Canonica_EU Respiratory Disease 21/04/2011 09:00 Page 67

Allergic Rhinitis

A Review of Allergic Rhinitis

Erminia Ridolo,1 Enrico Compalati,2 Elisa Olivieri1 and Giorgio Walter Canonica2
1. Department of Clinical Sciences, University of Parma; 2. Allergy and Respiratory Diseases Clinic, Department of Internal Medicine, University of Genoa

Abstract
Allergic rhinitis (AR) is the most widespread type of non-infectious rhinitis. In 2001, the Allergic Rhinitis and its Impact on Asthma (ARIA)
group classified AR as intermittent/persistent or mild/moderate-severe, based on the duration/chronicity and the severity of symptoms
and the impact on patients quality of life. It is generally associated with co-morbid disorders such as conjunctivitis, sleep disturbances
and obstructive sleep apnoea, with a severe impact on quality of life. The most relevant co-morbidity is asthma (38% of all AR patients
present with asthma symptoms) in accordance with the recent definition of united airway disease (UAD). Pharmacotherapy must be
considered as the cornerstone intervention and, particularly, antihistamines and intranasal corticosteroids. The treatment for AR is
effective in the majority of patients, a remaining 20% do not achieve symptom control with an adequate pharmacological treatment; they
suffer from severe chronic upper airway diseases (SCUADs). Specific immunotherapy (SIT) is considered the only curative treatment
against AR. It reduces the clinical manifestations of the disease and drug consumption with a carry-over effect (long-lasting persistence
of effects after discontinuation) and it seems to prevent the onset of new sensitisations, reducing the risk of asthma onset. Sublingual
immunotherapy (SLIT) was first accepted as a viable alternative to subcutaneous immunotherapy (SCIT) in the 1998 World Health
Organization (WHO) position paper; it is widely used in Europe and other countries, and registrative studies are ongoing in the US.
Chemically altered allergens, allergoids, recombinant allergens and relevant T-cell epitope peptides are expected to be promising
approaches for the future of SIT.

Keywords
Allergy, rhinitis, comorbidity, treatment, specific immunotherapy
Disclosure: The authors have no conflicts of interest to declare.
Acknowledgements: The drafting of this article has been partially supported by Global Allergy and Asthma European Network (GA2LEN) and Associazione Ricerca Malattie
Immunologiche e Allergiche (ARMIA).
Received: 13 January 2011 Accepted: 14 March 2011 Citation: European Respiratory Disease, 2011;7(1):6772
Correspondence: Giorgio Walter Canonica, Allergy and Respiratory Diseases, Department of Internal Medicine, Genoa University, Pad. Maragliano L.go R. Benzi 10, 16132
Genova, Italy. E: canonica@unige.it

Allergic rhinitis (AR) is usually defined as an inflammatory disease of the

nasal mucosa educed by an interaction of environmental allergens and
immunoglobulin E (IgE) in sensitised patients.1 Aeroallergens stem from
a extensive range of flora and fauna or job-related sources and are
usually classified as indoor (primarily mites, pets and insects) or
outdoor (pollens or moulds).2
AR is the most widespread type of non-infectious rhinitis. Its symptoms
are sneezing, nasal itching, rhinorrhoea and obstruction. Ocular signs
such as eye itching, redness and tearing occur in a large percentage of
patients with AR.1
Epidemiologically, AR represents a health problem for both children and
adults on a global basis. The rate of AR across Europe is around 18% of
the population.1 In the US, AR affects a range of 1030% of adults and
up to 40% of children.3 This percentage, equivalent to 2040 million
patients, corresponds to sixth position among the chronic illnesses.4
In many countries, particularly those where AR is relatively infrequent2
and among patients of paediatric age,2,5 AR incidence is increasing.
Nevertheless, around one-third of allergic patients has never been
visited by a physician.1 This observation suggests that the actual

