EAACI Guidelines on Allergen Immunotherapy: Allergic rhinoconjunctivitis

2.1 Clarifying the scope and purpose of the guidelines

The scope of this EAACI Guideline is multifaceted, providing statements that assist clinicians in the optimal use of AIT in the management of patients with AR and identifying gaps for further research.

2.2 Ensuring appropriate stakeholder involvement

Members of the EAACI Taskforce on AIT for AR represented a range of 18 countries and disciplinary and clinical backgrounds, including allergists (specialist and subspecialists), pediatricians, primary care specialists, ophthalmologists, otolaryngologists, pharmacists, immunologists, nurses, and patient representatives. Methodologists took the lead in undertaking the underpinning SR, while clinical academics took the lead in formulating recommendations for clinical care. Representatives of immunotherapy product manufactures were given the opportunity to review and comment on the draft guidelines as part of the peer review and public comment process at the final stage. These comments were considered by Taskforce members, and, where appropriate, revisions were made.

2.3 Systematic reviews of the evidence

The initial full range of clinical questions that were considered important was rationalized through several rounds of iteration to agree on 1 key question: What are the effectiveness, cost-effectiveness, and safety of AIT in patients with AR? This was then pursued through a formal SR of the evidence by independent methodologists as previously published14, 19; only double-blind RCTs were included in the effectiveness analyses. We continued to track evidence published after our SR cutoff date of October 31, 2015, and, where relevant, studies were considered by the Taskforce chairs. This evidence will formally be considered in the systematic review update that will precede the update of this Guideline (discussed below).

2.4 Formulating recommendations

We graded the strength and consistency of key findings from the SR and performed meta-analyses, using a random-effects model to take into account the heterogeneity of findings.14 These were used to formulate evidence-based recommendations for clinical care20 (Box 2). This involved formulating clear recommendations with the strength of evidence underpinning each recommendation. Where the systematic review did not cover the clinical area, we took a hierarchical approach reviewing other evidence until we could formulate a recommendation, that is: (i) other systematic reviews on the subject to see whether these provided any clarity on the topic; (ii) RCTs within these systematic reviews; (iii) other RCTs known to Taskforce members; and (iv) a consensus-based approach within the Taskforce. This evidence was graded as described in Box 2 using the SR results14 and clearly labeled in the recommendation tables. Recommendations apply to all ages unless otherwise indicated in the tables. When there were insufficient pediatric data, we extrapolated from the adult recommendation where it was biologically likely that the intervention would also be effective in children, but downgraded the recommendation by at least 1 level. Taskforce members identified the resource implications of implementing the recommendations, barriers, and facilitators to the implementation of each recommendation, advised on approaches to implementing the recommendations, and suggested audit criteria that can help with assessing organizational compliance with each recommendation.

2.5 Peer review and public comment

A draft of these guidelines was externally peer-reviewed by invited experts from a range of organizations, countries, and professional backgrounds. Additionally, the draft guideline was made available on public domain on the EAACI Web site for a 3-week period in May 2017 to allow a broader array of stakeholders to comment. All feedback was considered by the Taskforce members and, where appropriate, final revisions were made in light of the feedback received. We will be pleased to continue to receive feedback on this guideline, which should be addressed to the corresponding author.

2.6 Identification of evidence gaps

The process of developing this Guideline has identified a number of evidence gaps which are prioritized (Table 10).

2.7 Editorial independence and managing conflict of interests

This Guideline was funded and supported by EAACI. The funder did not have any influence on the guideline production process, on its contents or on the decision to publish. Taskforce members’ conflicts of interest were declared at the start of the process and taken into account by the taskforce chairs as recommendations were formulated. Final decisions about strength of evidence for recommendations were checked by the methodologists who had no conflict of interests in this area.

2.8 Updating the guidelines

European Academy of Allergy and Clinical Immunology plans to update this guideline in 2022 unless there are important advances before then.

