Allergen immunotherapy (AIT) is a proven therapeutic option for the treatment of AR and/or asthma for many standardized products by sublingual (SLIT) or subcutaneous (SCIT) routes [5, 72,73,74,75,76,77]. The efficacy of approved AIT products has been demonstrated in double-blind, placebo-controlled, randomized clinical trials (DBPCRCTs) and confirmed in real-life . For AIT, a good patient selection should be made such that indications and contraindications are adequately addressed .
A major advantage for AR patients in the German health care system is the special feature of having direct access to a specialist (including an allergist). In contrast to many other countries, the entire treatment chain in Germany can be performed by an allergological competent specialist or a physician with additional allergology training, from the anamnesis to allergen avoidance, pharmacological treatment, indication and implementation of AIT (see also Figs. 5, 6 and 8). Among other things, this enables the early use of AIT, thereby taking advantage of the preventive effects of this form of therapy.
In many countries, the initial phase of AIT is more expensive than other medical treatments for AR or asthma [43, 79]. In particular, for the German health care system, it has been shown that socioeconomic cost–benefit and cost-effectiveness analyses for long-term effects always favor AIT compared to symptomatic pharmacotherapy for both AR and allergic asthma. AIT is therefore more cost effective in the longer term [80,81,82]. Accordingly, an AIT pays off after already 4–7 years in terms of cost–benefit aspects in the German health care system [80,81,82]. Here, the long-term effect of AIT, which extends beyond the duration of the therapy, is particularly significant. However, such cost–benefit analyses are based on model variables that may include systematic errors .
Numerous AIT guidelines have been developed [5, 72,73,74,75,76,77, 83] and some of the methodologies for evaluating evidence vary considerably. So far, none of these guidelines use ICPs.
As requested by an EAACI Task Force , ARIA 2019 has created ICPs for both SCIT and SLIT , as presented below.
Allergens to use
Selection of the therapeutic allergen
The decision to prescribe an AIT should be based on the symptoms of allergen exposure, evidence of sensitization, clinical relevance, and the availability of high-quality therapeutic extracts [72, 86].
AIT products must be effective and safe, in accordance with regulatory requirements [87,88,89]. Therapeutic allergen extracts cannot be considered generic. In the EU, every single product (single allergen or mixture) has to be proven in an authorization procedure for efficacy and safety [87, 90]. There is restriction within the so-called homologous groups, which define allergen sources with significant clinical cross-reactivity among which defined extrapolations are allowed . In addition, provisions exist in the Directive 2001/83/EC as well as in the German Medicines Act (Arzneimittelgesetz [AMG]), according to which a derogation from the authorization requirement is possible in defined special cases (e.g. for the preparation of a rare therapeutic allergen for a patient, so-called a named patient product [ NPP]).
In Germany, as in many other countries, NPPs are used to treat patients individually. The German and European legislation on allergen extracts has created exemptions that make it possible to place these on the market [75, 91]. The details will be discussed in the next section.
NPPs that are manufactured using industrial processes should consider both quality aspects and, depending on the frequency of the allergen source, clinical data on a limited scale. A draft version of a position paper on the development of allergen products for which only a few patients are available for clinical trials (concept paper on a guideline for allergen products development in moderate to low-sized study populations) has recently been published by the EMA for public consultation (EMA/712919/2018).
Where appropriate RCT studies are not possible due to rare occurrence and very small patient populations, RWE studies may provide clinical data. Due to the importance of these aspects for the availability and selection of therapy extracts, the legal provisions valid for Germany and Europe are presented below.
Legal requirements for allergen products in Germany and the European Union (EU)
Allergens have been subject to European law since 1989 (Directive 89/342/EEC)  and, as defined in Directive 2001/83/EC , both test and therapeutic allergens are drugs. According to Article 6 of this European Directive, a drug may not be placed on the market in a Member State unless the competent authority of that Member State has granted a marketing authorization [72, 86]. All European Union Member States have at least one national regulatory authority, which cooperates within the network or under the coordination of the European Medicines Agency (EMA) .
