Official Journal of the
`Official Journal of the
`European Academy of Allergology
`European Academy of Allergology
`and Clinical Immunology
`and Clinical
`Immunology
`
`

`

`Official Journal of the
`Official Journal of the
`European Academy of Allergology
`European Academy of Allergology
`and Clinical Immunology
`Immunology
`and Clinical
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`applied allergology and immunology, and articles which contribute to this purpose are
`applied allergology and immunology,
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`are
`especially welcomed. Allergy is an international journal with contributors and readers_ in all
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`
`

`

`Allergy
`Printed
`
`2000: 55: 116-134
`in UK All rights
`
`reserved
`
`Position paper
`
`Copyright © Munksgaard
`
`2000
`
`ALLERGY
`ISSN 0105-4538
`
`Consensus statement* on the treatment of allergic rhinitis
`
`P. van Cauwenberge (Belgium)
`C. Bachert (Belgium)
`G. Passalacqua (Italy)
`J. Bousquet (France)
`G. W. Canonica (Italy)
`S. R. Durham (UK)
`W. J. Fokkens (Netherlands)
`P. H. Howarth (UK)
`V. Lund (UK)
`H.-J. Mailing (Denmark)
`N. Mygind (Denmark)
`D. Passali (Italy)
`G. K. Scadding (UK)
`D.-V. Wang (Singapore)
`Department of Otorhinolaryngology, Ghent University
`Hospital, De Plntelaan 185. B-9000 Ghent. Belgium
`
`Prof. P. van Cauwenberge
`Department of Otorhinolaryngology
`Ghent University Hospital
`De Pintelaan 185
`B-9000 Ghent
`Belgium
`
`Accepted for publication 12 October 1999
`
`1.
`
`Introduction
`
`disease in
`is a high-prevalence
`(AR)
`Allergic rhinitis
`many developed countries, affecting about 10-20% of
`the general population
`(1-5). Several studies based on
`questionnaire
`and objective testing or medical exam-
`ination
`indicate
`an increasing prevalence of AR in
`European countries over the last decades (6, 7).
`AR is characterized by nasal itching, sneezing, watery
`rhinorrhoea,
`and nasal obstruction. Additional
`symp-
`toms such as headache,
`impaired smell, and conjunc-
`tival symptoms can be associated. According to the time
`of exposure, AR can be subdivided
`into perennial,
`seasonal,
`and
`occupational
`disease. Perennial AR
`(PAR)
`is most
`frequently caused by dust mites and
`animal dander. Seasonal AR (SAR) is related to a wide
`
`"European Academy of Allergology and Clinical Immunology.
`
`116
`
`variety of pollen allergens including grasses, Parietaria,
`Ambrosia, Artemisia, birch, olive, hazelnut, and cypress.
`The morbidity
`of SAR obviously depends
`on the
`geographic region,
`the pollen season of the plants, and
`the local climate.
`Several other conditions can cause similar symptoms
`and are referred
`to as nonallergic
`(noninfectious)
`rhinitis: NARES (nonallergic rhinitis with eosinophilia
`syndrome); aspirin sensitivity; endocrine, occupational,
`postinfectious, and side-effects of systemic drugs; abuse
`of topical decongestants
`(rhinitis medicamentosa);
`and
`idiopathic rhinitis. Furthermore,
`diseases such as nasal
`polyposis, chronic sinusitis, cystic fibrosis, Wegener's
`disease, benign or malignant
`tumours, etc. have to be
`excluded carefully. Therefore,
`current guidelines
`(4)
`emphasize the importance of an accurate diagnosis of
`patients presenting with rhinitis
`symptoms.
