2019 ARIA Care pathways for allergen immunotherapy

4.1 Relevant extract

The decision to prescribe AIT for the patient should be based on allergen relevance and on the persistence of clinical symptoms, despite appropriate medications according to guidelines, as well as on the availability of good-quality extracts.

Adequate quality is essential for any medicinal product to be eligible for marketing.10, 22 Only regulated, standardized allergen extracts that are efficacious and safe should be used for AIT.23, 24

4.2 Extrapolation to untested products

AIT products have to show efficacy and safety in line with regulatory requirements.25 Allergen extracts cannot be regarded as generics. In the EU, each individual product (individual product or mixtures), with the exceptions made by EMA (European Medicines Agency) or PEI (Paul Ehrlich Institute), must prove its efficiency.23

In some cases, exceptions related to the concept of homologous groups defining allergens with a significant clinical important cross-reactivity can be accepted without specific clinical documentation. These homologous groups include a range of pollen allergen extracts and house dust mites which are defined in the respective EMA guides for allergen products.23

There is no evidence that mixing different allergens will have the same effect as separately administering individual allergens. Mixing different allergens can result in a dilutional effect—underdosing of the treatment and potential specific allergen degradation—due to the  enzymatic activity of certain allergens.26 The risk of allergic side effects can increase, especially by the degradation, when a new batch is used.27 Therefore, the EMA has recommended only to use mixed allergen products of allergens represented by the allergen sources from homologous groups.23

4.3 Named patient products

In many countries, named patient products (NPP) are used by practitioners in an effort to apply precision treatment to patients. However, this practice requires appropriate confirmatory trials and real-world evidence since clinical data with some allergens cannot be directly extrapolated to NPP practice. NPPs are marketed on exception from the European legislation on allergen extracts.14, 28

4.4 Polysensitized patients

Allergic diseases are among the most complex and diverse diseases. Patients are often sensitized (IgE) to many allergens (polysensitization), but not all of these sensitizations may be clinically relevant. Therefore, it is important to treat the allergies that give rise to allergic symptoms and not the sensitizations potentially irrelevant for the patient. There is a broad range of evidence for the clinical efficacy of single extracts in polysensitized patients.29-31

Instead of mixing extracts, the different allergens can be applied separately.12 However, it has been proposed without data that two extracts can be given with a 30-minute interval in two different injection spots. By doing so, each allergen can be monitored separately for the local reaction and potential systemic side effects.

In general, the question regarding the efficacy of poly-allergen compared to oligo-allergen or mono-allergen immunotherapy in polysensitized patients has not been addressed in carefully designed clinical trials. A recent report from an NIH-sponsored international workshop on aeroallergen immunotherapy outlines trial concepts to address this important knowledge gap.32

5.1 Concept of patient stratification

Precision medicine aims to customize health care with medical decisions, practices and/or products tailored to the individual patient. It also refers to the tailoring of medical treatment to the clinical and social characteristics of each patient and not necessarily to genomics.33 The stratification of patients into subpopulations is the basis of clinical decision-making for increased diagnostic and treatment efficacy.34, 35 Patient stratification also integrates cost trends and social determinant risk models to match the patient to the right care management. This model applies to AIT.36

In non–life-threatening diseases with a very high prevalence, such as allergic diseases, patient stratification is required (a) to identify the best candidates for intervention through complex care management, (b) to reduce the amount of time and resources needed to match the right patient to a care management programme and (c) to optimize costs as some therapeutic interventions cannot be administered to all patients. Patient stratification may also help to improve the patient's engagement.37

Molecular diagnosis, when used with other tools and patients' clinical records, can help clinicians to better select the most appropriate patients and allergens for AIT38 and, in some cases, predict the risk of adverse reactions.39 The pattern of sensitization to allergens could potentially predict the efficacy of allergen immunotherapy provided that these immunotherapy products contain a sufficient amount of these allergens. Nevertheless, multiplex assay remains a third-level approach, not to be used as a screening method in current practice.39

VAS may also be useful for monitoring AIT effectiveness and medication use as it is easy to use and has been validated for AR control of severity. It has also been used as a secondary endpoint in both adult and paediatric trials.40, 41

The role of precision medicine in selecting an AIT regimen was proposed further to an expert meeting36 (Table 2).

The flow of the precision medicine approach in allergic disease has been adapted (Figure 2) from (Ref.16) and(Ref.36). In some instances, AIT can be offered to patients whose AR is controlled by pharmacotherapy such as those who may develop thunderstorm-induced asthma.42, 43 AIT should also be considered even in moderate AR, particularly (but not necessarily only) in patients who have had asthma exacerbations during the pollen season and who live in geographically at-risk regions.

5.2 Biomarkers in AIT

Biomarkers - clinical or laboratory characteristics that reflect biological processes - are essential for monitoring the health of patients. They include clinical signs identified by physical examination, biological assays, mHealth outcomes, genomic indices and others that can be objectively measured and used as indicators of pathophysiological processes.44 They can be used individually or in combination, but they require further studies.