3.1 General considerations

Allergen immunotherapy is only indicated in the presence of symptoms strongly suggestive of AR, with or without conjunctivitis (Table 1).8, 14, 21 Many patients will also have co-existing asthma. There should be symptoms on aeroallergen exposure with evidence of allergen-specific IgE sensitization (positive SPT or serum-specific IgE).14 Identification of the allergen(s) driving symptoms is the first level of patient stratification ensuring that the correct allergen solution is used for AIT. Occasionally, SPT or specific IgE results may not clearly identify the key allergen(s) causing the AR symptoms in polysensitized patients. Component resolved diagnostics may have a role in deciding which aeroallergen(s) should be chosen but definitive trials are awaited. An alternative approach is to use nasal or conjunctival provocation testing to prove the clinical relevance of the allergic sensitization in the relevant (target) organs before initiation of AIT but again definitive evidence is awaited.

Allergen immunotherapy is indicated in those patients with moderate-to-severe symptoms (e.g, Allergic Rhinitis and its Impact on Asthma (ARIA) categories moderate-to-severe intermittent or persistent22), despite avoidance measures and pharmacotherapy, that interfere with their usual daily activities or sleep. AIT may also be considered in cases with less severe AR where the patient wishes to have the benefit of its long-term effect on rhinitis and a potential disease-modifying effect to prevent asthma.23 AIT products with evidence of efficacy for AR should be used when available.11, 24

3.2 Absolute and relative contraindications

Even when AIT is suitable for a patient with AR, clinicians must consider whether there are any specific patient-related absolute or relative contraindications (Table 2), where the risk from AIT may outweigh the expected benefits. The summary of product characteristics (SmPC) should be reviewed for specific contraindications for individual preparations.

4.1 Other approaches of AIT for AR

Other approaches aim to improve patient convenience and adherence with shorter courses, while improving or maintaining efficacy and reducing the risk of systemic side-effects (Table 4). As such, adjuvants to AIT extracts are possible candidates.112 For example, TLR-4 agonists (Th1-inducing adjuvant monophosphoryl lipid A) in combination with a grass allergoid have demonstrated effectiveness,113 although in a phase 3 trial, efficacy was modest114 (Grade A for adults, B for children) and there are no head-to-head comparisons with conventional preparations. There is also 1 trial demonstrating efficacy for this approach with ragweed pollen172 and one with tree pollen.95 The TLR-9 agonist (Bacterial DNA oligonucleotides containing a CpG motif) fused to Amb a 1, the major allergen of ragweed showed efficacy in a phase 2 trial115 although this was not observed in a subsequent phase 3 trial. The combination of anti-IgE injections with conventional and rush AIT with nonmodified extracts has been proven to be effective with a marked reduction in systemic side-effects in studies of children116 and adults117 (Grade A recommendation). This is an expensive approach, and there is concern as to when and how to discontinue the anti-IgE when AIT maintenance therapy is achieved.118

Recombinant AIT is attractive as it allows accurate standardization of allergen products, has potential for personalized therapy based on individual allergen sensitivities and a hypothetical lower risk of inducing new sensitizations. Subcutaneous recombinant birch (Bet v 1)119 and a five-recombinant grass allergen mix75 have been shown to be efficacious with no safety concerns (Grade A for adults, B for children). However, there are no commercially products available at present. A recombinant B-cell epitope-based vaccine, comprising a recombinant hybrid grass allergen mix combined with a hepatitis B domain surface Pre-S protein as an immunologic carrier has shown efficacy in a phase 2 trial.120 T-cell peptide immunotherapy for cat allergy using mixtures of short T-cell epitopes via the intradermal route had promising results in environmental chamber phase 2 studies121; however, it has been reported that a subsequent phase 3 study did not demonstrate effectiveness.122 Studies with other allergen peptide approaches are in progress.124

There has been recent interest in the use of alternative modalities of delivery including the epicutaneous, intradermal and intralymphatic routes. In RCTs, epicutaneous grass pollen immunotherapy (EPIT) has shown modest benefit125 although accompanied by local eczematous reactions at the patch application site. Intradermal grass pollen immunotherapy inhibited allergen-induced cutaneous late responses although in a subsequent RCT, it was ineffective and there was evidence of exacerbation of seasonal outcomes and Th2 inflammation in the skin.126 The intralymphatic route, using a grass pollen extract and a modified cat allergen extract, showed efficacy in some trials127, 128 but not in others.129

