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EAACI AIT prevention Guidelines V5.12.04.2017 1
EAACI Guideline on Allergen immunotherapy: Prevention of allergy 1
Draft V6-21.04.2017 2
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Expert panel: 8
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Address for correspondence: 12
Antonella Muraro, Department of Mother and Child Health, Referral Centre for Food Allergy Diagnosis 13
and Treatment Veneto Region, - University of Padua, Via Giustiniani 3, 35128 Padua, Italy 14
Tel. +39 049 821 2538 - Fax +39 049 8218091 – Email [email protected] 15
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Short title: EAACI Guidelines on AIT for Allergy Prevention 17
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EAACI AIT prevention Guidelines V5.12.04.2017 2
Keywords: Allergen immunotherapy, allergic diseases, allergy, atopy, prevention, sensitization, 1 AGREE II, asthma, allergic rhinitis 2 3
Words: <4500. At present 4077 without tables and boxes 4
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Abbreviations: 6
AD: Atopic dermatitis (atopic eczema) 7
AIT: Allergen Immunotherapy 8
AR: Allergic rhinitis 9
ARC: Allergic rhinoconjunctivitis 10
CBA: Controlled before and after study 11
HDM: House dust mites 12
OAS: Oral allergy syndrome 13
RCT: Randomized controlled trial 14
SCIT: Subcutaneous immunotherapy 15
SLIT: Sublingual immunotherapy 16
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EAACI AIT prevention Guidelines V5.12.04.2017 3
Abstract 1
Max 250 words – now 248 2
Allergic diseases are very common and frequently coexist. Allergen immunotherapy (AIT) is a 3
potentially disease-modifying intervention for IgE-mediated allergic disease that may also have 4
important preventive effects. The European Academy of Allergy and Clinical Immunology (EAACI) has 5
developed clinical practice guidelines that aim to provide evidence-based recommendations for the 6
use of AIT for prevention of allergic sensitization, development of early life allergic conditions and 7
development of allergic comorbidities in those with established allergic diseases. These guidelines 8
have been developed using the AGREE II framework, which involved convening a multi-disciplinary 9
expert working group, a systematic review of the underpinning evidence, and external peer-review of 10
draft recommendations. Our key recommendations are that AIT cannot currently be recommended to 11
individuals for the prevention of allergic sensitization or first allergic disease. Children and 12
adolescents up to 18 years with persistent seasonal allergic rhinitis (AR) triggered by grass/birch 13
pollen allergy may benefit from a 3 year course of subcutaneous or sublingual AIT, for the short-term 14
(i.e. <2 years post-treatment) prevention of asthma, but it is uncertain whether this benefit is 15
maintained over a longer period. However, there is no current evidence to suggest that it has a similar 16
preventive effect in children and adolescents with AR triggered by house dust mites or other 17
allergens. There is no evidence that AIT may prevent the development of allergic co-morbidities in 18
those with other allergic diseases. Before initiating AIT, the possible benefits, disadvantages, potential 19
harms and costs should be discussed with the patient/family on an individual basis. 20
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EAACI AIT prevention Guidelines V5.12.04.2017 4
Introduction 1
Allergic diseases are now the commonest chronic diseases and encompass atopic 2
eczema/dermatitis, asthma, allergic rhinoconjunctivitis (ARC), food allergy and venom allergy [1-5]. 3
They frequently start in early childhood and continue throughout adulthood. Allergies cause 4
considerable burden to individuals leading to impaired quality of life [6]. At a societal level, they have 5
additional costs, particularly in terms of healthcare and impact on activities of daily living. The latter 6
may include loss of school days, work absence, presenteism and early retirement [7;8]. For asthma 7
and ARC, many patients respond well to pharmacotherapy, whereas others do not or need treatment 8
with more than one product. However, many may respond to therapeutic allergen immunotherapy 9
(AIT) reducing symptoms and the need for symptomatic treatment. Management for venom and food 10
allergy is more challenging and often reliant on avoidance strategies and rescue therapy; for these 11
conditions AIT may be a useful adjunctive strategy to avoid considerable personal, healthcare and 12
societal costs. 13
AIT is considered to be a potentially disease-modifying intervention in IgE-mediated allergic disease, 14
with the potential for preventive as well as therapeutic effects [9-11]. For example, we know that 15
children with allergic rhinitis (AR) have a 3-fold increase risk of developing allergic asthma [12]. 16
Studies assessing the long-term effectiveness of AIT in children with ARC indicate that AIT might 17
reduce the risk of developing asthma [13;14]. There is good evidence for the clinical efficacy of AIT for 18
allergic rhinitis, allergic asthma and severe venom allergy throughout multiple trials and meta-19
analyses of this treatment (x: SR ARC, SR Asthma, SR venom). We know that AIT can induce 20
immunological changes that result in disease modification [10]. The potential for AIT as a preventive 21
strategy should therefore be considered. 22
These Guidelines have been developed by the European Academy of Allergy and Clinical 23
Immunology (EAACI) Taskforce on AIT for Allergy Prevention and form part of the EAACI AIT 24
Guidelines. The aim is to provide evidence-based recommendations for the use of AIT for prevention 25
of development of allergic sensitization, first allergic disease and further allergic co-morbidities in 26
those with established allergic disease. These Guidelines do not cover weaning and dietetic 27
strategies, which are considered in the ‘EAACI food allergy and anaphylaxis guidelines. Primary 28
prevention of food allergy’ [15]. 29
EAACI AIT prevention Guidelines V5.12.04.2017 5
The primary audience for these Guidelines are clinical allergists (specialists and subspecialists) and 1
all healthcare professionals e.g., doctors, nurses and pharmacists working across a range of primary, 2
secondary and tertiary care settings managing patients with allergic diseases and healthy individuals 3
at risk of developing allergic diseases. 4
Methods 5
Development of the Guidelines has been informed by a formal systematic review and meta-analysis 6
of AIT for prevention [16] with systematic review principles being used to identify additional evidence, 7
where necessary. 8
These Guidelines were produced using the Appraisal of Guidelines for Research & Evaluation 9
(AGREE II) approach [17;18]. This structured methods for guideline production is designed to ensure 10
appropriate representation of the full range of stakeholders, an exhaustive search for and critical 11
appraisal of the relevant literature, a systematic approach to the formulation and presentation of 12
recommendations, and steps to ensure that the risk of bias is minimized at each step of the process. 13
The process began in April 2015 with detailed face-to-face discussion of the nature of guidelines for 14
clinical practice and a review of approaches to generating these. Then followed a series of face-to-15
face and WebEx discussions to agree the main aims of the guidelines, target conditions, intended 16
end-users for the recommendations, and ensuring adequate professional and lay representation in 17
the guidelines development process. We elaborate on these various steps below. Key terms are 18
described in Box 1. 19
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EAACI AIT prevention Guidelines V5.12.04.2017 6
Box 1. Key terms
Allergic diseases Atopic eczema (AE), food allergy (FA), allergic asthma (AA), allergic
rhinitis/conjunctivitis (ARC) at any age
AIT (Allergen
immunotherapy)
Repeated allergen exposure at regular intervals to modulate immune
response to reduce symptoms and need for medication for clinical
allergies and to prevent the development of new allergies and asthma
(adapted from European Marketing Agency (EMA)). This is also
sometimes known as allergen specific immunotherapy, desensitization
and hyposensitization*
Healthy individuals Individuals with or without IgE sensitization, but without any
manifestations of current allergic disease
Prevention
Prevention of the development of new sensitization or new allergic
disease in healthy individuals without sensitizations, in healthy
individuals with sensitizations and in those who already have allergic
disease.
