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ARIA Guideline 2019 Treatment of Allergic Rhinitis
ARIA Guideline 2019 Treatment of Allergic Rhinitis
Allergo J Int
https://doi.org/10.1007/s40629-019-00110-9
N. Mülleneisen G. W. Canonica
Asthma and Allergy Centre, Leverkusen, Germany Allergy Section, Allergy and Respiratory Diseases, DIMI,
University of Genoa, Genoa, Italy
K. Nemat
Department of Pediatrics, University Hospital Carl Gustav V. Cardona
Carus, Technical University of Dresden, Dresden, Germany Department of Internal Medicine, Hospital Universitari Vall
d’Hebron, Barcelona, Spain
U. Rabe
Department of Allergology, Johanniter-Krankenhaus im T. B. Casale
Fläming Treuenbrietzen GmbH, Treuenbrietzen, Germany Division of Allergy and Immunology, University of South
Florida, Tampa, FL, USA
J. Ring
Department and Outpatient Clinic for Dermatology and W. Czarlewski
Allergology am Biederstein, Technical University of Munich, Medical Consulting Czarlewski, Levallois, France
Munich, Germany
W. J. Fokkens
Christine Kühne Center for Allergy Research and Education Department Otorhinolaryngologie, Academic Medical
(CK-Care), Davos, Switzerland Centers, Amsterdam, The Netherlands
J. Saloga · P. Staubach E. Hamelmann
Department of Dermatology, University Medical Center Children’s Center, Protestant Hospital Bethel, Bielefeld,
Mainz, Mainz, Germany Germany
W. Schlenter Allergy Center, Ruhr University, Bochum, Germany
Klinik für Hals-Nasen-Ohrenheilkunde, Medizinische
Universität zu Lübeck, Lübeck, Germany P. W. Hellings
Department of Otorhinolaryngology, University Hospitals
C. Schmidt-Weber Leuven, Leuven, Belgium
Center for Allergy and Environment (ZAUM), Member of
the German Center of Lung Research (DZL) and the M. Jutel
Inflammation and Immunology Helmholtz Initiative, Department of Clinical Immunology, Wroclaw Medical
Technical University of Munich and Helmholtz Center University, Wroclaw, Poland
Munich, Munich, Germany ALL-MED Medical Research Institute, Wroclaw, Poland
H. Seyfarth D. Larenas-Linnemann
Pharmacy Association in Hesse, Offenbach, Germany Hospital Médica Sur, México City, Mexico
T. Spindler J. Mullol
Lungenzentrum Süd-West, Klinik für Pädiatrische Unitat de Rinologia i Clínica de l’Olfacte, Servei d’ORL,
Pneumologie und Allergologie, Wangen im Allgäu, Germany Hospital Clínic, Clinical and Experimental Respiratory
Immunoallergy, IDIBAPS, University of Barcelona,
S. Strieth Barcelona, Spain
Department of Otolaryngology, University Medical Center
Mainz, Mainz, Germany N. G. Papadopoulos
Department of Allergy, 2nd Pediatric Clinic, University of
R. Treudler Athens, Athens, Greece
Department of Dermatology, Venereology and Allergology,
LICA—Leipzig Comprehensive Allergy Center, University of S. Toppila-Salmi
Leipzig, Leipzig, Germany Haartman Institute, University of Helsinki, Helsinki, Finland
C. Vogelberg T. Werfel
Department of Pediatric Pneumology and Allergology, Division of Immunodermatology and Allergy Research,
University Hospital Carl Gustav Carus, Technical University Department of Dermatology and Allergy, Hannover Medical
of Dresden, Dresden, Germany School, Hannover, Germany
Fig. 3 Lifetime prevalence (in %) of common allergic diseases and point prevalence (in %) of allergic sensitizations in children
and adolescents in Germany. Results of the KiGGS baseline survey 2003–2006. (Reprinted with kind permission from [22])
[23]). Here, 28.1% of adults were reported as being ICPs are structured, multidisciplinary care plans
currently affected by allergies. Women (31.6%) were that describe key steps in patient care [24]. They
significantly more affected than men (24.5%). In addi- promote the implementation of guideline recom-
tion, younger and middle-aged adults (up to 65 years mendations into local protocols and their application
of age) reported allergies more often than the elderly, in clinical practice [25, 26]. Typically, ICPs improve
a circumstance leading to a further increase in the recommendations by iteratively combining interven-
population. In childhood and adolescence, allergic tions, integrating quality assurance, and promoting
diseases were even the most common health prob- the coordination of treatment. AIRWAYS ICPs (Inte-
lems. In the course of time, the authors noted that, grated Care Pathways for Airway Diseases) [27] were
above all, the proportion of children with asthma the first steps in the development of ICPs for patients
and hay fever up to 6 years increased [23]. Early hay with rhinitis and asthma as a comorbidity, or for
fever increased the risk of asthma by 3.6 times in boys patients with multimorbidities.
and by 2.3 times in girls. The authors of the Robert New guidelines for pharmacotherapy and ICPs for
Koch Institute concluded that these data support the allergen-specific immunotherapy (AIT) are currently
demand for early causal treatment of hay fever, as being developed for allergic rhinitis (AR). Following
the risk of the allergic march is at its greatest when the Paris meeting, two separate documents were pro-
children develop hay fever in early childhood [23]. duced [28, 29]. The present publication is a summary
of these documents and transfers them to the German based guideline for the pharmacological treatment
health system (Fig. 4). In the future, this adaptation of AR [3–5, 33]. These recommendations were tested
will also be carried out for various other countries and with RWE using the MASK-air health app [20, 42].
regions in order to adapt the results to the local con- The algorithm proposed by the consensus group is
ditions and corresponding national health systems. based on a summary of all this information [33]. In
this publication, these recommendations are adapted
Next-generation ARIA-GRADE guidelines to the situation of the German health care system.
