EAACI Guidelines on Allergen Immunotherapy: allergic ... · 2 Allergic rhinoconjunctivitis (AR) is...

Rhinoconjunctivitis AIT guideline – draft Draft 1.0; 12th May 2017 1

EAACI Guidelines on Allergen Immunotherapy: allergic rhinoconjunctivitis 1

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Draft 1.0; 12th May 2017 3

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Short title: EAACI Rhinoconjunctivitis Allergen Immunotherapy Guidelines 6

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Key words: allergen immunotherapy, allergy, allergic conjunctivitis, allergic rhinitis, 8

rhinoconjunctivitis 9

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Abbreviations: 11

AR, allergic rhinoconjunctivitis; AIT, allergen immunotherapy; AGREE II, Appraisal of 12

Guidelines for Research & Evaluation; ARIA, Allergic Rhinitis and it Impact on Asthma; EPIT, 13

epicutaneous immunotherapy; EAACI, European Academy of Allergy and Clinical 14

Immunology; EMA, European Medicines Agency; HDM, house dust mite; ICER, incremental 15

cost-effectiveness ratio; NARES, non-allergic rhinitis with eosinophilia syndrome; QALY, 16

quality-adjusted life years; RCT, randomized controlled trial; SPT, skin prick test; SMD, 17

standardized mean difference; SCIT, subcutaneous immunotherapy; SLIT, sublingual 18

immunotherapy; SmPC, manufacturer‘s product information (SmPC), summary or product 19

characteristics. 20


ABSTRACT 1

Allergic rhinoconjunctivitis (AR) is an allergic disorder affecting the nose and eyes with a 2

prevalence of about 20% of the general population. Symptoms are frequently controlled with 3

avoidance measures and pharmacotherapy. However, many patients continue to have 4

ongoing symptoms and impaired quality of life. Allergen immunotherapy (AIT) represents an 5

important additional therapeutic option. These Guidelines have been prepared by the 6

European Academy of Allergy and Clinical Immunology’s (EAACI) Taskforce on AIT for AR 7

and are part of the EAACI presidential project ‘AIT Guidelines’. They aim to provide evidence-8

based clinical recommendations and have been informed by a formal systematic review and 9

meta-analysis. Their generation has followed the Appraisal of Guidelines for Research and 10

Evaluation (AGREE II) approach. The process included representation of the full range of 11

stakeholders. Key sections cover ‘general considerations before initiating AIT for AR’, ‘allergen 12

immunotherapy for AR: evidence-based, clinical recommendations’, ‘other approaches for 13

AIT’, ‘allergen factors that may affect the efficacy of AIT for AR’, ’patient factors that may affect 14

the efficacy of AIT for AR’, ‘how long should AIT be continued for in AR’, ‘adverse events with 15

ASIT for AR’, ‘preventive effects of AIT for AR’, ‘pharmacoeconomic aspects of AIT versus 16

pharmacotherapy for AR’ and ‘summary, gaps in the evidence and future perspectives’. In 17

general, broad evidence for the clinical efficacy of AIT exists but a product-specific evaluation 18

of evidence is recommended. 19

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SECTION A: INTRODUCTION 1

Allergic rhinoconjunctivitis (AR) is an allergic disorder affecting the nose and eyes, resulting 2

in chronic, mostly eosinophilic, inflammation of the nasal mucosa and conjunctiva [Eifan 2016; 3

Greiner 2011]. Allergic rhinitis, with or without conjunctivitis, is one of the most prevalent 4

allergic diseases affecting around a fifth of the general population [Singh 2010; Meltzer 2009; 5

Ait-Khaled 2009]. It is associated with considerable loss of productivity and impaired school 6

performance [Walker 2007]. 7

AR can usually be diagnosed from its typical presentation (Figure A). Symptoms include 8

itching, sneezing, watery nasal discharge often nasal congestion [Roberts 2013]. There is 9

often associated eye symptoms (watery, red and/or itchy eyes). Symptoms may be described 10

as seasonal and/or perennial; as intermittent or persistent; or mild, moderate or severe 11

according to its impact on quality of life (Bousquet 2008). Symptoms are related to exposure 12

to the offending allergen as well as to non-specific triggers such as smoke, dust, viral 13

infections, strong odors and cold air [Roberts 2013]. Evidence of allergen-specific IgE 14

sensitization to one or more aeroallergens suggested by the history supports the diagnosis. 15

AR may co-exist with other forms of rhinitis (Figure A). Additionally, AR may be associated 16

with sinusitis symptoms, auditory dysfunction and asthma [Roberts 2013]. 17

The aims of AR management are to control symptoms and reduce inflammation. Where 18

possible, allergen avoidance can be recommended although effective allergen avoidance is 19

not always feasible [Terreehorst 2003; Sheikh A Cochrane review 2010]. Many patients rely 20

on pharmacotherapy with e.g., oral or topical antihistamines, intranasal corticosteroids, topical 21

cromoglycate or leukotriene receptor antagonists [Roberts 2013]. However, these therapies 22

do not alter the natural history of AR. Additionally, despite medication, a significant number of 23

patients continue to experience symptoms that impair their quality of life. Allergen 24

immunotherapy (AIT) that involves regular subcutaneous (SCIT) or sublingual (SLIT) 25

administration of the culprit allergen(s) may not only desensitize a patient thereby ameliorating 26

symptoms but also modify the underlying natural history of the disease [Pfaar 2014; Jutel 27

2015; Jutel 2016]. 28

These Guidelines have been prepared by the European Academy of Allergy and Clinical 29

Immunology’s (EAACI) Taskforce on Allergen Immunotherapy (AIT) for Rhinoconjunctivitis 30

and are part of the EAACI AIT Guidelines. These Guidelines aim to provide evidence-based 31

recommendations for the use of AIT for patients with allergic rhinitis with or without 32

conjunctivitis. AR will be used to signify either allergic rhinitis or allergic rhinoconjunctivitis. 33

The primary audience are clinical allergists, although the guidelines are of relevance to other 34

healthcare professionals (e.g. primary care workers, other specialist doctors, nurses and 35

Formatted: English (United Kingdom)


pharmacists working across a range of clinical settings) dealing with AR. The development of 1

the Guidelines has been informed by a formal systematic review and meta-analysis of AIT for 2

AR [Dhami 2017], with systematic review principles being used to identify additional evidence, 3

where necessary. 4

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6 7

Figure A. Differential diagnosis of allergic rhinoconjunctivitis 8

Adapted from Roberts 2013. Local allergic rhinitis may be seen where there is only evidence 9

of local nasal allergic sensitization [Campo 2015; Carmen 2010]. There are numerous other 10

causes of non-allergic, non-infectious rhinitis, examples are non-allergic rhinitis with 11

eosinophilia syndrome (NARES) and gastro-oesophageal reflux [Roberts 2013]. In individual 12

patients, symptoms may be driven by more than one trigger. Rhinosinusitis is not included in 13

the scope of these Guidelines. 14


Box 1. Key terms

Rhinitis Inflammation of the nasal epithelium resulting in at least two nasal

symptoms: rhinorrhea, blockage, sneezing or itching.

Conjunctivitis Inflammation of the conjunctiva characterized by watery, itchy, red

eyes.

Sensitization Detectable allergen specific IgE antibodies, either by means of skin

prick test (SPT) or specific IgE antibodies in a blood sample

Allergen

immunotherapy (AIT) Repeated allergen administration at regular intervals to modulate

immune response in order to reduce symptoms and the need of

medication for clinical allergies and to prevent the development of new

allergies and asthma (adapted from European Medicines Agency

(EMA)). This is also sometimes known as allergen specific

immunotherapy, desensitization and hypo-sensitization

Subcutaneous

immunotherapy (SCIT) Form of allergen immunotherapy where the allergen is administered as

a series of subcutaneous injections.

Sublingual

immunotherapy (SLIT) Form of allergen immunotherapy where the allergen is administered

under the tongue.

Short-term efficacy Clinical benefit to the patient while they are receiving AIT

Long-term efficacy Clinical benefit to the patient for at least one year after cessation of the

AIT course. This implies that the AIT has altered the natural history of

the patient’s allergic disease.

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SECTION B: METHODOLOGY 1

These Guidelines were produced using the Appraisal of Guidelines for Research & Evaluation 2

(AGREE II) approach [Agree Collaboration 2003; Brouwers 2010], a structured approach to 3

guideline production. This is designed to ensure appropriate representation of the full range 4

of stakeholders, a careful search for and critical appraisal of the relevant literature, a 5

systematic approach to the formulation and presentation of recommendations and steps to 6

ensure that the risk of bias is minimized at each step of the process. The process started in 7

April 2015 beginning with detailed face-to-face discussions agreeing the process and the key 8

clinical areas to address, followed by face-to-face meetings and regular web-conferences in 9

which professional and lay representatives participated. 10

11

Clarifying the scope and purpose of the guidelines 12

The scope of these EAACI Guidelines is multifaceted, providing statements that assist 13

clinicians in the optimal use of AIT in the management of patients with AR and identifying gaps 14

for further research. 15

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Ensuring appropriate stakeholder involvement 17

Participants in the EAACI Taskforce on AIT for Allergic Rhinoconjunctivitis represented a 18

range of 16 countries and disciplinary and clinical backgrounds, including allergists, 19

paediatricians, primary care doctors, ophthalmology, ENT, pharmacists, immunologists, 20

nurses and patient representatives. Representatives of immunotherapy product manufactures 21

were given the opportunity to review and comment on the draft guidelines as part of the peer 22

review and public comment process. These comments were considered by the Taskforce and, 23

where appropriate, revisions were made. 24

25

Systematic reviews of the evidence 26

The initial full range of clinical questions that were considered important were rationalized 27

through several rounds of iteration to agree on one key question: what is the effectiveness, 28

cost-effectiveness and safety of AIT in patients with allergic rhinoconjunctivitis. This was then 29

pursued through a formal systematic review of the evidence [Dhami 2016; Dhami 2017]. 30

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Formulating recommendations 32


We graded the strength and consistency of key findings from these systematic reviews (Dhami 1

2017) to formulate evidence-based recommendations for clinical care [Oxford Centre for 2

Evidence-based Medicine] (Box 2). This involved formulating clear recommendations with the 3

strength of evidence underpinning each recommendation. Where the systematic review did 4

not cover the clinical area, we took a hierarchical approach reviewing other evidence until we 5

could formulate a recommendation, i.e.: (i) other systematic reviews on the subject to see if 6

these provided any clarity on the topic; (ii) randomized controlled trials (RCTs) within these 7

systematic reviews; (iii) other RCTs known to Taskforce members; and (iv) a consensus-8

based approach. Recommendations apply to all ages unless otherwise indicated in the tables. 9

Experts identified the resource implications of implementing the recommendations, barriers, 10

and facilitators to the implementation of each recommendation, advice on approaches to 11

implementing the recommendations and suggested audit criteria that can help with assessing 12

organizational compliance with each recommendation (see Supporting Information Tables SX, 13

….) 14

15

Peer review and public comment 16

A draft of these guidelines was externally peer-reviewed by invited experts from a range of 17

organizations, countries, and professional backgrounds. Additionally, the draft guidelines were 18

made available on the EAACI Website for a 3 week period in May 2017 to allow a broader 19

array of stakeholders to comment. All feedback was considered by the Taskforce and, where 20

appropriate, final revisions were made in the light of the feedback received. We will be pleased 21

to continue to receive feedback on these Guidelines, which should be addressed to the 22

corresponding author. 23

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Identification of evidence gaps 25

The process of developing these Guidelines has identified a number of evidence gaps which 26

are prioritized (see Online supplement). 27

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Editorial independence and managing conflict of interests 29

The production of these Guidelines was funded and supported by EAACI. The funder did not 30

have any influence on the guideline production process, on its contents or on the decision to 31

publish. Taskforce members’ conflict of interests were declared at the start of the process and 32

taken into account by the Taskforce Chairs as recommendations were formulated. Final 33


decisions about strength of evidence for recommendations were checked by the 1

methodologists who had no conflict of interests in this area. 2

Updating the guidelines 3

EAACI plans to update these guidelines in 2022 unless there are important advances before 4

then. 5

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7 8

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Box 2: Assigning levels of evidence and recommendations [Oxford Centre for Evidence-based Medicine]

Level of evidence

Level I Systematic reviews, meta-analysis, randomized controlled trials

Level II Two groups, nonrandomized studies (e.g., cohort, case–control)

Level III One group nonrandomized (e.g., before and after, pretest, 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 /high quality studies

Moderate Evidence from studies at moderate risk of bias /moderate quality studies

Weak Evidence from studies at high risk of bias /low quality studies

Recommendations are phrased according to the strength of recommendation: strong: “is recommended”; moderate: “can be recommended”; weak: “may be recommended in specific circumstances”; negative: “can not be recommended”.