`In fact,
`several causes may commonly
`coexist
`in the same
`
`

`

`patient, requiring separate consideration. The diagnosis
`patient, requiring separate consideration. The diagnosis
`of allergic rhinitis is frequently straightforward, but
`of allergic rhinitis
`is frequently
`straightforward,
`but
`may also be very complex and difficult. The mainstay is
`may also be very complex and difficult. The mainstay is
`an accurate history including an allergy history, based
`an accurate history including an allergy history, based
`on familial and personal history, recent clinical aspects,
`on familial and personal history,
`recent clinical aspects,
`and prior treatment. The possible presence of lower
`and prior
`treatment. The possible presence of lower
`respiratory tract disease, skin symptoms, or pollen(cid:173)
`respiratory
`tract disease,
`skin symptoms,
`or pollen-
`related food allergies should always be investigated,
`related food allergies
`should always be investigated,
`since they are commonly associated with rhinitis. This is
`since they are commonly associated with rhinitis. This is
`followed by a clinical examination of the nose. A major
`followed by a clinical examination of the nose. A major
`advance has been the introduction of rigid and flexible
`advance has been the introduction
`of rigid and flexible
`nasal endoscopes and, if sinusitis is considered, the
`nasal endoscopes
`and,
`if sinusitis
`is considered,
`the
`availability of CT scanning.
`availability of CT scanning.
`When an allergic pathogenesis of the disease is
`is
`the disease
`of
`When an allergic pathogenesis
`suspected, the skin prick test (SPT) with standardized
`suspected,
`the skin prick test (SPT) with standardized
`allergens should be performed. The measurement of
`allergens
`should be performed. The measurement
`of
`allergen-specific IgE in serum (as single allergens or
`allergen-specific
`IgE in serum (as single allergens or
`groups) is a useful diagnostic approach in selected cases
`groups) is a useful diagnostic approach in selected cases
`(skin test with difficult interpretation or not feasible,
`(skin test with difficult
`interpretation
`or not
`feasible,
`children, allergen not available for SPT, etc.). As
`children,
`allergen not
`available
`for SPT,
`etc.). As
`sensitization to an allergen does not necessarily mean
`sensitization to an allergen does not necessarily mean
`that the individual patient suffers from clinical disease,
`that
`the individual patient suffers from clinical disease,
`the clinical relevance of skin or specific IgE results
`the clinical
`relevance of skin or specific IgE results
`should be demonstrated before introducing therapies
`should be demonstrated
`before introducing
`therapies
`such as immunotherapy or environmental control.
`such as immunotherapy
`or environmental
`control.
`Whereas the clinical relevance in SAR usually can be
`Whereas the clinical relevance in SAR usually can be
`demonstrated by carefully analysing patient history,
`demonstrated
`by carefully analysing patient
`history,
`nasal allergen challenge tests may be useful in PAR.
`nasal allergen challenge tests may be useful
`in PAR.
`Allergen-specific diagnosis (as well as therapy) should
`Allergen-specific diagnosis
`(as well as therapy)
`should
`be based on purified standardized allergen extracts.
`be based on purified standardized
`allergen extracts.
`AR appears to impose variable restrictions on the
`AR appears
`to impose variable restrictions
`on the
`physical, psychologic, and social aspects of patients'
`physical, psychologic,
`and social aspects of patients'
`lives, and may have an impact on their careers. AR is
`lives, and may have an impact on their careers. AR is
`underestimated as a cause of suffering and impaired
`underestimated
`as a cause of suffering and impaired
`quality of life (8- 10). If symptoms of AR are not well
`quality of life (8-10).
`If symptoms of AR are not well
`controlled, they may contribute to learning problems
`controlled,
`they may contribute
`to learning problems
`and sleep disturbances (11, 12).
`and sleep disturbances
`(II, 12).
`For AR, direct yearly costs are estimated at 1.0- 1.5
`For AR, direct yearly costs are estimated at 1.0-1.5
`billion Euro, while indirect costs are estimated at
`billion Euro, while indirect
`costs are estimated
`at
`1.5- 2.0 billion Euro in Europe (13). Finally, the possible
`1.5-2.0 billion Euro in Europe (13). Finally, the possible
`association between AR and other conditions including
`association between AR and other conditions including
`asthma, sinusitis, otitis media, nasal polyposis, lower
`asthma,
`sinusitis, otitis media, nasal polyposis,
`lower
`tract infection, and even dental mal(cid:173)
`respiratory
`respiratory
`tract
`infection,
`and
`even dental mal-
`occlusion should be considered in evaluating the
`occlusion
`should
`be considered
`in evaluating
`the
`socio-economic impact of the disease (14).