Pharmacotherapy for AR patients is considered to Care-relevant evaluation of drugs for the treatment
control the disease. It depends on (i) patient empow- of allergic rhinitis
erment and preferences, (ii) prominent symptoms,
symptom severity and multimorbidity, (iii) efficacy Over the counter (OTC) medicines cannot generally be
and safety of the treatment [30], (iv) speed of onset of prescribed at the expense of the statutory health in-
action of treatment, (v) current treatment, (vi) historic surance (SHI) of the German health care system. The
response to treatment, (vii) impact on sleep and work majority of AR drugs, such as many antihistamines,
productivity [31, 32], (viii) self-management strategies numerous INCSs (intranasal corticosteroids), or alpha
and (ix) resource use. sympathomimetics or low-effective mast cell stabiliz-
An algorithm was devised [33] and digitalized [34] ers, are nonprescription drugs. They cannot therefore
to propose step-up or step-down AR treatment (Figs. 5 be prescribed at the expense of the statutory health in-
and 6). The guideline group aims to adapt this algo- surance to adolescents from 12 years on and to adults
rithm to the availability of medicines and resources in according to Annex I of the pharmaceutical directives
different countries. Moreover, algorithms require test- (Arzneimittel-Richtlinien [AMR]) (Infobox 1).
ing using randomized controlled trials (RCTs) and ob- According to the specifications of many SHI phar-
servational research called real-world evidence (RWE) macotherapy consultants, OTC preparations should
[35–37]. preferably be prescribed on a green prescription or
National and international guidelines are mostly should only be recommended. As a rule, the costs for
based on the database of randomized controlled trials nonprescription medicines are borne by the insured
(RCTs). In fact, the GRADE method (Grading of Rec- persons themselves. However, exceptions apply to se-
ommendations Assessment, Development and Evalu- riously ill AR patients and should be considered so
ation) explicitly takes into account all types of study that these patients with severe disease can be treated
designs, from RCTs to observational studies and case under medical supervision.
reports [38–40]. GRADE also considers data on pref- Exceptions apply to OTC preparations which are
erences, acceptability and feasibility or accuracy of used as the standard therapy for serious diseases for
results. children up to the age of 12 and adolescents with de-
For the applicability of guidelines in the routine velopmental disabilities up to the age of 18 years.
care of patients, the results of RCTs are, in part, lim- According to the OTC exemption list in Annex I of
ited by the parameters of clinical trials [41]. There- the Medicines Directive, the serious diseases in which
fore, information from real-world evidence (RWE) is nonprescription antihistamines can be prescribed for
increasingly being considered in the creation of prac- special cases are:
tice-oriented guidelines. Ideally, both approaches will only in emergency kits for treatment of bee, wasp,
be merged. hornet poison allergies
During the Paris meeting, next-generation recom- only for the treatment of severe, recurrent urticaria
mendations were developed leading to a GRADE-
Fig. 5 Step-up algorithm in untreated patients (adolescents the entire treatment chain beginning at the anamnesis, to al-
over 12 years and adults) based on visual analogue scales. lergen avoidance, pharmacological therapy, indication and im-
The proposed algorithm considers the patient’s preferences: If plementation of AIT can also be performed by an allergological
ocular symptoms persist after initiation of treatment, local con- competent specialist or a physician with additional training in
junctival therapy should be added. Due to the characteristics allergology, which enables an early AIT
in the German health care system of direct specialist access,
only in severe, persistent pruritus Exemptions exist for serious disorders affecting qual-
only for the treatment of severe allergic rhinitis, ity of life. In August 2018, the Joint Federal Committee
where topical nasal treatment with glucocorticos- (J-FC) decided that it is once again possible to pre-
teroids is not sufficient scribe INCSs with the active ingredient beclometha-
sone, fluticasone and mometasone at the expense of
In these cases, nonprescription antihistamines can the statutory health insurance “for the treatment of
also be the economic alternative, regardless of age. persistent allergic rhinitis with severe symptoms”.
Intranasal glucocorticosteroids (INCSs) are the gold In addition, the J-FC acknowledged that serious
standard in the pharmacological therapy of AR, as also forms of AR—permanently impairing quality of life
outlined in the results of the Paris ARIA conference. in the long term due to severity of the disorder—are
Since 15 October 2016, however, many INCSs for a serious disease within the meaning of the Pharma-
adult-insured patients with Seasonal AR can no longer ceuticals Directive.
be prescribed on a red SHI prescription. Specifically, AR is considered serious “if it is a persistent allergic
this affects beclometasone, fluticasone and mometa- rhinitis” in which the symptoms occur “at least 4 days
sone with their esters under the following conditions: a week and over a period of at least 4 weeks” and must
The medication may only be given by a doctor after therefore be classified as severe. The J-FC followed
the first diagnosis of seasonal allergic rhinitis this definition from an earlier ARIA guideline for its
A maximum daily dose of 400/200 μg must be main- supporting reasons (Fig. 7; [19, 43]).
tained If there are no serious symptoms or if the symptoms
Containers and outer shells must provide appropri- are present for less than 4 weeks, patients must pay
ate information for the product themselves.