5.1 Standardization of allergen extracts

For the common allergens, many companies now provide characterized, standardized, stable preparation for AIT as recommended by EMA.47, 132 For others, such as molds, there are problems with the complexity, variability, and stability of the allergens.133 The lack of standardized extracts may hamper the diagnosis of eligible patients for AIT and may impede the effectiveness of AIT.133, 134 Additionally, nonstandardized preparations may vary between batches increasing the potential for side-effects. Further purification and characterization of such allergens134-136 may result in better extracts for the future. Where possible, standardized allergen products should be used for AIT. Further discussion is available in a position paper on regulatory aspects of AIT.47

5.2 Formulation of SLIT preparations

In deciding on the appropriate preparation to use for AIT, the formulation should be taken into account. For example, 3 large studies have shown efficacy for HDM SLIT tablets,52-54 whereas 3 HDM SLIT studies with sublingual drops were negative,107, 140, 146 and another only demonstrated efficacy in the first and not the second year.50 However, many factors such as differences in allergen content,141 administered volume, number of participants, and statistical power of the study may explain the differences between tablets and drop trials. We recommend that AIT products with evidence of efficacy in the clinical documentation should be used when they are available.

5.3 Allergen mixtures

Both mixtures of grass pollen and mixtures of tree pollen are frequently used in AIT and such an approach is effective.14 The use of different, nontaxonomically related allergens mixed in 1 AIT product has been evaluated in a very limited number of studies. One SCIT study showed that a depigmented-polymerized mixed grass/birch pollen extract was effective over placebo.142 A small study in children demonstrated efficacy using a mixture of grass pollen and HDM SLIT.143 SLIT drops that employed a monomeric Phleum pratense grass pollen extract was more effective when given alone compared to when given in an equivalent dose as part of a combination with a 9-pollen, multi-allergen, sublingual extract.100

There are a number of potential drawbacks of mixing allergens including a dilutional effect, potential allergen degradation due to enzymatic activity of some allergens and the difficulties of adequately demonstrating efficacy of a high number of allergen combinations and/or different products. The EMA has recommended that only homologous allergens (usually ones that are taxonomically related132, for example, a mixture of grass pollen extracts56) should be mixed and that allergens with enzymatic activity (e.g, HDM) should be never used in a mixture. We therefore recommend only homologous allergens to be mixed in AIT preparations until further evidence is available substantiating the efficacy of other mixtures (Grade A) (Table 5) (Table S1). Alternatively, extracts should be given separately.

5.4 Specific allergens

In the recent meta-analysis, there were sufficient SCIT and SLIT studies for subgroup analyses by specific allergens.14 Short-term effectiveness was demonstrated for HDM (symptoms score SMD −0.73; 95% CI −1.37, −0.10), grass pollen (−0.45; −0.54, −0.36), tree pollen (−0.57; −0.92, −0.21), and weed pollen (−0.68; −1.06, −0.30). However, there was substantial heterogeneity for all allergens, particularly molds (−0.56; −2.29, 1.18), suggesting that different preparations may be more or less effective. Before a product is used, an individual product-based evaluation of the evidence for efficacy is recommended.

There are some orphan allergens where robust data from RCTs are sparse or nonexistent. Where there is a clinical need, the available evidence of efficacy and safety needs to be weighed against the needs of the individual patient. Where therapy is considered in the patient's best interest, an early evaluation of its impact on the patient's clinical symptoms is required to determine whether or not therapy should be continued. The generation of controlled clinical trial data to assess efficacy and safety of these orphan products should be encouraged. There will always be orphan allergens where such studies are uneconomic and have to be regulated as named patient products.47

6.1 Polysensitized patients

Epidemiological data indicate that most patients with AR are polysensitized.148 Consequently, consideration needs to be given as to whether patients are (i) clinically monoallergic (where only 1 allergen is driving symptoms) and polysensitized or (ii) poly-allergic (symptoms with overlapping exposure to multiple different allergens) and polysensitized. Immunotherapy with a single allergen extract is effective in the first,149 while immunotherapy has been shown to be ineffective150 or less effective in the last situation.151 This may be apparent from the history or may need investigation with component-resolved diagnostics or assessment with nasal or conjunctival provocation challenges where the clinician is experienced in these diagnostic procedures.137 Polysensitized patients who are monoallergic are recommended to receive AIT for the specific allergen that is driving their AR symptoms (Grade A).