Short-term prevention: effect until 2 years post-treatment
Long-term prevention: effect maintained at least 2 years post-
treatment
Sensitization Detectable IgE antibodies, either by means of skin prick test or
determination of specific-IgE antibody levels in a serum sample
* Dietary interventions in infants aimed at the prevention of food allergy are not covered in
these Guidelines: they form part of the ‘EAACI food allergy and anaphylaxis guidelines. Primary
prevention of food allergy’ https://www.ncbi.nlm.nih.gov/pubmed/24697491 [15](ref).
1
Clarifying the scope and purpose of the guidelines 2
These Guidelines aim to provide evidence-based statements that assist clinicians in the optimal use 3
of AIT for prevention of development of 1) allergic sensitization, 2) first allergic disease and 3) further 4
allergic co-morbidities in those with established allergic disease and 4) to identify gaps for further 5
research. The Guidelines builds on a SR conducted to explore these aims (Box 2) 6
EAACI AIT prevention Guidelines V5.12.04.2017 7
Box 2: Summary of the aim and outcomes in the supporting systematic review (SR ref)
Aim:
To provide a rigorous overview of current systematic review evidence on the effectiveness, safety
and cost-effectiveness of AIT for prevention of allergic disease
Study outcomes:
Primary
Development of the first allergic manifestation in healthy individuals, or of a new allergic
manifestation in those with a previous allergic condition (e.g. atopic eczema/dermatitis or
allergic rhinitis), assessed over the short term (< 2 years) or the longer term (≥ 2 years)
post-treatment
Secondary
Development of new allergic sensitization(s), spreading of allergic sensitization(s) from one
allergen to other non-related allergen(s), spreading of allergic sensitization(s) at molecular
level, from one allergenic molecule to other molecules
Development of previously non-existent oral allergy syndrome
Safety as assessed by local and systemic reactions in accordance with the World Allergy
Organization’s grading system of side-effects [19;20].
Health economic analysis from the perspective of the health system/payer as reported in
studies
1
Ensuring appropriate stakeholder involvement 2
Participants in the EAACI Taskforce on AIT for Prevention represented a range of countries, and 3
disciplinary and clinical backgrounds, including allergists, primary care physicians, allied health 4
professionals, public health and representatives from patient interest organisations. Methodologists 5
took the lead in undertaking the underpinning systematic review and clinical academics took the lead 6
in formulating recommendations for care. Additionally, producers of immunotherapy products were 7
given the opportunity to review and comment on the draft guidelines to allow any omissions or errors 8
in the evidence-base to be highlighted. The Taskforce considered these comments and revised where 9
appropriate. 10
EAACI AIT prevention Guidelines V5.12.04.2017 8
Systematic reviews of the evidence 1
The initial full range of questions that were considered important were rationalized through several 2
rounds of iteration to agree on one key overarching question: “What is the effectiveness, safety and 3
cost-effectiveness of AIT for prevention of allergic disease and sensitization in all populations”, which 4
was then pursued through a formal systematic review of the evidence [16;21]. 5
Formulating recommendations 6
We graded the strength and consistency of key findings from the systematic review to formulate 7
evidence-based recommendations for clinical care using an approach that was adapted from that 8
proposed by the Oxford Centre for Evidence-Based Medicine (Oxford Centre for Evidence-based 9
Medicine) (Box 3) [22]. The adaptation involved providing a summary of the quality of the 10
underpinning evidence and highlighting other potentially relevant contextual information, formulating 11
clear recommendations and making clear the evidence-base underpinning each recommendation, 12
taking into consideration not only possible beneficial effects, but also any possible disadvantages and 13
harms. Experts identified the resource implications of implementing the recommendations, barriers, 14
and facilitators to the implementation of each recommendation, advice on approaches to 15
implementing the recommendations and suggested audit criteria that can help with assessing 16
organizational compliance with each recommendation (see Supporting Information Tables SX, ….). 17
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EAACI AIT prevention Guidelines V5.12.04.2017 9
1
Box 3. Assigning levels of evidence and grade and strength of recommendations (12)
Level of evidence
Level I Systematic reviews, meta-analyses, randomized controlled trials
Level II Two group, non-randomized studies (e.g. cohort, case-control)
Level III One-group, non-randomized studies (e.g. 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 level II or III studies
Grade D Level V evidence or troublingly inconsistent or inconclusive studies at any level
Strength of recommendations
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
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”
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EAACI AIT prevention Guidelines V5.12.04.2017 10
Peer review and public comment 1
A draft of these guidelines was externally peer-reviewed by invited external experts from a range of 2
organizations, countries and professional backgrounds. Additionally, the draft guidelines were made 3
available on the EAACI Website for a 2-week period in May 2017 to allow a broader array of 4
stakeholders to comment. All feedback was considered by the Taskforce and, where appropriate, final 5
revisions were made in light of the feedback received. We will be pleased to continue to receive 6
feedback on these Guidelines, which should be addressed to the corresponding author. 7
Identification of evidence gaps 8
The process of developing these Guidelines has identified a number of evidence gaps which are 9
prioritized in Table 5. 10
Editorial independence and managing conflict of interests 11
The production of these Guidelines was funded and supported by EAACI. The funder did not have 12
any influence on the guideline production process, on its contents, or on the decision to publish. 13
Taskforce members’ conflict of interests were taken into account by the Taskforce Chairs as 14
recommendations were formulated. Methodologists, who had no conflict of interests in this area, 15
checked final decisions about strength of evidence for recommendations. 16
Updating the guidelines 17
EAACI plans to update these guidelines using the AGREE II approach in 2022 unless there are 18
important advances before then. 19
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Overarching considerations 21
These guidelines are based on a comprehensive systematic review evaluating the evidence 22
according to predefined well established methods [16]. As in other systematic reviews, heterogeneity 23
in the populations under study, methods employed and outcomes studied made it challenging to 24
interpret the evidence. It is well known that factors related to the population, such as atopic heredity 25
play a role for the risk of development of allergic disease. In addition, children with sensitization 26
and/or early manifestations of atopic diseases e.g. atopic dermatitis (AD) and food allergy or later 27
EAACI AIT prevention Guidelines V5.12.04.2017 11