SECTION C: GENERAL CONSIDERATIONS BEFORE INITIATING AIT FOR AR 1

General indications 2

AIT is only indicated in the presence of symptoms strongly suggestive of allergic rhinitis, with 3

or without conjunctivitis (Table 1) [Dhami 2017]. Many patients will also have co-existing 4

asthma. There should be symptoms on aeroallergen exposure and evidence of IgE-5

sensitization (positive SPT or serum specific-IgE) to one or more clinically relevant allergens 6

[Dhami 2017]. Component resolved diagnostics may have a role in optimizing AIT therapy, 7

but definitive trials to show this approach enhances AIT outcomes are awaited. SPT or 8

specific-IgE results may not identify the important allergens, particularly in polysensitized 9

patients with perennial symptoms. In these circumstances, nasal or conjunctival provocation 10

testing may be helpful, but again there is no definitive evidence that this approach can optimize 11

the selection of the correct allergen for AIT therapy. For AIT to be indicated, a patient should 12

be experiencing moderate-to-severe symptoms (e.g. ARIA categories moderate-to-severe 13

intermittent or persistence [ARIA]), despite avoidance measures and optimal 14

pharmacotherapy, that interfere with their usual daily activities or sleep. AIT may also be 15

considered in less severe AR where a patient wishes to take advantage of its long term effect 16

on rhinitis and potential to prevent asthma [ref prevention guidelines]. Lastly, only AIT products 17

with evidence of efficacy for AR should be used (Pfaar et al. 2014; Bachert et al. 2015). The 18

approach to using AIT for AR across the healthcare system is summarized in Figure B. 19

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Absolute and relative contraindications 21

Even when AIT is the suitable therapy for a patient with AR, there may be absolute 22

contraindications for its use (Table 2). There are also relative contraindications for 23

conditions/concomitant diseases, where the risks from AIT may outweigh the expected 24

benefits. 25

26 27 28 29



Table 1. General indications for AIT for AR

General indications Key references

Contextual considerations

AIT should be considered when all of these criteria are met:

has symptoms strongly suggestive of allergic rhinitis, with or without conjunctivitis

there is evidence of IgE-sensitization (positive SPT and / or serum specific-IgE) to one or more clinically relevant allergen

experiencing moderate-to-severe symptoms interfering with their usual daily activities or sleep despite regular and appropriate pharmacotherapy and / or avoidance strategies

Dhami 2017

A diagnosis of allergic rhinitis and evidence of IgE-sensitisation were entry criteria for RCTs in the systematic review.

AIT may also be considered in less severe AR where a patient wishes to take advantage of its long term effect on rhinitis and potential to prevent asthma

[ref prevention AIT guidelines]

AIT has the potential to alter the natural history of disease reducing AR symptoms after cessation of therapy and preventing the development of asthma.

Standardized AIT products with evidence of efficacy in the clinical documentation should preferably be used

Dhami 2017 These products have consistent formulations and so different batches are likely to have similar effects.

However, the systematic review reveals a considerable heterogeneity in effectiveness between products and therefore a product-specific evaluation of efficacy is demanded.




Table 2. General contraindications for AIT for AR

Key references Contextual considerations

The following are considered to be contraindications:

Uncontrolled asthma Pitsios 2015; Cox 2011; Bousquet 1989; Lockey 2001 Bernstein 2004; CSM 1986; Normansell 2015; Calderon 2012

Weak evidence of risk from case reports or case series of adverse events with AIT. Taskforce considered that these were contraindications to AIT.

Active, systemic, autoimmune disorders

Cabrera 1993; Sánchez-Morillas 2005; Fiorillo 2011

Active malignant neoplasia Wöhrl 2011; Palomares 2010; Larenas-Linnemann 2016

AIT initiation during pregnancy Metzger 1978; Chaudhuri 2008]

With the following, AIT should only be used with caution when benefits outweigh potential risks in an individual patient:

Beta-blocker therapy Hiatt 1985; Matsumura 1976; Cleaveland 1972; Lang 1995

Weak evidence of risk. These may both compromise a patient’s ability to tolerate an episode of anaphylaxis; this must be considered when deciding whether AIT is appropriate.

Severe cardiovascular diseases, e.g. coronary artery disease

Linneberg 2012; Larenas-Linnemann 2016

Systemic autoimmune disorders in remission/organ specific (Eg autoimmune thyroiditis)

Pitsios 2015; Cox 2011; Walker 2011; Linneberg 2012; Larenas-Linnemann 2016

Weak evidence of risk from case reports or case series of adverse events with AIT. Taskforce considered that careful consideration and discussion with patient and the treating physician and a case-by-case decision is required before commencing AIT.

Severe psychiatric disorders Pitsios 2015

Poor adherence Pitsios 2015

Primary and secondary Immunodeficiencies

Pitsios 2015; Larenas-Linnemann 2016

ACE-inhibitors Epstein 2016


Figure B. Approach to using AIT for allergic rhinoconjunctivitis Schematic illustration of the approach to using AIT for AR starting with self-medication and management in primary care moving to assessment by an allergist for consideration and initiation of AIT in suitable patients. Structure of healthcare systems differs between countries.


SECTION D: ALLERGEN IMMUNOTHERAPY FOR AR: EVIDENCE-BASED, 1

CLINICAL RECOMMENDATIONS 2

3

AIT is recommended for the treatment of AR in selected adults and children who respond 4

inadequately to regular treatment with anti-allergic drugs and/or experience 5

unacceptable side-effects with anti-allergic medication. This is based on pooled data 6

from an EAACI commissioned meta-analysis [Dhami 2017] of 58 studies of SCIT and 7

SLIT which found a standardized mean difference (SMD) of -0.53 (95% confidence 8

intervals (CI) -0.63, -0.42) for symptoms of rhinoconjunctivitis in favor of AIT compared 9

to placebo, consistent with a moderate clinical effect. This finding was also supported by 10

reductions in medication use (45 studies, SMD -0.37 [95%CI -0.49, -0.26] and also in 11

combined symptom-medication scores (15 studies, SMD -0.49 [95%CI -0.69, -0.30). The 12

high grade of heterogeneity between the trials evaluated underlines the urgent need of 13

an individual product-based evaluation of the evidence for efficacy (Pfaar et al. 2014; 14

Bachert et al. 2015). 15

However, SCIT immunotherapy is in general recommended for the treatment of AR in 16

adults and children with moderate-to severe disease that is sub-optimally controlled 17

despite optimum pharmacotherapy [Dhami 2017](Table 3). The evidence for short-term 18

benefit is stronger for seasonal rhinitis (Grade A for adults) than for perennial rhinitis 19

(Grade B for adults), where few studies have been performed and results are more 20

heterogeneous (Table 3). SCIT is recommended for seasonal disease whether given 21

continuously or pre- or pre/co-seasonally (Table 3, Grades A or B for adults). Pre/co-22

seasonal therapy benefits from a shorter course of treatment; the two regimens have not 23

been directly compared in terms of efficacy or adverse events. 24

SCIT may be administered in aqueous formulation (rarely in Europe) or as a depot 25

adsorbed on aluminum hydroxide or tyroxine. SCIT using either unmodified or modified 26

allergen extracts is recommended for treatment of allergic rhinitis and provides short-27

term benefit (Table 3, Grade A for adults). This is based on evidence from the systematic 28

review [Dhami 2017] that showed both unmodified allergen extracts (SMD [95%CI]) -29

0.65 (-0.93, -0.36) and allergoids/polymerized extracts (SMD [95%CI] -0.60 [-0.89, -0.31] 30

to be effective in reducing symptoms compared to placebo, with additional support from 31

reduced medication requirements and combined symptom-medication scores. Although 32

clinical trials of modified allergens involved shorter courses of treatment, there have been 33

no head-to-head comparisons with unmodified preparations evaluating efficacy or 34

adverse events. 35


Grass pollen SCIT is recommended (Grade A in adults) to be given for a minimum of 1

three years in order to achieve long-term clinical efficacy following discontinuation of 2

treatment (Table 7). This is supported by three RCTs of continuous treatment with the 3

same aluminum hydroxide-adsorbed allergen extract, two in adults [Durham 1999, 4

James 2011] and one in children [Jacobsen L Allergy 2007]. 5

In general, SLIT is recommended for the treatment of seasonal allergic rhinitis in adults 6

and children. SLIT has been shown to provide short term benefit during therapy with 7

moderate-to severe disease that is sub-optimally controlled despite optimum 8

pharmacotherapy (Table 3) [Dhami 2017]. SLIT is recommended to be taken either 9

continuously or pre-/co-seasonally commencing a minimum of two months and ideally 10

four months prior to the start of the pollen season (Grade A for adults). 11

SLIT may be taken daily either as drops or as tablets that are retained under the tongue 12

for at least one minute and then swallowed. Both are recommended (Grade A or B for 13

adults) based on short-term reductions in symptoms and rescue medication, 14

respectively, for sublingual drops: SMD (95%CIs) -0.41 (-0.65, -0.18) and -0.35 (-0.55, -15

0.14) and for sublingual tablets: -0.56 (-0.80, - 0.33) and -0.42 (-0.64, -0.19) [Dhami 16

2017]. 17

Grass pollen SLIT is recommended (Grade A) to be taken for a minimum of three years 18

in order to provide long-term benefit for at least two years after discontinuation (Table 7). 19

This recommendation is based on four large RCTs [Durham 2012, Didier Clin Trans 20

Allergy 2015, Ott 2009, Valovirta Clin Ther. 2011] (Table 3). This recommendation is 21

further supported by a recent trial that showed that both subcutaneous and sublingual 22

immunotherapy were effective whereas two years treatment was insufficient for long-23

term clinical efficacy after discontinutaion, reinforcing the need for immunotherapy via 24

both routes to be continued for at least 3 years (Scadding GW 2017). 25

Sublingual house dust mite tablet immunotherapy for at least one year is recommended 26

(Grade A) for the short-term treatment of perennial HDM AR in adults [Didier 2015, 27

Durham 2012, Ott 2009, Bergmann 2014, Mosbech 2015, Demoly 2016](Table 3). In one 28

trial of one year of sublingual HDM tablet treatment [Bergman 2013], short-term benefit 29

was followed by reduced symptoms assessed at one year after discontinuation. 30

Where RCTs involving increasing allergen concentrations have been performed there 31

has been clear evidence of a dose-response relationship for both SCIT and SLIT. While 32

higher doses are more effective, they are associated with more side-effects, such that 33

dose selection has been based on a balance of efficacy and side-effects [Didier 2015, 34

Durham 2012, Valovirta 2006, Frew 2006, Jacobsen L Allergy 2007; Calderon 2011]. 35


Table 3 Recommendations: AIT for treatment of AR: schedules, products, formulations

Recommendation Adults Children and adolescents

Strength of

recommendation Other considerations Key references

E

vid

en

ce l

evel

Gra

de o

f

reco

mm

en

dati

on

Evid

en

ce l

evel

Gra

de o

f

reco

mm

en

dati

on

SCIT

Continuous SCIT is recommended for seasonal AR for short-term benefit in those with moderate-to severe disease

I A I B Strong recommendations for adults based on high quality studies (eg Varney 1991, Walker 2001, Charpin 2007, Ferrer 2005). Moderate recommendation for children as minimal moderate quality studies reporting solely paediatric data (Roberts 2006).

Consistent, moderate-high effect size and low risk of severe systemic allergic side-effects. Most studies reported pediatric and adult data together.

Dhami 2017 SR, eg Adult: Frew 2006, Varney 1991, Walker 2001, Charpin 2007, Ferrer 2005, Dolz 1996, Scadding GW 2017 Paediatric: Roberts 2006

Continuous SCIT is recommended for perennial AR due to house dust mites for short-term benefit

I B I C Strong recommendation for adults based on high quality studies (Tabar 2005, Varney 2003, Dokic 2005). Weak recommendation for children as no exclusive pediatric data.

Moderate effect size, few small adult studies, considerable heterogeneity and risk of systemic allergic side-effects.

Dhami 2017 SR, eg Adult: Tabar 2005, Varney 2003, Dokic 2005, Ewan 1988



Pre- and pre-/co-seasonal SCIT is recommended for seasonal AR for short-term benefit

I A I B Strong recommendation for adults based on high quality studies (Balda 1998, Bodtger 2002, Varney 1991, Zenner 1997). Moderate recommendation for children as only combined adult/pediatric data of high (Weyer 1981) and unclear (Bousquet 1990) quality.

Consistent, moderate-high effect size in adult studies; low risk of severe systemic allergic side-effects.

Dhami 2017 SR, eg Adult: Balda 1998, Bodtger 2002, Bousquet 1990, Frew 2006, Jutel 2005, Varney 1991 Zenner 1997 Adult/paed: Bousquet 1990, Weyer 1981, Scadding GW JAMA 2017.

Both modified (allergoids) and unmodified allergen extracts are recommended for AR for short-term benefit

I A I B Strong recommendation for adults based on high quality studies for both modified (Brunet 1992, Zenner 1997, Charpin 2007, Dokic 2005, Klimek, 2005) and non-modified (Balda 1998, Bodtger 2002, Charpin 2007, Ortolani 1994, Tabar 2008, Varney 1991, Varney 2003, Walker 2001, Weyer 1981, Zenner 1997) allergen extracts. Weak recommendation for children as no exclusive pediatric data.

Consistent, moderate-high effect size in adult studies; low risk of severe systemic allergic side effects. No exclusive pediatric data.

