adults
 Mild-moderate
asthma
 HDM
* asthma control was measured in various heterogenous ways

Table 5: Recommendations for AIT in allergic asthma to reduce asthma exacerbations

Recommendation Evidence Grade Strength of Other Key References
level recommendation considerations
No recommendation IV D Weak, inconsistent [80]
can be made for or evidence based on 2
against using SCIT to RCTs
decrease asthma
exacerbations
SLIT can be I B Moderate based on [31-34, 81,82]
recommended in results from well-
allergic asthma to designed, well-
decrease asthma conducted studies
exacerbations with some
 Children and adults inconsistency
 Mild-moderate between studies
asthma and heterogeneity in
 HDM definition of
exacerbations*
* exacerbations were defined in various heterogenous ways
The AIT studies evaluating the impact of AIT on lung function are of limited
size and moderate to low quality, with heterogeneity in assessing the end-points and
provide inconsistent results thus the strength of recommendations is weak (table 6).
However the EAACI systematic review and other studies showed a significant effect
on small airways.

Table 6: Recommendations for AIT in allergic asthma to improve lung function in asthma
Recommendation Evidence Grade Strength of Other considerations Key
level recommendation References
No recommendation I B Weak based [26]
can be made for or inconsistent results
against using AIT to with limited number
improve PEF or FEV 1in and size and
allergic asthma moderate/low quality
of studies

SLIT may be I B Weak based on very EAACI SR

recommended in limited number or [26, 60,
special circumstances size of studies 83.84]
for allergic asthma to
improve FEF 25-75 in:
 Children
 Mild-moderate
asthma
 HDM, grass and
Parietaria pollen

SCIT can be useful alongside other effective treatment options in allergic asthma to
decrease allergen specific AHR. There are not enough data to provide
recommendations for SLIT and allergen specific AHR and for AIT and non-specific
AHR (table 7).

Table 7: Recommendations for AIT in allergic asthma to reduce airway hyper-reactivity in asthma
Recommendation Evidence Grade Strength of Other considerations Key
level recommendation References
SCIT is recommended I A Strong based on [26]
in allergic asthma to consistent results
reduce the allergen from well-designed,
specific AHR for: well-conducted
 Children and adults studies included in
 Mild-moderate several SR
asthma
• HDM, cat or dog
dander, birch, grass
and Artemisia pollen,
Cladosporium
No recommendation I B Weak based [84,85]
can be made for or inconsistent results
against using SLIT to with limited number
reduce the allergen and size and
specific AHR in allergic moderate/low quality
asthma of studies

AIT may be I B Weak based [26]

recommended in inconsistent results
specific circumstances with limited number
in allergic asthma to and size and
decrease non-specific moderate/low quality
AHR for: of studies
 Children and adults
 SCIT and SLIT
 Mild-moderate
asthma
 HDM, cat and dog
dander, birch, grass
and Parietaria
pollen, Alternaria

SCIT can be useful alongside other effective treatment options in allergic asthma to
improve quality of life. There are not enough data to provide recommendations for
SLIT (table 8).
Table 8: Recommendations for AIT in allergic asthma to improve asthma quality of life
Recommendation Evidence Grade Strength of Other Key References
level recommendation considerations
SCIT can be I B Moderate based on [26, 38, 40, 64 ]
recommended results from well-
alongside other designed, well-
effective treatment conducted studies
options in allergic included in several SR
asthma to improve QoL with between-study
in: inconsistency
 Children and adults
 Mild-moderate
asthma
 HDM and Alternaria
No recommendation I B Inconsistent results [31-34, 77-79, 86]
can be made for or from studies that use
against using SLIT to different outcome
improve asthma QoL measures *
 asthma QoL was measured in various heterogeneous ways