manifestation such as AR have a higher risk for development of other allergic manifestations such as 1
asthma [23] [12]. The age of the population is important as phenotypic expression may change with 2
age and some manifestations may even disappear spontaneously [24]. The results of individual 3
studies are difficult to compare because studies use different outcome measures, different diagnostic 4
criteria (if any, e.g. the exact definition of asthma, intermittent versus persistent asthma), different 5
methods, and cut-off values for measuring sensitization. Furthermore, the mode of administration and 6
the products used for AIT differ as regards allergens, formulation, strength, dose, and duration of the 7
intervention. Additionally, many studies are small without sufficient power and adjustment for 8
confounders. Where possible, these factors are taken into consideration in the risk of bias and quality 9
assessment in the systematic review on which these guidelines are based. 10
Using AIT for prevention of development of new allergic disease or sensitization requires a high level 11
of safety, especially in healthy individuals. However, if AIT is indicated due to treatment of an allergic 12
disease that has already developed, and the preventive effect is regarded as an additional effect, then 13
the safety profile should be considered in that context. 14
Strategies to prevent development of a new sensitization or of a new allergic disease by AIT may vary 15
for different populations at different stages in life. It may thus be relevant for those planning 16
pregnancy to take measures such as AIT to reduce the likelihood of their child becoming allergic. 17
Strategies for healthy infants and young children with early manifestations such as AD, older children 18
with manifest allergic disease such as AR, healthy adolescents/adults and adolescents/adults with 19
already developed allergic disease need to be pursued. 20
In order to recommend AIT for the prevention of allergic diseases, evidence is required that there is a 21
relevant and substantial beneficial effect on outcomes for the individual. Furthermore, safety aspects, 22
quality of life, evaluation of health economics and other factors should be taken into consideration. 23
Thus, an optimal balance between benefits, harms, costs and other possible disadvantages should be 24
achieved (Table 1). 25
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EAACI AIT prevention Guidelines V5.12.04.2017 12
AIT for prevention: Evidence and clinical recommendations 1
AIT for short- and long-term prevention of development of new allergic disease 2
AIT for prevention of allergy in the offspring of allergic individuals 3
This topic has not been included in the protocol or in the systematic review. However, after finalizing 4
the systematic review, we found one low quality case-control study including 194 children of parents 5
subjected to and completing AIT at least 9 months before birth, who were compared with 195 controls 6
[25]. This study found that the odds ratios of any allergic disease and asthma was significantly lower 7
in children with one or both parents with allergy after AIT compared with those having parents with 8
allergy but without AIT (odds ratio: 0.73, 95% confidence interval 0.59-0.86). The authors hypothesise 9
that AIT in allergic parents might reduce the risk of allergies in their offspring, but this remains to be 10
established. 11
Based on the very scarce and very low quality evidence, we cannot recommend AIT for allergic 12
adult’s for prevention of allergic disease in their offspring (Table 2) 13
AIT in healthy individuals: Short- and long-term preventive effects 14
Two RCTs, one of high [26] and one of low quality [27], investigated the possible effect of AIT in 15
healthy individuals on the risk for development of their first allergic disease among infants with family 16
history of allergic diseases and asymptomatic adults sensitized to Japanese cedar pollen, 17
respectively. Meta-analysis [16] did not demonstrate a short-term preventive effect of oral HDM AIT 18
and Japanese cedar pollen SLIT in these two trials [26;27]. No data on long-term effects was 19
identified. Based on the results from the systematic review [16] there is no high quality evidence to 20
recommend use of AIT for the prevention of first allergic disease in healthy individuals (Table 2). 21
AIT in individuals with AD: Short- and long-term preventive effects 22
One medium quality RCT investigated the effects of 12 months of daily SLIT on prevention of asthma 23
and new sensitizations in children with AD and sensitization to one or more food allergens [28]. The 24
investigators included early immunological changes as a stopping rule and, as these a priori 25
immunological changes were not met,, recruitment was terminated and the trial reduced to pilot study 26
status. After 48 months of follow-up, there were no differences in asthma prevalence between the two 27
groups [28]. 28
EAACI AIT prevention Guidelines V5.12.04.2017 13
Based on the results from the systematic review [16], we cannot recommend AIT for prevention of 1
development of first allergic disease in individuals with AD (Table 3). 2
AIT in individuals with AR: Short- and long-term preventive effects 3
The systematic review [16] identified six RCTs investigating the short-term preventive effect (i.e. up to 4
two years post-treatment) of AIT on development of asthma in individuals with allergic rhinitis. These 5
RCTs included three SCIT studies (one of high [29], one of medium [30] and one of low quality [31]), 6
one medium quality on oral AIT [32] and one high quality SLIT study [33]. Three of these [29;30;32] 7
were small studies with a trend towards less development of asthma in the AIT group but no 8
significant differences. The remaining three studies [31;33;34] showed a significant reduction of 9
development of asthma in the AIT groups as compared to the control groups. Meta-analysis [16] 10
demonstrated a significant preventive effect of AIT on the development of asthma up to two years 11
post-treatment in patients with AR. Subgroup analyses showed that AIT with either SLIT or SCIT was 12
beneficial for those aged <18 years but not ≥18 years and for pollen AIT but not for HDM AIT. 13
Further, one large-scale real life retrospective non-randomized controlled before-after (CBA) study [35] 14
investigated the short-term effect of AIT in patients with AR and reported a preventive effect of AIT on 15
the progression from AR to asthma overall, and in those receiving SCIT but not SLIT. 16
For the long-term preventive effect (i.e. two or more years post-treatment) the systematic review 17
identified two low quality SCIT RCTs [36;37] in patients with AR. Both showed a significantly lower 18
risk for developing asthma in the SCIT groups as compared to the controls, up to seven years post-19
treatment [36], and two years post-treatment [37]. A large yet unpublished high quality RCT [38] 20
explored the effect of a three-year course of SLIT tablets on the prevention of asthma in 812 mono-21
allergic children with AR and grass pollen allergy. Based on data available in EudraCT [39] this study 22
failed to demonstrate the preventive effect of AIT on the development of asthma diagnosed by very 23
strict criteria including reversibility to beta-2-agonists (OR=0.91; 95%CI 0.58 to 1.41)[38;39] two years 24
post-treatment. It was, however, also reported that the number of subjects with asthma symptoms or 25