Dhami 2017 SR, eg Modified: Bousquet 1990, Brunet 1992, Zenner 1997, Charpin 2007, Corrigan 2005, Dokic 2005, Klimek, 2005 Non-modified: Balda 1998, Bodtger 2002, Charpin 2007, Frew 2006, Jutel 2005, Ortolani 1994, Tabar 2008, Varney 1991, Varney 2003, Walker 2001, Weyer 1981, Zenner 1997,Scadding GW JAMA 2017

Continuous grass pollen SCIT is recommended for AR for short and long-term benefit

I A I B Strong recommendation for adults based on above evidence plus two high quality long-term studies (Durham 1999, James 2011). Weak recommendation for children as only one low quality (open design) paediatric long-term study (Jacobsen 2007).

A few adult studies and one pediatric study (designed to assess whether SCIT prevents asthma) demonstrating long-term effectiveness.

Dhami 2017 SR, eg Adult: Durham 1999, James 2011 Paed: Jacobsen L Allergy 2007 H


SLIT

Pre-/co-seasonal SLIT is recommended for seasonal ARs for short-term benefit

I A I A Strong recommendation based on high quality adult (Dahl 2006a, Dahl 2006b, Durham 2006 L) and paediatric (Caffarelli, 2000, Pajno, 2003 L, Stelmach, 2012) studies.

Consistent, moderate effect size; low risk of severe systemic allergic side-effects.

Dhami 2017 SR, eg Adult: Creticos 2013, Dahl 2006a, Dahl 2006b, Didier 2007, Durham 2006, Hordijk 1998, Palma-Carlos 2006 Paediatric: Caffarelli, 2000, Halken 2010. Pajno, 2003, Stelmach, 2012

Continuous SLIT can be recommended for seasonal AR for short-term benefit

I A I B Moderate-to-strong recommendation based on high (Amar 2009) and low (Ariano 2001, Panzner 2008) quality adult studies plus moderate (Bufe 2004) and unclear (Valovirta 2006) quality paediatric studies.

Moderate effect size; some heterogeneity between studies particularly paediatric ones, low risk of severe systemic allergic side effects.

Dhami 2017 SR, eg Adult: Amar 2009, Ariano, 2001, Panzner, 2008 Paed: Valovirta 2006, Bufe 2004

SLIT with aqueous solutions can be recommended for AR for short-term benefit.

I B I A Moderate recommendation for adults based on a mixture of high (Feliziani 1995), low (Ariano 2001, Bowen 2004, Tari 1990) and unclear (Guez 2000, Hordijk 1998) quality studies. Strong recommendation for pediatrics based on high quality studies (Pajno 2003, Stelmach, 2012).

Moderate effect size, some heterogeneity between adult studies, low risk of severe systemic allergic side-effects.

Dhami 2017 SR, eg Adult: Ariano 2001, Bowen 2004, Feliziani 1995, Guez 2000, Hordijk 1998, Tari 1990 Paed: Pajno 2003, Wahn 2009, Stelmach, 2012


SLIT with tablets is recommend for AR for short-term benefit.

I A I A Strong recommendation based on high quality adult (Dahl 2006a, Dahl 2006b, Durham 2006, Nolte 2016) and paediatric (Bufe 2009, Caffarelli 2000, Wahn 2009) studies.

Moderate effect size; little heterogeneity between studies, low risk of severe systemic allergic side effects.

Dhami 2017 SR, eg Adult: Dahl 2006a, Dahl 2006b, Durham 2006, Horak 2009, Passalacqua 2006 Paed: Bufe 2009, Caffarelli 2000 Wahn 2009 Scadding GW JAMA 2017, Nolte 2016

Grass pollen SLIT tablets or solution is recommended for allergic rhinoconjunctivitis for long-term benefit.

I A I B Strong recommendation for adults based on high quality studies (Durham 2012, Didier Clin Trans Allergy 2015, Ott 2009). One high quality paediatric study with results only available online on EudraCT(Valovirta Clin Ther. 2011)

Consistent moderate effect size up to 2 years after cessation in adults. One paediatric study (designed to look at prevention of asthma) indicates the same, but full publication is pending.

Dhami 2017 SR, eg Adult: Durham 2012, Didier Clin Trans Allergy 2015, Ott 2009 Paediatric: Valovirta Clin Ther. 2011

HDM SLIT tablet can be recommended for allergic rhinoconjunctivitis for long-term benefit.

I B - C Moderate recommendation based on one large, high quality (Bergmann 2014). No paediatric data.

One study demonstrates effectiveness for a year post-treatment. No paediatric data.

Bergmann 2013

Continuous: year round therapy. Pre-seasonal: before a pollen season. Co-seasonal: during a pollen season. Not all AIT preparations are

licensed for children and adolescents.



SECTION E: Other approaches for AIT 1

2 Other approaches aim to improve patient convenience and compliance with shorter 3

courses, whilst improving or maintaining efficacy and reducing the risk of systemic side 4

effects (Table 4). As such, adjuvants to AIT extracts are possible candidates (Pfaar et 5

al. 2012). For example, TLR-4 agonists (monophosphoryly lipid A) in combination with a 6

grass allergoid has demonstrated effectiveness, although in a phase 3 trial, efficacy was 7

modest and there are no head to head comparisons [Drachenberg 2001]. The TLR-9 8

agonist (Bacterial DNA oligonucleotides containing a CpG motif) fused to Amb a 1, the 9

major allergen of ragweed showed efficacy in a phase 2 trial [Creticos 2006] although 10

this was not observed in a subsequent phase 3 trial. The combination of anti-IgE 11

injections with conventional and rush AIT with non-modified extracts has been proved to 12

be effective with a marked reduction in systemic side-effects in studies of children 13

[Rolinck-Werninghaus 2004] and adults [Casale 2006], although it is expensive and there 14

is concern when and how to discontinue the anti-IgE when AIT maintenance therapy is 15

achieved [Larenas Linnemann 2014]. 16

Recombinant AIT is attractive as it allows accurate standardization of allergen products 17

and has potential for personalized therapy based on individual allergen sensitivities, and 18

with a hypothetical lower risk of inducing new sensitizations. Subcutaneous recombinant 19

birch (Bet v 1) [Pauli 2008] and a 5- recombinant grass allergen mix [Jutel 2005] have 20

been shown to be efficacious with no safety concerns. A recombinant B cell epitope-21

based vaccine, comprising a recombinant hybrid grass allergen mix combined with a 22

hepatitis B domain surface Pre-S protein as an immunologic carrier has shown efficacy 23

in a phase 2 trial [Zieglmayer 2016]. T cell peptide immunotherapy for cat allergy using 24

mixtures of short T cell epitopes via the intradermal route, had promising results in 25

environmental chamber phase 2 studies [Patel 2013]; it has been reported that a 26

subsequent phase 3 study did not demonstrate effectiveness. Studies with other allergen 27

peptide approaches are in progress [Ellis 2017; Spertini 2016]. 28

There has been recent interest in the use of alternative modalities of delivery including 29

the epicutaneous, intradermal and intra-lymphatic routes. In RCTs, epicutaneous grass 30

pollen immunotherapy (EPIT) has shown modest benefit [Senti 2012] although 31

accompanied by local eczematous reactions at the patch application site. Intradermal 32

grass pollen immunotherapy inhibited allergen-induced cutaneous late responses 33

although in a subsequent RCT it was ineffective and there was evidence of exacerbation 34

of seasonal outcomes and Th2 inflammation in the skin [Slovick JACI 2017]. The intra-35


lymphatic route, using a grass pollen extract and a modified cat allergen extract, showed 1

efficacy in some trials [Senti 2012, Patterson, A] but not in others [Witten 2013]. 2

3


Table 4 Recommendations: other approaches for AIT for treatment of AR

Recommendation Adults Children and adolescents

Strength of recommendation Other considerations Key references

Evid

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A combination of the TLR-4 agonist monophosphoryly lipid A with pollen allergoid is recommended for AR

I B III C Strong recommendation for adults based on one high quality study (Drachenberg 2001). Weak recommendation for children (Drachenberg 2003).

Moderate effect size, limited randomised controlled data. Only one uncontrolled before and after study paediatric study.

Drachenberg 2001, Drachenberg 2003

Combining anti-IgE injections with AIT for AR is recommended for reducing side-effects

I A I A Strong recommendation based on one high quality adult (Casale 2006) and one high quality paediatric (Rolinck-Werninghaus 2004) study.

Strong consistent evidence but the required length of co-therapy unclear.

Casale 2006, Rolinck-Werninghaus 2004

Recombinant AIT may be recommended for birch and grass pollen allergy

I A - B Quality of studies unclear (Pauli 2008; Jutel 2005).

Some evidence of benefit for adults, no pediatric data.

Pauli 2008; Jutel 2005


SECTION F: ALLERGEN FACTORS THAT MAY AFFECT THE EFFICACY OF AIT 1

for AR 2

3

Standardization of allergen extracts 4

For the common allergens, many companies now provide characterized, standardized, 5

stable preparation for AIT as recommended by European Medicines Agency (EMA) 6

[EMA 2008, regulatory position paper]. For others, such as molds, there are problems 7

with the complexity, variability and stability of the allergens [Coop 2014]. The lack of 8

standardized extracts may hamper the diagnosis of eligible patients for AIT and may 9

impede the effectiveness of AIT [Coop 2014, Twaroch 2015]. Additionally, non-10

standardized preparations may vary between batches increasing the potential for side 11

effects. Further purification and characterization of such allergens [Twaroch 2015, Lizaso 12

2006, Slater 2014] may result in better extracts for the future. Where possible, 13

standardized allergen products should be used for AIT. Further discussion is available 14

in a position paper on regulatory aspects of AIT [regulatory position paper]. 15

Formulation of SLIT preparations 16

In deciding on the appropriate preparation to use for AIT, the formulation should be taken 17

into account. For example, three large studies have showed efficacy for HDM SLIT 18

tablets [Bergmann 2014, Demoly 2016, Mosbech 2014] whereas three HDM SLIT 19

studies with sublingual drops were negative [Bahçeciler, 2007, Guez, 2000, Hirsch, 20

1997], and another only demonstrated efficacy in the first and not the second year 21

[Passalacqua 2006]. However, many factors such as differences in allergen content, 22

administered volume, number of participants and statistical power of the study may 23

explain the differences between tablets and drops. We recommend that AIT products 24

with evidence of efficacy in the clinical documentation should preferentially be used. 25

Allergen mixtures 26

Both mixtures of grass pollen and mixtures of tree pollen are frequently used in AIT and 27

such an approach is effective [Dhami 2017]. The use of different, non-taxonomically 28

related allergens mixed in one AIT product has been evaluated in a very limited number 29

of studies. One SCIT study showed that a depigmented-polymerized mixed grass/birch 30

pollen extract was effective over placebo [Pfaar 2013]. A small study in children 31

demonstrated efficacy using a mixture of grass pollen and HDM SLIT [Swaney 2012]. 32

One study assessed the efficacy of multi-inhalant allergen subcutaneous AIT (tree, grass 33


and weed pollen; moulds; cat and dog dander; dust and storage mites), it demonstrated 1

no efficacy over placebo [Radcliffe 2003]. Sublingual immunotherapy that employed a 2

momomeric Phleum pratense grass pollen extract was more effective when given alone 3

compared to when given in an equivalent dose as part of a combination with a 9-pollen 4

multi-allergen sublingual extract [Amar 2009]. 5

There are a number of potential drawbacks of mixing allergens including a dilutional 6

effect, potential allergen degradation due to enzymatic activity of some allergens and the 7

difficulties of adequately demonstrating efficacy of a high number of allergen 8

combinations and/or different products. The European Medicines Agency has 9

recommended that only homologous allergens (usually ones that are taxonomically 10

related, for example a mixture of grass pollen extracts [Didier A JACI 2006]) should be 11

mixed and that allergens with enzymatic activity (e.g. HDM) should be never used in a 12

mixture [EMA-AIT GL 2008]. We therefore recommend only homologous allergens to be 13

mixed in AIT preparations until further evidence is available substantiating the efficacy 14

of other mixtures (see Online supplement). Alternatively, extracts should be given 15

separately. 16

17

Specific allergens 18

In the recent meta-analysis, there were sufficient SCIT and SLIT studies for subgroup 19

analyses by specific allergens (Dhami 2017). Short-term effectiveness was 20

demonstrated for HDM (symptoms score SMD -0.73; 95%CI -1.37, -0.10), grass pollen 21

(-0.45; -0.54,-0.36); tree pollen (-0.57; -0.92, -0.21) and weed pollen (-0.68; -1.06, -0.30). 22

However, there was lots of heterogeneity for all allergens, particularly molds (-0.56; -23

2.29, 1.18), suggesting that different preparations may be more or less effective. 24


Table 5 Recommendations: allergen factors that affect the efficacy of AIT for AR

Recommendation Adults Children and Adolescents

Strength of recommendation Other considerations Key references

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Either a single allergen or a mixture of well documented homologous allergens from that biological family that covers the major allergens are recommended for patients with AR who are allergic to grass pollens, tree pollens or HDM

I B I B Strong recommendations on basis of high quality grass pollen (single grass, eg Bufe 2009, Dahl 2006a; mixture of grasses, eg Didier 2007, Ott 2009), tree pollen (single tree, eg Bodtger 2002 Charpin 2007; mixture of trees, eg Balda 1998) and house dust mite (single, eg De Bot 2011, Hirsch, 1997; mixture, eg Passalacqua 1998) studies.