TOUCH BRIEFINGS 2011

prevalence may be underestimated6 and the condition may be

mistreated as well. As AR is often categorised as a multifactorial disease,
many hypotheses have been suggested to explain its rising occurrence.2
As in the case of asthma, genetic factors may influence the
development of AR; these diseases reveal strong familial and intraindividual clustering, implying an overlapping disease aetiology.7
The socio-environmental hypothesis is based on several studies
demonstrating that the urbanisation process, high levels of motor
engine pollution and western lifestyle are significantly linked to the high
incidence of respiratory allergy diseases (rhinitis, above all), prevailing
for those who inhabit metropolitan regions compared with those who
live in the countryside.
Some studies found out how ethnic origins affected the development of
AR: migrants from emerging to industrialised countries showed a higher
predisposition to develop allergy and asthma in the receiving
countries.2 This finding suggests that a genetic background is not
necessarily required to develop this kind of allergy; way of life and
environmental issues in industrialised areas would be more relevant
than ethnicity.8

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Allergic Rhinitis
Figure 1: Classification of Allergic Rhinitis in
Untreated Patients
Intermittent

Persistent

<4 days per week

or <4 weeks

4 days per week

and 4 weeks

Mild
Normal sleep
and no impairment of daily
activities, sport, leisure
and normal work and school
and no troublesome symptoms

Moderatesevere
(one or more items)
Abnormal sleep
Impairment of daily activities,
sport, leisure
Abnormal work and school
Troublesome symptoms

Source: Bousquet J, van Cauwenberge P, Khaltaev N, ARIA Workshop Group; Health

Organization, Allergic rhinitis and its impact on asthma, J Allergy Clin Immunol,
2001;108(Suppl. 5):S147334.1

Climate changes have recently been held responsible for the

increasing prevalence of AR and asthma, since it affects aeroallergens,
principally pollens and moulds. In the case of warmer temperatures,
pollen concentration rises,914 with earlier onset7,8 and extended
duration9,10 of seasonal allergens and a consequent strong impact
on the severity of allergic diseases. Even though changes in pollen
levels experienced in the long run will probably vary by area,
the climate change perspective could worsen AR incidence in the
coming decades.

Antigen-presenting cells (APCs) in the nasal epithelial mucosa process

aeroallergens; this is followed by the presentation of allergenic peptides
by major histocompatibility complex (MHC) class II molecules to T-cell
receptors on resting CD4 T-lymphocytes in regional lymph nodes.
Allergen-stimulated T-cells, under co-stimulatory signals, proliferate
into T-helper type 2 (Th2)-biased cells and release different cytokines
such as interleukin-3 (IL-3), IL-4, IL-5 and IL-13. They are able to
promote B-cell isotype switching. This process causes a subsequent
local and systemic production of allergen-specific IgE antibody by
plasma cells, eosinophilic and mast cell proliferation and infiltration of
airway mucosa.17,18
Local IgE has been found in a variety of tissues, including nasal and
bronchial mucosa. IgE is produced within these tissues and does not
necessarily migrate from regional lymphoid tissue or blood. Local IgE
has been identified in most AR patients and in both atopic and
non-atopic asthmatic patients. In fact, around 40% of patients with
idiopathic rhinitis and with positive nasal provocation tests show local
production of IgE.19 The late-phase response is characterised by
activated eosinophil and neutrophil infiltration and accumulation of
their products.20 Clinical symptoms during the early and late phases
might be similar to each other; nonetheless, the latter shows more
prominent nasal congestion.

AR can be classified as seasonal or perennial according to the time of

exposure to allergens. The latter is commonly produced by indoor
allergens such as moulds, insects, dust mites and animal danders. The
former is related to a wide variety of outdoor allergens, pollens and
moulds.2 This classification, although still used in some parts of the

Identified by Connell in 1969, the priming effect is the process of

upregulation of the sensitivity to allergen by which, when challenges are
continuously repeated, a lower allergen amount is needed to elicit an
immediate response. The nasal mucosa becomes gradually more
irritated and receptive to allergen. This is why patients might have
more severe symptoms than previously experienced regardless of low
aeroallergen concentration. Connell also demonstrated that priming
with one allergen can result in hypersensitivity to other kinds of
allergens.21 More recently, the knowledge of the biochemical and cellular

world, is not really valid.

mechanisms implicated in priming has considerably grown.