`socio-economic impact of the disease (14).
`
`Table 1. Characteristics of allergic rhinitis
`rhinitis
`of allergic
`Table L Characteristics
`
`Characteristic
`Characteristic
`
`Obstruction
`Obstruction
`Secretion
`Secretion
`
`Sneezing
`Sneezing
`Smell disturbance
`Smell disturbance
`Eye symptoms
`Eye symptoms
`Asthma
`Asthma
`Chronic sinusitis
`Chronic sinusitis
`
`Seasonal
`Seasonal
`
`Variable
`Variable
`Watery, common
`Watery, common
`
`Always
`Always
`Variable
`Variable
`Common
`Common
`Variable
`Variable
`Occasional
`Occasional
`
`Perennial
`Perennial
`
`Always, predominant
`Always, predominant
`Seromucous, postnasal
`Seromucous.
`postnasal
`drip, variable
`drip, variable
`Variable
`Variable
`Common
`Common
`Rare
`Rare
`Common
`Common
`Frequent
`Frequent
`
`Consensus statement
`Consensus statement
`
`In recent years, new information on the patho(cid:173)
`on the patho-
`years, new information
`In recent
`physiologic mechanisms underlying allergic inflamma(cid:173)
`physiologic mechanisms underlying allergic inflamma-
`tion has accumulated. Based on these recent data, the
`tion has accumulated. Based on these recent data,
`the
`therapeutic strategies have been partly modified or
`therapeutic
`strategies
`have been partly modified or
`improved, and new drugs or new routes of administra(cid:173)
`improved, and new drugs or new routes of administra-
`tion, dosages, and schedules have been studied and
`tion, dosages,
`and schedules have been studied and
`validated. Intended for the specialist as well as the
`validated.
`Intended
`for
`the specialist as well as the
`general practitioner, this paper presents the state of the
`general practitioner,
`this paper presents the state of the
`art of AR treatment, and provides a well-documented
`art of AR treatment,
`and provides a well-documented
`review of the drugs available and their place in the
`review of the drugs available
`and their place in the
`management of the disease.
`management
`of the disease.
`
`2. Mechanisms of AR
`2. Mechanisms of AR
`AR results from lgE-mediated allergy, associated with
`allergy, associated with
`AR results from IgE-mediated
`cellular inflammation of the nasal mucosa of variable
`cellular
`inflammation
`of the nasal mucosa of variable
`intensity. The mechanisms of AR have been largely
`intensity. The mechanisms
`of AR have been largely
`clarified within the last 15 years from studies in
`clarified within
`the last 15 years
`from studies
`in
`naturally occurring disease and by the use of nasal
`naturally
`occurring disease and by the use of nasal
`challenge models in which cell infiltration and cell
`challenge models
`in which cell
`infiltration
`and cell
`activation have been assessed (15-18). These studies
`activation
`have been assessed (15-18). These studies
`highlight the presence of eosinophilic airway inflamma(cid:173)
`highlight
`the presence of eosinophilic airway inflamma-
`tion and identify the enhanced expression of endothelial
`tion and identify the enhanced expression of endothelial
`and epithelial adhesion molecules (19, 20), as well
`and epithelial
`adhesion molecules
`(19, 20), as well
`as chemokines and cytokines (21, 22). The release
`as chemokines
`and cytokines
`(21, 22). The release
`of mediators from infiltrating leukocytes as well as
`of mediators
`from infiltrating leukocytes
`as well as
`resident tissue cells, such as mast cells, is implicated in
`resident
`tissue cells, such as mast cells, is implicated in
`both the symptoms and the development of nasal
`both the symptoms
`and the development
`of nasal
`nonspecific hyperreactivity.