Strong RCT evidence that these are effective approaches. Supported by regulators.

Dhami 2017, Demoly 2016, EMA 2008

Mixtures of allergens from non-related biological families are not recommended as AIT preparations except for products with supportive published evidence

I B - B Strong recommendation based on a negative high quality study with multiple allergens (Radcliffe 2003). One positive high quality study combining grass and tree pollens (Pfaar 2013).

No evidence of effectiveness for almost all mixtures.

EMA 2008, regulatory position paper. Radcliffe 2003, Pfaar 2013

Examples of homologous, taxonomically related allergens from the same biological family are the grasses or tree pollens. Also see Table 3.


SECTION G: PATIENT FACTORS THAT EFFECT THE EFFICACY OF AIT FOR AR

Polysensitized patients

Epidemiological data indicate that most patients with AR are polysensitized [Migueres et al.

2014]. Consequently, consideration needs to be given as to whether patients are (i) clinically

mono-allergic (where only one allergen is driving symptoms) and polysensitised or (ii) poly-

allergic (with clear cut symptoms on exposure to multiple different allergens) and

polysensitised. This may be apparent from the history or may need investigation with

component resolved diagnostics or assessment with nasal or conjunctival provocation

challenges [Demoly 2016]. Immunotherapy with a single allergen extract is effective in the

former while immunotherapy has been shown to be ineffective (Adkinson F jr NEJM) or less

effective in the later situation (Amirr/Nelson JACI).

For a poly-sensitized patient who is poly-allergic for homologous (biologically related) allergens

(e.g. two grass pollens), a single allergen preparation or a mixture of two homologous allergens

is recommended [Demoly 2016]. For polysensitized patients where allergens are not

homologous, separate AIT preparations for one or two of the clinically most important allergens

are recommended with doses given 30-60 minutes apart at separate locations when two are

selected [Demoly 2016; Calderon 2012. This represents a trade-off between efficacy and

safety as both are dose-dependent.

Co-existing asthma

Uncontrolled or poorly controlled asthma is considered to be an absolute contraindication to

AIT [Pitsios 2015; Cox 2011; Bousquet 1989; Lockey 2001 Bernstein 2004; CSM 1986;

Normansell 2015]. Studies that have assessed the impact of co-existing asthma on the efficacy

of AIT [Bufe 2004] have reported no effect.. Co-existing asthma is seen in many participants

in the published AR studies [Dhami 2017]. When controlled, mild-to-moderate asthma does

not seem to be a safety issue with AIT [Dhami 2017; Virchow 2016; Asthma AIT guidelines;

Pfaar et al. 2014].

Specific pediatric issues

Similarly to adults, AIT should be considered in pediatric patients with AR with evidence of

IgE-sensitization to clinically relevant allergens (Table 1, 3).


The evidence for the efficacy of AIT for AR is limited in children younger than five years of

age. Some clinical studies have shown the efficacy and safety of both SCIT and SLIT in

preschool children (Pajno 2012; Shao 2014; Fiocchi 2005; Agostinis 2005; Roberts 2006),

and children were included from four years onward in several of the big SLIT trials (Bufe

2009, Wahn 2009). However, repeated injections of SCIT can be traumatic in small children

[Pajno 2013; Arroabarren 2015]. The decision to start the treatment has to be taken on a

case by case basis together with the patients and their family. It depends on several factors,

such as the severity of the allergic disease, the clear exposure-symptoms pattern supported

by allergic sensitisation testing, the impairment of the health related quality of life and the

expected acceptance and adherence to the AIT.

There are more data to drive recommendations for school age children and adolescents

although major gaps still exist (Table 3). Many of the SCIT trials are now relatively old, many

enrolled a few children or do not present pediatric only analyses. Continuous and pre- and

pre/co-seasonal SCIT can be recommended (Grade B) for children with seasonal AR (Table

3). Continuous SCIT is also recommended for perennial AR, but with a weaker evidence

grade due to the inconsistency in the trial data (Grade C)(Table 3). There are no exclusive

pediatric data for allergoid preparations. One open RCT suggests that SCIT for grass pollen

driven AR does have a long-term benefit [Jacobsen L Allergy 2007]. For SLIT, there are

recent pediatric trial data to support this approach. In general, pre-co-seasonal SLIT is

recommended for seasonal AR (Grade A). For continuous SLIT, the results are more

heterogeneous, probably because of the products used (Grade B) (Table 3). Both tablet

and aqueous formulations are recommended although there is more heterogeneity in

results with the latter (Table 3). There is now one unpublished trial supporting the long-term

effectiveness for the grass pollen tablet and reduction in asthma synmptoms [Valovirta Clin

Ther. 2011](Grade B), there are no similar evidence for the aqueous preparations nor the

HDM tablet.

Elderly

A detailed allergy history is especially important when evaluating older adults suffering with

rhinitis as other types of rhinitis that may mimic AR symptoms. There are very few studies

specifically evaluating the use of AIT in the elderly but SLIT with grass pollen and HDM has

been demonstrated to be effective and safe in two studies [Bozek 2014 and 2016]. AIT elicits

responses comparable to studies with younger patients. Another important considerations in


this age group, when contemplating treatment with AIT, is the higher prevalence of

comorbidities. Examples are hypertension, coronary artery disease, cerebrovascular disease,

and/or cardiac arrhythmias. Also, treatment with medication such as beta-blockers that may

impair the treatment of anaphylaxis with adrenaline (epinephrine) (see Box 2).

Pregnancy

There is one prospective study investigating the safety of AIT in pregnancy [Shaikh 2012] and

several retrospective studies suggest that there is no greater risk of prematurity, fetal

abnormality, or other adverse pregnancy outcome in women who receive AIT during

pregnancy [Metzger 1978]. Observations about anaphylaxis in pregnant and breastfeeding

women are largely derived from case reports [Chaudhuri 2008] and are generally reassuring

[Oykhman 2015]. However, the balance between benefits and potential risks in pregnant

patients changes, these should be discussed with the patient. AIT takes months to work, but

systemic reactions and their resultant treatment can potentially harm the baby and/or mother.

It is therefore recommended that AIT is not initiated during pregnancy but, if already initiated,

AIT may be continued during pregnancy or breastfeeding in consultation with the patient’s

general practitioner and obstetrician if former AIT treatment has always been tolerated well.

Adherence

There is a great variance between studies (both real life studies and clinical trials) in the criteria

used for evaluating compliance and in the rates of compliance [Incorvaria-- Incorvaia 2010;

Scurati 2010; Egert-Schmidt 2014; Keil JACI 2013, Vaswani 2015; Leader 2016; Savi 2013].

The range of reported compliance varied from 18% to over 90%, higher in clinical studies than

real-life surveys. The main causes for poor adherence are reported to be side effects,

inconvenience, lack of efficacy or forgetting to use [Incorvaria-- Incorvaia 2010; Scurati 2010;

Egert-Schmidt 2014; Vaswani 2015; Leader 2016; Makatsori M 2014]. A few other factors have

been associated with poor adherence, for example age and patient’s educational level.

Potential ways to improve adherence are the use of reminder mechanisms (e.g. alarm on

mobile phone, internet based tools, service (SMS) electronic reminders, social networks,

mobile applications (apps) and monitoring systems – the approach should be tailored to the

patient), approaches to improving patient-doctor communication and patient education [Savi

2013; Demoly 2016]. One randomized study suggests that adherence is much better with 3


monthly follow up appointments compared to 6 or 12 monthly follow up [Vita 2010].

Recommendations are summarized in Table 6.


Table 6: Recommendations: patient factors that affect the efficacy of AIT for AR

Recommendation Evidence level

Grade of recommendation

Strength of recommendation

Other considerations Key references

Polysensitized patients

Polysensitized patients who are mono-allergic are recommended to receive AIT for the specific allergen that is driving their AR symptoms

I A Based on expert review of RCT and observational data plus clinical experience.

Demoly 2016, Kim 2006

Polysensitized patients who are poly-allergic for taxonomically related homologous allergens can be recommended to receive either a single allergen or a mixture of homologous allergens from that biological family that covers all the major allergens

II B Based on expert review of RCT and observational data plus clinical experience.

Demoly 2016, EMA advice.

Patients who are poly-allergic for non-homologous allergens may be recommended to start AIT with either the allergen responsible for most of their allergic rhinoconjunctivitis symptoms or separate treatment with the two clinically most important allergens

II C Based on expert review of RCT and observational data plus clinical experience.

Demoly 2016, EMA advice; Radcliffe 2003, Kim 2006, Pfaar 2013.

.Co-existing asthma

Controlled asthma is not a contraindication to AIT I A Strong recommendation based on high quality studies (asthma AIT SR)

Evidence described in asthma AIT systematic review.

Dhami 2017; Virchow 2016; Asthma AIT SR and asthma AIT guidelines

Specific pediatric issues


Consideration of AIT is recommended in pediatric patients with AR with evidence of IgE-sensitization to clinically relevant allergens

I A Strong recommendations from high quality studies (eg Caffarelli 2000, Pajno 2003, Stelmach 2012, Bufe 2009, Caffarelli 2000)

See Table 3 for detailed review.

Caffarelli 2000, Pajno 2003, Stelmach 2012, Bufe 2009, Caffarelli 2000

In children aged less than 5 years of age, it is recommended that consideration should be given to likely benefits and risks associated with AIT for AR

IV D May be more difficult to make a definitive diagnosis of AR in pre-school children. Safety seems to be similar in this age group as per older patients.

Rodriguez-Santos 2008; Rienzo VD 2005

Elderly

AIT can be recommended in otherwise healthy elderly patients with AR whose symptoms cannot be adequately controlled by pharmacotherapy

I A (SCIT), B (SLIT) Moderate to strong recommendation based on one high quality SCIT study (Bozek 2016) and two SLIT studies of unclear quality (Bozek 2014, Bozek 2012).

Consistent RCT data for SLIT, only one SCIT study. Also see Table 2. A detailed clinical assessment is recommended as other types of rhinitis may mimic allergic rhinitis in older patients.

Bozek 2012, 2014, 2016

Pregnancy

If patients have not started AIT and are pregnant, it is recommended to wait until after pregnancy to initiate therapy

V D Based on balance of additional risk versus benefits.

Expert opinion

If have commenced AIT and still in up-dosing phase, it may be recommended that the current dose is continued and up-dosing is resumed when pregnancy is completed

IV C Based on observational data.

Metzger 1978


If on maintenance AIT, it may be recommended that the current dose is continued

III C Weak recommendation based on propsective cohort study [Shaikh 2012]

Expert opinion

Adherence

It is recommended that patients understands about how AIT works and the need to take regular doses

II B Based on observational data.

Savi 2013

It may be recommended that patients use reminders to maximize adherence with SLIT therapy

V D Based on observational data.

Savi 2013, Demoly 2016

It can be recommended that patients on SLIT are followed up every 3 months to maximize adherence

I B Moderate recommendation based on a pseudo-randomized study (Vita 2010).

Vita 2010



SECTION H: HOW LONG SHOULD AIT BE CONTINUED FOR IN AR? 1

2

Most clinical studies evaluating the efficacy of AIT follow participants for one or two years 3

on therapy. The EMA currently recommends an experimental, randomized, controlled 4

design involving three years of therapy with a two year follow up period off treatment. 5

These studies demonstrate a sustained benefit for SLIT grass pollen therapy for two 6

years off therapy for one tablet [Durham 2010], for one year off for another tablet [Didier 7

2015] and for one year off drops [Ott 2009]. There are some data to suggest that HDM 8

SLIT drops gives sustained benefit for at least one year after three years of therapy in 9

one RCT [Lin 2016] and another observational one [Stelmach 2012]. There is less 10

evidence on the optimal duration of therapy. In a randomized cessation of therapy study, 11

participants who stopped therapy after 3 or 4 years of grass pollen SCIT did as well three 12

years later as participants who continued therapy [Durham 1999]. Similarly, children 13

randomized to 3 or 5 years HDM SCIT had similar outcomes at five years [Arroabarren 14

2015] as did adults randomized to 3 years of ragweed SCIT [Naclerio 1997]. A recent 15

study of grass pollen allergic patients showed that two years treatment with either SCIT 16

or SLIT tablets were effective compared to placebo whereas two years was insufficient 17

for long-term efficacy that was measured at 3 years, one year off treatment (Scadding 18

GW 2017). So for patients with AR a minimum of three years of immunotherapy is 19

recommended in order to achieve long-term efficacy after treatment discontinuation 20

(Table 7). 21

22


Table 7. Recommendations: How long should AIT for allergic rhinoconjunctivitis be continued?