The medicines may only be given to adults Furthermore, the conditions for the prescription of
nonprescription antihistamines for patients with SHI
Fig. 6 Step-up algorithm in treated patients (adolescents the entire treatment chain beginning at the anamnesis, to al-
over 12 years and adults) based on visual analogue scales. lergen avoidance, pharmacological therapy, indication and im-
The proposed algorithm considers the patient’s preferences: If plementation of AIT can also be performed by an allergological
ocular symptoms persist after initiation of treatment, local con- competent specialist or a physician with additional training in
junctival therapy should be added. Due to the characteristics allergology, which enables an early AIT
in the German health care system of direct specialist access,
have been adjusted in the wording. Again, it must be preparations and drug groups, whereas only the fixed
a “persistent allergic rhinitis with serious symptoms”. combination MPAzeFlu (combined intranasal FP and
To date, in Germany, there is no arrangement for azelastine (Aze) in a nasal spray) has evidence-based
SHI patients with severe AR symptoms, for whom an- efficacy in the therapeutic area. Currently, in Ger-
tihistamines and INCSs are not effective. These pa- many, no generic drugs exist for fixed combinations,
tients usually use arbitrary combinations of different and there is no possibility of OTC use, since the fixed
Infobox 1 Legal basis for the exemption from Infobox 2 Recommendations for pharma-
the obligation to prescribe at the expense of the cotherapy for allergic rhinitis
SHI
Legal basis
Oral or intranasal H1-antihistamines are less ef-
According to § 34 (1) sentence 1 SGB V, non- fective in controlling all rhinitis symptoms than
prescription medicines are excluded from the sup- intranasal corticosteroids (INCSs) [5–10]. How-
ply according to § 31 SGB V. In accordance with ever, they are effective in many patients with
§ 34 (1) sentence 2 SGB V, the Joint Federal Com- mild to moderate disease and many prefer oral
mittee stipulates in the guidelines pursuant to medication.
§ 92 (1) sentence 2 no. 6 SGB V which nonprescrip-
The comparisons between oral and intranasal
tion medicines that are considered to be standard H1-antihistamines differ in their results; no fi-
therapies for the treatment of serious illness are nal conclusions have been drawn.
to be used for these diseases may exceptionally
In patients with severe rhinitis, INCSs are the
be prescribed by the contract doctor. In doing first-choice in treatment. Onset of action takes
so, account must be taken of therapeutic diversity place after a few days.
(§ 34 (1) sentence 3 SGB V).
The concomitant use of an oral H1-antihistamine
According to § 34 (1) sentence 5 SGB V, exclusion and an INCS does not provide better efficacy
under sentence 1 does not apply to than INCSs alone [3, 4], although this is a com-
1. insured children until the age of 12 years, mon practice worldwide.
2. insured adolescents up to the age of 18 with
MPAzeFlu, the fixed combination of intranasal
developmental disabilities. FP and azelastine (Aze) in a nasal spray, is
The legal criteria are specified in § 12 (3) and (4) more effective than INCS or H1-antihistamine
of the current Medicines Directive as follows: monotherapy and is indicated for patients in
§ 12 (3) A disease is serious if it is life-threaten- whom INCS monotherapy is considered inad-
ing or if, due to the severity of the health disorder equate [11–15], with severe AR or for patients
caused by it, it permanently affects the quality of who want a quick relief of symptoms [3, 4]. In
life. a pollen exposure chamber study, the speed of
§ 12 (4) A pharmaceutical product is considered onset of the combination was confirmed [16,
to be the standard of care if the therapeutic benefit 17].
for the treatment of the serious disease is in line
All recommended medications are considered
with the generally accepted state of medical knowl- safe in the usual dosage. Oral H1-antihistamines
edge. of the first generation are sedating and should
be avoided [18], as well as the prolonged use
of nasal alpha-sympathomimetics (in vasocon-
strictive nasal sprays).
combinations were not exempted from the prescrip- Depot corticosteroids i.m. are not indicated in
tion. A differentiation by the J-FC and the SHI to free
allergic rhinitis.
and arbitrary drug combinations would be desirable
because such drug combinations have no proven evi-
dence in controlled clinical trials. Moreover, contrary guidelines [3–5, 33]. In one review, a similar potency
evidence exists that the simultaneous use of an oral was assumed for AR drugs [47]. But this study used
H1-antihistamine and INCSs has no better effective- a methodology that did not allow distinction between
ness than INCSs alone [3, 4]. drugs. However, the AR GRADE Guidelines agree in
some important respects [3–5, 33] (Infobox 2):
Basic principles for the development of ARIA ICPs The revision of the ARIA Guideline 2016 [3] and the
US Practice Parameters 2017 [4], which were devel-
MASK algorithm for the pharmacological treatment of oped independently, used the same methodological
AR approach with GRADE [38–40]. Interestingly, identical
The MASK algorithm, based on the visual analogue questions were analyzed. In the treatment of moder-
scale (VAS) [44], was developed by the ARIA Expert ate to severe rhinitis, two main factors were consid-
Group for the selection of pharmacotherapy and the ered: effectiveness and onset of action (Infoboxes 3
gradual step-up or step-down of therapy depending and 4).
on symptom control ([33]; Figs. 5 and 6). However, for all these recommendations, the evi-
dence level is low (2 and 3) or very low (1).