In Germany, the scope of Directive 2001/83/EC has been fully transposed into the German Medicines Act (AMG) . According to § 21 (1) AMG, drugs may only be placed on the market in Germany if they have been approved by the competent higher federal authority, the Paul-Ehrlich-Institut (PEI) in Langen. For approval, the drugs must be of adequate quality, efficacy and safety according to the current state of knowledge. The PEI is responsible for the regulation of allergen products based on the applicable national and European legislation and guidelines of the EMA .
In the European Union there are four different procedures for authorizing a medicinal product :
National approval procedure: Authorization is sought by the applicant in a Member State (MS). The evaluation of the application for authorization and the granting of authorization in the Member State concerned will be carried out by the national competent authority.
“Mutual Recognition Procedure” (MRP): A national authorization already existing in one Member State (Reference Member State: RMS) may be extended to one or more other Member States at the request of the pharmaceutical company.
“Decentralized Procedure” (DCP): The applicant seeks simultaneous authorization in several EU countries.
“Centralized Procedure” (CP): The applicant seeks simultaneous authorization in all EU countries.
Currently, most approvals for allergen products in Germany and Europe are national approval procedures. In Germany, they are granted approval by the PEI.
State batch verification
A characteristic of the German market is the state batch release of therapeutic and test allergens according to § 32 of the German Medicinal Products Act of 24 August 1976 (Federal Law Gazette p. 2445, as amended) [72, 86]. The review and assessment of the PEI is not only based on documentation, but also on the basis of its own experimental tests in the context of state batch release and inspections of license holders and applicants . According to the legislation in Germany, a batch can be released only if the state batch test has shown that the batch has been manufactured and tested according to manufacturing and control methods that correspond to the current state of scientific knowledge. Furthermore, the batch must have the required level of quality, effectiveness and safety.
With the statutory testing of allergen products, the Paul-Ehrlich-Institut contributes significantly to ensuring the efficacy and safety of allergen products on the German market.
Named patient products and therapy allergen regulation
According to the European Directive 2001/83/EC, there are various exemptions from the authorization requirement for drugs. Thus, under Article 5 of Directive 2001/83/EC, a Member State may exempt drugs from the provisions of this Directive in specific circumstances, in accordance with applicable legislation (e.g. for individualized drugs). The AMG valid in Germany also contains an exception according to § 21 (2). An authorization is not required for drugs that […] “are prepared as therapeutic allergens for individual patients based on a formulation” [72, 86, 94]. This exemption is useful and important for the availability of allergen-specific immunotherapies for allergies to rare allergens .
Mixing therapy allergen extracts
There is no evidence that the mixing of different allergens has the same effect as the separate administration of individual allergens. Mixing allergen extracts may result in a dilution effect and an allergen degradation due to the enzymatic activity of certain allergens . For allergen mixtures that do not belong to the same homologous group, the EMA demands a separate justification . A recent report from an NIH-sponsored international workshop for AIT on aeroallergens presents study concepts to address this important knowledge gap .
Allergic diseases are complex and diverse. Patients are often simultaneously sensitized to multiple allergens (polysensitization), but not all these sensitizations may be clinically relevant. Therefore, it is important to use only those therapeutic allergens that are directed against the proven symptom-causing sensitization for the AIT and not against a clinically irrelevant sensitization. AIT with single extracts is effective in polysensitized patients [98,99,100]. Therefore, it makes sense to use different (mono) allergen extracts separately in polysensitized patients instead of mixing extracts . In Germany, mixing therapeutic allergens is not possible with the Therapeutic Allergen Order (Therapieallergene-Verordnung [TAV]) for the common therapeutic allergens defined herein, since any mixture of a TAV therapeutic allergen with one or more other allergens requires TAV approval. As a result, the number of available mixtures has decreased sharply. When multiple therapy extracts were used in parallel, it was suggested to administer the extracts at different injection sites with a 30-minute interval. However, only few confirming data exist for this procedure.
The costs of AIT in the German statutory health insurance (SHI)
The prescription of therapy extracts for specific immunotherapy in the SHI physician sector, like all forms of therapy, must be based on the specifications of the German Medicines Act. The specifications of the economic efficiency requirements according to § 12 SGB V and the guidelines of the Federal Committee of Physicians and Health Insurance Funds on the prescription of drugs in medical care (AMR) both regulate therapy within the SHI. Recommendations on the economic prescription usually refer to the price list of AIT products .