`nonspecific hyperreactivity.
`Histamine appears to be a major mediator released
`released
`Histamine
`appears
`to be a major mediator
`by mast cells in seasonal and perennial allergen
`allergen
`by mast
`cells
`in seasonal
`and perennial
`exposure (23), but other mediators such as leukotrienes,
`exposure (23), but other mediators such as leukotrienes,
`prostaglandins, and kinins may also contribute to the
`prostaglandins,
`and kinins may also contribute
`to the
`symptomatology through their interaction with neural
`symptomatology
`through their interaction with neural
`and vascular receptors (24, 25). In addition to these
`and vascular
`receptors
`(24, 25). In addition to these
`events, there is also neural involvement in the disease,
`events
`there is also neural
`involvement
`in the disease,
`with neuropeptide release from cholinergic and pepti(cid:173)
`with neuropeptide
`release from cholinergic and pepti-
`dergic nerves. Some different aspects of the two forms
`dergic nerves. Some different aspects of the two forms
`of AR are summarized in Table 1.
`of AR are summarized in Table I.
`The enhanced expression of TH2-like cytokines, such
`The enhanced expression of TH2-like cytokines, such
`as interleukin (IL)-4 and IL-5, within the nasal mucosa,
`as interleukin (IL)-4 and IL-5, within the nasal mucosa,
`generated by T cells, as well as mast cells, is a hallmark
`generated by T cells, as well as mast cells, is a hallmark
`of AR and is relevant to the selective recruitment and
`of AR and is relevant
`to the selective recruitment
`and
`survival of eosinophils (26, 27). The local generation of
`survival of eosinophils (26, 27). The local generation of
`cytokines such as IL-5 and GM-CSF by eosinophils
`cytokines
`such as IL-5 and GM-CSF by eosinophils
`themselves, along with the generation of cytokines and
`themselves, along with the generation of cytokines and
`chemokines by the epithelium, leads to the persistence
`chemokines by the epithelium,
`leads to the persistence
`of the eosinophil within the tissue. The epithelium is
`of the eosinophil within the tissue. The epithelium is
`increasingly recognized as an active cell population,
`increasingly
`recognized
`as an active cell population,
`providing cytokines and chemokines relevant to the
`providing
`cytokines
`and chemokines
`relevant
`to the
`local tissue cell recruitment (28), with an accumulation
`local tissue cell recruitment
`(28), with an accumulation
`of mast cells, basophils, eosinophils, and T cells evident
`of mast cells, basophils, eosinophils, and T cells evident
`at this location in AR. Once induced, this inflammatory
`at this location in AR. Once induced,
`this inflammatory
`process within the nasal mucosa persists for several
`process within the nasal mucosa persists
`for several
`weeks after allergen exposure (29). In cases of PAR
`weeks after allergen exposure
`(29). In cases of PAR
`
`117
`117
`
`

`

`van Cauwenberge et al.
`van Canwenberge et aI.
`
`where there is continuous low-dose allergen exposure,
`where there is continuous low-dose allergen exposure,
`there is persistent nasal mucosa! inflammation (30).
`there is persisteut nasal mucosal inflammation (30).
`The concept that the mechanisms of disease genera(cid:173)
`The concept that the mechanisms of disease genera-
`tion provide a framework for rational therapy in this
`tion provide a framework for rational
`therapy in this
`disorder is based on the complex inflammatory reaction
`disorder is based on the complex inflammatory reaction
`rather than on the symptoms alone.
`rather than on the symptoms alone.
`
`3. Allergen avoidance
`3. Allergen avoidance
`The triggering event of AR is the contact of the
`The triggering event of AR is the contact of the
`responsible allergen with the nasal mucosa. This event,
`responsible allergen with the nasal mucosa. This event,
`mainly through the degranulation of mast cells, leads to
`mainly through the degranulation of mast cells, leads to
`the clinical early-phase response and initiates the
`the clinical early-phase
`response and initiates
`the
`subsequent allergic inflammatory process. The severity
`subsequent allergic inflammatory process. The severity
`of the disease and its natural course correlate well with
`of the disease and its natural course correlate well with
`the allergen concentration in the environment (31-33).