Revision of ARIA 2010, 2016 and US Practice The ARIA 2016 revision [3] and the US Practice Pa-
Parameters 2017 rameters 2017 [4], which are mainly based on RCTs,
Although only few direct comparative drug studies support the MASK algorithm [33].
are available in RCTs [11, 12, 45, 46], a comparison
of AR drugs was made in several reviews [30] and
Infobox 5 Results of RWE for the treatment of able for treatment. Molecular component diagnostics
AR for the determination of major allergens is still poorly
used in Germany but could further improve the diag-
nosis and thus the effectiveness of the therapy. There-
1. Patients do not follow guideline recommenda- fore, further studies should be carried out on this di-
tions and often treat themselves. agnostic possibility. In addition, high adherence in
2. Adherence to treatment is poor. the treatment of allergies is necessary for a successful
3. Patients treat themselves as needed, depending therapy.
on symptom control, and enhance their therapy
if they feel unwell. However, the concomitant use Next-generation ARIA-GRADE guidelines
of arbitrary combinations of various medications
does not improve symptom control. The algorithm proposed a stepwise approach for the
4. MPAzeFlu is superior to ICNSs which are superior selection of AR medications based on GRADE recom-
to oral H1-antihistamines. mendations refined with RWE and chamber studies
(Table 1).
The proposed approach confirms the validity of
was not available with other methods [62–68]. To our most GRADE recommendations for AR, allows some
knowledge, there is no other mHealth study that as- conditional evidence to be supported by RWE and
sesses the efficacy of different medications at large provides some new insights.
scale. In particular:
The efficacy of combined oral H1-antihistamines
Physician’s view and INCSs was not found to be more effective than
There are major differences between the physician’s INCSs alone,
recommendations and the patient’s behavior in the The efficacy of combined nasal H1-antihistamines
treatment of pollen-induced AR. Regular use through- and INCSs was found more effective than INCSs
out the season, even on days with few symptoms, is alone,
generally recommended. In fact, most patients use Intranasal H1-antihistamines are effective within
AR drugs only when needed—if their AR symptoms minutes,
are not well controlled [42, 69]. An interesting finding Higher costs of a fixed combination of INCSs and
is that physicians who are suffering from AR behave nasal H1-antihistamines are justified if the symp-
in the same way as their patients and do not follow toms cannot be controlled otherwise [3].
the guidelines’ recommendations [70].
The ARIA algorithm for AR was tested with random-
Patient’s view ized controlled trials (RCTs), observational research
According to the German Allergy and Asthma Associ- RWE and chamber studies. The overall algorithm was
ation (Deutscher Allergie- und Asthmabund [DAAB]), found appropriate and no change was needed.
a significant part of the problem can be attributed
to the inadequate care situation of patients with AR. Conclusion
The worsening in care due to the elimination of reim-
bursement for antihistamines and INCSs is eminent. The approach for next-generation ARIA guidelines
For this reason, many patients are not under medical with the integration of GRADE guidelines, considering
supervision as they have to pay for their own pharma- RWE and additive studies (pollen chamber exposure
cotherapy and therefore do not see any point in visit- studies), could be a model for other chronic diseases
ing a doctor. As a result, other therapeutic options as well. The inclusion of ICPs and health apps with
such as allergen avoidance and premature AIT are integrated, person-centered care represents the ARIA
used too rarely. The DAAB therefore generally calls for phase 4 change management strategy [19].
the possibility of prescribing over-the-counter anti-al- Special features in the German healthcare system
lergic drugs at the expense of the statutory health in- arise from the OTC availability of most AR drugs and
surances. the statutory provision that OTC medicines may only
If an allergy is suspected, an early diagnosis should be prescribed in exceptional cases at the expense of
take place, so that patients know their triggers. Fur- the SHI.
thermore, therapeutic options need to be considered
with the aid of allergen avoidance, pharmacotherapy ARIA care pathways for allergen immunotherapy
and causal treatment by AIT. The allergy diagnostics
should be made by allergological experienced physi- Allergen immunotherapy (AIT) is a proven therapeu-
cians, possibly with an additional allergologist qualifi- tic option for the treatment of AR and/or asthma for
cation. An accurate diagnosis of allergy is particularly many standardized products by sublingual (SLIT) or
important in order to decide if patients are eligible subcutaneous (SCIT) routes [5, 72–77]. The efficacy
for AIT and if a suitable therapy preparation is avail- of approved AIT products has been demonstrated in
double-blind, placebo-controlled, randomized clini- cation and implementation of AIT (see also Figs. 5, 6
cal trials (DBPCRCTs) and confirmed in real-life [78]. and 8). Among other things, this enables the early
For AIT, a good patient selection should be made such use of AIT, thereby taking advantage of the preventive
that indications and contraindications are adequately effects of this form of therapy.