In fact, more recently, in 2001, the Allergic Rhinitis and its Impact on
Asthma (ARIA) group put forwards a new classification, in order to
determine the issues not explained by the previous classification, such
as individuals sensitised to seasonal allergens experiencing symptoms
throughout the year, and others sensitised to perennial allergens
showing intermittent symptoms.

Canonica et al., in 2001, established that a state of subclinical

inflammation due to a subliminal exposure to allergen is present in
asymptomatic patients and associated with the occurrence of
eosinophils and neutrophils in the nasal mucosa, with a larger presence
of intercellular adhesion molecule-1 (ICAM-1) expression on epithelial
cells. This, defined as minimal persistent inflammation (MPI), is the
rationale of the priming effect. This evidence has been documented in
patients with AR caused by indoor and outdoor triggers during
symptom-free periods.20 Based on this evidence, patients with MPI
have a higher risk of developing symptoms, needing continuous
anti-inflammatory therapy also during symptom-free intervals.

The new classification is based on the duration/chronicity and the

grading of severity (mild or moderatesevere) of symptoms. It also
takes into account the impact of the disease on daily activities,
work/school performance and impaired sleep.
Regarding duration of symptoms, intermittent AR is defined when they
occur on less than four days per week or less than four consecutive
weeks per year. Conversely, persistent AR occurs when symptoms are
present for more than four days per week and more than four
consecutive weeks per year1 (see Figure 1).

Aetiopathogenesis
A classic immediate hypersensitivity reaction causes AR: the binding
of allergen to mast cell-bound IgE produces mast cell degranulation,
and consequently increased levels of inflammatory mediators and
local infiltration of inflammatory cells.15,16 These events are defined as
the early-phase response.

68

Co-morbidity
Isolated AR is rare; it needs to be considered within systemic allergic
disease, generally associated with co-morbid disorders such as
conjunctivitis, chronic middle ear effusions, irregular sleep, sinusitis,
lymphoid hypertrophy and obstructive sleep apnoea. All these
problems affect patient behaviour, school or job performances.
Among these disorders the most relevant co-morbidity is asthma. The
numerous past observations of the link between upper and lower
airways recently generated the united airway disease (UAD) definition.
The relationship between the two compartments, verified at
experimental level, is clinical, epidemiological, functional and

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A Review of Allergic Rhinitis