The real prices of the products, massively influenced by current legal framework conditions, are often ignored in this field . Therefore, the price list and the real price tend to differ widely, with a significant impact on the actual costs of AIT.
Since April 2014, all AIT manufacturers are governed by § 130a (1) SGB V to an amended mandatory rebate of 7% on the price list . This compulsory levy is the same for all reimbursable products. But much stronger affects a so-called price moratorium, which has also been enshrined by law until 2022 (§ 130a (3a) SGB V and AM-VSG). This price moratorium, which came into effect in July 2010, froze all prices at the time of 31 July 2009 . All price increases since this date have subsequently been reclaimed by the health insurance companies via the pharmacy computer centers. This amount, known as the “manufacturer’s discount”, must be refunded by the manufacturer to the respective health insurance company . Therefore, the manufacturers are currently obtaining only the prices that were valid for their preparations on 31 July 2009, further reduced by a mandatory discount of 7% .
In addition, these significant discounts are not the same for all AIT products. Due to different increases in raw material prices and other costs since 2009, there were very different price increases on the part of the manufacturers. Thus, a look at officially available price lists reveals a highly distorted picture which significantly affects the economics of immunotherapy. This means that the treatment is much cheaper than suggested by the price list. Of course, for all price comparisons, there are preparation-specific differences, e.g. fill volumes, injection volumes, injection distances, up-dosing schemes, making it difficult to compare the prices at the annual or 3‑year level .
Thus, the calculation of daily treatment costs (DTCs)—as usual in other areas of indication—is not useful for AIT preparations. In the “Official ATC Code” of DIMDI, there is also no DTC information on AIT preparations .
Therefore, it should be kept in mind that the real costs of AIT treatment are (almost) always lower than the costs calculated on the basis of the price lists. However, these reductions vary for different preparations .
The patient’s view should always be considered to enable a tailor-made approach to shared decision-making (SDM). In case studies on state of knowledge, awareness as a therapy option, expectations and satisfaction with the AIT, there were sometimes very different assessments between the physician’s view and the patient’s view [102, 103]. Most studies complain about a lack of information on the patient side. Therefore, every effort should be made to improve communication between the physician and the patient, thus contributing to a better understanding and patient satisfaction [104, 105]. Before initiating an AIT, patients should be informed about the procedure, type and duration of treatment, expected effects, potential risks and possible alternatives. The Physician’s Association of German Allergists (AeDA) has recently given a comprehensive statement on this topic .
This self-determination for consent to a medical procedure according to § 630e BGB (1) (sentences 1 and 2) determines the cooperation of the patient with the knowledge of the essential circumstances of the treatment. In particular, this includes information on the nature, extent, implementation, expected consequences and risks, the measure and its need, urgency, suitability and chances of success in terms of diagnosis or therapy. This enables shared decision-making in the sense of the SDM and should be applied from a medical–legal perspective using current medical knowledge on treatment options, risks and benefits [106, 107].
According to the German Allergy and Asthma Association (Deutscher Allergie- und Asthmabund [DAAB]), the indication for AIT in AR, especially in childhood and adolescence, should be generous in order to reduce the risk of allergic asthma [73, 108]. Here, the RKI and EAACI’s demand for early causal treatment of hay fever is supported, as the risk of a change in level from AR to allergic asthma is apparently at its greatest when children are young and developing AR .
Adherence to allergen immunotherapy (AIT) is critical to its effectiveness. A SCIT requires regular (usually monthly) visits during the maintenance phase, while a SLIT is performed with a daily intake of allergy tablets or drops at home. Noncompliance with an AIT schedule and premature termination of therapy are common problems . There are controversial results on termination rates in AIT—but overall adherence is low . A good organization plan by allergists not only increases safety, but also provides the ability to accurately track and improve patient adherence and compliance .
The pharmacist’s view
Most patients treat their AR without any interaction with their physician . Pharmacists are the most accessible health professionals to the general public and AR is one of the most common diseases managed by pharmacists [112, 113].
Due to the large number of OTC products for AR, pharmacist consultation plays a key role for most pharmaceuticals.
In Germany, AIT products are available only in pharmacies and the pharmacist is an important partner in the entire treatment concept. He/she is involved in both organizational issues of drug procurement as well as in the adequate storage and transport of AIT preparations. He/she may also have essential advisory functions on fundamental issues, such as the importance of AIT in inhalation allergies. In addition, the pharmacist can inform the patient about the risk–benefit balance, as well as the benefits of an adequate therapy duration.
