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a report by

G i o r g i o W Canon i c aand

En r i c o Compa l a t i

Al le rg y and Re sp iratory Di se ases Cl inic , Universi ty of Genoa

Allergic rhinitis (AR) is an inflammatory disorder

of the nose induced by allergen exposure of the

mucous membranes lining the nose, characterised

by rhinorrhoea, itching, sneezing and nasal

obstruction. A high percentage (42%) of patients

with AR, typically patients with seasonal pollinosis,

have symptoms of allergic conjunctivitis. Nasalsymptoms are often trivialised, but can lead to a

significant reduction in quality of life for both

patients and their family, with a negative impact on

work productivity, school performance and social

activities. Loss of productivity, doctors

appointments and pharmacotherapy represent the

relevant direct and indirect costs of AR to society.

Ep i dem io l o g y

In the last five decades, the prevalence of AR has

increased from 6% to 18% worldwide. A geneticpredisposition to atopy is currently a subject of on-

going research and many polymorphisms have been

correlated to the disease; however, this matter still

involves several controversies. Aeroallergens are

the most frequently involved allergens in AR.

Indoor allergens are derived from house dust mites,

cats and dogs, cockroaches and moulds, while

outdoor allergens include pollens from trees,

grasses and weeds, moulds and fungal spores.

Symptoms can be aggravated by the inhalation of

urban pollutants. Diesel exhaust has been

demonstrated as an enhancer of immunoglobulin(Ig)E production and of allergic inflammation.

Research conducted over the last 20 years has

considered changes in lifestyle as the most probable

factors for providing an explanation for the

vertiginous rise of the prevalence of atopic diseases.

The principal hypothesis, the hygiene hypothesis,

is based on the effect of a lower microbial

exposition during infancy and is linked to a

westernised lifestyle as a promoting factor for the

development of allergic diseases. However, the

immunological changes following this phenomenaare not clear. A reduced shift to the T-helper (Th)1

subset is probably related to lower production of

natural immunity cytokines stimulated by bacterial

products via the Toll-like receptor system (immune

deviation theory). According to another theory

(reduced immune suppression theory), lower

exposition to infections should involve a reduced

activity of regulatory T-cells. These models are still

the subject of current research.

C l a s s i f i c a t i o n

Traditionally, the AR has been classified into three

subgroups seasonal, perennial and occupational.

Recently, the World Health Organization (WHO)

Allergic Rhinitis and its Impact on Asthma (ARIA)

working group has revised the classification,

considering intermittent to be a disease lasting less

than one month or four days a week and

persistent as a disease of longer than one month or

more than four days a week. The new classification

takes into consideration the severity of the disease

and its impact on the patients quality of life;therefore, a mild disease classification is

characterised by few troublesome symptoms, not

interfering with daily activities and/or sleep and a

moderate to severe disease classification is

characterised by troublesome symptoms that

interfere with daily activities and/or sleep.

Co -morb i d i t i e s

The most common co-morbid conditions of AR are

represented by asthma and eczema. Forty per cent to

50% of patients with AR suffer from asthma andmore then 90% of asthmatics also have rhinitis.

Chronic nasal congestion may result in rhinosinusitis

and the obstruction of sinus ostia due to infections

predisposed by negative pressure and mucous

stagnation. This condition presents with nasal

congestion, post-nasal drip, hyposmia, cough and

sometimes facial pain or headache. The same

mechanism leads to tubaric involvement and the

development of otitis media.

Nasal polyposis may result from the chronicinflammation of nasal mucosa. Polyps frequently

prolapse from sinusal mucosae down to the middle

meatus, inducing nasal blockage, hyposmia, facial

pain and encouraging the rise of rhinosinusitis.

Al le rg ic Rhin i t i s

B U S I N E S S B R I E F I N G : E U R O P E A N P H A R M A C O T H E R A P Y 2 0 0 6

39

Al lergies

Giorgio W Canonica

Enrico Compalati

Giorgio W Canonica is Chairman ofthe Allergy and Respiratory Diseases

Clinic and Director of the Specialty

School of Pulmonary Diseases at

the University of Genoa. Professor

Canonica is President-elect of the

World Allergy Organization (WAO),

Vice-President of International

Association of Asthmology

(Interasma) and President of the

Italian Society of Respiratory

Medicine (SIMeR). He trained at the

University of Nancy INSERM,

the University of Uppsala and

the Medical University of

South Carolina.

Enrico Compalati is undertaking a

research doctorate in allergy and

respiratory physiopathology at the

University of Genoa. Dr Compalati

is co-author of more than 10 full

papers in international journals and

is a member of the European

Academy of Allergy and Clinical

Immunology (EAACI) and of the

Italian Society of Allergy and

Clinical Immunology (SIAIC).

Dr Compalati graduated in 2001

from the Genoa University Medical

School and achieved a speciality

degree in allergy and clinical

immunology in 2005.

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Immunopa tho l o g y

The importance of recognising the underlying

immunopathology of allergic disease is related to

directing treatment more precisely to the complex

inflammatory reaction. Allergens penetrating the

epithelial layer of the respiratory tract are processedby antigen-presenting cells and are introduced to

the histocompatibility complex molecules,

resulting in the development of specific T-cell

clones (sensitisation). The B-cell immunoglobulin

class switch, as well as the promotion of IgE

synthesis by plasmacells, is regulated by interleukins

4 and 13 and by the interaction of membrane-based

molecules. Any further contact with allergens leads

to fast-response IgE-mediation characterised by

mast cells and basophil degranulation with the

release of preformed and newly synthesised

mediators, which are able to provoke the typicalsymptoms within minutes.