V. Safety and contraindications

AIT is a safe treatment for well-controlled allergic asthma in children and in adults
(table 9).
Table 9: Summary statement concerning safety of AIT in allergic asthma
Statement Evidence Grade Rate ratio Strength of Key References
level statement
AIT delivered by any I A 1.74 (95%CI 1.38, Moderate based on [26, 51,52,53]
route (SCIT and SLIT) 2.2) overall results from well-
has a small risk of 2.22 (95% CI 1.48, designed, well-
adverse events (AE) in 3.33) for SCIT conducted studies
children and in adults 1.49 (95%CI 1.13, included in several
1.98) for SLIT SR with between-
study inconsistency
SCIT has a small risk of I A 1.92 (95%CI 1.19, Moderate based on [26, 51,52,53]
systemic AEs 3.09) results from well-
designed, well-
conducted studies
included in several
SR with between-
study inconsistency
SLIT has a small risk of IV D 1.39 (95%CI 0.67, Weak based on 2 [26, 51,52,53]
systemic AEs 2.92) studies included in
the SR and results
of 2 surveys
SCIT may increase the I A 0.96(95%CI Weak; in the SR the [26]
risk of local AEs 0.74,1.24) risk is suggested
but not confirmed
SLIT can increase the I A 6.45(95% 3.67, Moderate based on [26,50]
risk of local AEs 11.31) results from well-
designed, well-
conducted studies
included in several
SR with between-
study inconsistency

Severe or uncontrolled asthma is the major independent risk factor for both
nonfatal and fatal adverse reactions and is therefore a major contraindication for both
SLIT and SCIT. Other contraindications and precautions are listed in table 10.
Table 10: Contraindications and precautions for AIT in patients with allergic asthma
Recommendation Evidence level Grade Authors Other Key
recommendations considerations reference
(level of certainty)
AIT is contraindicated IV/V D Strong based on Due to safety [51-53,74,
in poorly controlled safety concerns concerns 87-91]
asthma performance of
RCT studies in
poorly controlled
asthma is not
recommended

AIT should not be IV/V D Very weak due to Individual [51-53,74,

considered in gaps in the chain of differences 87-91]
children and adults evidence between allergens
with severe asthma should be
considered with
mites inducing less
SRs compared to
grass and probably
molds and animal
dander
AIT should not be IV/V D Very weak due to
initiated in gaps in the chain of
pregnancy (but can evidence
be continued in
pregnancy)
AIT should not be IV/V D Very weak due to
initiated in patients gaps in the chain of
with active evidence
autoimmune
disorders
AIT should not be IV/V D Very weak due to
initiated in patients gaps in the chain of
with active evidence
malignancies
AIT may be IV/V D Very weak due to Only in specialised
considered with gaps in the chain of settings.
caution in asthmatic evidence
patients under
treatment with beta-
blockers or ACE
inhibitors
AIT is not IV/V D Very weak due to
recommended in gaps in the chain of
patients with immune evidence
deficiencies, active
infections and
infestations and
uncontrolled diseases
like diabetes, IBD,
gastric ulcer etc

Recommendations around risk management when administering AIT in allergic

asthma are detailed in table 11 ((level IV/D, weak recommendation).

Table 11: Recommendations for risk management of AIT in allergic asthma

SCIT for allergic asthma
Home based SLIT for allergic asthma
Supervised administration by a healthcare professional (HCP) trained in the
evaluation of patients with allergic conditions in a setting facilitating proper
management of systemic reactions
Assessment of the patient’s current health status before the administration of
SCIT to determine whether there have been any recent changes in the patient’s
health that may require modifying or withholding treatment (e.g.,
uncontrolled/symptomatic asthma or exacerbation of allergy symptoms
Observation for at least 30 minutes after injection
Patient education for management and reporting late reactions
Supervised initiation by a HCP trained in the evaluation of patients with allergic
conditions in a setting facilitating proper management of systemic reactions
Observation for at least 30 minutes after the first dose
Consider an adrenaline (epinephrine) auto-injector and training in how to use
the device
Patient education and written instructions on how to recognize and manage
adverse reactions and when to contact the HCP for adverse reactions, treatment
 gaps, or other events that may affect treatment (eg, new medication or illness),
how to manage missed doses and the situations when they should withhold SLIT
In cases of oral inflammation, such as mouth ulcers, lichen planus, or dental
extractions, administration of SLIT should be temporarily discontinued until
there is complete healing of the oral cavity
Recommendations for when to withhold SLIT dose to avoid potential situations
when systemic allergic reactions may be more likely should also be provided.
Regular follow-up care with a HCP trained in the evaluation of patients with
allergic conditions to monitor safety