asthma medication usage at the end of the five-year trial period in the SLIT group was significantly 26
lower than in the placebo group (OR 0.66; 95%CI [0.45; 0.97] ; P=0.036). As published in the 27
systematic review [16], meta-analysis showed no overall evidence of reduction in the long-term (i.e. at 28
least 2 years post-treatment) risk of developing asthma. However, the studies may suggest a long-29
EAACI AIT prevention Guidelines V5.12.04.2017 14
term effect as regards development of asthma symptoms and medication but we need more data and 1
more studies to confirm if this is the case. 2
The studies on asthma prevention in AR included patients with a history of AR and need for 3
medication combined with documented pollen allergy for at least one previous season. There is no 4
published information on severity thus subjects may have had a milder disease than those included in 5
studies on efficacy of AIT. However, based on baseline descriptions of the populations in these 6
studies, it is reasonable to assume that most of the patients included have persistent and not 7
intermittent symptoms. 8
As discussed in another manuscript of this series of guidelines on AIT (ref: AR SR + Guideline)), 9
patients with AR and pollen allergy also may benefit from AIT in reducing AR symptoms and need for 10
medication for their AR. Thus, AIT is recommended for treatment of patients with moderate-to-severe 11
pollen induced AR if not optimally controlled on antihistamines and nasal corticosteroids. 12
There are however also potential harmful effects, disadvantages and costs associated with the 13
treatment, but these seem to be outweighed by the beneficial effects for this group of patients (Table 1) 14
giving a favorable risk benefit profile. 15
In addition, there is moderate to high quality evidence indicating that AIT (SCIT or SLIT) can be 16
recommended for short-term prevention (up to two years post-treatment) of asthma in children with 17
moderate - severe AR and pollen allergy who are sub-optimally controlled despite appropriate 18
pharmacotherapy, though there is no robust data indicating that this benefit persists after two years 19
post-treatment. However, AIT may be considered in patients with milder AR disease given that it is 20
able to modify the natural history including a long-term effect and the preventive effect as regards 21
development of asthmaon of the progression of disease unlike pharmacotherapy. 22
The indication and initiation of AIT should be preceded by a discussion of the possible benefits, harms 23
and disadvantages, and costs as well as the mode of AIT (SCIT vs SLIT) with the patient / family on 24
an individual basis (Table 4). 25
AIT for prevention of development of new allergic sensitization 26
The systematic review identified three high quality RCTs [26;40;41], one moderate [42] and two low 27
quality [33;43] RCTs that investigated the short-term effects of AIT on the risk of developing new 28
EAACI AIT prevention Guidelines V5.12.04.2017 15
sensitizations. One high quality RCT [26] on oral HDM AIT for healthy infants at high risk of 1
developing allergic disease found a significant reduction in sensitization to any common allergen in 2
the active group compared with the placebo group at the end of the trial but no difference in HDM 3
sensitization between the AIT and control groups [26]. The other two high quality RCTs found no 4
effect of SLIT in adult patients allergic to peach [40] post-treatment and after SLIT with grass pollen or 5
HDM extract in mono-sensitized children [41]. Three additional RCTs of medium to low quality 6
[33;42;43] found a significantly lower incidence of new sensitizations among children and adults with 7
AR treated with SLIT [33;43] and SCIT [42] as compared to controls. 8
Meta-analysis showed an overall reduction in the risk of allergic sensitization but the sensitivity 9
analyses, excluding the two low quality studies by Marogna [33;43], failed to confirm this risk 10
reduction [16]. 11
The inconsistent evidence found in RCTs was also reflected in the included low quality CBA studies 12
with three finding a lower occurrence of new sensitizations among AIT treated subjects compared 13
with controls [44-46] with one study reporting higher occurrence in the AIT group compared with 14
controls [47] and three studies reporting no differences between groups [48;49] [50] 15
The systematic review on long-term (i.e. at least two years post-treatment) preventive effects on 16
prevention of new sensitivities identified one medium [51] and one low quality RCT [51] showing no 17
preventive effect of SCIT among children with moderate-to-severe asthma followed into adulthood 18
[51] and SCIT in adults with ARC three years post-treatment [52]. Another low quality RCT [37] found 19
that patients with AR treated with HDM SCIT less frequently developed new sensitizations compared 20
with controls two years post-treatment [37]. 21
Meta-analyses of these studies [16] showed no evidence of a reduction in the long-term risk of allergic 22
sensitization. 23
The seven low quality CBA studies investigating long-term preventive effects of AIT found 24
inconsistent results, one study found no difference in onset of new sensitizations between intervention 25
and control group [53], four studies showed reduced onset of new sensitizations in the AIT groups 26
[45;54-57] and one found a significantly higher occurrence of new sensitization among AIT treated 27
compared with controls [58]. 28
EAACI AIT prevention Guidelines V5.12.04.2017 16
The development of new sensitivities may impose a higher risk for development of new symptomatic 1
allergies and it therefore might be relevant to try to prevent the development of new sensitizations. 2
However, this has not been investigated sufficiently. Based on the present evidence, there is no high 3
quality evidence to recommend the use of AIT for either the short- or the long-term prevention of 4
development of new sensitizations in healthy individuals, children with atopic predisposition (Table 2), 5
children with AD / food allergy (Table 3) nor in children and adults with AR / asthma (Table 4). 6
7 8
9
EAACI AIT prevention Guidelines V5.12.04.2017 17
Table 1. Benefits and harms / disadvantages of AIT in different populations 1
Population Benefits Harms / disadvantages
Healthy +/- sensitization Possible preventive effect
Daily intake of tablets/drops (SLIT/oral) or regular injections (SCIT) for 3 years
Frequency of visits in the clinic (SCIT)
Risk for adverse events
Costs
Children with atopic dermatitis Possible preventive effect not documented
Daily intake of tablets/drops (SLIT/oral) or regular injections (SCIT) for 3 years
Frequent visits in the clinic (SCIT)
Risk of adverse events
Costs
Patients with allergic rhinitis
Documented beneficial effect on symptoms and reduction in medication, short - and long-term
Possible preventive effect
Short term
Long term?
Daily intake of tablets/drops (SLIT/oral) or regular injections (SCIT) for 3 years
Frequency of visits in the clinic (SCIT)
Risk for adverse events
Costs
2
3
4
5
EAACI AIT prevention Guidelines V5.12.04.2017 18
Table 2. AIT for prevention: recommendations for healthy individuals 1
Recommendations for healthy individuals all ages Evidence
level Grade of
recommendation Strength of
recommendation Other
considerations Key
references
AIT is not recommended in adult allergic patients for prevention of onset of allergic diseases in their offspring
IV-V D Weak recommendation: Based on results from 1 low quality study