addressed [1]. In many countries, the initial phase of AIT is more
A major advantage for AR patients in the German expensive than other medical treatments for AR or
health care system is the special feature of having di- asthma [43, 79]. In particular, for the German health
rect access to a specialist (including an allergist). In care system, it has been shown that socioeconomic
contrast to many other countries, the entire treatment cost–benefit and cost-effectiveness analyses for long-
chain in Germany can be performed by an allergo- term effects always favor AIT compared to symp-
logical competent specialist or a physician with ad- tomatic pharmacotherapy for both AR and allergic
ditional allergology training, from the anamnesis to asthma. AIT is therefore more cost effective in the
allergen avoidance, pharmacological treatment, indi- longer term [80–82]. Accordingly, an AIT pays off after
Infobox 6 Indication to the AIT [1, 2] reactivity among which defined extrapolations are al-
lowed [87]. In addition, provisions exist in the Direc-
tive 2001/83/EC as well as in the German Medicines
1. Accurate diagnosis with medical history, skin Act (Arzneimittelgesetz [AMG]), according to which
test and/or specific IgE and optionally compo- a derogation from the authorization requirement is
nent-based in vitro diagnostic (CRD). In certain possible in defined special cases (e.g. for the prepa-
cases, provocation tests are required. ration of a rare therapeutic allergen for a patient, so-
2. Approved indications are allergic rhinitis/con- called a named patient product [ NPP]).
junctivitis and/or allergic asthma. In Germany, as in many other countries, NPPs are
3. Allergic symptoms must be caused predomi- used to treat patients individually. The German and
nantly by the respective allergen exposure. European legislation on allergen extracts has created
4. Patient selection: Poor symptom reduction de- exemptions that make it possible to place these on the
spite adequate pharmacotherapy (according to market [75, 91]. The details will be discussed in the
guidelines) during the allergy season and/or next section.
change in natural allergy history. mHealth tech- NPPs that are manufactured using industrial pro-
nologies such as the MASK-air allergy app can cesses should consider both quality aspects and, de-
be of relevant importance for the selection of pending on the frequency of the allergen source, clin-
patients (mHealth-Biomarkers). ical data on a limited scale. A draft version of a po-
5. Verification of the efficacy and safety of the se- sition paper on the development of allergen products
lected product through appropriate studies. For for which only a few patients are available for clin-
TAV therapy allergens, at least one DBPC trial ical trials (concept paper on a guideline for allergen
with an adequate number of patients and state- products development in moderate to low-sized study
of-the-art statistical evaluation is required for an populations) has recently been published by the EMA
official approval. for public consultation (EMA/712919/2018).
6. Shared decision-making considering the wishes Where appropriate RCT studies are not possible
of the patient (and the caregiver) are an essential due to rare occurrence and very small patient pop-
part of the indication. ulations, RWE studies may provide clinical data. Due
to the importance of these aspects for the availability
and selection of therapy extracts, the legal provisions
already 4–7 years in terms of cost–benefit aspects in valid for Germany and Europe are presented below.
the German health care system [80–82]. Here, the
long-term effect of AIT, which extends beyond the Legal requirements for allergen products in Germany
duration of the therapy, is particularly significant. and the European Union (EU)
However, such cost–benefit analyses are based on Allergens have been subject to European law since
model variables that may include systematic errors 1989 (Directive 89/342/EEC) [92] and, as defined in
[81]. Directive 2001/83/EC [93], both test and therapeutic
Numerous AIT guidelines have been developed [5, allergens are drugs. According to Article 6 of this Eu-
72–77, 83] and some of the methodologies for evalu- ropean Directive, a drug may not be placed on the
ating evidence vary considerably. So far, none of these market in a Member State unless the competent au-
guidelines use ICPs. thority of that Member State has granted a marketing
As requested by an EAACI Task Force [84], ARIA authorization [72, 86]. All European Union Member
2019 has created ICPs for both SCIT and SLIT [85], as States have at least one national regulatory authority,
presented below. which cooperates within the network or under the co-
ordination of the European Medicines Agency (EMA)
Allergens to use [94].
In Germany, the scope of Directive 2001/83/EC has
Selection of the therapeutic allergen been fully transposed into the German Medicines Act
The decision to prescribe an AIT should be based on (AMG) [95]. According to § 21 (1) AMG, drugs may
the symptoms of allergen exposure, evidence of sen- only be placed on the market in Germany if they have
sitization, clinical relevance, and the availability of been approved by the competent higher federal au-
high-quality therapeutic extracts [72, 86]. thority, the Paul-Ehrlich-Institut (PEI) in Langen. For
AIT products must be effective and safe, in accor- approval, the drugs must be of adequate quality, effi-
dance with regulatory requirements [87–89]. Thera- cacy and safety according to the current state of knowl-
peutic allergen extracts cannot be considered generic. edge. The PEI is responsible for the regulation of al-
In the EU, every single product (single allergen or mix- lergen products based on the applicable national and
ture) has to be proven in an authorization procedure European legislation and guidelines of the EMA [94].