Is spite of some case reports suggesting that AIT might be associated with
the development of autoimmunity [92] the evidence from long term observational
studies in patients with asthma does not confirm this hypothesis [93]. In total, 1,144
patients with allergic asthma and/or AR, were observed up to 20 years after
immunotherapy and compared to a control group consisting of 1,154 allergic patients
with only symptomatic treatment. No significant differences in the prevalence of
autoimmune diseases was observed between the groups [93], however due to lack
of data AIT is not recommended in patients with active autoimmune diseases.

VI. Special considerations

Polysensitized patients, allergen mixes and multiple vaccines

The majority of patients with allergic asthma seen by specialists are

polysensitized. However, polysensitization does not necessarily mean that all
sensitivities are clinically significant. In Europe the one or two most important
sensitivities are typically treated. In contrast, in the United States mixtures including
many or most of the sensitizing allergens are administered [94]. Related allergen
mixes proved efficacy in polysensitized patients [95]. An alternative to allergen mixes
for both SLIT and SCIT is the administration of multiple allergen extracts at different
occasions or locations [96-98].
A literature survey identified 13 studies simultaneously using 2 or more
distinct allergen extracts (11 SCIT, 1 SLIT and 1 SCIT and SLIT) [99]. In studies with
adequate information, administration of 2 extracts by means of either SCIT or SLIT
was effective. In studies using multiple allergens, 3 studies showed clear efficacy,
whereas in the other 2 studies, lack of efficacy might have been due to inadequate
doses of extract or omission of clinically relevant allergens in the treatment regimen.
It is concluded that simultaneous administration of more than 1 allergen extract is
clinically effective. However, more studies are needed, particularly with more than 2
allergen extracts and with SLIT [99].
For polysensitised patients with allergic asthma we recommend either mono-
allergen immunotherapy or multiple vaccines pending on the burden of allergen of
symptoms (level IV/D, weak recommendation). If a mixture of related allergens is
used the AIT product characteristics should include the following: high efficacy and
optimal safety profile, standardized production, and documented presence and
titration of the major allergen.
Allergens not included in the systematic review and rare allergens
Several forms of ragweed SCIT and SLIT were tested mainly in patients with
AR, with or without seasonal asthma [100-102]. We recommend SCIT or SLIT with
ragweed natural extracts in patients with allergic asthma with proven symptoms
induced by weeds (level IV/D, weak evidence). There are not enough data to
formulate a recommendation for AIT with other allergens such as Bermuda grass,
cockroach, laboratory animals (mouse, rat, rabbit) or latex. AIT in such cases can be
considered on an individual basis pending on the burden of asthma symptoms
induced exposure to the relevant allergens. For more details on these rare allergens
see supplementary material.
Recombinant allergens for AIT in allergic asthma
The use of recombinant allergens for immunotherapy is a very promising
approach. Murine models of allergic airway inflammation have provided important
proof of concept findings. For example, using a murine model of birch pollen allergic
asthma, both sublingual recombinant Bet v 1a or epicutaneous immunotherapy with
a hypoallergenic recombinant Bet v 1B2 suppressed lung inflammatory responses
such as eosinophil recruitment, type 2 cytokine levels and AHR[103,104].
While a number of studies have examined the use of recombinant birch
pollen allergen in humans, none of these published studies have focused specifically
on asthma patients, although typically 30-40% of the study populations being tested
in these studies have asthma. Future studies on recombinant allergens need to
specifically focus on sensitized asthma patients.
Based on the current evidence we cannot make recommendations on the use
of recombinant allergens for allergic asthma