Bozek A, 2016
AIT is not recommended for prevention of onset of allergic diseases in healthy individuals with or without sensitization
I A Weak recommendation: Based on 1 high and 1 low quality RCTs
One RCT with infant and one
with adult population
Zolkipli 2015, Yamanaka 2015
AIT is not recommended for prevention of new sensitizations in healthy children
I B
Weak to moderate recommendation: Based on results from 2 high quality RCTs
One RCT with infant and one with preschool
population
Zolkipli 2015, Szepfalusi 2014
AIT is not recommended for prevention of new sensitizations in healthy adults
V D Expert opinion. No studies
2
3
4
EAACI AIT prevention Guidelines V5.12.04.2017 19
1
Table 3. AIT for prevention: recommendations for individuals with early life atopic manifestations, e.g. atopic dermatitis or food allergy 2
3 4
5
6
7
Recommendations for individuals with early atopic manifestations Evidence
level Grade of
recommendation Strength of
recommendation Other
considerations Key
references
AIT is not recommended in children with atopic dermatitis for the prevention of onset of later allergic manifestations
I B Weak recommendation: Based on 1 small medium quality study
Holt P 2013
AIT is not recommended for the prevention of onset of other allergic manifestations in individuals at all ages with other early atopic manifestations e.g. food allergy
V D Expert opinion. No studies
EAACI AIT prevention Guidelines V5.12.04.2017 20
Table 4. AIT for prevention: recommendations for school age children, adolescents and adults with allergic rhinitis or asthma 1
Recommendations for individuals with manifest allergic disease(s), e.g. allergic rhinitis
Evidence level
Grade of recommendation
Strength of recommendation
Other considerations Key references
A 3 year course of AIT (SCIT or SLIT) can be recommended for short-term (i.e. < 2 years post treatment) prevention of the onset of asthma in children and adolescents with AR and grass/birch pollen allergy who are sub-optimally controlled despite appropriate treatment with antihistamines / nasal corticosteroids
I A
Moderate recommendation: Based on consistent significant results from 2 medium (Möller1986, Novembre) and 2 low quality (Möller2002, Marogna2008) RCTs and some CBA studies
The indication should be discussed with the patients / families including the asthma preventive effect as well as the effect on AR and risk of adverse effects, costs and preferences
Möller1986, Möller2002, Novembre2004, Marogna2008
No recommendation can be made in favor for or against the use of AIT (SCIT or SLIT) for the long-term (≥ 2 years post treatment) prevention of the onset of asthma in children and adolescents with AR and grass/birch pollen allergy
I B
Weak recommendation: Based on consistent results from 2 low quality RCTs, non-significant results from 1 high quality RCT (Valovirta2016), and the meta-analyses being not significant
The study by Valovirta not yet published
Jacobsen2007, Song2015, Valovirta2017
No recommendation can be made in favor for or against the use of AIT (SCIT or SLIT) for short-term (i.e. < 2 years post treatment) or long-term (i.e. ≥ 2 years post treatment) prevention of the onset of asthma in children and adolescents with AR and allergy to HDM or other allergens except for birch/grass pollen
I B
Weak recommendation: Based on inconsistent results from 1 low (Marogna2008) and 1 high quality RCTs (Grembiale2002)
Only HDM, parietaria and mix of these and grass/birch pollen investigated
Marogna2008, Crimi2004, Grembiale2002
AIT (SCIT or SLIT) is not recommended for short-term (i.e. < 2 years post treatment) or long-term (i.e. ≥ 2 years post treatment) prevention of the onset of asthma in adults with AR and HDM or pollen allergy
I B Weak recommendation: Based on 1 small medium quality study
Crimi 2004
AIT is not recommended for prevention of new sensitizations, either in children or adults with allergic rhinitis and/or asthma
I B
Weak recommendation: Based on inconsistent results from 4 low, 2 medium and 3 high quality RCTs
SR
2
EAACI AIT prevention Guidelines V5.12.04.2017 21
Safety 1
The systematic review only included safety data from studies on the preventive effect of AIT and it is 2
therefore not complete with this regard. However, the safety issues are fully covered by other 3
systematic reviews and guidelines in this AIT guideline series (AR SR and Guideline). Fatalities are 4
very rare and not described for SLIT. The safety profile for the present purpose is not regarded as 5
being different from AIT for treatment of AR. Due to its better safety profile SLIT might be a better 6
choice for prevention than SCIT. 7
Cost-effectiveness 8
The systematic review did not identify any studies investigating the cost-effectiveness of AIT for the 9
prevention of allergy. 10
11
Summary, gaps in the evidence and future perspectives 12
This guideline on AIT for prevention of allergy has been developed as part of the EAACI AIT 13
Guidelines project. The recommendations in this guideline are based on a thorough systematic review 14
performed by a group of experienced and independent methodologists and have been developed by 15
a multidisciplinary collaboration in an EAACI Task Force representing a range of countries and 16
disciplines and clinical backgrounds. 17
The guideline provides evidence based recommendations for the use of AIT for prevention of new 18
allergic disease(s) and new allergic sensitization(s) in all populations. The guidelines should provide 19
help to all healthcare professionals as regards evaluation of AIT for prevention of allergic disease 20
/sensitization, and when to refer which individuals to further evaluation. The main results are 21
summarized in box 4. 22
There are many areas, for which there is no evidence or no high quality evidence representing gaps 23
in the current evidence as indicated in Table 5. Thus, for the possible preventive effect of AIT in 24
healthy individuals or in children with early atopic manifestations such as atopic dermatitis or food 25
allergy as well as for the possible long-term effect in children with AR there is a lack of evidence. Also, 26
we did not find studies related to spreading of allergic sensitization(s) at the molecular level, nor did 27
we identify studies exploring the development of new oral allergy syndrome (OAS) or health economic 28
EAACI AIT prevention Guidelines V5.12.04.2017 22
analyses of AIT used for prevention. In addition, there is a lack of evidence as regards patient 1
selection (e.g. optimal age and characteristics) for preventive AIT or for the optimal allergen 2
preparation, mode and duration of AIT administration; there is a need for standardized relevant 3
outcomes including Quality of life (Qol) for future studies. 4
The current evidence does not allow differentiation between SCIT and SLIT; therefore, this choice has 5
to depend on availability, patients / families preferences, and other considerations such as safety and 6
costs. Studies, which demonstrate a preventive effect upon which we have based our 7
recommendations, included three-year courses of perennial AIT. 8
Based on current evidence, AIT can be recommended for the short-term prevention of development of 9
asthma in children and adolescents with AR and pollen allergy, primarily birch and grass, however it is 10
not documented whether this effect is a postponement or whether it can be extended to the longer-11
term (i.e. at least two years post-treatment). AIT should in particular be considered for those with 12