Recommendation Evidence

level Grade of recommendation

Strength of recommendation Contextual comments

Key references

AIT is recommended as efficacy is seen from the first year of therapy

I A Strong recommendation based on high quality studies (eg Balda 1998, Bergmann 2013, Bousquet 1990, Didier Clin Trans Allergy 2015, Zenner 1997)

Generally consistent data.

Dhami 2017, Bergmann 2013, Didier Clin Trans Allergy 2015

To achieve long-term efficacy, it is recommended that a minimum of 3 years of therapy is used

I A Strong recommendation based on high quality longterm adult studies (Durham 1999, James 2011, Durham 2012, Didier Clin Trans Allergy 2015, Ott 2009, Bergmann 2014), one low quality pediatric study (Jacobsen 2007) plus one pediatric study with data only on EudraCT (Valovirta Clin Ther. 2011).

Consistent data. Durham 2012, Dider 2015, Ott 2009, Lin 2016, Stelmach 2012, Arroabarren 2015, Naclerio, Durham 1999 Scadding JAMA 2017






SECTION I: ADVERSE EVENTS WITH AIT FOR AR 1

2

SCIT 3

SCIT is a safe and well-tolerated treatment in selected patients when the injections are 4

given in a medical setting experienced with this kind of treatment [Alvarez-Cuesta 2006; 5

Cox 2012; Malling 2000; EAACI SR; Pfaar 2014]. 6

Systemic allergic adverse reactions to SCIT can range between mild to severe adverse 7

reactions of the skin, upper and lower airways, gastrointestinal tract, or the 8

cardiovascular system (Table SB in online supplement). In a three year survey that 9

included over 20 million injection visits, systemic reactions were reported in 0.1% of 10

injections; there were no fatalities [Epstein 2011] although 4 were reported in the follow 11

up survey [Epstein 2016]. Fatal, allergic, adverse reactions have though been reported 12

in earlier surveys [Lockey 2001; Bernstein 2004]. Over 80% of reactions occurred within 13

30 minutes after injection; very few of the delayed ones were severe. It is therefore 14

recommended that patients stay in clinic for at least 30 minutes after an injection. There 15

are a number of possible risk factors for systemic adverse reactions (Table 9). 16

Interestingly, rush [Brehler 2010] and ultra-rush [Cardona 2012 and Casanovas 2006] 17

build up schedules with modified allergens are not associated with more adverse events 18

than conventional ones. When one or more severe adverse reactions occur, the allergist 19

should re-discuss the benefits and risks of SCIT therapy with the patient and decide 20

whether or not treatment should be continued. 21

Redness, itching or swelling represent local reactions at the injection site. These occur 22

frequently after around half of injections [Dhami 2017]. Local measures (e.g., cooling or 23

topical glucocorticoids) or oral antihistamines may be helpful for these reactions. 24

Increased local adverse reactions do not predict an increased individual risk of a 25

systemic adverse reaction [Kelso 2004]. In case of enlarged local adverse reactions 26

(redness and/or swelling >10 cm in diameter) occur at the injection site, the 27

manufacturer‘s product information (SmPC) leaflet provides adaptions of the dosing-28

schemes for the next injection. When local adverse effects occur, pre-medication with 29

an H1-antihistamine can be used to reduce the frequency and severity of adverse 30

reactions but this prophylactic treatment does not prevent the onset of systemic adverse 31

reactions [Nielsen 1996; Reimers 2000]. Alternatively, case series indicate that modified 32

allergen extracts are associated with less adverse effects [Brehler 2010, Cardona 2012, 33

Casanovas 2006 & 2007]. For aluminum hydroxide containing SCIT products, rarely 34

granulomas have been described from a foreign body reaction mainly caused by 35


incorrect intradermal administration as well as contact allergic reactions, new onset of 1

protein contact dermatitis or a vasculitic inflammatory reactions have been reported 2

[Vogelbruch 2000, Netterlid 2009, Frost et al., Allergy 1985]. If these reactions to SCIT 3

occur, treatment with another aluminum hydroxide-free product is preferred [Pfaar 2014]. 4

5

SLIT 6

SLIT is regarded to be a safe and well-tolerated treatment [Radulovic 2010; Canonica 7

2014; Dhami 2017; Pfaar 2014]. 8

Severe systemic reactions with SLIT are much less likely than with SCIT although the 9

overall rate of any adverse reactions is similar in both SCIT and SLIT [Dhami 2017]. In a 10

review of 66 SLIT studies (over 4000 patients who received over a million doses), there 11

was one systematic reaction for approximately every four years of treatment and only 12

one severe systematic reaction per 384 treatment years [Cox 2006]. There are no new 13

safety concerns in more recent studies [Dhami 2017]. Several severe reactions - in some 14

cases with severe anaphylaxis - are described in the literature occurring within 30 15

minutes of sublingual administration of allergens in droplet or tablet form [Calderon 16

2012]. In these cases, SLIT was not administered according to the standards (non-17

standardized extracts, rush protocols, excessive allergen dose, patients in whom SCIT 18

had previously been interrupted due to severe reactions). As in SCIT, concomitant, 19

poorly controlled asthma has been reported to be associated with severe systemic 20

reactions after SLIT [Calderon 2012]. The majority of adverse events in SLIT develop at 21

home without any medical observations (as after SCIT). Patients should therefore be 22

informed about how to recognize and manage reactions, particularly severe ones. 23

Patients also need education on what to do if a dose is forgotten and when SLIT should 24

be temporarily interrupted (e.g. oropharyngeal lesions) [Pfaar 2014]. When one or more 25

severe adverse reactions occur, the allergist should re-discuss the benefits and risks of 26

SLIT with the patient and decide whether or not treatment should be continued. 27

The frequency of local adverse events during SLIT correlates with the dosage and has 28

been reported to be 40% to 75%, for example temporary local mucosal reactions (oral 29

pruritus or dysesthesia, swelling of the oral mucosa, throat irritation) or abdominal pain 30

[Canonica 2014, Cox 2006; Calderon 2012; Passalacqua 2013]. Most of these reactions 31

occur during the initial phase of the treatment course (commonly in the first three weeks). 32

They are commonly considered to be of mild intensity mild and generally [Canonica 33

2014]. Nethertheless, these reactions may occasionally lead to cessation of treatment, 34

as observed in 4-8% of cases reported in recent trials of SLIT tablets (Blaiss 2011, 35


Mosbech 2014, Didier 2007, Dahl 2006).(see section “adherence”). As in SCIT, local 1

adverse reactions may be diminished by the intake of (oral) antihistamines. 2

3

4

Box 3. Risk factors for systemic reactions during AIT

Current allergy symptoms and potential allergen exposure

Current infections

Mast cell disease

Previous systemic reaction to SCIT or SLIT

Hyperthyroidism

Unstable or uncontrolled or severe asthma

A high degree of sensitization

Excess dose escalation during initiation

Beta-blockers use

Poor injection technique

Overdose of allergen extract

Failure to follow manufacturer's recommendation for dose reduction when change to new production batch

High-intensity physical exercise

Sauna

5 From Pfaar et al., Allergo J Int., 2014 6

7



Table 8. Recommendations: adverse events with AIT for AR

Recommendation Evidence level

Grade of recommendation

Strength of recommendation

Contextual comments Key references

SCIT or SLIT

For correctly selected patients, SCIT or SLIT is recommended as, appropriately administered, it is safe and well tolerated

I A Strong recommendation based on high quality RCT studies and observational studies (Dhami 2017)

Consistent evidence. Dhami 2017

It is recommended that asthma should be controlled before commencing AIT as insufficiently controlled asthma is a risk factor for both SCIT and SLIT

III C Expert opinion from observational studies

Bernstein 2004; Amin 2006; Calderon 2012

Premedication with an antihistamine is recommended as it reduces the frequency and severity of local and systemic cutaneous reactions but does not eliminate the risk of other systemic adverse reactions

I A Strong recommendation based on high quality studies (Nielsen 1996, Reimers 2000).

Consistent strong evidence from RCT studies

Nielsen 1996; Reimers 2000

When one or more severe adverse reactions occur, it may be recommended that the allergist should re-discuss the benefits and risks of AIT therapy with the patient and decide whether or not treatment should be continued

V D Expert opinion from clinical experience

Expert opinion

SCIT


It is recommended that patients should wait in the clinic for at least 30 minutes after a SCIT injection

III C Consistent observational data

Epstein 2011

If granulomas develop with aluminum hydroxide containing SCIT products, it may be recommended that treatment should be continued with an allergen extract that does not contain aluminum hydroxide

V D Expert opinion

It is recommended that SCIT should be administered by competent staff with immediate access to resuscitation equipment and a doctor trained in managing anaphylaxis.

I C Consistent observational data

Dhami 2017

SLIT

Where there is concern about the possibility that AIT may cause systemic adverse reactions, SLIT can be recommended as the preferred approach as it is associated with a lower risk of such reactions than SCIT.

II B Expert opinion based on consistent observational data

Epstein 2011; Cox 2006

It is recommended that patients should wait in clinic for at least 30 minutes after an initial SLIT dosage

III C Expert opinion based on consistent observational data

Calderon 2012

It is recommended that patients receiving SLIT should be informed about how to recognized and manage reactions, particularly severe ones. Patients also need to know what to do if a SLIT preparation is forgotten and when SLIT should be temporarily interrupted (e.g. oropharyngeal lesions).

V D Expert opinion from clinical experience

Expert opinion


SECTION J: PREVENTIVE EFFECTS OF AIT FOR AR 1

2

A three years course of AIT reduces the likelihood that children and adolescents with 3

allergic rhinitis and pollen allergy go on to develop asthma until at least 2 years 4

posttreatment [EAACI Prevention SR]. There is no documentation for a preventive effect 5

of HDM AIT or for prevention of new sensitivities. It is important to be aware that patients 6

included in these studies had less severe AR than those included in studies on AIT for 7

treatment. This is further discussed in the EAACI AIT Prevention Guidelines [prevention 8

AIT guideline]. 9

10

SECTION K: PHARMACOECONOMIC ASPECTS OF AIT VERSUS 11

PHARMACOTHERAPY FOR AR 12

13

Pharmacoeconomic studies that only analyze costs in monetary units have reported 14

beneficial health care expenditure of AIT in the long-run although savings in the first year 15

are not expected to be economic over symptomatic anti-allergic medications. The 16

majority of pharmacoeconomics studies support the viewpoint that AIT gives value for 17

money, with cost-effectiveness within 6 years of treatment initiation (Meadows 2013). 18

Retrospective and prospective observational studies have shown that SCIT and SLIT 19

positively affects health care expenditure in pharmacotherapy with a reduction between 20

12% and 80% (Ariano 2006, Berto 2005, Hankin et al. 2008; Hankin et al. 2010; Hankin 21

et al. 2013). A reduction in medical costs in the AIT versus placebo groups have been 22

repeatedly reported, but these savings did not compensate the costs of AIT (Creticos et 23

al. 1996; Berto et al. 2008; Ariano et al. 2006). 24

In contrast to cost-only studies, cost-effectiveness and cost-utility analysis evaluates the 25

effects of treatment in terms of clinical benefits or health-related quality of life (i.e., 26

quality-adjusted life years [QALYs]). An incremental cost-effectiveness ratio (ICER), 27

which is defined as costs divided by benefits, can be calculated to estimate the costs of 28

a certain gain. Several health economics studies that include cost-effectiveness and cost 29

utility calculations have demonstrated that SCIT and SLIT are economically 30

advantageous (Schadlich et al. 2000; Petersen et al. 2005; Berto et al. 2006; Bachert et 31

al. 2007). 32

Seven studies based on RCT data conducted from a health system perspective and 33

using QALYS as their outcome measure suggest that SLIT and SCIT would be 34


considered cost-effective in this patient population in England at the standard National 1

Institute for Health and Care Excellence (NICE) cost-effectiveness threshold of £20,000 2

(€24616) per QALY (Nasser 2008, Poulsen 2008, Keidig 2007, Ronaldson 2014, 3

Westerhout 2012, Verheggen 2015, Reinhold 2016). ICERs for AIT seemed to vary 4

substantially between different health systems suggesting that straightforward 5

conclusions may not be generalizable even across seemingly similar countries.(Keidig 6

2007). Finally, the quality of the studies and the general lack of attention to characterizing 7

uncertainty and handling missing data should be taken into account when interpreting 8

these results. 9

SECTION L: SUMMARY, GAPS IN THE EVIDENCE AND FUTURE 10

PERSPECTIVES 11

12

The EAACI Taskforce on AIT for Rhinoconjunctivitis has developed these guidelines as 13

part of the EAACI AIT Guidelines project. The guidelines has been informed by a formal 14

systematic review and meta-analysis of AIT for AR [Dhami 2017], The guidelines provide 15

evidence-based recommendations for the use of AIT for patients with allergic rhinitis with 16

or without allergic conjunctivitis. A summary of the guidelines is provided in Box 3. The 17

recommendations should be of value to all healthcare professionals involved in the 18

management of patients with AR. 19

There are many areas in these guidelines where there is no high quality evidence, these 20

signify the gaps in the current evidence base. The key ones are highlighted here and in 21