Preseasonal versus continuous schedules

There is only one study directly comparing SLIT administered pre-coseasonal
or continuous in a 2-year prospective, randomized, double-blind, placebo-controlled
trial including children allergic to grass pollen with rhinitis and concomitant asthma.
Both protocols were effective compared with placebo and showed similar decreases
for combined SMS and all secondary endpoints (medication, ocular and asthma
scores) [105].
Based on the current evidence we cannot make recommendations on the
choice of preseasonal versus continuous schedules for AIT in allergic asthma. The
use of either schedule depends on doctors and patients preference
Novel adjuvants and alternative routes for AIT in asthma
The use of novel adjuvants and alternative routes of administration have
brought a lot of attention over the last years [106,107]. Although there are still few
studies demonstrating the benefits of novel adjuvants or alternative routes of
administration in large cohorts of patients in the context of asthma, promising
alternatives have been reported in preclinical mouse models and humans [108-111]
Novel adjuvants with demonstrated clinical efficacy and security in human clinical
trials for AIT in asthma include Toll-like receptors (TLRs) agonists, viral-like particles
(VPLs) and 1,25-dihydroxy vitamin D3 [108-111]. Further clinical trials should show
whether these or other alternative routes could improve efficacy, safety and patient
compliance for AIT in asthma.
Based on the current evidence we cannot make specific recommendations on
adjuvant use or for alternative routes in AIT in allergic asthma.
Combination with biologics
A few trials have been performed with pre-administration or co-administration
with omalizumab to either improve safety of SCIT up-dosing [112] or improve efficacy
of SCIT [113,114]. 248 asthmatics not controlled by ICS received rush SCIT (cat,
dog, HDM) combined with placebo or omalizumab. Adding omalizumab reduced the
systemic AEs rate from 26.2% to 13.5% and 87.3% of subjects on omalizumab
reached the maintenance dose of SCIT versus 72.1% of placebo patients [112].
Co-administration of omalizumab and SCIT with a depigmented grass pollen–
rye pollen extract was investigated in 140 patients with seasonal AR and mild-to-
moderate allergic asthma incompletely controlled by pharmacotherapy. Significant
difference for AIT and omalizumab co-administration was noted for reducing
symptom severity and improving asthma control and quality of life [113]. The
combination had no prolonged effect during treatment with AIT only [114]. A slight
increase in FEV1 in patients formerly treated with the omalizumab/SIT combination
therapy was shown in the second year of observation which should encourage
further evaluation of long-term effects of omalizumab [114].
A recent trial in AR patients evaluated the induction of sustained tolerance to
allergen when anti-IL-4 was combined with a suboptimal course of SCIT grass pollen
using the allergen-induced skin late-phase response (LPR) and exploratory immune
monitoring as surrogate markers of therapeutic response. Both treatment arms led to
a substantial and sustained reduction of the LPR with no additional suppression with
addition of anti-IL-4. However the combination anti-IL-4/SCIT compared with SCIT
alone led to a sustained reduction in allergen-specific IL-4-producing cell counts
[115].
Evidence is lacking to recommend co-administration of biologics and AIT for
allergic asthma.

Provocation tests for selecting patients with allergic asthma for AIT or efficacy
assessment
Nonspecific bronchial provocation tests with metacholine/histamine and
specific challenges that utilize allergen extracts assist in identifying AHR, a major
feature of asthma. To validate AHR the most adequate provocation test is the
bronchial challenge, although nasal and conjunctival allergen provocations are
performed under some circumstances, especially at higher risk groups [116,117]. In
AIT trials allergen provocation tests (cat, mites and grass pollen) are sometimes
used as inclusion criteria or to measure the efficacy of AIT[118-121]. The drawback
of provocation testing is that it may not reflect natural exposure [116].
We cannot make recommendations on the use of provocation tests for patient
selection or efficacy assessment.