for efficacy and safety [87, 90]. There is restriction In the European Union there are four different pro-
within the so-called homologous groups, which de- cedures for authorizing a medicinal product [94]:
fine allergen sources with significant clinical cross-
Since April 2014, all AIT manufacturers are gov- ciation of German Allergists (AeDA) has recently given
erned by § 130a (1) SGB V to an amended mandatory a comprehensive statement on this topic [106].
rebate of 7% on the price list [101]. This compul- This self-determination for consent to a medical
sory levy is the same for all reimbursable products. procedure according to § 630e BGB (1) (sentences 1
But much stronger affects a so-called price morato- and 2) determines the cooperation of the patient with
rium, which has also been enshrined by law until 2022 the knowledge of the essential circumstances of the
(§ 130a (3a) SGB V and AM-VSG). This price morato- treatment. In particular, this includes information on
rium, which came into effect in July 2010, froze all the nature, extent, implementation, expected conse-
prices at the time of 31 July 2009 [101]. All price quences and risks, the measure and its need, urgency,
increases since this date have subsequently been re- suitability and chances of success in terms of diag-
claimed by the health insurance companies via the nosis or therapy. This enables shared decision-mak-
pharmacy computer centers. This amount, known as ing in the sense of the SDM and should be applied
the “manufacturer’s discount”, must be refunded by from a medical–legal perspective using current medi-
the manufacturer to the respective health insurance cal knowledge on treatment options, risks and bene-
company [101]. Therefore, the manufacturers are cur- fits [106, 107].
rently obtaining only the prices that were valid for According to the German Allergy and Asthma
their preparations on 31 July 2009, further reduced by Association (Deutscher Allergie- und Asthmabund
a mandatory discount of 7% [101]. [DAAB]), the indication for AIT in AR, especially in
In addition, these significant discounts are not the childhood and adolescence, should be generous in
same for all AIT products. Due to different increases order to reduce the risk of allergic asthma [73, 108].
in raw material prices and other costs since 2009, Here, the RKI and EAACI’s demand for early causal
there were very different price increases on the part treatment of hay fever is supported, as the risk of
of the manufacturers. Thus, a look at officially avail- a change in level from AR to allergic asthma is ap-
able price lists reveals a highly distorted picture which parently at its greatest when children are young and
significantly affects the economics of immunother- developing AR [23].
apy. This means that the treatment is much cheaper Adherence to allergen immunotherapy (AIT) is crit-
than suggested by the price list. Of course, for all ical to its effectiveness. A SCIT requires regular (usu-
price comparisons, there are preparation-specific dif- ally monthly) visits during the maintenance phase,
ferences, e.g. fill volumes, injection volumes, injection while a SLIT is performed with a daily intake of al-
distances, up-dosing schemes, making it difficult to lergy tablets or drops at home. Noncompliance with
compare the prices at the annual or 3-year level [81]. an AIT schedule and premature termination of ther-
Thus, the calculation of daily treatment costs apy are common problems [109]. There are contro-
(DTCs)—as usual in other areas of indication—is versial results on termination rates in AIT—but overall
not useful for AIT preparations. In the “Official ATC adherence is low [110]. A good organization plan by
Code” of DIMDI, there is also no DTC information on allergists not only increases safety, but also provides
AIT preparations [81]. the ability to accurately track and improve patient ad-
Therefore, it should be kept in mind that the real herence and compliance [109].
costs of AIT treatment are (almost) always lower than
the costs calculated on the basis of the price lists. The pharmacist’s view
However, these reductions vary for different prepa-
rations [81]. Most patients treat their AR without any interaction
with their physician [111]. Pharmacists are the most
Patient’s view accessible health professionals to the general public
and AR is one of the most common diseases managed
The patient’s view should always be considered to by pharmacists [112, 113].
enable a tailor-made approach to shared decision- Due to the large number of OTC products for AR,
making (SDM). In case studies on state of knowledge, pharmacist consultation plays a key role for most
awareness as a therapy option, expectations and satis- pharmaceuticals.
faction with the AIT, there were sometimes very differ- In Germany, AIT products are available only in
ent assessments between the physician’s view and the pharmacies and the pharmacist is an important
patient’s view [102, 103]. Most studies complain about partner in the entire treatment concept. He/she is
a lack of information on the patient side. Therefore, involved in both organizational issues of drug pro-
every effort should be made to improve communi- curement as well as in the adequate storage and
cation between the physician and the patient, thus transport of AIT preparations. He/she may also have
contributing to a better understanding and patient essential advisory functions on fundamental issues,
satisfaction [104, 105]. Before initiating an AIT, pa- such as the importance of AIT in inhalation allergies.
tients should be informed about the procedure, type In addition, the pharmacist can inform the patient
and duration of treatment, expected effects, potential about the risk–benefit balance, as well as the benefits
risks and possible alternatives. The Physician’s Asso- of an adequate therapy duration.