General practitioner’s view
In many European countries, the diagnosis and treatment of allergic diseases takes place in the family practice [114, 115], but an AIT is rarely prescribed there. In Germany, this situation is at least partly different. A high number of specialists combined with close networking between general practitioners (GPs) and specialists could be even more important for a good care with AIT in the future. The continuous, accessible and holistic situation of GP treatment is important and can support the identification of allergy patients, enable early diagnosis, and be used for periodic follow-up of allergy patients to assess disease control, treatment adjustments, and patient-centered SDM [116,117,118]. But only few general practitioners receive formal basic training in allergology [119, 120]. AIT risks can be minimized when AIT is performed by experienced physicians with well-trained personnel and only suitable patients are treated in an environment with available emergency care facilities for the treatment of systemic anaphylactic reactions [121,122,123,124].
Practical approach to patient selection in AIT
According to the German S2k guideline, AIT is to be performed by physicians who have either the additional training in allergology or adequate therapy experience and are able to treat emergency adverse drug reactions (anaphylactic shock, severe asthma attack, etc.) .
Since 1 January 1996, the instructions for use and the summary of product characteristics of the hyposensitization solutions used in Germany must contain the following warning: “Hyposensitizing vaccines for injection may only be prescribed and used by allergological trained or experienced physicians.” (Paul-Ehrlich-Institut, decision of 5 April 1995) .
In principle, the patient perspective should always be considered in the sense of shared decision-making (SDM).
Written information (“Therapy Information Sheet”) on the conduct of the AIT and on the handling of possible side effects is available as an appendix in the German S2k  guideline and should be made available to the patient.
If AIT is performed or continued by another physician after the indication has been given, then close collaboration is required to ensure the consistent implementation and low-risk performance of the AIT . This is especially true for the occurrence of adverse drug reactions (ADR).
Selection of suitable patients by molecular component diagnostics
The approach of precision medicine for the selection of an AIT regime is gaining more and more attention [2, 125,126,127]. The determination of allergen components may bring potential benefits in the indication for AIT, especially in pollen allergies. Patients without sensitization to major pollen allergens are expected to have low or no response to AIT with commercial allergen extracts as these are standardized for their major allergen content [125,126,127]. Panallergens such as profiline or polcalcine are mostly clinically not significant but explain false-positive results in skin tests and in in vitro laboratory diagnostics. Sensitization to panallergens is not an indication for AIT [125,126,127]. Data from a retrospective study confirm a better success of AIT with pollen allergens in patients with sensitization to major allergens . Other studies show that the additional determination of allergen components led to a change in the decision by the prescribing specialists on AIT in around half of the children with allergic seasonal rhinoconjunctivitis [125, 127]. Further prospective studies as to whether the therapeutic benefit of AIT with pollen allergens including molecular allergy diagnostics can be improved are necessary and still pending.
Infobox 6 Indication to the AIT [1, 2]
Accurate diagnosis with medical history, skin test and/or specific IgE and optionally component-based in vitro diagnostic (CRD). In certain cases, provocation tests are required.
Approved indications are allergic rhinitis/conjunctivitis and/or allergic asthma.
Allergic symptoms must be caused predominantly by the respective allergen exposure.
Patient selection: Poor symptom reduction despite adequate pharmacotherapy (according to guidelines) during the allergy season and/or change in natural allergy history. mHealth technologies such as the MASK-air allergy app can be of relevant importance for the selection of patients (mHealth-Biomarkers).
Verification of the efficacy and safety of the selected product through appropriate studies. For TAV therapy allergens, at least one DBPC trial with an adequate number of patients and state-of-the-art statistical evaluation is required for an official approval.
Shared decision-making considering the wishes of the patient (and the caregiver) are an essential part of the indication.
A flow chart for the step-by-step approach to the indication of an AIT has been developed (Fig. 8; [1, 2]).