For a polysensitized patient who is poly-allergic for homologous (biologically related) allergens (e.g, 2 grass pollens), a single allergen preparation or a mixture of 2 homologous allergens is recommended (Grade B).137 For poly-allergic patients where allergens are not homologous, separate AIT preparations for 1 or 2 of the clinically most important allergens might be recommended with doses given 30-60 minutes apart at separate locations when 2 are selected (Grade C).32, 137 This represents a trade-off between efficacy and safety as both seem to be dose-dependent. More studies are needed to further address this important clinical challenge.

6.2 Co-existing asthma

Co-existing asthma is seen in many participants in the published AR AIT studies.14 Co-existing asthma has no impact on the efficacy of AIT for AR103 and may also lead to improvement in asthma.43 When controlled, mild-to-moderate asthma does not seem to be a safety issue with AIT (Grade A recommendation).41, 43 In 1 large recent asthma SLIT trial, participants with not well-controlled asthma based on an Asthma Control Questionnaire (ACQ-6) were included safely in the study.41 We await confirmatory evidence and emphasize that efforts should be taken to control asthma before commencing AIT. Uncontrolled or severe asthma are definitely considered to be an absolute contraindication to AIT.25-31

6.3 Specific pediatric issues

Similar to adults, AIT should be considered in pediatric patients with AR with evidence of IgE sensitization to clinically relevant allergens (Grade A) (Tables 1 and 3).

The evidence for the efficacy of AIT for AR is limited in children younger than 5 years of age. Some clinical studies have shown the efficacy and safety of both SCIT and SLIT in preschool children,88, 152-155 and children were included from 5 years onward in several of the well-powered SLIT tablet trials.98, 156 Experience suggests that repeated injections of SCIT may be stressful in preschool children. It is recommended that the decision to start the treatment has to be taken on a case-by-case basis together with the patients and their family (Grade D). The decision should depend on several factors, such as the severity of the allergic disease, the clear exposure-symptoms pattern supported by allergic sensitization 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 only a few children and/or did not present pediatric only analyses. Continuous and pre- and pre/coseasonal 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 grade due to the lack of exclusive pediatric data (Grade C) (Table 3). There are no exclusive pediatric, placebo-controlled data for allergoid preparations, but 1 controlled trial with a preseasonal treatment regimen has indicated long-term efficacy of preseasonal grass pollen immunotherapy in this age group.157 Two further open RCTs also suggest that SCIT for grass pollen-driven AR does have a long-term benefit.63, 158

For SLIT, there are more recent pediatric trial data to support this approach. In general, pre-/coseasonal and continuous SLIT is recommended for seasonal AR (Grade A) (Table 3). Both tablet and aqueous formulations are recommended (Grade A) (Table 3). There is now one recently published trial supporting the long-term effectiveness for a grass pollen tablet and reduction in asthma symptoms110, 111 (Grade A). For perennial allergic rhinitis, the evidence is not as good. There are no consistent data to recommend SLIT with aqueous solutions for perennial allergic rhinitis, but the SLIT tablet approach has been demonstrated to be effective in the short term in mixed adult/adolescent studies51, 55(grade A).