`the allergen concentration in the environment (31-33).
`Thus, the first therapeutic approach to the control of
`Thus,
`the first therapeutic approach to the control of
`symptoms is prevention, by identification and avoid(cid:173)
`symptoms is prevention, by identification and avoid-
`ance of the causal allergen(s) (4, 34). The removal of the
`ance of the causal allergen(s) (4,34). The removal of the
`allergen has been proven to result in improvement in the
`allergen has been proven to result in improvement in the
`severity of the allergic disease (35) and reduction of the
`severity of the allergic disease (35) and reduction of the
`need for drugs. The beneficial effect of environmental
`need for drugs. The beneficial effect of environmental
`control may take weeks or months to be fully perceived.
`control may take weeks or months to be fully perceived.
`In most cases, complete avoidance of the allergen is not
`In most cases, complete avoidance of the allergen is not
`feasible due to practical and/or economic reasons.
`feasible due to practical and/or economic reasons.
`Nevertheless, allergen-avoidance measures should be
`Nevertheless, allergen-avoidance measures should be
`considered before or in association with pharmacologic
`considered before or in association with pharmacologic
`treatment, where appropriate.
`treatment, where appropriate.
`As far as house-dust mites are concerned, there are
`As far as house-dust mites are coucerned, there are
`some general and specific measures to be adopted for
`some general and specific measures to be adopted for
`reducing the mite population and the allergen exposure.
`reducing the mite population and the allergen exposure.
`These measures ideally include:
`These measures ideally include:
`1) removal of carpets and soft toys from the bedroom
`1) removal of carpets and soft toys from the bedroom
`2) use of allergen-impermeable (water-vapour per(cid:173)
`2) use of allergen-impermeable
`(water-vapour
`per-
`meable) covers for mattresses, duvets, and pillows
`meable) covers for mattresses, duvets, and pillows
`3) careful vacuum-cleaning of beds every week with a
`3) careful vacuum-cleaning of beds every week with a
`paper filter cleaner and damp-cleaning of furniture
`paper filter cleaner and damp-cleaning of furniture
`in the bedroom
`in the bedroom
`4) washing bedclothes at 60°C.
`4) washing bedclothes at 60"C.
`
`Some acaricides (benzyl benzoate, tannic acid, etc.)
`tannic acid, etc.)
`Some acaricides (benzyl benzoate,
`appear to be effective in reducing the mite population
`appear to be effective in reducing the mite population
`if used regularly (36-38), but their clinical outcome
`if used regularly (36-38), but
`their clinical outcome
`remains unproven, and the use of allergen-impermeable
`remains unproven, and the use of allergen-impermeable
`covers for mattresses seems to be more effective (39-41).
`covers for mattresses seems to be more effective (39-41).
`A recent meta-analysis in asthma did not reveal clear
`A recent meta-analysis in asthma did not reveal clear
`evidence of the benefits of measures to avoid house-dust
`evidence of the benefits of measures to avoid house-dust
`mites (42). However, optimal reduction of mite levels
`mites (42). However, optimal reduction of mite levels
`was frequently not achieved, thus not allowing a
`was frequently not achieved,
`thus not allowing a
`reduction of symptoms, and similar studies in rhinitis
`reduction of symptoms, and similar studies in rhinitis
`are not available.
`are not available.