Table 9. There is a major gap in the evidence base for the clinical effectiveness of AIT 22

in children and adolescents with recommendations at least one grade lower than for 23

adults in most areas. As AR usually starts in childhood and AIT changes the natural 24

history of the disease and prevents the development of asthma, this age group has most 25

to benefit. Once safety is established in adult studies, pediatric studies need to be 26

commenced using common outcome measures (Pfaar 2014). There is also little data in 27

the elderly particularly for patients with multi-morbidity. Additionally, more randomized 28

controlled trials need to follow participants post cessation of therapy to establish long-29

term clinically effectiveness. Agreement about the clinically meaningful effect size of AIT 30

treatment would assist in the interpretation of clinical trial data. Additionally we need data 31

from randomized cost-effectiveness and cost utility studies to use in discussions with 32

healthcare funders. We need biomarkers to predict and quantify the effectiveness of AIT 33

to assist in patient selection (Shamji 2017). The poor adherence associated with SLIT is 34

likely to be impacting on its effectiveness; we need to develop novel approaches to 35



improve effectiveness in partnership with patients. Finally, to allow better comparison of 1

safety between approaches, a unified approach to classifying side effects is required. 2

Despite all these gaps we have clear evidence for the clinical effectiveness of AIT for 3

moderate-to-severe AR that is otherwise uncontrolled despite optimal pharmacotherapy 4

with evidence-based recommendations for specific patient groups and specific 5

approaches. There is now a need to ensure that primary care healthcare professionals 6

know which patients might benefit from AIT, that national healthcare providers 7

understand that AIT is cost-effective and that patients and patient support groups are 8

aware of this approach. 9


Table 9. Gaps in the evidence

Gaps Plan to address Priority

Value of provocation tests in identifying the most appropriate allergen to use in AIT

Prospective controlled studies to assess benefit of provocation testing

Moderate

Good evidence base for contraindications to AIT Registries recording patient details, AIT, outcome and adverse effects

Low

Lack of biomarkers to predict and quantify the effectiveness of AIT Prospective observational studies to validate potential predictive biomarkers

High

Agreement about the clinically meaningful effect size of AIT treatment (active versus placebo treated patients)

Consensus discussion High

High quality randomized controlled data for children and adolescents More prospective controlled trials High

For some AIT productions there is poor data for clinical effectiveness Additional prospective controlled trials; use of products with proven effectiveness

Moderate

Evidence for clinical effectiveness post treatment cessation More prospective controlled trials with follow up post treatment cessation

High

Effectiveness of mixtures of homologous allergens from the same, related or different biological families

More prospective controlled trials Moderate

Management of AIT in patients who become pregnant on therapy More prospective observational studies Moderate

Standardization of grading of adverse effects of AIT Future clinical trials should use the WAO systemic reaction grading system

High

Approaches to minimize adverse effects More prospective observation and controlled trials Moderate

Approaches to improve adherence with SLIT Working patients to develop to develop novel approaches that can be tested in prospective controlled trials

High

Lack of standardized AIT preparations for orphan allergens Multi-centre studies Low

Randomized cost-effectiveness and cost utility studies adjusted to socioeconomic differences within and between countries

Additional studies with a health economics focus High


Box 3. Summary of the EAACI Rhinoconjunctivitis AIT Guidelines

The EAACI Guidelines on Allergen Immunotherapy (AIT) for allergic rhinitis (AR) aim to provide evidence-based recommendations for the use of AIT for patients with AR.

Development of the guidelines has been based on a formal systematic review and meta-analysis of AIT for AR.

AIT should be considered with symptoms strongly suggestive of allergic rhinitis, with

or without conjunctivitis; evidence of IgE-sensitization to one or more clinically

relevant allergen; and moderate-to-severe symptoms despite regular and

appropriate pharmacotherapy and / or avoidance strategies.

AIT may also be considered in less severe AR where a patient wishes to take

advantage of its long term effect on rhinitis and potential to prevent asthma.

A product based evaluation of evidence is recommended.

Standardized AIT products with evidence of efficacy in the clinical documentation

should preferably be used.

Key contraindications are uncontrolled asthma; active, systemic autoimmune

disorders; active malignant neoplasia. Careful review of benefits and risks are

required with beta-blocker or ACE-inhibitor therapy, severe cardiovascular disease,

other autoimmune disorders, severe psychiatric disease, poor adherence and

immunodeficiency.

Continuous SCIT is recommended for seasonal (Grade A, B for children) or

perennial (Grade B, C for children) AR for short-term benefit in those with moderate-

to severe disease

Pre- and pre-/co-seasonal SCIT is recommended for seasonal AR for short-term benefit

(Grade A, B for children)

Both modified (allergoids) and unmodified allergen extracts are recommended for AR

for short-term benefit (Grade A, B for children)

Continuous grass pollen SCIT is recommended for AR for short and long-term

benefit (Grade A, B for children)

Pre-/co-seasonal or continuous SLIT is recommended for seasonal ARs for short-

term benefit (Grade A, B for continuous in children)

SLIT with tablets (Grade A) or aqueous solutions (Grade B, A in children) can be

recommended for AR for short-term benefit.

Grass pollen SLIT tablets or solution is recommended for allergic rhinoconjunctivitis

for long-term benefit (Grade A, B for children).

HDM SLIT tablet can be recommended for allergic rhinoconjunctivitis for long-term

benefit (Grade B, C for children).

Polysensitized patients who are poly-allergic for taxonomically related homologous allergens

can be recommended to receive either a single allergen or a mixture of homologous allergens

from that biological family that covers all the major allergens (Grade B)


Patients who are poly-allergic for non-homologous allergens may be recommended

to start AIT with either the allergen responsible for most of their allergic

rhinoconjunctivitis symptoms or separate treatment with the two clinically most

important allergens (Grade C).

In children aged less than 5 years of age, it is recommended that consideration

should be given to likely benefits and risks associated with AIT for AR (Grade D).

AIT can be recommended in otherwise healthy elderly patients with AR whose

symptoms cannot be adequately controlled by pharmacotherapy (Grade A for SCIT,

B for SLIT)

If patients have not started AIT and are pregnant, it is recommended to wait until

after pregnancy to initiate therapy (Grade D).

It can be recommended that patients on SLIT are followed up every 3 months to

maximize adherence (Grade B).

To achieve long-term efficacy, it is recommended that a minimum of 3 years of

therapy is used (Grade A).

Premedication with an antihistamine is recommended as it reduces the frequency

and severity of local and systemic cutaneous reactions but does not eliminate the

risk of other systemic adverse reactions (Grade A).

It is recommended that patients should wait in the clinic for at least 30 minutes after

a SCIT injection (Grade C).

It is recommended that SCIT should be administered by competent staff with

immediate access to resuscitation equipment and a doctor trained in managing

anaphylaxis. (Grade C).

It is recommended that patients should wait in clinic for at least 30 minutes after an initial

SLIT dosage (Grade C).

It is recommended that patients receiving SLIT should be informed about how to

recognized and manage reactions, particularly severe ones (Grade D).

Many gaps in the underpinning evidence have been identified and prioritized.


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Calderon MA, Alves B, Jacobson M, Hurwitz B, Sheikh A, Durham S. Allergen injection immunotherapy for seasonal allergic rhinitis. The Cochrane database of systematic reviews. 2007(1):Cd001936.

L. S. Cox, T. B. Casale, A. S. Nayak, D. I. Bernstein, P. S. Creticos, L. Ambroisine, et al. Clinical efficacy of 300IR 5-grass pollen sublingual tablet in a US study: the importance of allergen-specific serum IgE. J Allergy Clin Immunol. Dec;130(6):1327–34.

P. S. Creticos, J. Maloney, D. I. Bernstein, T. Casale, A. Kaur, R. Fisher, et al. randomized controlled trial of a ragweed allergy immunotherapy tablet in North American and European adults. J Allergy Clin Immunol. May;131(5):1342–9.

P. S. Creticos, R. E. Esch, P. Couroux, D. Gentile, P. D’Angelo, B. Whitlow, et al. Randomized, double-blind, placebo-controlled trial of standardized ragweed sublingual-liquid immunotherapy for allergic rhinoconjunctivitis.[Erratum appears in J Allergy Clin Immunol. 2014 May;133(5):1502]. J Allergy Clin Immunol. Mar;133(3):751–8.

R. Dahl, A. Stender, S. Rak. Specific immunotherapy with SQ standardized grass allergen tablets in asthmatics with rhinoconjunctivitis. Allergy. Feb;61(2):185–90

A. Didier, H.J. Malling, M. Worm, F. Horak, S. Jäger, A. Montagut, et al.Optimal dose, efficacy, and safety of once-daily sublingual immunotherapy with a 5-grass pollen tablet for seasonal allergic rhinitis. J Allergy Clin Immunol, 120 (2007), pp. 1338–1345.

Alain Didier Hans-Jørgen Malling, Margitta Worm, Friedrich Horak and Gordon L Sussman. Prolonged efficacy of the 300IR 5-grass pollen tablet up to 2 years after treatment cessation, as measured by a recommended daily combined score.Clinical and Translational Allergy 20155:12. DOI: 10.1186/s13601-015-0057-8.

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M. Ferrer, E. Burches, A. Peláez, A. Muñoz, D. Hernández, A. Basomba, et al. Double-blind, placebo-controlled study of immunotherapy with Parietaria judaica: Clinical efficacy and tolerance. J Investig Allergol Clin Immunol. 2005;15(4):283-92.

Jacobsen L, Niggemann B, Dreborg S, Ferdousi HA, Halken S, Høst A, Koivikko A, Norberg LA, Valovirta E, Wahn U, Möller C; (The PAT investigator group). Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study. Allergy. 2007 Aug;62(8):943-8..

Jutel M, A. L. Jaeger, R. Suck, H. Meyer, H. Fiebig, O. Cromwell. Allergen-specific immunotherapy with recombinant grass pollen allergens. J Allergy Clin Immunol. Sep;116(3):608–13.

L. Klimek, J. Uhlig, R. Mosges, K. Rettig, O. Pfaar. A high polymerized grass pollen extract is efficacious and safe in a randomized double-blind, placebo-controlled study using a novel up-dosing cluster-protocol. Allergy. 2014;Dec;69(12):1629–38.

Mosbech H, Canonica GW, Backer V, de Blay F, Klimek L, Broge L, et al. SQ house dust mite sublingually administered immunotherapy tablet (ALK) improves allergic rhinitis in patients with house dust mite allergic asthma and rhinitis symptoms. Ann Allergy Asthma Immunol 2015;114:134-40.

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Maloney J, Prenner BM, Bernstein DI, Lu S1, Gawchik S, Berman G, Kaur A, Li Z, Nolte H. Safety of house dust mite sublingual immunotherapy standardized quality tablet in children allergic to house dust mites. Ann Allergy Asthma Immunol. 2016 Jan;116(1):59-65. doi: 10.1016/j.anai.2015.10.024. Epub 2015 Nov 6.

Nolte, Hendrik et al. Efficacy of house dust mite sublingual immunotherapy tablet in North American adolescents and adults in a randomized, placebo-controlled trial. Journal of Allergy and Clinical Immunology , Volume 138 , Issue 6 , 1631 – 1638

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Powell RJ, Corrigan CJ, Durham SR, U. K. Immunotherapy Study Group. Efficacy and safety of specific immunotherapy with SQ allergen extract in treatment-resistant seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol. 2006 Feb;117(2):319–25.

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Scadding GW, Calderon MA, Shamji MH, Eifan AO, Penagos M, Dumitru F, Sever ML, Bahnson HT, Lawson K, Harris KM, Plough AG, Panza JL, Qin T, Lim N, Tchao NK, Togias A, Durham SR; Immune Tolerance Network GRASS Study Team. Effect of 2 Years of

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Treatment with Sublingual Grass Pollen Immunotherapy on Nasal Response to Allergen Challenge at 3 Years Among Patients with Moderate to Severe Seasonal Allergic Rhinitis: The GRASS Randomized Clinical Trial. JAMA. Feb.2017;14;317:615-625

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Alternative novel approaches for immunotherapy

Casale TB, Busse WW, Kline JN, Ballas ZK, Moss MH, Townley RG, Mokhtarani M, Seyfert-Margolis V, Asare A, Bateman K, Deniz Y; Immune Tolerance Network Group Omalizumab pretreatment decreases acute reactions after rush immunotherapy for ragweed-induced seasonal allergic rhinitis. J Allergy Clin Immunol. 2006;117:134-40.

Creticos PS1, Schroeder JT, Hamilton RG, Balcer-Whaley SL, Khattignavong AP, Lindblad R, Li H, Coffman R, Seyfert V, Eiden JJ, Broide D; Immune Tolerance Network Group. Immunotherapy with a ragweed-toll-like receptor 9 agonist vaccine for allergic rhinitis. N Engl J Med. 2006 Oct 5;355(14):1445-55.

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Drachenberg KJ, Heinzkill M, Urban E, Woroniecki SR. Efficacy and tolerability of short-term specific immunotherapy with pollen allergoids adjuvanted by monophosphoryl lipid A (MPL) for children and adolescents. Allergol Immunopathol (Madr). 2003;31(5):270-7.