Biomarkers and AIT for allergic asthma

Many studies on AIT report on potential biomarkers for measuring efficacy or
useful for responders to AIT. In type-2 asthma sputum or blood eosinophilia or serum
can be correlated with response to ICS or targeted interventions such as antiIgE, anti
IL-5 or anti IL-4,13 [10-12,20]. Some in vivo, ex vivo or in vitro parameters correlate
with the clinical efficacy of AIT (Table 12). It may be assumed that AIT biomarkers
described for AR or food allergy might predict response to AIT in allergic asthma as
well, but none of them is validated or qualified [10,122].
Based on current evidence for biomarkers in AIT for allergic asthma we
cannot formulate any recommendation for their use in routine practice, with the
exception of course of specific IgE to allergen.

Table 12: Biomarkers of allergen immunotherapy efficacy

Methodology Parameter/test Documented changes during AIT* Reference
In vivo Skin prick tests; late cutaneous Decrease in early and late skin [40, 61, 123-126]
response reactivity
Nasal allergen provocation test Decrease in nasal sensitivity to allergen [127-129]
challenge
Conjunctival allergen provocation test Decrease in conjunctival sensitivity to [123, 130]
allergen challenge
Bronchial allergen provocation test Decrease in bronchial sensitivity to [38, 42-43, 49,61]
allergen challenge
Ex vivo (in Immunoglobulins: Early increase and progressive decrease [43, 121, 122, 124-126,
biological fluids) s-IgE, s-IgG1, s-IgG4,s-IgA in s-IgE; increases in s-IgG1, s-IgG4 in 128, 131-132]
serum and s-IgA at mucosal sites,
together with the increase of their
blocking capacities;
Higher s-IgE/t-IgE ratio correlated
with AIT efficacy
s-IgE/t-IgE ratio [133, 134]

Allergen-specific T cell responses Increase in IL-10 and TGF- [128, 135-138]


Allergen-specific B cell responses
Polarization of dendritic cells (DC)
response
Functional in vitro Basophil activation test (BAT)
assays
Facilitated allergen binding assay (FAB)
Allergen-induced T cell proliferation
Chip allergen microarray
producing Treg cells (TR1) and
induction of Th1; decrease in Th2
cytokines in serum and increase of IL-
10
Increase in IL-10 producing Breg cells [139, 140]
(BR1) and production by them of s-
IgG4
Increase in expression of markers [141, 142]
associated with DC regulatory
phenotype; decrease in markers
associated with Th2-inducing DC2
Decrease in basophil activation due to [143-147]
the induction of specific IgG with
blocking capacities in the patients’
serum
Decrease of complexes IgE-allergen [148]
bound to the B-cell via CD23 due to
the increase in blocking IgGs in the
patients’ serum
Decrease of allergen-induced CD4+ T [146]
cells proliferation due to the increase
in blocking IgGs in the patients’ serum
Quantitative increase in the serum of [150-,151]
IgG blocking antibodies

*The presented changes were replicated in the majority but not all studies. s-IgE, s-IgG1, s-IgG4, s-IgA; specific IgE,
IgG1, IgG4, IgA; t-IgE; total-IgE