`The only effective measure for avoiding animal(cid:173)
`The only effective measure for avoiding animal-
`dander allergens is to remove the pet ( cat, dog) from the
`dander allergens is to remove the pet (cat, dog) from the
`house and to vacuum-clean carefully all carpets,
`honse
`and to vacuum-clean carefully all carpets,
`mattresses, and upholstered furniture. However, even
`mattresses, and upholstered furniture. However, even
`with these measures, it may not be possible to eradicate
`with these measures, it may not be possible to eradicate
`
`118
`118
`
`cat allergens. Although frequent washing of cats
`eat allergens. Although
`frequent washing of cats
`reduces allergen recovery in the lavage (43), clinical
`reduces allergen recovery in the lavage (43), clinical
`studies have not shown clear benefit from
`this
`studies have not
`shown clear benefit
`from this
`procedure when carried out once a week (44). If
`procedure when carried out once a week (44). If
`removal of the cat is not acceptable to the patient, the
`removal of the eat is not acceptable to the patient,
`the
`pet should at least be excluded from the bedroom or
`pet should at least be excluded from the bedroom or
`kept outdoors. Avoidance of pollen is often impossible
`kept outdoors. Avoidance of pollen is often impossible
`due to its ubiquitous nature.
`due to its ubiquitous nature.
`
`4. Oral antihistamines
`4. Oral antihistamines
`General aspects
`General aspects
`Histamine is a major mediator involved in the
`involved in the
`is a major mediator
`Histamine
`development of AR symptoms: the increase of hista(cid:173)
`development of AR symptoms:
`the increase of hista-
`mine concentration in nasal secretions of atopic patients
`mine concentration in nasal secretions of atopic patients
`after nasal allergen challenge and during natural
`after nasal
`allergen challenge and during natural
`allergen exposure has been clearly demonstrated ( 45,
`allergen exposure has been clearly demonstrated (45,
`46). The role of histamine in the nasal allergic reaction
`46). The role of histamine in the nasal allergic reaction
`is also confirmed by
`the reproduction of nasal
`is also confirmed by the
`reproduction
`of nasal
`symptoms after provocation with histamine. These
`symptoms
`after provocation with histamine. These
`symptoms - with the exception of obstruction - can be
`symptoms - with the exception of obstruction - can be
`reduced by administering H 1-antagonists. Three hista(cid:173)
`reduced by administering Hj-antagonists. Three hista-
`mine receptors are presently recognized, but the nasal
`mine receptors are presently recognized, but the nasal
`effects of histamine are predominantly H 1-rnediated.
`effects of histamine are predominantly Hj-mediated.
`H 1-receptor antagonists reduce the clinical expression
`Hj-receptor antagonists reduce the clinical expression
`of nasal itching, sneezing, and rhinorrhoea, but they are
`of nasal itching, sneezing, and rhinorrhoea, but they are
`less effective in controlling nasal obstruction (47, 48).
`less effective in controlling nasal obstruction (47, 48).
`
`Efficacy
`Efficacy
`The use of the first-generation antihistamines (clor(cid:173)
`(clor-
`The use of the first-generation antihistamines
`pheniramine, diphenhydramine, prornethazine, and
`pheniramine,
`diphenhydramine,
`promethazine,
`and
`tripolidine) is considerably limited by their sedative
`tripolidine)
`is considerably limited by their sedative
`and anticholinergic effects; in addition, their short half(cid:173)
`and anticholinergic effects; in addition, their short half-
`lives discourage the use of these antihistamines for
`lives discourage the use of these antihistamines
`for
`AR treatment. The newer antihistamines (acrivastine,
`AR treatment. The newer antihistamines (aerivastine,
`astemizole, azelastine, cetirizine, ebastine, fexofenadine,
`astemizole, azelastine, cetirizine, ebastinc, fexofenadine,
`loratadine, mizolastine, and terfenadine) are effective
`loratadine, mizolastine, and terfenadine) are effective
`in reducing nasal symptoms such as itching, sneezing,
`in reducing nasal symptoms such as itching, sneezing,
`and watery rhinorrhoea but have less effect on nasal
`and watery rhinorrhoea but have less effect on nasal
`blockage (49, 50) (for review, see refs. 4, 51-57)
`blockage (49, 50) (for
`review, see refs. 4, 51-57)
`(Table 2). Antihistamines taken orally have the addi(cid:173)
`(Table 2). Antihistamines taken orally have the addi-
`tional advantage of reducing nonnasal symptoms such
`tional advantage of reducing nonnasal symptoms suc