moderate-severe AR as it has been shown to be effective in controlling this condition in addition to the 13
preventive effect on the short-term development of asthma (ref AR SR and guideline). Furthermore, 14
some patients with less severe AR may prefer AIT due its long-term and asthma preventive effect or 15
to avoid side effects of other treatments. 16
Children and adolescents included in the prevention studies did not necessarily fulfil the criteria for 17
recommendations for AIT for treatment of AR as well as they did not necessarily meet the ARIA 18
criteria for moderate/severe symptoms. At present, the indications for AIT for prevention of allergic 19
disease are the same as for treatment of AR (i.e. documented IgE-mediated disease caused by the 20
relevant allergens and not sufficiently controlled by antihistamines and nasal corticosteroids). 21
Contraindications are the same as for treatment of AR. The asthma preventive effect may in the future 22
influence the threshold for AIT by reducing the level of severity of AR required for the indication of AIT 23
in children and adolescents with AR and pollen allergy, especially grass pollen allergy. Therefore, 24
based on the preventive effect, it may be relevant to discuss AIT as a relevant treatment option for 25
children and adolescents up to 18 years of age with less severe but persistent AR due to pollen 26
allergy and need for medication during the relevant season. During and after AIT patients should 27
receive relevant pharmacological treatment as needed. At this moment, there is no high quality 28
evidence to support this approach for HDM allergic patients with AR. 29
EAACI AIT prevention Guidelines V5.12.04.2017 23
For implementation of these guidelines there is a need to ensure that primary care healthcare 1
professionals recognise AIT as a treatment option for some allergic diseases and have clear 2
guidelines to aid patient selection for referral to specialist care. Patients and patient organizations 3
need to be aware of AIT as a treatment option. Political awareness should be increased to ensure 4
sufficient availability, knowledge, competences, skills and resources in the health care system by 5
demonstrating total economic benefits of such therapy by exploration of its positive impact on 6
economic productivity.7
EAACI AIT prevention Guidelines V5.12.04.2017 24
Table 5. Gaps in the evidence 1 2
3
4
Gaps Plan to address Priority
AIT for the prevention of new allergic sensitizations
spreading from one allergen to related and unrelated allergen(s)
spreading at molecular level, from one allergenic molecule to other molecules
RCTs Low
AIT for prevention of first allergic disease RCT Medium
AIT for prevention of AR / asthma in children and adults with AD / food allergy RCTs Medium
AIT for prevention of the Oral Allergy Syndrome RCT Low
AIT for prevention of asthma in children with AR - long term effect
AIT for prevention of asthma in children with AR due to HDM
RCTs
Further evaluation of GAP trial High
Optimal age of introduction for AIT for prevention RCT High
Optimal duration of AIT for prevention RCT High
Evaluation of health economics of AIT for prevention Cost-effectiveness analysis of RCT Medium
Evaluation of influence of AIT for prevention on Qol in different age groups Qol as outcome in RCTs High
Evaluation of adherence in AIT for prevention in different age groups Adherence measured in RCTs and
real life studies Medium
Evaluation of acceptability of AIT for prevention in different age groups RCTs Medium
EAACI AIT prevention Guidelines V5.12.04.2017 25
1
2
Box 4. Summary
AIT is not recommended for the prevention of new sensitizations
o in healthy individuals
o in individuals with established allergic disease
AIT is not recommended for prevention of new allergic manifestations in
o Children with atopic dermatitis / food allergy
A three year course of AIT (SCIT or SLIT) can be considered in children with moderate –
severe AR and grass/birch pollen allergy, not sufficiently controlled with optimal
pharmacotherapy, for short-term (i.e. < 2 years post-treatment) prevention of the onset of
asthma in addition to improving the control of AR. It is uncertain, whether this asthma
preventive effect is maintained over a longer period
o Before initiating AIT the possible benefits including the beneficial effects on
controlling AR symptoms, disadvantages and potential harms and costs should be
discussed with the patient / family on an individual basis
AIT (SCIT or SLIT) cannot be recommended for prevention of the onset of asthma in
children with AR and allergy to HDM or other allergens than birch/grass pollen – neither for
short-term or long-term prevention
Dietary interventions in infants aimed at the prevention of food allergy are not covered in
these Guidelines: they form part of the ‘EAACI food allergy and anaphylaxis guidelines
EAACI AIT prevention Guidelines V5.12.04.2017 26
1
Box 5 Key messages for primary care about referral to allergy services
AIT to prevent allergy is not recommended for:
o Parents who are planning a family
o Healthy infants/children
o Infants/children with AD and/or food allergy
AIT may have a role in delaying/preventing progression from seasonal AR/ARC to asthma
o Primary care teams should consider referring children with troublesome AR/ARC
not responding sufficiently to optimal pharmacotherapy for a specialist assessment
with a view to considering AIT to improve control of AR/ARC and also
simultaneously delay/prevent asthma
o In such families, there will need to be an assessment made of the potential
benefits, risks and costs of AIT
AIT may be indicated in those with perennial AR/ARC on clinical grounds but not only for
delaying/preventing progression to asthma
2 3 4 Acknowledgements 5 6
We would like to acknowledge the support of EAACI and the EAACI Allergen Immunotherapy 7
Guidelines Group in developing these guidelines. We would like to thank xxxxxx for their assistance in 8
preparing the guidelines. We would also like to thank our expert panel and everyone who provided 9
comments on the draft guidelines (xxxxxxxxxx) and the EAACI Executive Committee for their helpful 10
comments and suggestions. 11
12
Authors’ contribution 13
14
xxxxxxxxxx 15
16
17
Conflicts of interest 18
19
xxxxxxxxx 20
21
22
EAACI AIT prevention Guidelines V5.12.04.2017 27
Online supplement: Barriers and facilitators to implementation, audit criteria and resource implications of recommendations 1
2
Recommendations for individuals with allergic rhinitis: barriers and facilitators to implementation, audit criteria and resource implications of 3
recommendations 4
Prevention of development of
asthma in patients with AR
Ev
ide
nc
e
lev
el
Gra
de Key references
Barriers to
implementation
Facilitators to
implementation Audit criteria
Resource
implications
In children with AR and grass/birch pollen allergy a 3 year course of AIT(SCIT or SLIT) can be recommended for short-term (i.e. < 2 years post treatment) prevention of the onset of asthma in children with daily symptoms and need for medication
I A Failure to recognize manifestations Lack of knowledge amongst patients, caregivers and professionals about the benefits of AIT Lack of access to AIT Unavailability of AIT Concerns about side-effects Economic aspects Link to AR Guideline
Information amongst patients, caregivers and professionals about the benefits of AIT Reimbursement of AIT Link to AR Guideline
Proportion of potentially eligible patients referred from primary care for a specialist assessment Proportion of potentially eligible patients formally considered for AIT