General practitioner’s view nents may bring potential benefits in the indication
for AIT, especially in pollen allergies. Patients without
In many European countries, the diagnosis and treat- sensitization to major pollen allergens are expected to
ment of allergic diseases takes place in the family have low or no response to AIT with commercial aller-
practice [114, 115], but an AIT is rarely prescribed gen extracts as these are standardized for their major
there. In Germany, this situation is at least partly dif- allergen content [125–127]. Panallergens such as pro-
ferent. A high number of specialists combined with filine or polcalcine are mostly clinically not significant
close networking between general practitioners (GPs) but explain false-positive results in skin tests and in in
and specialists could be even more important for vitro laboratory diagnostics. Sensitization to panaller-
a good care with AIT in the future. The continuous, gens is not an indication for AIT [125–127]. Data from
accessible and holistic situation of GP treatment is a retrospective study confirm a better success of AIT
important and can support the identification of al- with pollen allergens in patients with sensitization to
lergy patients, enable early diagnosis, and be used for major allergens [126]. Other studies show that the ad-
periodic follow-up of allergy patients to assess disease ditional determination of allergen components led to
control, treatment adjustments, and patient-centered a change in the decision by the prescribing specialists
SDM [116–118]. But only few general practition- on AIT in around half of the children with allergic sea-
ers receive formal basic training in allergology [119, sonal rhinoconjunctivitis [125, 127]. Further prospec-
120]. AIT risks can be minimized when AIT is per- tive studies as to whether the therapeutic benefit of
formed by experienced physicians with well-trained AIT with pollen allergens including molecular allergy
personnel and only suitable patients are treated in an diagnostics can be improved are necessary and still
environment with available emergency care facilities pending.
for the treatment of systemic anaphylactic reactions A flow chart for the step-by-step approach to the
[121–124]. indication of an AIT has been developed (Fig. 8; [1,
2]).
Practical approach to patient selection in AIT
Rhinitis and rhinoconjunctivitis in adolescents and
According to the German S2k guideline, AIT is to be adults
performed by physicians who have either the addi- Guidelines and various recommendations from ex-
tional training in allergology or adequate therapy ex- perts in AR pharmacotherapy usually suggest the ap-
perience and are able to treat emergency adverse drug proach summarized in Infobox 1 [3–5]. All recom-
reactions (anaphylactic shock, severe asthma attack, mended medications are considered safe at the usual
etc.) [75]. dosage, with the exception of first-generation oral H1-
Since 1 January 1996, the instructions for use and antihistamines and depot-corticosteroids that should
the summary of product characteristics of the hy- be avoided [18]. MACVIA has developed a simple algo-
posensitization solutions used in Germany must con- rithm for step-up and step-down management (Fig. 6;
tain the following warning: “Hyposensitizing vaccines [33]).
for injection may only be prescribed and used by al- In children and adolescents with AR, there is evi-
lergological trained or experienced physicians.” (Paul- dence from clinical trials that an AIT may reduce the
Ehrlich-Institut, decision of 5 April 1995) [75]. risk of developing asthma [73, 108]. Therefore, the
In principle, the patient perspective should always early use of a causal form of therapy in the sense of
be considered in the sense of shared decision-making AIT should be demanded, especially in these patients.
(SDM).
Written information (“Therapy Information Sheet”) Asthma in adolescents and adults
on the conduct of the AIT and on the handling of AIT should not be used in patients with severe asthma.
possible side effects is available as an appendix in the Biologicals in severe asthma and AIT in allergic dis-
German S2k [75] guideline and should be made avail- eases target two different patient populations. An
able to the patient. algorithm for asthma is not yet available. Uncon-
If AIT is performed or continued by another physi- trolled asthma is still a contraindication for AIT [128].
cian after the indication has been given, then close GINA (Global INitiative for Asthma) has included
collaboration is required to ensure the consistent im- a SLIT in its treatment recommendations for house
plementation and low-risk performance of the AIT dust mite-induced asthma [129]. The summary of
[75]. This is especially true for the occurrence of ad- product characteristics for the approved SLIT house
verse drug reactions (ADR). dust mite tablet [130] shows that (i) the patient should
not have had a severe asthma exacerbation within the
Selection of suitable patients by molecular component last 3 months after the onset of AIT, (ii) in patients
diagnostics with asthma and acute respiratory infection, the start
The approach of precision medicine for the selection of treatment should be postponed until the infec-
of an AIT regime is gaining more and more attention tion has subsided and (iii) AIT is not indicated for
[2, 125–127]. The determination of allergen compo- the treatment of acute exacerbations and patients
must be informed of the need to consult a physi- adults. A limited number of studies have shown that
cian immediately if their asthma suddenly worsens, AIT can also be effective in a population of elderly
(iv) furthermore, AIT against HDM should initially patients [140, 141]. For a universal recommendation,
be used as adjunctive therapy for the treatment of however, more data are required.
anti-asthmatic pharmacotherapy, and the reduction
of asthma medication should be carried out step by mHealth in the AIT precision medicine approach
step under the supervision of a physician according
to the management guidelines. So far, only one AIT The selection of patients for AIT can be facilitated by
product has been approved for asthma as a major electronic diaries accessed via smartphones [20, 21,
indication in a European procedure. 42] or other mHealth tools. Such diaries should query
the symptoms of AR as well as the drug consump-
Multimorbidity tion. For this, they should provide a complete list of
Multimorbidity—the simultaneous presence of more medications available in the country for that partic-
than one disease in a patient—is very common in al- ular condition. Based on patient-documented data,
lergic diseases, and over 85% of patients with asthma physicians can assess whether (i) a moderate uncon-
also suffer from AR. On the other hand, only 20–30% trolled disease is present, (ii) symptoms are associated
of patients with AR have asthma at the same time. AR with a pollen season or other allergen exposure and
multimorbidity increases the severity of asthma [131]. (iii) the pharmacological treatment is following the
AIT is able to control AR, conjunctivitis, and asthma- recommendations for uncontrolled symptoms. Physi-
multimorbidity, which was considered in the market- cians can also assess the duration of uncontrolled
ing authorization for a SLIT HDM tablet [130]. Other symptoms and the impact on productivity or aca-
atopic disorders, such as atopic dermatitis and/or demic performance. An electronic clinical decision
food allergies due to cross-reactivity of food allergens support system may help in selecting AIT patients in
with inhaled allergens, as well as other known comor- the future [34].