Background asthma treatment: ICS versus no ICS

There is no evidence that background ICS may influence the outcome of AIT,
however they should be used as first line asthma controllers to ensure the maximum
safety of AIT.
AIT in allergic asthma with allergic co-morbidities
Allergic asthma and AR frequently co-exist and share similar triggers and
similar pathophysiology [24]. Patients with asthma and AR will have benefits
following AIT from both the upper and lower airways, thus the association of AR is a
recommendation for AIT in well-controlled allergic asthma (level I/A, strong
recommendation).
The association with AD is mentioned in five AIT for allergic asthma studies.
In three studies, the presence of AD is a descriptive parameter for the study
population [44, 77, 152]. In one study, patients with severe AD were excluded,
however no definition of severe AD is provided. [153] In another AIT study for dog
allergic patients symptoms of AD were recorded in the active and placebo group
[143]. Only one study reported that patients “had the subjective impression, that also
AD improved during AIT for asthma [154]. No study reported however that adverse
effects in patients with AD were more frequent under AIT.
Food allergy is not mentioned as comorbidity or as exclusion criterion.
Our recommendation is that neither AD nor food allergy are contraindications
for AIT in asthma (level IV/D, weak recommendation).

VII. Dissemination and implementation: barriers, facilitators, audit criteria (66

words)
The data on the efficacy and safety of AIT in allergic asthma provide an
incentive to use AIT in a much larger number of patients with allergic asthma than
currently indicated. The major barriers and facilitators as well as audit criteria are
presented in table 13. In general a holistic approach to patients is required with joint
commitment of various stakeholders to offer the patients the optimal care [155, 156,
157].
Table 13: Barriers, facilitators and audit criteria for AIT in asthma
Barriers Facilitators Audit criteria
Definition of asthma as a lower Revised definition of asthma to Increased prescription of AIT for the
airway condition, ignoring the include the one airways disease one airways disease (AR and
frequent association with AR and concept and asthma enotypes allergic asthma)
disease endotypes
Low awareness of AIT potential by Joint commitment and coordinated Increased prescription of AIT in
the general public and healthcare actions among academia, patient allergic asthma
professionals outside allergy organisations, regulators, industry to
speciality, eg paediatricians, find solutions that properly answer
pulmonologists, ENT, dermatology, the health expectations of the
primary care physicians, allergic patients
The application of AIT in asthma is Higher quality large phase 3 DBPC AIT is included in general asthma
limited due to efficacy and safety trials with patient centered outcomes guidelines (GINA, national
concerns and postmarketing data guidelines)
Availability and affordability Pharmacoeconomics studies and AIT included in national health
implementation of better programmes
reimbursement policies
Improved patient selection Better selection of responders using Lower rate of AIT failures
diagnostic tools for accurate
identification of clinically relevant
patient’s sensitization profile
Adherence to AIT Educational programmes, more Lower rate of drop-outs
convenient AIT regimens

VIII. Evidence gaps and unmet needs

Measuring outcomes
Most of the clinical trials of AIT in asthma evaluated clinically relevant
parameters such as symptom and medication score (with an emphasis on the
corticosteroid sparing effect) and lung function. A standardized and globally
harmonized method for analysing the clinical efficacy of AIT products in RCTs is
required, as recently highlighted by the EAACI Position Paper for AIT in AR [28].
According to the European Medicine Agency clinical trials on AIT in asthma start as
add on therapy, which has to be considered in the evaluation of the primary endpoint
(e.g. evaluation in the context of a stepwise reduction of controller medication). Lung
function, number of exacerbations or reduced need for controller medication should
be considered as primary endpoints in addition to the symptoms and medication
scores.

AIT positioning in the context of general asthma management (controller, biologics,

avoidance)
The application of AIT does not interfere or substitute the pharmacological
treatment for asthma as recommended by various asthma guidelines. It should be
applied only when asthma is well controlled providing the perspective of stepping-
down controller treatment while decreasing the future risk of asthma exacerbations
and drug-related adverse events.
The concept of AIT complements the biologics use in asthma in several
aspects including the possibility of early implementation aiming at achieving
prevention and disease-modifying effects. AIT and biologics target different asthma
subpopulations with AIT addressing early and/or milder cases and biologics for more
severe long-duration asthma.
Given that effective allergen avoidance is hardly achievable in real-life AIT
offers the opportunity to achieve tolerance to common allergens.
The AIT for allergic asthma working group identified several gaps in evidence
(table 14)

Table 14: Gaps in evidence for AIT in allergic asthma and plan to address
Gaps in evidence Plan to address Priority
Establishing and standardising the optimal Investigate and validate optimal High
outcome measures outcome measures in adults and
 children.
Poor alignment of studies with guidelines from Work in partnership with regulatory High
regulatory bodies. bodies to continually review trial
methodology and outcomes.