Thorough investigation of the patient including proper assessment of relevant allergies. AITneed to be prescribed, made available and administered to patients Link to AR Guideline
5
EAACI AIT prevention Guidelines V5.12.04.2017 28
1 2
References 3
4
1. Christiansen ES, Kjaer HF, Eller E, Bindslev-Jensen C, Host A, Mortz CG, Halken S. The 5 prevalence of atopic diseases and the patterns of sensitization in adolescence. Pediatr 6 Allergy Immunol 2016; 27:847-53. 7
2. Henriksen L, Simonsen J, Haerskjold A, Linder M, Kieler H, Thomsen SF, Stensballe LG. 8 Incidence rates of atopic dermatitis, asthma, and allergic rhinoconjunctivitis in Danish and 9 Swedish children. J Allergy Clin Immunol 2015; 136:360-6. 10
3. Tejedor Alonso MA, Moro MM, Mugica Garcia MV. Epidemiology of anaphylaxis. Clin Exp 11 Allergy 2015; 45:1027-39. 12
4. Patil VK, Kurukulaaratchy RJ, Venter C, Grundy J, Roberts G, Dean T, Arshad SH. Changing 13 prevalence of wheeze, rhinitis and allergic sensitisation in late childhood: findings from 2 Isle 14 of Wight birth cohorts 12 years apart. Clin Exp Allergy 2015; 45:1430-8. 15
5. Nwaru BI, Hickstein L, Panesar SS, Muraro A, Werfel T, Cardona V, Dubois AE, Halken S, 16 Hoffmann-Sommergruber K, Poulsen LK, Roberts G, van RR, Vlieg-Boerstra BJ, Sheikh A. The 17 epidemiology of food allergy in Europe: a systematic review and meta-analysis. Allergy 2013. 18
6. Muraro A, Dubois AE, DunnGalvin A, Hourihane JO, de Jong NW, Meyer R, Panesar SS, 19 Roberts G, Salvilla S, Sheikh A, Worth A, Flokstra-de Blok BM. EAACI Food Allergy and 20 Anaphylaxis Guidelines. Food allergy health-related quality of life measures. Allergy 2014; 21 69:845-53. 22
7. Zuberbier T, Lotvall J, Simoens S, Subramanian SV, Church MK. Economic burden of 23 inadequate management of allergic diseases in the European Union: a GA(2) LEN review. 24 Allergy 2014; 69:1275-9. 25
8. Bahadori K, Doyle-Waters MM, Marra C, Lynd L, Alasaly K, Swiston J, FitzGerald JM. 26 Economic burden of asthma: a systematic review. BMC Pulm Med 2009; 9:24. 27
9. Bousquet J, Lockey R, Malling HJ. Allergen immunotherapy: therapeutic vaccines for allergic 28 diseases. A WHO position paper. J Allergy Clin Immunol 1998; 102:558-62. 29
10. Jutel M, Agache I, Bonini S, Burks AW, Calderon M, Canonica W, Cox L, Demoly P, Frew AJ, 30 O'Hehir R, Kleine-Tebbe J, Muraro A, Lack G, Larenas D, Levin M, Martin BL, Nelson H, 31 Pawankar R, Pfaar O, van RR, Sampson H, Sublett JL, Sugita K, du TG, Werfel T, Gerth van 32 WR, Zhang L, Akdis M, Akdis CA. International Consensus on Allergen Immunotherapy II: 33 Mechanisms, standardization, and pharmacoeconomics. J Allergy Clin Immunol 2016; 34 137:358-68. 35
11. Jutel M, Agache I, Bonini S, Burks AW, Calderon M, Canonica W, Cox L, Demoly P, Frew AJ, 36 O'Hehir R, Kleine-Tebbe J, Muraro A, Lack G, Larenas D, Levin M, Nelson H, Pawankar R, 37 Pfaar O, van RR, Sampson H, Santos AF, du TG, Werfel T, Gerth van WR, Zhang L, Akdis CA. 38 International consensus on allergy immunotherapy. J Allergy Clin Immunol 2015; 136:556-39 68. 40
EAACI AIT prevention Guidelines V5.12.04.2017 29
12. Burgess JA, Walters EH, Byrnes GB, Matheson MC, Jenkins MA, Wharton CL, Johns DP, 1 Abramson MJ, Hopper JL, Dharmage SC. Childhood allergic rhinitis predicts asthma incidence 2 and persistence to middle age: a longitudinal study. J Allergy Clin Immunol 2007; 120:863-9. 3
13. Jacobsen L, Nuchel PB, Wihl JA, Lowenstein H, Ipsen H. Immunotherapy with partially 4 purified and standardized tree pollen extracts. IV. Results from long-term (6-year) follow-up. 5 Allergy 1997; 52:914-20. 6
14. Nieto A, Wahn U, Bufe A, Eigenmann P, Halken S, Hedlin G, Host A, Hourihane J, Just J, Lack 7 G, Lau S, Matricardi PM, Muraro A, Papadopoulos N, Roberts G, Simpson A, Valovirta E, 8 Weidinger S, Wickman M, Mazon A. Allergy and asthma prevention 2014. Pediatr Allergy 9 Immunol 2014; 25:516-33. 10
15. Muraro A, Halken S, Arshad SH, Beyer K, Dubois AE, du TG, Eigenmann PA, Grimshaw KE, 11 Hoest A, Lack G, O'Mahony L, Papadopoulos NG, Panesar S, Prescott S, Roberts G, de SD, 12 Venter C, Verhasselt V, Akdis AC, Sheikh A. EAACI food allergy and anaphylaxis guidelines. 13 Primary prevention of food allergy. Allergy 2014; 69:590-601. 14
16. Kristiansen M, Dhami S, Netuveli G, Halken S, Muraro A, Roberts G, Larenas-Linnemann D, 15 Calderon MA, Penagos M, du TG, Ansotegui IJ, Kleine-Tebbe J, Lau S, Matricardi PM, Pajno G, 16 Papadopoulos NG, Pfaar O, Ryan D, Santos AF, Timmermanns F, Wahn U, Sheikh A. Allergen 17 immunotherapy for the prevention of allergy: A systematic review and meta-analysis. 18 Pediatr Allergy Immunol 2017; 28:18-29. 19
17. Brouwers MC, Kho ME, Browman GP, Burgers JS, Cluzeau F, Feder G, Fervers B, Graham ID, 20 Grimshaw J, Hanna SE, Littlejohns P, Makarski J, Zitzelsberger L. AGREE II: advancing 21 guideline development, reporting and evaluation in health care. CMAJ 2010; 182:E839-E842. 22
18. Development and validation of an international appraisal instrument for assessing the 23 quality of clinical practice guidelines: the AGREE project. Qual Saf Health Care 2003; 12:18-24 23. 25
19. Cox L, Larenas-Linnemann D, Lockey RF, Passalacqua G. Speaking the same language: The 26 World Allergy Organization Subcutaneous Immunotherapy Systemic Reaction Grading 27 System. J Allergy Clin Immunol 2010; 125:569-74, 574. 28
20. Passalacqua G, Baena-Cagnani CE, Bousquet J, Canonica GW, Casale TB, Cox L, Durham SR, 29 Larenas-Linnemann D, Ledford D, Pawankar R, Potter P, Rosario N, Wallace D, Lockey RF. 30 Grading local side effects of sublingual immunotherapy for respiratory allergy: speaking the 31 same language. J Allergy Clin Immunol 2013; 132:93-8. 32
21. Dhami S, Nurmatov U, Halken S, Calderon MA, Muraro A, Roberts G, Toit GD, Kleine-Tebbe J, 33 Larenas-Linnemann D, Lau S, Matricardi PM, Pajno G, Papadopoulos NG, Pfaar O, Ryan D, 34 Santos AF, Timmermanns F, Wahn U, Sheikh A. Allergen immunotherapy for the prevention 35 of allergic disease: protocol for a systematic review. Pediatr Allergy Immunol 2016; 27:236-36 41. 37
22. Oxford Centre for Evidence-based medicine. Levels of Evidence and Grades of 38 Recommendation. 2013. 31-3-2013. 39
Ref Type: Online Source 40
23. Guerra S, Sherrill DL, Martinez FD, Barbee RA. Rhinitis as an independent risk factor for 41 adult-onset asthma. J Allergy Clin Immunol 2002; 109:419-25. 42
EAACI AIT prevention Guidelines V5.12.04.2017 30
24. Nissen SP, Kjaer HF, Host A, Nielsen J, Halken S. The natural course of sensitization and 1 allergic diseases from childhood to adulthood. Pediatr Allergy Immunol 2013; 24:549-55. 2
25. Bozek A, Jarzab J, Bednarski P. The effect of allergen-specific immunotherapy on offspring. 3 Allergy Asthma Proc 2016; 37:59-63. 4
26. Zolkipli Z, Roberts G, Cornelius V, Clayton B, Pearson S, Michaelis L, Djukanovic R, 5 Kurukulaaratchy R, Arshad SH. Randomized controlled trial of primary prevention of atopy 6 using house dust mite allergen oral immunotherapy in early childhood. J Allergy Clin 7 Immunol 2015; 136:1541-7. 8
27. Yamanaka K, Shah SA, Sakaida H, Yamagiwa A, Masuda S, Mizutani H, Takeuchi K. 9 Immunological parameters in prophylactic sublingual immunotherapy in asymptomatic 10 subjects sensitized to Japanese cedar pollen. Allergol Int 2015; 64:54-9. 11
28. Holt PG, Sly PD, Sampson HA, Robinson P, Loh R, Lowenstein H, Calatroni A, Sayre P. 12 Prophylactic use of sublingual allergen immunotherapy in high-risk children: a pilot study. J 13 Allergy Clin Immunol 2013; 132:991-3. 14