bidities (e.g. depression), may increase the disease
burden [132–134]. Follow-up of patients with AIT The same approach
can be used to assess efficacy, provided there is a re-
AIT in children liable data input, for the progress monitoring and fol-
AIT in children may have short-term effects like symp- low-up of AIT patients [81, 84].
tom-relieving, anti-inflammatory and drug-saving, as
well as positive long-term effects. For specific prod- Conclusion
ucts, efficacy has been demonstrated in pediatric
studies [135] as have long-term beneficial effects Because of their incidence and chronicity, massive
[136]. A recent SLIT study [137], an earlier grass health restrictions for those affected, and the enor-
pollen SCIT study [138], and a meta-analysis [139] mous direct, indirect, and intangible costs involved,
all provided evidence for the products under study allergic diseases are a massive social problem for the
that AIT may delay the onset of childhood asthma health systems of many countries, as well as a health
[138] or prevent the short-term risk of asthma devel- economic problem for many national economies. As
opment [139]. The meta-analysis showed a limited structured, multidisciplinary care plans, ICPs describe
reduction in the short-term risk of developing asthma the key aspects of patient care and promote the im-
in patients with AR but with unclear benefit over plementation of guidelines and their application to
a longer period [139]. In children with AR without the healthcare situation. Before many other diseases,
asthma, consideration should be given to the pos- ICPs for respiratory diseases (AIRWAYS ICPs) were de-
sibility of preventing the onset of asthma, although veloped. Digitalized algorithms facilitate the applica-
further studies are needed for an unrestricted recom- tion and improve the effectiveness and safety of the
mendation [73]. The authors of this article emphasize therapy, self-management strategies and resource uti-
that the use of the only causally and potentially pre- lization.
ventively effective therapy form of AR, namely AIT, ICPs can improve the management of both phar-
should be considered at an early stage, especially in macotherapy and AIT. With the present publication,
children. In children with moderate/severe AR, an this international recommendation of ARIA is trans-
AIT should be initiated early if all other conditions ferred to the German healthcare situation.
are met. Direct specialist access in the German health
Funding Article processing charges were provided by the
system, also to an allergist, pediatric allergist or pedi- German Society of Allergology (AeDA).
atric pulmonologist, facilitates the early use of AIT by
utilizing its preventive effects. Conflict of interest C. Bachert reports personal fees from
Mylan, Stallergenes and ALK, outside the submitted work.
AIT in elderly patients S. Becker reports personal fees from ALK, Allergopharma,
HAL Allergy, Bencard Allergy, Sanofi-Genzyme, Thermo
The immunological situation of elderly allergic pa- Fisher Scientific and B.R.A.I.N AG, grants and personal fees
tients may differ from that of children and younger
from PARI GmbH, outside the submitted work. T. Bieber Linnemann, V. Mahler, N. Mülleneisen, K. Hörmann, K. Jung,
reports personal fees from Sanofi, Novartis, AbbVIe, Gal- W. Fokkens, T. Fuchs, M. Gerstlauer, E. Hamelmann, J. Ring,
derma, Pfizer, Lilly, Kymab, outside the submitted work. W. Schlenter, H. Seyfarth, A. Sperl, T. Spindler, P. Staubach,
J. Bousquet reports personal fees from Chiesi, Cipla, Hikma, A. Wallrafen, W. Wehrmann, T. Werfel, H. Wrede and T. Zu-
Menarini, Mundipharma, Mylan, Novartis, Purina, Sanofi- berbier declare that they have no competing interests.
Aventis, Takeda, Teva, Uriach, other from KYomed-Innov,
outside the submitted work. R. Brehler reports personal Open Access This article is distributed under the terms of
fees form Berufsgenossenschaften, Gerichten, ÄK Nord- the Creative Commons Attribution 4.0 International License
württemberg, ÄK Westfalen-Lippe, ALK, Allergopharma, (http://creativecommons.org/licenses/by/4.0/), which per-
Allmiral, Apothekerkammer, Astra Zeneca, Bencard, DPC, mits unrestricted use, distribution, and reproduction in any
Gesellschaft zur Förderung der Dermatologischen Forschung medium, provided you give appropriate credit to the origi-
und Fortbildung, GSK, HAL, HNO-Gesellschaft, Leti, Novar- nal author(s) and the source, provide a link to the Creative
tis, Pohl-Boskamp, Pfleger, Phadia, Update GmbH, Staller- Commons license, and indicate if changes were made.
genes, grants from Biotechtools, Genentech, Novartis, Ben-
card, HAL, AstraZeneca, ALK, outside the submitted work.
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