immunological; subsequently, it has been declared in official

statements. In particular, rhinitis, both allergic and non-allergic, has
been acknowledged as a risk factor for asthma.22 This permits the
modulation of immunological and clinical response in rhinitic patients in
order to prevent asthma onset.
Epidemiologically, recent surveys show that around 38% of all AR
patients present asthma symptoms too. On the other hand, 78% of
asthma patients present rhinitis symptoms.2
This correlation is particularly relevant among adults characterised by a
family history of asthma and rhinitis. For these subjects, developing
rhinitis and asthma is, respectively, two to six and three to four times
greater than adults without such a history.2 The same occurrence has
been observed by Ponte, who claims high correlation between more
severe rhinitis and more severe asthma.23
This finding is based not only on epidemiological data but also on
physiological evidence. In fact, patients with AR (even without asthma)
show a higher frequency of bronchial hyper-reactivity. This could be
linked to the duration of AR and the number of sensitisations of
the patient.24
Moreover, Crimi et al. in 2008 carried out methacholine challenge
tests on AR patients (without airway hyper-responsiveness by
standard testing) and on healthy controls, finding a decreased
improvement in lung function parameters in deep inhalation taken
after the methacholine challenge. Their conclusion is that airway
smooth muscle function is altered in patients with AR.25
Furthermore, AR can be considered a risk factor for asthma
exacerbation. In asthmatic patients AR induces worse asthma control
and more frequent asthma attacks and admission to the emergency
room; in addition, the use of drugs for asthma significantly increases
with the severity of AR, as shown by Magnan and Bousquet.26,27
Other co-morbid disorders often linked to AR are as follows.
Allergic conjunctivitis (complex sometimes referred as allergic
rhinoconjunctivitis), which results in conjunctival injection and
chemosis and symptoms of itchy eyes and tearing.28 These
symptoms have been observed in more than 75% of patients with
AR caused by pollens. Moreover, patients sensitised to pollens
report ocular symptoms more than patients sensitised to house
dust mites.
AR patients, compared with non-allergic subjects, more
frequently show rhinosinusitis. These findings could suggest an
association between AR and rhinosinusitis via IgE-mediated
hypersensitivity.29
On the other hand, patients with AR, particularly those sensitised
to house dust mites, rarely exhibit nasal polyps.30
Some studies show that around 21% of AR patients are affected
by otitis media.31,32 In the case of AR children, the incidence of
otitis media is twice that of non-allergic children. Other studies
determined the functional link between AR and otitis.3335
Among AR children, particularly those sensitised to dust mites,
adenoid hypertrophy (AH) occurred significantly more frequently
than in children with other allergic diseases (asthma/atopic
dermatitis) or without allergies.36 Other observations show that
child sensitisation to mould is linked to adenoid hypertrophy.37

EUROPEAN RESPIRATORY DISEASE

No clear evidence has been found between rhinitis and hearing

impairment, 38 even though Toubi et al. reported a slightly
increased prevalence of atopy among subjects diagnosed with
sensorineural hearing loss.39
Finally, AR is considered one of the major causes of impaired
nasal function, with its related sleep disturbances, affecting
patients daytime concentration and sleepiness.40,41

Quality of Life and Financial Impact

Both the presence of AR and its required treatment affect quality of life
for adults42 and children. Negative aspects usually recorded among AR
patients include:
poor-quality sleep;
daytime tiredness;
school/job distraction, with subsequent low performance and
productivity; and
emotional problems,43 such as ill humour, lower efficiency and
greater proneness to work-related accidents, shyness, depression
and anxiety.
The assessment of health-related quality of life in rhinitis, and asthma
as well, can be measured through specific and validated tools.44
Despite the treatment for AR helping to manage symptoms in the
majority of patients, a remaining 20% of patients do not achieve
symptom control with the best possible treatment; they suffer from
severe chronic upper airway diseases (SCUADs).45 In these cases,
symptoms seriously affect quality of life, social life, sleep and
school/work performance. Therefore, SCUAD patients require more
effective treatment.
On the other hand, this disease generates significant costs, usually
categorised as direct and indirect. Direct costs are related to outflows
due during the disease period; indirect costs are connected with
missing work/school and decreased productivity. Other hidden
costs are associated with the co-morbidities of AR, such as asthma
and sinusitis.46

Diagnosis
The concordance of a typical history of allergic symptoms and diagnostic
tests is at the basis of AR diagnosis. The medical history takes account
of symptoms reported by patients, such as the pattern, chronicity,
seasonality and triggers of nasal and related symptoms; family history;18
current medications and response to previous treatments; the presence
of co-existing conditions; occupational exposure; and a detailed
environmental history.
A skin prick test is usually considered the standard procedure to
support an allergic basis for the patients symptoms, confirm suspected
causes of the patients symptoms, and/or assess sensitivity to a
specific allergen. The reasons for prefering skin prick tests over the
determination of specific IgE (sIgE) by in vitro tests are high sensitivity,
rapidity of performance, simplicity, ease of use and low cost.
Nonetheless, particular situations (extensive skin disease, skin test
suppressive therapy such as antihistamines that cannot be
discontinued, or uncooperative patients, etc.) suggest using sIgE
immunoassays. Many studies report that sIgE immunoassay sensitivity,
when compared with skin prick tests, is around 7075%.4750