29. Grembiale RD, Camporota L, Naty S, Tranfa CM, Djukanovic R, Marsico SA. Effects of specific 15 immunotherapy in allergic rhinitic individuals with bronchial hyperresponsiveness. Am J 16 Respir Crit Care Med 2000; 162:2048-52. 17
30. Crimi N, Li GF, Mangano G, Paolino G, Mastruzzo C, Vancheri C, Lisitano N, Polosa R. A 18 randomized, controlled study of specific immunotherapy in monosensitized subjects with 19 seasonal rhinitis: effect on bronchial hyperresponsiveness, sputum inflammatory markers 20 and development of asthma symptoms. Ann Ital Med Int 2004; 19:98-108. 21
31. Moller C, Dreborg S, Ferdousi HA, Halken S, Host A, Jacobsen L, Koivikko A, Koller DY, 22 Niggemann B, Norberg LA, Urbanek R, Valovirta E, Wahn U. Pollen immunotherapy reduces 23 the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study). J 24 Allergy Clin Immunol 2002; 109:251-6. 25
32. Moller C, Dreborg S, Lanner A, Bjorksten B. Oral immunotherapy of children with 26 rhinoconjunctivitis due to birch pollen allergy. A double blind study. Allergy 1986; 41:271-9. 27
33. Marogna M, Tomassetti D, Bernasconi A, Colombo F, Massolo A, Businco AD, Canonica GW, 28 Passalacqua G, Tripodi S. Preventive effects of sublingual immunotherapy in childhood: an 29 open randomized controlled study. Ann Allergy Asthma Immunol 2008; 101:206-11. 30
34. Novembre E, Galli E, Landi F, Caffarelli C, Pifferi M, De ME, Burastero SE, Calori G, Benetti L, 31 Bonazza P, Puccinelli P, Parmiani S, Bernardini R, Vierucci A. Coseasonal sublingual 32 immunotherapy reduces the development of asthma in children with allergic 33 rhinoconjunctivitis. J Allergy Clin Immunol 2004; 114:851-7. 34
35. Schmitt J, Schwarz K, Stadler E, Wustenberg EG. Allergy immunotherapy for allergic rhinitis 35 effectively prevents asthma: Results from a large retrospective cohort study. J Allergy Clin 36 Immunol 2015; 136:1511-6. 37
36. Jacobsen L, Niggemann B, Dreborg S, Ferdousi HA, Halken S, Host A, Koivikko A, Norberg LA, 38 Valovirta E, Wahn U, Moller C. Specific immunotherapy has long-term preventive effect of 39 seasonal and perennial asthma: 10-year follow-up on the PAT study. Allergy 2007; 62:943-8. 40
EAACI AIT prevention Guidelines V5.12.04.2017 31
37. Song W, Lin X, Chai R. [Efficacy evaluation of standardized dust mite allergen specific 1 immunotherapy to patients of allergic rhinitis]. Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za 2 Zhi 2014; 28:300-2. 3
38. Valovirta E, Berstad AK, de BJ, Bufe A, Eng P, Halken S, Ojeda P, Roberts G, Tommerup L, 4 Varga EM, Winnergard I. Design and recruitment for the GAP trial, investigating the 5 preventive effect on asthma development of an SQ-standardized grass allergy 6 immunotherapy tablet in children with grass pollen-induced allergic rhinoconjunctivitis. Clin 7 Ther 2011; 33:1537-46. 8
39. GAP Investigators. Clinical Trial Results: GAP - Grazax Asthma Prevention. EU Trial Register, 9 EudraCT . 2016. 10
Ref Type: Online Source 11
40. Garcia BE, Gonzalez-Mancebo E, Barber D, Martin S, Tabar AI, Diaz de Durana AM, Garrido-12 Fernandez S, Salcedo G, Rico P, Fernandez-Rivas M. Sublingual immunotherapy in peach 13 allergy: monitoring molecular sensitizations and reactivity to apple fruit and Platanus pollen. 14 J Investig Allergol Clin Immunol 2010; 20:514-20. 15
41. Szepfalusi Z, Bannert C, Ronceray L, Mayer E, Hassler M, Wissmann E, Dehlink E, Gruber S, 16 Graf A, Lupinek C, Valenta R, Eiwegger T, Urbanek R. Preventive sublingual immunotherapy 17 in preschool children: first evidence for safety and pro-tolerogenic effects. Pediatr Allergy 18 Immunol 2014; 25:788-95. 19
42. Pifferi M, Baldini G, Marrazzini G, Baldini M, Ragazzo V, Pietrobelli A, Boner AL. Benefits of 20 immunotherapy with a standardized Dermatophagoides pteronyssinus extract in asthmatic 21 children: a three-year prospective study. Allergy 2002; 57:785-90. 22
43. Marogna M, Spadolini I, Massolo A, Canonica GW, Passalacqua G. Randomized controlled 23 open study of sublingual immunotherapy for respiratory allergy in real-life: clinical efficacy 24 and more. Allergy 2004; 59:1205-10. 25
44. Des Roches A, Paradis L, Menardo JL, Bouges S, Daures JP, Bousquet J. Immunotherapy with 26 a standardized Dermatophagoides pteronyssinus extract. VI. Specific immunotherapy 27 prevents the onset of new sensitizations in children. J Allergy Clin Immunol 1997; 99:450-3. 28
45. Inal A, Altintas DU, Yilmaz M, Karakoc GB, Kendirli SG, Sertdemir Y. Prevention of new 29 sensitizations by specific immunotherapy in children with rhinitis and/or asthma 30 monosensitized to house dust mite. J Investig Allergol Clin Immunol 2007; 17:85-91. 31
46. Reha CM, Ebru A. Specific immunotherapy is effective in the prevention of new sensitivities. 32 Allergol Immunopathol (Madr ) 2007; 35:44-51. 33
47. Asero R. Injection immunotherapy with different airborne allergens did not prevent de novo 34 sensitization to ragweed and birch pollen north of Milan. Int Arch Allergy Immunol 2004; 35 133:49-54. 36
48. Harmanci K, Razi CH, Toyran M, Kanmaz G, Cengizlier MR. Evaluation of new sensitizations in 37 asthmatic children monosensitized to house dust mite by specific immunotherapy. Asian Pac 38 J Allergy Immunol 2010; 28:7-13. 39
EAACI AIT prevention Guidelines V5.12.04.2017 32
49. Tella R, Bartra J, San MM, Olona M, Bosque M, Gaig P, Garcia-Ortega P. Effects of specific 1 immunotherapy on the development of new sensitisations in monosensitised patients. 2 Allergol Immunopathol (Madr ) 2003; 31:221-5. 3
50. Ohashi Y, Nakai Y. Immunotherapy for cure and prophylaxis of allergic rhinitis. Clinical and 4 Experimental Allergy Reviews 2009; 9:6-10. 5
51. Limb SL, Brown KC, Wood RA, Eggleston PA, Hamilton RG, Adkinson NF, Jr. Long-term 6 immunologic effects of broad-spectrum aeroallergen immunotherapy. Int Arch Allergy 7 Immunol 2006; 140:245-51. 8
52. Dominicus R. 3-years' long-term effect of subcutaneous immunotherapy (SCIT) with a high-9 dose hypoallergenic 6-grass pollen preparation in adults. Eur Ann Allergy Clin Immunol 2012; 10 44:135-40. 11
53. Di R, V, Marcucci F, Puccinelli P, Parmiani S, Frati F, Sensi L, Canonica GW, Passalacqua G. 12 Long-lasting effect of sublingual immunotherapy in children with asthma due to house dust 13 mite: a 10-year prospective study. Clin Exp Allergy 2003; 33:206-10. 14
54. Purello-D'Ambrosio F, Gangemi S, Merendino RA, Isola S, Puccinelli P, Parmiani S, Ricciardi L. 15 Prevention of new sensitizations in monosensitized subjects submitted to specific 16 immunotherapy or not. A retrospective study. Clin Exp Allergy 2001; 31:1295-302. 17
55. Eng PA, Borer-Reinhold M, Heijnen IA, Gnehm HP. Twelve-year follow-up after 18 discontinuation of preseasonal grass pollen immunotherapy in childhood. Allergy 2006; 19 61:198-201. 20
56. Marogna M, Spadolini I, Massolo A, Canonica GW, Passalacqua G. Long-lasting effects of 21 sublingual immunotherapy according to its duration: a 15-year prospective study. J Allergy 22 Clin Immunol 2010; 126:969-75. 23
57. Pajno GB, Barberio G, De Luca F, Morabito L, Parmiani S. Prevention of new sensitizations in 24 asthmatic children monosensitized to house dust mite by specific immunotherapy. A six-year 25 follow-up study. Clin Exp Allergy 2001; 31:1392-7. 26
58. Gulen F, Zeyrek D, Can D, Altinoz S, Koksoy H, Demir E, Tanac R. Development of new 27 sensitizations in asthmatic children monosensitized to house dust mite by specific 28 immunotherapy. Asian Pac J Allergy Immunol 2007; 25:7-11. 29
30 31