6.4 Elderly

A detailed allergy history is especially important when evaluating older adults suffering with rhinitis as other types of rhinitis may mimic AR symptoms. There are very few studies specifically evaluating the use of AIT in the elderly (defined here as >65 years as this is usually exclusion criteria in AIT trials) but SLIT with grass pollen and HDM has been demonstrated to be effective and safe in 2 studies.159, 175 AIT elicits clinical responses comparable to studies with younger patients. Another important consideration in this age group, when contemplating treatment with AIT, is the higher prevalence of comorbidities. Examples are hypertension, coronary artery disease, cerebrovascular disease, malignancy and/or cardiac arrhythmias. Also, treatment with medication such as beta-blockers may impair the treatment of anaphylaxis with adrenaline (epinephrine) (see Table 2). AIT can be recommended in otherwise healthy elderly patients with AR whose symptoms cannot be adequately controlled by pharmacotherapy (Grade A for SLIT, B for SCIT).

6.5 Pregnancy

There is 1 prospective study investigating the safety of AIT in pregnancy161 and several retrospective studies that suggest that there is no greater risk of prematurity, fetal abnormality, or other adverse pregnancy outcome in women who receive AIT during pregnancy.39 Observations about anaphylaxis in pregnant and breastfeeding women are largely derived from case reports and are generally reassuring.162 However, the balance between benefits and potential risks in pregnant patients needs to be discussed with the patient. 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 (Grade D) but, if already initiated, AIT may be continued during pregnancy or breastfeeding in agreement with the patient's general practitioner (GP) and obstetrician if former AIT treatment has previously been tolerated well (Grade C).

6.6 Adherence

There is a great variance between studies (both real-life studies and clinical trials) in the criteria used for evaluating adherence and in the rates of adherence.163-169 The range of reported adherence varied from 18% to over 90%, higher in clinical studies than real-life surveys with overlapping ranges for SCIT and SLIT. The main causes for poor adherence are reported to be side-effects, inconvenience, lack of efficacy or forgetting to use.163-165, 167, 168, 170 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, short message service (SMS) electronic reminders, social networks, mobile applications (apps), and monitoring systems—this approach should be tailored to the patient (Grade C). Patient education and good communication between physician and patient are key (Grade C).169 One randomized study suggests that adherence is much better with 3-monthly follow-up appointments compared to 6 or 12-monthly follow-up (Grade B).171 Recommendations are summarized in Table 6.

8.1 SCIT

Subcutaneous immunotherapy is a safe and well-tolerated treatment when the injections are given in a medical setting by experienced personnel trained in the early recognition of systemic reactions and how to manage them (Table 8).11, 180-182 There must be immediate access to resuscitation equipment and a physician trained in the management of anaphylaxis (Grade C).

Systemic allergic adverse reactions to SCIT can range between mild-to-severe adverse reactions of the skin, upper and lower airways, gastrointestinal tract, or the cardiovascular system (see Table S2 in online supplement for details of classification).123 In a 3-year real-life US survey study that included over 20 million injection visits, systemic reactions were reported in 0.1% of injections; there were no fatalities182 although 4 were reported in a follow-up survey by the same group.183 Fatal allergic adverse reactions have though been reported in earlier surveys.30, 31 Over 80% of reactions occurred within 30 minutes after injection; very few of the delayed ones were severe. It is therefore recommended that patients stay in clinic for at least 30 minutes after an injection (Grade C).

A European real-life, prospective, survey performed by members of the Immunotherapy Interest Group of EAACI on 4316 patients in France, Germany, and Spain was published after our SR was completed.184, 185 It demonstrated that SCIT and SLIT for respiratory allergy are safe in general in the pediatric and adult population and found only a low number of systematic reactions (SRs). For SCIT, SRs were found in 2.1% of all SCIT-treated patients. Independent risk factors for SRs during SCIT were the use of natural extracts, the absence of symptomatic allergy medications, asthma diagnosis, sensitization to animal dander or pollen, cluster regimens (vs rush), and a previous episode of anaphylaxis. Further possible risk factors for systemic adverse reactions have been described (Box 311). When 1 or more severe adverse reactions occur, the allergist (specialist and subspecialists) should re-evaluate the benefits and risks of SCIT therapy with the patient and decide whether or not treatment should be continued (Grade D). In any case, cessation of treatment or adaptation of the dosing schemes for the next injection should follow the summary of product characteristics (SmPC).