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Allergic Rhinitis
Table 1: Step-wise Approach in the Pharmacotherapy of
Allergic Rhinitis
Step

AR intensity

Treatment

Mild intermittent rhinitis

Oral or intranasal H1-antihistamines with

Moderate-to-severe

Oral or intranasal H1-antihistamines or

intermittent and mild

intranasal corticosteroids with limited use

limited use of decongestants, or LTRAs

persistent rhinitis

of decongestants or LTRAs (or chromones)

Moderate-to-severe

Intranasal corticosteroids with step-down

persistent rhinitis

and step-up options, antihistamines or

Finally, positive nasal smear (>10% eosinophils) shown by nasal

cytology for eosinophils may suggest nasal challenge when a high
suspicion of allergy in a history-positive patient remains and skin
prick tests are negative.58

Treatment
The optimal behaviour minimising AR symptoms and, consequently,
required medical treatment, would be the elimination of contact with the
allergen. This approach is important in therapeutic terms, but
unfortunately often impractical or unsatisfactory.

LTRAs and in addiction ipratropium or

nasal decongestants and oral steroids for a
short term
AR = allergic rhinitis; LTRA = leukotriene receptor antagonist.

To evaluate skin tests or in vitro tests it is crucial to find out which kind
of aeroallergens are locally observed and their cross-reactivity with
botanically related species. The limited value of measurement of total
IgE for the diagnosis of AR suggests avoiding its frequent application.
Useful to determine IgE-mediated allergy, the component-resolved
diagnosis (CRD) is a test that originated with the cloning of the allergen
Der p 1 from house dust mite, proposed in the late 1980s.51 The benefit
of CRD is the quantification of sIgE antibodies to single purified or
recombinant components, and it includes marker allergens to determine
the actual sensitisation of patients to a given allergen source and/or
cross-reactive molecules that point to cross-sensitisation to several
allergen sources.52
Unfortunately, since the number of different purified and recombinant
allergen components has steadily increased, analysing all the
single allergen components in a patient by traditional singleplex sIgE
tests has become virtually impossible. The CRD concept has been
widened to multiplex testing with more than 4,000 components on
microarrays.5355 This multiplexing allows identification of the diagnostic
patterns, facilitating diagnostic algorithm formulation. Before extending
multiplexed CRD on a general basis, additional comprehensive studies
are required.
Tests applied outside of routine diagnosis of AR are useful in
particular patients.
Pulmonary function tests are useful to detect symptoms of asthma.
These tests are helpful since some patients may find it difficult
to recognise their symptoms, suffer from variable symptoms
throughout the day, have a normal-appearing physical examination
of the respiratory system18 and show atypical symptoms.
Fibre optic nasal endoscopy can be effective in case of atypical
symptoms or physical findings, complications or other suspected
conditions, or when symptoms apparently do not respond to
therapy. For suspected complications or co-morbidities such as
nasal polyposis with sinusitis, computed tomography (CT) scan and
magnetic resonance imaging (MRI) may be useful.
To define the severity of anatomical abnormalities causing nose
airway obstruction, including nasal valve abnormalities, septal
deviation and polyposis, rhinomanometry could be suggested;
moreover, to confirm sensitisation to an allergen and the efficacy of
drugs and allergen immunot, nasal allergen challenge is generally
applied. When local AR is associated with nasal production of sIgE
antibodies in the absence of atopy (observed in >40% of non-allergic
rhinitis patients), a nasal allergen challenge test is suggested.56,57

70

This conclusion is based on much experimental evidence. In particular,

regarding indoor allergy, an updated Cochrane review concluded that
the use of acaricides and extensive bedroom-based environmental
control programmes may be of some benefit in reducing rhinitis
symptoms but the isolated use of house-dust-mite-impermeable
bedding frequently is not effective.59
Therefore, in the vast majority of AR cases, pharmacotherapy must be
considered as the cornerstone intervention and, particularly,
antihistamines and intranasal corticosteroids should be considered as
the first-line agents, as first recommended by the ARIA document.
In the case of patients whose symptoms are under control, ARIA
recommends a minimum quantity of medication to manage the
exacerbations of symptoms. Three steps have been defined within the
ARIA guidelines as a treatment for AR patients, as shown in Table 1.