There are currently no validated genetic or blood biomarkers for predicting or monitoring the efficacy of AIT at an individual patient level although several candidates have been investigated.45 Biomarkers associated with mHealth and a clinical decision support system (CDSS)46 may change the scope of AIT as they will help monitor the patient's disease control47, 48 for (a) patient stratification, (b) clinical trials and real-world evidence, (c) monitoring efficacy and safety of targeted therapies (a critical process for identifying appropriate reimbursement) and (d) implementation of stopping rules (Figure 3). Clinical stopping rules should be developed for AIT, similarly to what is currently considered for biologics in severe asthma, as a guidance for continuing or stopping treatment after a short (early stopping rule) or long (late stopping rule) period. As an example, a global treatment evaluation after 16 weeks is used as an early stopping rule for omalizumab treatment.49, 50

5.3 ARIA

In ARIA 2008,16 it was indicated that DB-PC-RCTs have confirmed the efficacy of SCIT and SLIT. However, trial-based clinical efficacy is one of the many factors in a clinician's decision-making process for the use of AIT, especially since AIT RCTs are designed to fulfil regulatory demands for marketing authorization.51 Before starting AIT, it is essential to appreciate the relative value of pharmacotherapy and AIT as well as the degree of disease control achieved using pharmacotherapy. Furthermore, it is important to consider the rest of the patient's medical history as well as his/her social and geographical environment. The indications for SCIT in ARIA 2008 were similar to those published in 199852 and 2001.53

7.1 Subcutaneous immunotherapy

A typical reaction (local reaction) is redness and swelling at the injection site immediately or several hours after the injection. Sometimes, sneezing, nasal congestion or hives can occur (systemic reactions).67 Serious reactions to injections are very rare but require immediate medical attention. Symptoms of an anaphylactic reaction can include swelling in the throat, wheezing or tightness in the chest, nausea and dizziness. The most serious reactions develop within 30 minutes after the injections and it is therefore recommended that patients wait in their doctor's surgery for at least 30 minutes after an injection.

7.2 Sublingual immunotherapy

Allergen drops or tablets have a more favourable safety profile than injections. SLIT can be administered at home after the first dose is administered under the supervision of a physician. The large majority of adverse events are local (mouth itching, lip swelling, nausea) and spontaneously subside after the first days of administration. The severity of local side effects is graded according to persistence and impact on the quality of life.68 In some countries outside of Europe, SLIT tablets include a warning about possible severe allergic reactions and adrenaline auto-injectors are routinely recommended. This is not the case in Europe although in the rare event that a general allergic reaction occurs after SLIT then the risk/benefit should be reassessed and a decision made whether to continue SLIT and, if appropriate, whether a rescue auto-injector should be provided.

11.1 Rhinitis and rhinoconjunctivitis in adolescents and adults

The selection of pharmacotherapy for AR patients depends on several factors, including age, predominant symptoms, severity, AR control, patient preferences and cost. Allergen exposure and resulting symptoms vary, for example based upon seasonal exposure or change in environment, making it necessary to make adjustments to therapy. CDSSs may be beneficial by assessing disease control.96 They should be based on the best evidence algorithms to aid patients and healthcare professionals to jointly decide on the treatment and its step-up or step-down strategy depending on AR control (shared decision-making).

The treatment of AR also requires consideration of (a) the phenotype (rhinitis, conjunctivitis and/or asthma) and severity of symptoms, (b) the relative efficacy of the treatment, (c) speed of onset of action of treatment, (d) current treatment, (e) historic response to treatment, (f) patient's preference, (g) interest to self-manage and (h) resource use. Guidelines and various statements by experts for AR pharmacotherapy usually propose the approach summarized in Table 3.8, 97, 98

All recommended medications are considered to be safe at the usual dosage except first-generation oral H₁ antihistamines which should be avoided.99 Notably, despite guidelines, the practice of prescribing both an INCS and an oral H₁ antihistamine is globally common.

For step-up and step-down management, a simple algorithm was devised by MACVIA, but its applicability varies depending on the availability of medications and resources in different countries (Figure 4).100

Algorithms inherently result from combining individual decision nodes that represent separate recommendations. To be fully validated, the algorithm needs to be tested as a complete management plan and compared to alternative plans to explore whether the combination of these separate recommendations leads to more benefit than harm when applied in practice. A large scale mobile technology study,47 a speed of onset study101 and new recommendations all supported the algorithm.97, 98

11.2 Asthma in adolescents and adults

An algorithm is not yet available for asthma. Uncontrolled asthma is a contraindication for AIT.102

GINA (Global INitiative for Asthma) has endorsed SLIT for house dust mite asthma.103 From the SmPC for the approved SLIT house dust mite tablet,95 (a) the patient should not have had a severe asthma exacerbation within the last 3 months of AIT initiation; (b) in patients with asthma and experiencing an acute respiratory tract infection, initiation of treatment should be postponed until the infection has resolved; (c) AIT is not indicated for the treatment of acute exacerbations and patients must be informed of the need to seek medical attention immediately if their asthma deteriorates suddenly; and (d) mite AIT should initially be used as an add-on therapy to controller treatment and reduction in asthma controllers should be performed gradually under the supervision of a physician according to management guidelines.