Rhinitis and rhinoconjunctivitis in adolescents and adults
Guidelines and various recommendations from experts in AR pharmacotherapy usually suggest the approach summarized in Infobox 1 [3,4,5]. All recommended medications are considered safe at the usual dosage, with the exception of first-generation oral H1-antihistamines and depot-corticosteroids that should be avoided . MACVIA has developed a simple algorithm for step-up and step-down management (Fig. 6; ).
In children and adolescents with AR, there is evidence from clinical trials that an AIT may reduce the risk of developing asthma [73, 108]. Therefore, the early use of a causal form of therapy in the sense of AIT should be demanded, especially in these patients.
Asthma in adolescents and adults
AIT should not be used in patients with severe asthma. Biologicals in severe asthma and AIT in allergic diseases target two different patient populations. An algorithm for asthma is not yet available. Uncontrolled asthma is still a contraindication for AIT . GINA (Global INitiative for Asthma) has included a SLIT in its treatment recommendations for house dust mite-induced asthma . The summary of product characteristics for the approved SLIT house dust mite tablet  shows that (i) the patient should not have had a severe asthma exacerbation within the last 3 months after the onset of AIT, (ii) in patients with asthma and acute respiratory infection, the start of treatment should be postponed until the infection has subsided and (iii) AIT is not indicated for the treatment of acute exacerbations and patients must be informed of the need to consult a physician immediately if their asthma suddenly worsens, (iv) furthermore, AIT against HDM should initially be used as adjunctive therapy for the treatment of anti-asthmatic pharmacotherapy, and the reduction of asthma medication should be carried out step by step under the supervision of a physician according to the management guidelines. So far, only one AIT product has been approved for asthma as a major indication in a European procedure.
Multimorbidity—the simultaneous presence of more than one disease in a patient—is very common in allergic diseases, and over 85% of patients with asthma also suffer from AR. On the other hand, only 20–30% of patients with AR have asthma at the same time. AR multimorbidity increases the severity of asthma . AIT is able to control AR, conjunctivitis, and asthma-multimorbidity, which was considered in the marketing authorization for a SLIT HDM tablet . Other atopic disorders, such as atopic dermatitis and/or food allergies due to cross-reactivity of food allergens with inhaled allergens, as well as other known comorbidities (e.g. depression), may increase the disease burden [132,133,134].
AIT in children
AIT in children may have short-term effects like symptom-relieving, anti-inflammatory and drug-saving, as well as positive long-term effects. For specific products, efficacy has been demonstrated in pediatric studies  as have long-term beneficial effects . A recent SLIT study , an earlier grass pollen SCIT study , and a meta-analysis  all provided evidence for the products under study that AIT may delay the onset of childhood asthma  or prevent the short-term risk of asthma development . The meta-analysis showed a limited reduction in the short-term risk of developing asthma in patients with AR but with unclear benefit over a longer period . In children with AR without asthma, consideration should be given to the possibility of preventing the onset of asthma, although further studies are needed for an unrestricted recommendation . The authors of this article emphasize that the use of the only causally and potentially preventively effective therapy form of AR, namely AIT, should be considered at an early stage, especially in children. In children with moderate/severe AR, an AIT should be initiated early if all other conditions are met. Direct specialist access in the German health system, also to an allergist, pediatric allergist or pediatric pulmonologist, facilitates the early use of AIT by utilizing its preventive effects.
AIT in elderly patients
The immunological situation of elderly allergic patients may differ from that of children and younger adults. A limited number of studies have shown that AIT can also be effective in a population of elderly patients [140, 141]. For a universal recommendation, however, more data are required.
mHealth in the AIT precision medicine approach
The selection of patients for AIT can be facilitated by electronic diaries accessed via smartphones [20, 21, 42] or other mHealth tools. Such diaries should query the symptoms of AR as well as the drug consumption. For this, they should provide a complete list of medications available in the country for that particular condition. Based on patient-documented data, physicians can assess whether (i) a moderate uncontrolled disease is present, (ii) symptoms are associated with a pollen season or other allergen exposure and (iii) the pharmacological treatment is following the recommendations for uncontrolled symptoms. Physicians can also assess the duration of uncontrolled symptoms and the impact on productivity or academic performance. An electronic clinical decision support system may help in selecting AIT patients in the future .
Follow-up of patients with AIT
The same approach can be used to assess efficacy, provided there is a reliable data input, for the progress monitoring and follow-up of AIT patients [81, 84].