Antihistamines
Antihistamines improve early-phase H1-receptor-mediated symptoms
such as sneezing, itching, rhinorrhoea and, to a lesser degree, nasal
congestion. They also exhibit a range of other anti-inflammatory
properties, affecting several events, such as chemotaxis and survival
of eosinophils, expression of adhesion molecules and release of
chemokines and Th2-type cytokines from different sources,
through receptor-dependent and -independent mechanisms (i.e.
downregulation of intracellular signalling pathways, such as nuclear
factor-kappa B [NF-B]).
Antihistamines are usually administrated on demand. Nonetheless,
some evidence shows that continuous use of these molecules
decreases MPI by diminishing the infiltration of inflammatory
cells. This means that continuous treatment requires the best safety
profile. This can be supplied by the second-generation antihistamines,
with a low sedation impact, low performance impairment and no
anticholinergic adverse effects.18
In terms of sedation, second-generation antihistamines show different
effects: some do not cause sedation at recommended doses
(fexofenadine, loratadine and desloratadine); others could cause
sedation at doses exceeding the recommended dose (loratadine
and desloratadine) and finally, cetirizine may cause sedation at
recommended doses.
In general terms, the second-generation antihistamines show a good
level of tolerability, since they do not provide changes of bioavailability
when administered concomitantly with food and alcohol.60 Moreover,
they are characterised by a long duration of action, even with a
once-daily dosing. Thanks to a new fast-dissolving tablet (FDT)
formulation, ebastine shows faster symptom relief.61

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Some of these molecules may affect allergic pathogenesis at different

levels, showing multiple receptor antagonism. Particularly, rupatadine,
unlike other types of antihistamines, contains two different portions
with antagonist activity, respectively to H1 and platelet-activating
factor (PAF) receptors. The efficacy of the latter mechanism affects
nasal congestion: this can be considered as the value added to control
rhinitis symptoms.6266

Oral Corticosteroids
In the rare cases of patients affected by severe nasal symptoms
uncontrolled by other treatments, oral corticosteroids (OC) are
suggested to be administered. An OC course of around fiveseven
days may be appropriate for the treatment of serious nasal
symptoms, particularly in adults.18

Specific Immunotherapy
Intranasal Corticosteroids
The therapy aimed at treating moderate-to-severe intermittent
and persistent rhinitis is based on intranasal corticosteroids. This
treatment is recommended to control more comprehensively allergic
symptoms for its powerful effect on nasal obstruction, along with
the advantages that characterise single-agent treatments (higher
adherence, cost-effectiveness, reduced risk of side effects).67 Other
features of the intranasal corticosteroid formulations developed
more recently (mometasone, fluticasone) are low systemic
bioavailability and mild adverse effects, such as nasal dryness or
blood-tinged secretions.68
In order to increase patient adherence it is important to help them
to appreciate the role of these agents and to demonstrate how to
dispense them properly, particularly because intranasal corticosteroids
are widely used in both adults and children.
To manage this matter, more recently a new generation of inhaled
corticosteroids (ciclesonide) administrated and activated on site
has been developed. Ciclesonide has demonstrated some advantages,
such as targeted activation in the nose and the lung, and minimal
systemic adverse effects, conjugated with a significant efficacy.69
This explains the potential to ameliorate compliance rates and
therapeutic results.70