Redness, itching, or swelling represents local reactions at the injection site and occurs frequently after around half of injections.14 Local measures (e.g, cooling or topical glucocorticoids) or oral antihistamines may be helpful for these reactions. Increased local adverse reactions do not predict an increased individual risk of a systemic adverse reaction.186 In case of enlarged local adverse reactions (redness and/or swelling >10 cm in diameter) occur at the injection site, the SmPC provides adaptation of the dosing schemes for the next injection. When local adverse effects occur, premedication with an H1-antihistamine can be used to reduce the frequency and severity of adverse reactions (Grade A recommendation), but this prophylactic treatment does not prevent the onset of SRs or anaphylaxis.187, 188 Also, studies indicate that modified allergen extracts are associated with less adverse effects.189-192 For aluminum hydroxide containing SCIT products, granulomas have been described from a foreign body reaction mainly caused by incorrect intradermal administration as well as contact allergic reactions, new onset of protein contact dermatitis, or a vasculitis inflammatory reactions have been reported.193-195 If these reactions to SCIT occur, treatment with another aluminum hydroxide-free product is preferred (Grade D).11

8.2 SLIT

Sublingual immunotherapy is regarded to be a safe and well-tolerated treatment (Table 8).11, 14, 196-198

Severe SRs with SLIT appear to be much less likely than with SCIT although the overall rate of any adverse reactions is similar in both SCIT and SLIT14, 184 (see Tables S2 and S3 in online supplement for details of classification123, 199). In a review of 66 SLIT studies (over 4000 patients who received over a million doses), there was 1 SR for approximately every 4 years of treatment and only 1 severe SR per 384 treatment years.198 There are no new safety concerns in more recent studies.14 Several severe reactions—in some cases with anaphylaxis—are described in the literature occurring within 30 minutes of sublingual administration of allergens in droplet or tablet form.34 In these cases, SLIT was not administered according to the standards (nonstandardized extracts, rush protocols, excessive allergen dose, patients in whom SCIT had previously been interrupted due to severe reactions). Patients should be observed for at least 30 minutes after the first dose (Grade C) and supervised by staff able to manage anaphylaxis (Grade C). As in SCIT, concomitant, uncontrolled asthma has been reported to be associated with severe systemic reactions after SLIT.34 In the recently published European Survey, the rate of SRs under SLIT was also reported to be low (1.1% of all SLIT-treated patients).184, 185

The majority of adverse events in SLIT develop at home without any medical observations. Patients should therefore be thoroughly informed about how to recognize and manage reactions, particularly severe ones (Grade D). Patients also need education on what to do if a dose is forgotten and when SLIT should be temporarily interrupted (e.g, oropharyngeal lesions) (Grade D).11 When 1 or more severe adverse reactions occur, the allergist (specialist and subspecialists) should rediscuss the benefits and risks of SLIT with the patient and decide whether or not treatment should be continued (Grade D). As for SCIT, cessation of treatment or adaptation of the dosage should follow the summary of product characteristics (SmPC).

The frequency of local adverse events during SLIT correlates with the dosage and has been reported to be 40-75%, for example, temporary local mucosal reactions (oral pruritus or dysesthesia, swelling of the oral mucosa, throat irritation) or abdominal pain.34, 197-199 Most of these reactions occur during the initial phase of the treatment course (commonly in the first 3 weeks). They are commonly considered to be of mild intensity and self-limiting.34, 97 Nevertheless, these reactions may lead to cessation of treatment, as observed in 4-8% of cases reported in recent trials of SLIT tablets.56, 85, 99, 138(see section “adherence”). As in SCIT, local adverse reactions may be diminished by the intake of oral antihistamines (Grade A).

For SLIT, temporary cessation of therapy may be advised in a number of situations to reduce the potential for adverse effects. For example, for 7 days following dental extraction or oral surgery or following shedding of a deciduous tooth; while an oral ulcer or open wound in the mouth heals; or during an upper respiratory tract infection in patients with asthma. Individual product SmPCs may list additional advice.