No other AIT product has been approved for asthma in the EU.

11.3 Multimorbidity

Multimorbidity, the co-existence of more than one allergic disease in the same patient, is very common in allergic diseases, and over 85% of patients with asthma also have AR. On the other hand, only 20%-30% of patients with AR have asthma. AR multimorbidity increases the severity of asthma.104

An advantage of AIT is that it can control many aspects of multimorbidity including AR, asthma and conjunctivitis. Although multimorbid patients appear to have more severe symptoms related to each component of their allergic disease constellation, it is not yet known whether AIT is equally or more effective in these patients, compared to patients with no multimorbidity. This can be tested using existing databases, but a controlled trial will also offer useful evidence. In the conditions and authorization of a SLIT mite tablet,95 multimorbidity was recognized as an indication for mite SLIT.

11.4 Children

In children, AIT is effective as shown by RCTs105 and may have long-term effects after it is stopped.106 A recent study of SLIT,107 a previous study of subcutaneous grass pollen immunotherapy in children108 and a meta-analysis109 have provided some evidence that AIT can delay or prevent the onset of asthma in children. However, (a) the meta-analysis showed a limited reduced short-term risk of developing asthma in those with AR with unclear benefit over the longer term109 and (b) costs cannot be supported by healthcare systems due to the very large number of patients who might be treated with uncertainty on cost-effectiveness.

Thus, AIT can be initiated in children with moderate/severe AR that is not controlled by pharmacotherapy. In such children without asthma, the possibility of preventing the onset of asthma should be taken into consideration, although more studies are needed for an unreserved indication.9

The lower age for initiating AIT has not been clearly established. In many countries, products are licensed for children without a lower age limit. Prospective observational trials and/or registries can help confirm AIT safety and performance in the youngest recipients, perhaps down to the age of 3 years.

AIT is a paradigm for precision medicine, as it takes into account the multitude of sensitization and multimorbidity profile of each patient, both cross-sectionally and in relation to their natural history. Indirect yet important evidence provides clues about young patients who may benefit the most: (a) the severity of respiratory allergic disease is associated with its persistence110; (b) epitope spreading and development of new sensitizations suggest benefit with early intervention 111; and (c) the effects of AR on school performance and education56 support focusing of treatment on developmental/career milestones. Therefore, the consideration of AIT at early time points, using risk in addition to severity as a key selection criterion, is expected to maximize impact on the natural history of the disease as well as on cost/burden.

More studies are needed to characterize the long-term effects of AIT. Such studies cannot be randomized and, even less, blinded. Therefore, observational approaches, such as registry research, need to be used.112

In addition, there are opportunities for disease prevention that have not been adequately explored, such as primary prevention. We need more evidence on whether AIT may play a role for the prevention of allergic sensitization, the first allergic disease.9 Support for such studies needs to come from governmental organizations/public sources, in order to identify optimal cost-efficacy strategies.

11.5 Allergen immunotherapy in older age adults

The immunologic and allergic characteristics of older allergic patients differ from those of young and middle-aged adults. Limited studies have found that AIT may be effective in this population.113, 114 More data are certainly required for a strong recommendation. At this point, and before making the decision to initiate AIT in older patients, physicians need to have strong indications for the role of specific allergens in these patients’ AR or asthma and to take into account nonallergic co-morbidities that may have impact on the safety of AIT.

12.1 Patient stratification

It is recommended to stratify AR patients who are uncontrolled despite appropriate treatment and adherence to treatment.115 This can easily be achieved using electronic diaries obtained by cell phones as demonstrated in MASK-air^®.2, 3, 47 Such diaries should include the full list of medications. After a single year of survey, physicians can assess whether SCUAD is present and could initiate AIT if (a) symptoms are associated with pollen season, (b) adherence to pharmacologic treatment is achieved, (c) the duration of uncontrolled symptoms was long enough and (d) an impact on work or school productivity was observed. Moreover, asthma and eye symptoms can be recorded, as in MASK-air^® 2 and other Apps, allowing the evaluation of the role of multimorbidity.

12.2 Follow-up of patients under AIT

The same approach can be proposed for the follow-up of patients on AIT to assess its efficacy as suggested by a panel of international experts in an AIT position paper.18

12.3 Electronic clinical decision support system

The AR algorithm has been digitalized in tablets for healthcare professionals.46