Leukotriene Receptor Antagonists

Leukotriene receptor antagonists (LTRAs) are successful in the
treatment of AR caused by indoor and outdoor allergens, well
tolerated and with a favourable safety profile; the efficacy of LTRAs
and antihistamines (loratadine) has been proved to be similar, but less
than that of the intranasal corticosteroid (fluticasone propionate).71
Their concomitant use with antihistamines may be additive and
useful for patients who are unresponsive to or not compliant with
intranasal corticosteroids but in general this approach is less
efficacious than intranasal steroid single-agent treatments.
Adding LTRAs (such montelukast) to a second-generation
antihistamine may generate a value-added benefit for AR and provide
better protection against seasonal decrease in lung function.72 Since
around 40% of patients with AR suffer from asthma, LTRA treatment
has resulted in significant improvements in both, compared with
placebo; particularly, montelukast is suggested when treatment may
provide a benefit for upper and lower airways.73

Intranasal Anticholinergics
Increased cholinergic hyper-reactivity has been found in some
patients with AR. A relevant proportion of histamine- and
antigen-induced secretion appears to be cholinergically mediated. In
this case, intranasal anticholinergics are recognised to be effective
in order to reduce rhinorrhoea. On the other hand, they have no
effect on other nasal symptoms. Although side effects are minimal,
dryness of the nasal membranes may be observed.74

EUROPEAN RESPIRATORY DISEASE

For its ability to modify the Th2-biased immune response, specific

immunotherapy (SIT) is considered the only curative treatment
against AR. 75,76 Randomised controlled trials with double-blind
placebo control (RCT DB) have demonstrated that SIT presents the
benefits of reducing the clinical manifestations of the disease and
drug consumption, improving the carry-over effect (long-lasting
persistence of effects after discontinuation), preventing the onset of
new sensitisations and reducing the risk of asthma onset.77,78 SIT is
able to improve quality of life of allergic patients. The administration
of SIT should start early in the disease process so as to modify,
through an immune-modulation process, the natural progression of
the disease, including small airway inflammation. The route for the
administration of SIT is either subcutaneous (SCIT) or sublingual
(SLIT), with the allergen kept under the tongue for one to two minutes
and then swallowed.
SCIT is effective in the treatment of AR in adults and adolescents.79 A
typical treatment course requires monthly injections over a period of
three to five years. The benefits of treatment may continue for many
years following cessation. According to RCT DB and large trials, this
treatment is effective and has a sustained and long-lasting positive
effect but potential adverse reactions still remain the key drawback.
Many studies have confirmed the clinical efficacy of SLIT in terms
of symptom and drug-intake reductions, with a doseeffect
relationship.80 Moreover, after SLIT treatment a significant reduction
in the development of a specific bronchial hyper-responsiveness has
been observed. All clinical trials and surveys agree that SLIT is safe
(no fatalities or events described as anaphylaxis), allowing for
administration of this treatment outside of the medical setting,
meaning SLIT is not a time-consuming treatment in contrast to SCIT.81
The majority of mild adverse reactions were mouth and lip itching,
other gastrointestinal symptoms, rhinoconjunctivitis or urticaria. All
these matters can be solved with a dose adjustment. Some
studies demonstrated the long-lasting effect, also showing that the
duration of the effect is partially dependent on the duration of
immunotherapy itself. The optimal duration of SLIT to achieve a
long-lasting effect is four years and a duration of five years adds only
marginal additional benefits.8284
SLIT first was accepted as a viable alternative to SCIT in the 1998
World Health Organization (WHO) position paper, then included in the
ARIA guidelines. It is widely used in Europe and other countries,
whereas no product is yet approved in the US. Even though used on
an experimental basis, chemically altered allergens, allergoids,
recombinant allergens and relevant T-cell epitope peptides are
expected to be promising approaches for the future of SLIT.
Very recently, the ARIA document was updated on some of the critical
issues on AR treatment using the grading of recommendation,
assessment, development and evaluation (GRADE) system to make
clinical recommendations.85 n

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Allergic Rhinitis
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14.

15.

16.
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18.

19.

20.

21.
22.

23.

24.

25.

26.

27.

28.

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