Ellis AK, Frankish CW, O'Hehir RE, Armstrong K, Steacy L, Larché M, Hafner RP.Treatment with grass allergen peptides improves symptoms of grass pollen-induced allergic rhinoconjunctivitis. J Allergy Clin Immunol. 2017 Feb 15. pii: S0091-6749(17)30037-4. doi: 10.1016/j.jaci.2016.11.043.

Jutel M, Jaeger L, Suck R, Meyer H, Fiebig H, Cromwell O. Allergen-specific immunotherapy with recombinant grass pollen allergens. J Allergy Clin Immunol 2005 ;116:608-13.

Larenas-Linnemann D, Wahn U, Kopp M. Use of omalizumab to improve desensitization safety in allergen immunotherapy. J Allergy Clin Immunol 2014; 133(3): 937-937.





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Pauli G, Larsen TH, Rak S, Horak F, Pastorello E, Valenta R, Purohit A, Arvidsson M, Kavina A, Schroeder JW, Mothes N, Spitzauer S, Montagut A, Galvain S, Melac M, André C, Poulsen LK, Malling HJ. Efficacy of recombinant birch pollen vaccine for the treatment of birch-allergic rhinoconjunctivitis.J Allergy Clin Immunol. 2008;122:951-60.

Pfaar O, Cazan D, Klimek L, Larenas-Linnemann D, Calderon MA (2012) Adjuvants for immunotherapy. Curr Opin Allergy Clin Immunol 12: 648-657

Rolinck-Werninghaus C, Hamelmann E, Keil T, Kulig M, Koetz K, Gerstner B, Kuehr J, Zielen S, Schauer U, Kamin W, Von Berg A, Hammermann J, Weinkauf B, Weidinger G, Stenglein S, Wahn U; The co-seasonal application of anti-IgE after preseasonal specific immunotherapy decreases ocular and nasal symptom scores and rescue medication use in grass pollen allergic children. Omalizumab Rhinitis Study Group. Allergy;2004;59:973-9.

Senti G, von Moos S, Tay F, Graf N, Sonderegger T, Johansen P, Kündig TM. Epicutaneous allergen-specific immunotherapy ameliorates grass pollen-induced rhinoconjunctivitis: A double-blind, placebo-controlled dose escalation study. J Allergy Clin Immunol. 2012;129:128-35.

Slovick A1, Douiri A2, Muir R3, Guerra A4, Tsioulos K4, Hay E4, Lam EP4, Kelly J5, Peacock JL2, Ying S4, Shamji MH6, Cousins DJ7, Durham SR6, Till SJ8 Intradermal grass pollen immunotherapy increases TH2 and IgE responses and worsens respiratory allergic symptoms. J Allergy Clin Immunol. 2016 Oct 20. pii: S0091-6749(16)31186-1. doi: 10.1016/j.jaci.2016.09.024.

Senti G, Crameri R, Kuster D, Johansen P, Martinez-Gomez JM, Graf N, Steiner M, Hothorn LA, Grönlund H, Tivig C, Zaleska A, Soyer O, van Hage M, Akdis CA, Akdis M, Rose H, Kündig TM. Intralymphatic immunotherapy for cat allergy induces tolerance after only 3 injections. J Allergy Clin Immunol. 2012;129:1290-6.

Spertini F, DellaCorte G, Kettner A, de Blay F, Jacobsen L, Jutel M, Worm M, Charlon V, Reymond C.Efficacy of 2 months of allergen-specific immunotherapy with Bet v 1-derived contiguous overlapping peptides in patients with allergic rhinoconjunctivitis: Results of a phase IIb study. J Allergy Clin Immunol. 2016 Jul;138(1):162-8. doi: 10.1016/j.jaci.2016.02.044. Epub 2016 May 6.

Witten M, Malling HJ, Blom L, Poulsen BC, Poulsen LK. Is intralymphatic immunotherapy ready for clinical use in patients with grass pollen allergy?J Allergy Clin Immunol. 2013;132:1248-1252.Intralymphatic immunotherapy for cat allergy induces tolerance after only 3 injections.

Zieglmayer P, Focke-Tejkl M, Schmutz R, Lemell P, Zieglmayer R, Weber M, Kiss R, Blatt K, Valent P, Stolz F, Huber H, Neubauer A, Knoll A, Horak F, Henning R, Valenta R. Mechanisms, safety and efficacy of a B cell epitope-based vaccine for immunotherapy of grass pollen allergy.EBioMedicine. 2016 Sep;11:43-57. doi: 10.1016/j.ebiom.2016.08.022.

Allergen factors that affect the efficacy of AIT

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IV. Shao J, Cui YX, Zheng YF, Peng HF, Zheng ZL, Chen JY, Li Q, Cao LF. Efficacy and safety of sublingual immunotherapy in children aged 3-13 years with allergic rhinitis. Am J Rhinol Allergy 2014; 28: 131-9.

Shaikh WA, Shaikh SW. A prospective study on the safety of sublingual immunotherapy in pregnancy. Allergy. 2012 Jun;67(6):741-3. doi: 10.1111/j.1398-9995.2012.02815.x. Epub 2012 Apr 5.

Slavin RG. Special considerations in treatment of allergic rhinitis in the elderly: role of intranasal corticosteroids. Allergy Asthma Proc. 2010;31(3):179–84.

How long

Ali I, Goksal K, Ozan B, Gulsen D. Long-term allergen-specific immunotherapy correlates with long-term allergen-specific immunological tolerance. Adv Ther. 2008 Jan;25(1):29-36.

Arroabarren E, Tabar AI, Echechipía S, Cambra K, García BE, Alvarez-Puebla MJ. Optimal duration of allergen immunotherapy in children with dust mite respiratory allergy. Pediatr Allergy Immunol. 2015 Feb;26(1):34-41.

Ariano R, Kroon AM, Augeri G, Canonica GW, Passalacqua G. Long-term treatment with allergoid immunotherapy with Parietaria. Clinical and immunologic effects in a randomized, controlled trial. Allergy. 1999 Apr;54(4):313-9.

Cools M, Van Bever HP, Weyler JJ, Stevens WJ. Long-term effects of specific immunotherapy, administered during childhood, in asthmatic patients allergic to either house-dust mite or to both house-dust mite and grass pollen. Allergy. 2000 Jan;55(1):69-73.

Cox L, Cohn JR. Duration of allergen immunotherapy in respiratory allergy: when is enough, enough? Ann Allergy Asthma Immunol. 2007 May;98(5):416-26.

Durham SR, Yang WH, Pedersen MR, Johansen N, Rak S. Sublingual immunotherapy with once-daily grass allergen tablets: a randomized controlled trial in seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol. 2006 Apr;117(4):802-9.

Ebner C, Kraft D, Ebner H. Booster immunotherapy (BIT). Allergy 1994; 49(1): 38-42.

Frati F , Dell’Albani I, Incorvaia C. Long-term efficacy of allergen immunotherapy: what do we expect? Immunotherapy. 2013 Feb;5(2):131-3.

Hedlin G, Heilborn H, Lilja G, Norrlind K, Pegelow KO, Schou C, Løwenstein H. Long-term follow-up of patients treated with a three-year course of cat or dog immunotherapy. J Allergy Clin Immunol. 1995 Dec;96(6 Pt 1):879-85.

Lin Z, Liu Q, Li T, Chen D, Chen D, Xu R. The effects of house dust mite sublingual immunotherapy in patients with allergic rhinitis according to duration. Int Forum Allergy Rhinol. 2016 Jan;6(1):82-7.

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https://www.ncbi.nlm.nih.gov/pubmed/?term=Hedlin%2520G%255BAuthor%255D&cauthor=true&cauthor_uid=8543744

https://www.ncbi.nlm.nih.gov/pubmed/?term=Heilborn%2520H%255BAuthor%255D&cauthor=true&cauthor_uid=8543744

https://www.ncbi.nlm.nih.gov/pubmed/?term=Lilja%2520G%255BAuthor%255D&cauthor=true&cauthor_uid=8543744

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https://www.ncbi.nlm.nih.gov/pubmed/?term=Lin%2520Z%255BAuthor%255D&cauthor=true&cauthor_uid=26575696

https://www.ncbi.nlm.nih.gov/pubmed/?term=Liu%2520Q%255BAuthor%255D&cauthor=true&cauthor_uid=26575696

https://www.ncbi.nlm.nih.gov/pubmed/?term=Li%2520T%255BAuthor%255D&cauthor=true&cauthor_uid=26575696

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https://www.ncbi.nlm.nih.gov/pubmed/?term=Chen%2520D%255BAuthor%255D&cauthor=true&cauthor_uid=26575696

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Marogna M, Spadolini I, Massolo A, Canonica GW, Passalacqua G. Long-lasting effects of sublingual immunotherapy according to its duration: a 15-year prospective study. J Allergy Clin Immunol 2010; 126(5): 969-75.

Meadows A, Kaambwa B, Novielli N, Huissoon A, Fry-Smith A, Meads C, Barton P, Dretzke J. A systematic review and economic evaluation of subcutaneous and sublingual allergen immunotherapy in adults and children with seasonal allergic rhinitis. Health Technol Assess. 2013 Jul;17(27):vi, xi-xiv, 1-322.

Naclerio RM, Proud D, Moylan B, et al. A double-blind study of the discontinuation of ragweed immunotherapy. J Allergy Clin Immunol 1997; 100:293-300.

Ott H, Sieber J, Brehler R, Fölster-Holst R, Kapp A, Klimek L, Pfaar O, Merk H. Efficacy of grass pollen sublingual immunotherapy for three consecutive seasons and after cessation of treatment: the ECRIT study. Allergy. 2009 Sep;64(9):1394-401.

Stelmach I, Sobocińska A, Majak P, Smejda K, Jerzyńska J, Stelmach W. Comparison of the long-term efficacy of 3- and 5-year house dust mite allergen immunotherapy. Ann Allergy Asthma Immunol. 2012 Oct;109(4):274-8.

Adverse events with AIT for allergic rhinoconjunctivitis

SCIT

Alvarez-Cuesta E, Bousquet J, Canonica GW, Durham SR, Malling HJ, Valovirta E. Standards for practical allergen-specific immunotherapy. Allergy 2006;61 Suppl 82:1–20.

Amin HS, Liss GM, Bernstein DI: Evaluation of near-fatal reactions to allergen immunotherapy injections. J Allergy Clin Immunol. 2006, 117: 169-175. 10.1016/j.jaci.2005.10.010.

Bernstein DI, Wanner M, Borish L, Liss GM: Twelve-year survey of fatal reactions to allergen injections and skin testing: 1990-2001. J Allergy Clin Immunol. 2004, 113: 1129-1136. 10.1016/j.jaci.2004.02.006.

Bernstein DI, JACI 2004; 113: 1129-36Cox L, Larenas-Linnemann D, Lockey RF, Passalacqua G. Speaking the same language: The World Allergy Organization Subcutaneous Immunotherapy Systemic Reaction Grading System. J Allergy Clin Immunol. 2010 Mar;125(3):569-74, 574.e1-574

Bernstein DI, Wanner M, Borish L, Liss GM, Immunotherapy Committee AaoAA, and Immunology: Twelve-year survey of fatal reactions to allergen injections and skin testing: 1990-2001. J Allergy Clin Immunol 2004; 113, 1129Burks AW, Calderon MA, Casale T et al. Update on allergy immunotherapy: American Academy of Allergy, Asthma & Immunology/European Academy of Allergy and Clinical Immunology/PRACTALL consensus report. J Allergy Clin Immunol 2013;131:1288–96.e3.

Calabria CW. Accelerated immunotherapy schedules. Curr Allergy Asthma Rep 2013;13:389–98.

Calabria CW, Cox L. Accelerated immunotherapy schedules and premedication. Immunol Allergy Clin North Am 2011;31:251–63, ix.

Cox L, Calderon M, Pfaar O. Subcutaneous allergen immunotherapy for allergic disease: examining efficacy, safety and cost-effectiveness of current and novel formulations. Immunotherapy 2012;4:601–16.

Cox L, Larenas-Linnemann D, Lockey RF, Passalacqua G. Speaking the same language: The World Allergy Organization subcutaneous immunotherapy systemic reaction grading system. J Allergy Clin Immunol 2010;125:569–74,574.e1–574.e7.

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https://www.ncbi.nlm.nih.gov/pubmed/?term=Fry-Smith%2520A%255BAuthor%255D&cauthor=true&cauthor_uid=23827204

https://www.ncbi.nlm.nih.gov/pubmed/?term=Meads%2520C%255BAuthor%255D&cauthor=true&cauthor_uid=23827204

https://www.ncbi.nlm.nih.gov/pubmed/?term=Barton%2520P%255BAuthor%255D&cauthor=true&cauthor_uid=23827204

https://www.ncbi.nlm.nih.gov/pubmed/?term=Dretzke%2520J%255BAuthor%255D&cauthor=true&cauthor_uid=23827204

https://www.ncbi.nlm.nih.gov/pubmed/?term=Dretzke%2520J%255BAuthor%255D&cauthor=true&cauthor_uid=23827204


https://www.ncbi.nlm.nih.gov/pubmed/?term=Ott%2520H%255BAuthor%255D&cauthor=true&cauthor_uid=19764942

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Epstein TG, Liss GM, Murphy-Berendts K, Bernstein DI. Risk factors for fatal and nonfatal reactions to subcutaneous immunotherapy: National surveillance study on allergen immunotherapy (2008-2013). Ann Allergy Asthma Immunol 2016; 116: 354-359.e2.