How to assess clinically relevant sensitisation Proof of concept studies evaluating High
beyond SPT/IgE in order to select responders to patient selection based on
AIT provocation tests and/or biomarkers
including components and other
measures
How to evaluate the impact of comorbidities Well-designed RCT and real-life Medium
(autoimmunity, diabetes, obesity, smoking) and studies focusing on AIT in asthma
the impact of age (>45) with co-morbidities
Safety: LF level cut-off and observation period Well-designed RCT with LF level cu- High
after dose off and observation period as
primary end-point
When to start RCTs and real-life studies testing Medium
How long to treat (optimal treatment duration) different approaches in AIT in terms
When to stop (efficacy and safety) of duration and allergen
Is duration of AIT variable with disease/allergen
Validation of different regimens (preseasonal, RCTs and real-life studies testing Medium
perennial), mode of updosing different regimens
Optimal dose for SCIT in asthma Mechanistic studies High
Optimal dose of SLIT in asthma Mechanistic studies High

Discussion and future perspectives

The major aim of this guideline is to provide recommendations according to

the evidence for efficacy and safety of AIT in the targeted patients populations (box
3). Since AIT remains underused the possible approaches to increase its application
in the asthma treatment are also outlined. Low awareness, limited access to
specialist care, the reimbursement policy, long duration, and often unjustified
concerns regarding safety and effectiveness are the main reasons of the limited (less
than 10% of eligible patients) utilization in asthma treatment worldwide. Among
allergy specialists there is practically no controversy about the importance of AIT in
the treatment of allergic asthma however indications and contraindications in
subgroups defined by disease severity, age groups, concomitant diseases,
sensitization pattern etc. are of utmost importance. The small number of even lack of
RCT in these modalities poses the major problem for making recommendations.
Constant monitoring of clinical evidence is necessary to improve and develop a
comprehensive consensus report to harmonize, disseminate, and implement the best
AIT practice in order to provide the optimal patient’s care.
There is room for improving as far as prescription, efficacy and safety are
concerned. The molecular-based diagnosis and endotyping allergic asthma would
certainly improve patient selection for AIT. Recent advances in immunology and
bioengineering such as cloning of allergen proteins and genetic engineering enable
the use of novel vaccines for AIT with increased efficacy and safety. Work is ongoing
for new routes of administration such as the intralymphatic and epicutaneous routes.
However, the quality level of evidence is variable and includes conceptual studies in
experimental models, proof-of-concept clinical studies with a limited number of
subjects and large-scale multicentre clinical studies are further needed.

Box 3: Key points for AIT in allergic asthma

When should AIT be considered in asthma = well controlled asthma under pharmacotherapy
where relevant clinical sensitization is proven
What is the expected benefit = a decrease in symptom and medication score with improved
quality of life and with a potential steroid sparing effect allowing step-down in well controlled
asthma; potential benefit in reducing the risk of exacerbations and improving lung function and
decrease in AHR
What products should be used = well characterised vaccines with proof of efficacy; eg HDM,
grasses and trees
Which route should be used = both SCIT and SLIT depending on patient preference, costs and
adherence to treatment
How is AIT integrated with asthma regular treatment = AIT should be additional to asthma
controller treatment

Conclusion
This guideline combines the best scientific evidence with expert opinion
aiming at providing the practical resource for all stakeholders dealing with AIT for
allergic astham including patients, health care professionals, competent authorities,
and industry. The data of systematic reviews and expert consensus provide sufficient
rationale for the increased use of AIT in the treatment of asthma as well as to foster
well-designed clinical and translational research in this field.

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