T.G. Epstein, G.M. Liss, K. Murphy-Berendts, D.I. Bernstein. Immediate and delayed-onset systemic reactions after subcutaneous immunotherapy injections: ACAAI/AAAAI surveillance study of subcutaneous immunotherapy: year 2. Ann Allergy Asthma Immunol, 107 (2011), pp. 426–431.e1

Epstein TG, Liss GM, Murphy-Berendts K, Bernstein DI. AAAAI and ACAAI surveillance study of subcutaneous immunotherapy, year 3: what practices modify the risk of systemic reactions? Ann Allergy Asthma Immunol 2013;110:274–8, 278.e1.

-36.

Frost L, Johansen P, Pedersen S, Veien N, Ostergaard PA, Nielsen MH. Persistent subcutaneous nodules in children hyposensitized with aluminium-containing allergen extracts. Allergy 1985;40:368–72.

Kelso JM. The rate of systemic reactions to immunotherapy injections is the same whether or not the dose is reduced after a local reaction. Ann Allergy Asthma Immunol 2004;92:225–7.

Lockey RF et. Al, Ann Allergy Asthma Immunol 2001; 87: 47-77

Malling HJ. Minimising the risks of allergen-specific injection immunotherapy. Drug Saf 2000;23:323–32.

Netterlid E, Hindsén M, Björk J et al. There is an association between contact allergy to aluminium and persistent subcutaneous nodules in children undergoing hyposensitization therapy. Contact Dermatitis 2009;60:41–9.

Nielsen L, Johnsen CR, Mosbech H, Poulsen LK, Malling HJ. Antihistamine premedication in specific cluster immunotherapy: a double-blind, placebo-controlled study. J Allergy Clin Immunol 1996;97:1207–13.

Passalacqua G, Baena-Cagnani CE, Bousquet J, Canonica GW, Casale TB, Cox L, Durham SR, Larenas-Linnemann D, Ledford D, Pawankar R, Potter P, Rosario N, Wallace D, Lockey RF.Grading local side effects of sublingual immunotherapy for respiratory allergy: speaking the same language. J Allergy Clin Immunol. 2013 Jul;132(1):93-8

Pfaar O, Bachert C, Bufe A, Buhl R, Ebner C, Eng P, et al. Guideline on allergen-specific immunotherapy in IgE-mediated allergic diseases: S2k Guideline of the German Society for Allergology and Clinical Immunology (DGAKI), the Society for Pediatric Allergy and Environmental Medicine (GPA), the Medical Association of German Allergologists (AeDA), the Austrian Society for Allergy and Immunology (ÖGAI), the Swiss Society for Allergy and Immunology (SGAI), the German Society of Dermatology (DDG), the German Society of Oto- Rhino-Laryngology, Head and Neck Surgery (DGHNO-KHC), the German Society of Pediatrics and Adolescent Medicine (DGKJ), the Society for Pediatric Pneumology (GPP), the German Respiratory Society (DGP), the German Association of ENT Surgeons (BV-HNO), the Professional Federation of Paediatricians and Youth Doctors (BVKJ), the Federal Association of Pulmonologists (BDP) and the German Dermatologists Association (BVDD). Allergo J Int. 2014;23(8):282-319.

Ragusa FV, Passalacqua G, Gambardella R et al. Nonfatal systemic reactions to subcutaneous immunotherapy: a 10-year experience. J Investig Allergol Clin Immunol 1997;7:151–4.

Reimers A, Hari Y, Müller U. Reduction of side-effects from ultrarush immunotherapy with honeybee venom by pretreatment with fexofenadine: a double-blind, placebo-controlled trial. Allergy 2000;55:484–8.


Vogelbruch M, Nuss B, Körner M, Kapp A, Kiehl P, Bohm W. Aluminium-induced granulomas after inaccurate intradermal hyposensitization injections of aluminium-adsorbed depot preparations. Allergy 2000;55:883–7.

Wedi B, Rueff F. [Pharmacoprophylaxis and co-medications in allergen-specific immunotherapy]. Hautarzt 2011; 62:663–70.

SLIT

Alvarez-Cuesta E, Bousquet J, Canonica GW, Durham SR, Malling HJ, Valovirta E. Standards for practical allergen- specific immunotherapy. Allergy 2006;61 Suppl 82:1–20.

Blaiss M1, Maloney J, Nolte H, Gawchik S, Yao R, Skoner DP.Efficacy and safety of timothy grass allergy immunotherapy tablets in North American children and adolescents. J Allergy Clin Immunol. 2011 Jan;127(1):64-71, 71.e1-4. doi: 10.1016/j.jaci.2010.11.034.

Canonica GW, Cox L, Pawankar R et al. Sublingual immunotherapy: World Allergy Organization position paper 2013 update. The World Allergy Organization journal 2014;7:6.

Cox LS, Larenas Linnemann D, Nolte H, Weldon D, Finegold I, Nelson HS. Sublingual immunotherapy: a comprehensive review. J Allergy Clin Immunol 2006;117:1021–35.

Calderon MA, Simons FE, Malling HJ, Lockey RF, Moingeon P, Demoly P. Sublingual allergen immunotherapy: mode of action and its relationship with the safety profile. Allergy 2012;67:302–11.

M.A. Calderón, F.E.R. Simons, H.-J. Malling, R.F. Lockey, P. Moingeon, P. Demoly. Sublingual allergen immunotherapy: mode of action and its relationship with the safety profile. Allergy, 67 (2012), pp. 302–311

Calderón MA, Larenas D, Kleine-Tebbe J, Jacobsen L, Passalacqua G, Eng PA, Varga EM, Valovirta E, Moreno C, Malling HJ, Alvarez-Cuesta E, Durham S, Demoly P. Allergy. 2011 Oct;66(10):1345-59. doi: 10.1111/j.1398-9995.2011.02669.x. Epub 2011 Jun 28.

Cox LS, Larenas Linnemann D, Nolte H, Weldon D, Finegold I, Nelson HS: Sublingual immunotherapy: a comprehensive review. J Allergy Clin Immunol. 2006, 117: 1021-1035. 10.1016/j.jaci.2006.02.040.

Dahl R1, Kapp A, Colombo G, de Monchy JG, Rak S, Emminger W, Rivas MF, Ribel M, Durham SR Efficacy and safety of sublingual immunotherapy with grass allergen tablets for seasonal allergic rhinoconjunctivitis.J Allergy Clin Immunol. 2006 Aug;118(2):434-40.

Didier A1, Malling HJ, Worm M, Horak F, Jäger S, Montagut A, André C, de Beaumont O, Melac M. Optimal dose, efficacy, and safety of once-daily sublingual immunotherapy with a 5-grass pollen tablet for seasonal allergic rhinitis. J Allergy Clin Immunol. 2007 Dec;120(6):1338-45. Epub 2007 Nov 1.

Epstein TG1, Liss GM2, Murphy-Berendts K3, Bernstein DI4. Risk factors for fatal and nonfatal reactions to subcutaneous immunotherapy: National surveillance study on allergen immunotherapy (2008-2013). Ann Allergy Asthma Immunol. 2016 Apr;116(4):354-359.e2. doi: 10.1016/j.anai.2016.02.001. Epub 2016 Mar 3.

European Academy of Allergy and Clinical Immunology task force report on 'dose-response relationship in allergen-specific immunotherapy'.

Lüderitz-Püchel U, Keller-Stanislawski B, Haustein D. [Risk reevaluation of diagnostic and therapeutic allergen extracts. An analysis of adverse drug reactions from 1991 to 2000]. Bundesgesundheitsbl Gesundheitsforsch Gesundheitsschutz 2001;44:709–18.

Mosbech H1, Deckelmann R2, de Blay F3, Pastorello EA4, Trebas-Pietras E5, Andres LP6, Malcus I7, Ljørring C8, Canonica GW9Standardized quality (SQ) house dust mite sublingual immunotherapy tablet (ALK) reduces inhaled corticosteroid use while maintaining asthma


control: a randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol. 2014 Sep;134(3):568-575.e7. doi: 10.1016/j.jaci.2014.03.019. Epub 2014 May 3.

Passalacqua G, Garelli V, Sclifo F, Canonica GW. Sublingual immunotherapy for allergic rhinitis and conjunctivitis. Immunotherapy 2013;5:257–64Radulovic S, Calderon MA, Wilson D, Durham S. Sublingual immunotherapy for allergic rhinitis. Cochrane Database Syst Rev 2010;(12):CD002893.

Passalacqua G, Baena-Cagnani CE, Bousquet J et al. Grading local side effects of sublingual immunotherapy for respiratory allergy: speaking the same language. J Allergy Clin Immunol 2013;132:93–8.

Wahn U1, Tabar A, Kuna P, Halken S, Montagut A, de Beaumont O, Le Gall M; SLIT Study Group. Efficacy and safety of 5-grass-pollen sublingual immunotherapy tablets in pediatric allergic rhinoconjunctivitis. J Allergy Clin Immunol. 2009 Jan;123(1):160-166.e3. doi: 10.1016/j.jaci.2008.10.009. Epub 2008 Nov 29.

Adherence

Egert-Schmidt AM, Kolbe JM, Mussler S, Thum-Oltmer S. Patients' compliance with different administration routes for allergen immunotherapy in Germany. Patient Prefer Adherence. 2014 Oct 24;8:1475-81.

Incorvaria—Incorvaia C, Masieri S, Berto P, Scurati S, Frati F. Specific immunotherapy by the sublingual route for respiratory allergy. Allergy Asthma Clin Immunol. 2010 Nov 9;6(1):29.

Leader BA, Rotella M, Stillman L, DelGaudio JM, Patel ZM, Wise SK. Immunotherapy compliance: comparison of subcutaneous versus sublingual immunotherapy. Int Forum Allergy Rhinol. 2016 May; 6(5):460-4.

Makatsori M, Scadding GW, Lombardo C, Bisoffi G, Ridolo E, Durham SR, Senna G. Dropouts in sublingual allergen immunotherapy trials – a systematic review. Allergy 2014; 69: 571–580.

Pascal Demoly, Giovanni Passalacqua, Oliver Pfaar, Joaquin Sastre, Ulrich Wahn. Patient engagement and patient support programs in allergy immunotherapy: a call to action for improving long-term adherence. Allergy Asthma Clin Immunol 2016; 12: 34.

Savi E, Peveri S, Senna G, Passalacqua G. Causes of SLIT discontinuation and strategies to improve the adherence: a pragmatic approach. Allergy. 2013 Sep;68(9):1193-5.

Scurati S, Frati F, Passalacqua G, Puccinelli P, Hilaire C, Incorvaia C; Italian Study Group on SLIT Compliance.. Adherence issues related to sublingual immunotherapy as perceived by allergists. Patient Prefer Adherence. 2010 Jun 24;4:141-5.-

Sondermann N, Shah-Hosseini K, Henkel K, Schwalfenberg A, Mösges R. [Factors of success for adherence in hyposensitization]. Allergologie 2011;34:441–6

Vaswani R, Garg A, Parikh L, Vaswani S. Non-adherence to subcutaneous allergen immunotherapy: inadequate health insurance coverage is the leading cause. Ann Allergy Asthma Immunol. 2015 Sep;115(3):241-3.

Pharmacoeconomic advantage of AIT versus pharmacotherapy

Ariano R, Berto P, Tracci D, et al. Pharmacoeconomics of allergen immunotherapy compared with symptomatic drug treatment in patients with allergic rhinitis and asthma. Allergy Asthma Proc 2006; 27:159–163

Ariano R, Berto P, Tracci D, Incorvaia C, Frati F. Pharmacoeconomics of allergen immunotherapy compared with symptomatic drug treatment in patients with allergic rhinitis and asthma. Allergy Asthma Proc 2006;27:159-63.


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Gaps

Pfaar O, Demoly P, Gerth van Wijk R, Bonini S, Bousquet J, et al. (2014) Recommendations for the

standardization of clinical outcomes used in allergen immunotherapy trials for allergic

rhinoconjunctivitis: an EAACI Position Paper. Allergy 69: 854-867.

Shamji MH, Kappen JH, Akdis M, Jensen-Jarolim E, Knol EF, et al. (2017) Biomarkers for monitoring

clinical efficacy of allergen immunotherapy for allergic rhinoconjunctivitis and allergic asthma: an EAACI

Position Paper. Allergy (Pfaar


Online supplement

Homologous allergen groups Reproduced from Table SA. From Demoly P 2016


Grading systems for adverse reactions We intended to use the WAO approach to grading adverse reactions. This proved impossible

as different authors have used different approaches to classifying these. This means that it is

difficult to synthesis the safety data and represents a gap.

Table SB


Pfaar et al., Allergo J Int., 2014

Table SC

Pfaar et al., Allergo J Int., 2014

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