Histamines are the major mediator of the early-

phase reaction; they stimulate sensory nerves,

causing sneezing and itching and are also

responsible for vasodilation, plasma exudation and

the stimulation of mucosal cells leading to

rhinorrhoea and nasal obstruction. Histamines

sustain inflammation through the upregulation of

adhesion molecules and the release of pro-

inflammatory cytokines.

A late-phase reaction occurs a few hours after

allergen exposure and is associated with cellulareosinophilic inflammation of the nasal mucosa and

expression of endothelial and epithelial adhesion

molecules, chemokines and cytokines. The release

of mediators from infiltrating leucocytes, as well as

resident tissue cells, such as mast cells, is implicated

in the symptoms and development of nasal

unspecific hyper-reactivity. Leukotrienes, released

by mast cells, eosinophils, basophils, macrophages,

neutrophils and epithelial cells play an important

role in the late-phase allergic reaction by

influencing nasal obstruction, mucus secretion and

cellular recruitment.

In persistent AR, the continuous low-dose allergen

exposure induces a persistent nasal mucosa

inflammation (minimal persistent inflammation)

with over-expression of the intercellular adhesion

molecule (ICAM)-1, which represents the principal

receptor for rhinoviruses.

D i a gno s i s

The diagnosis of AR is based on detailed personaland family history, clinical history of typical

symptoms, physical examination (nasal examination/

anterior rhinoscopy) and skin prick test or the

measurement of allergen-specific IgE antibodies.

Additional diagnostic tests include:

fibreoptic rhinoscopy;

cytology of nasal secretions;

nasal challenge with allergen and

rhinomanometry;

conventional radiography (RX); and CT scan.

These diagnostic tests are the measurement of total

IgE, but are poorly predictive.

A differential diagnosis must be assumed with:

non-AR

infectious and drug-induced rhinitis,

hormonal rhinitis,

rhinit is from other causes (food,

irritants, and emotion),

gastro-oesophageal reflux and

vasomotory and idiopathic rhinitis; polyposis;

ciliary defects;

cerebrospinal rhinorrhea;

benign/malignant tumours;

septum deviation;

foreign bodies;

blocked nostril (choanal atresia); and

granulomatous diseases.

T r ea tmen t

The avoidance of causal allergens represents thefundamental approach for preventing the rise of

allergy symptoms. However, this target is difficult to

achieve although a reduction in environmental

allergens can result in a reduction of the severity of40

Allergies

B U S I N E S S B R I E F I N G : E U R O P E A N P H A R M A C O T H E R A P Y 2 0 0 6

The importance of recognising the underlying

immunopathology of allergic disease is related to

directing treatment more precisely to the complex

inflammatory reaction.

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Allergies

42

the disease and can also reduce the requirement for

pharmacotherapy. Therapeutic interventions consider

the use of different tools on the basis of the severity of

the disease with a stepwise approach. A summary of

the management protocol and pharmacological

treatments for AR can be found in ARIA guidelines.

Many classes of drugs are currently available.

Antihistamines are commonly used as a first-line

treatment they are particularly effective at relieving

symptoms, such as sneezing, itching and watery

rhinorrhoea. First-generation antihistamines are no

longer recommended as they show poor selectivity

and their use is limited because of their sedative and

anticholinergic effects. Second-generation anti-

histamines have a higher potency and longer duration

of action compared with the first-generation drugs,

with minimal or no side effects. The rapid onset of

action and the duration of activity of up to 24 hoursallow once-daily administrations. Several studies have

shown that antihistamines have anti-inflammatory

properties, conferring a therapeutic advantage in the

management of the disease. Topical intranasal

glucocorticosteroids have a strong anti-inflammatory

action, reducing the release of inflammatory mediators

and decreasing cellular infiltration within the nasal

mucosa they are the first-line medication for

moderate to severe persistent AR. Mild local side

effects, such as nasal crusting, dryness and epistaxis,

may occur, but current preparations can be used for

long-term periods without atrophy of the mucosa.

Short courses of oral corticosteroids are particularlyeffective in severely symptomatic patients and when

nasal blockage compromises the effective penetration

of topical corticosteroids the risk of adverse effects

for systemic corticosteroids depends on the duration

of therapy.

Decongestant drugs inducing vasoconstriction by their

action on -adrenergic receptors may be administeredintranasally or orally for short-term treatment as

effective tools in the treatment of nasal obstruction.

Prolonged use of these drugs may lead to

tachyphylaxis and rhinitis medicamentosa (RM),mucosal rebound swelling and septal perforation. Oral

vasoconstrictors have a weaker effect with respect to

topical decongestants, but they do not cause rebound

vasodilatation. The two chromones disodium

cromoglycate and nedocromil have mast cell-

stabilising properties, although the precise mechanism

of action is still unknown they are a prophylactic

treatment less effective than antihistamines and with

the disadvantage of frequent administration in order to

achieve adequate results. The excellent safety profile

allows its use in children and pregnancy. Topicalanticholinergics, such as ipratropium bromide, only

appear to improve nasal hypersecretion and should

therefore be approved in patients in whom

rhinorrhoea is the primary symptom or when it is not

fully responsive to other therapies. The combination

of this with a nasal corticosteroid has been shown to

have a greater impact on rhinorrhoea than either the

systemic application of ipratropium or the nasal

steroid, respectively. Recently, a new class of drugs,

initially used for the treatment of bronchial asthma, has

been considered in the treatment of AR (anti-

leukotrienes). Leukotrienes are importantinflammatory mediators of the nasal allergic reaction

and have been shown to induce nasal obstruction. The

use of anti-leukotrienes in AR is currently strongly

recommended when asthma symptoms co-exist.

Allergen-specific immunotherapy, performed under

controlled conditions, plays a main role in the global

preventive approach to allergic disease and may be of

assistance for patients who do not wish to be treated

with pharmacotherapy and for patients in whom this

produces undesirable side effects.

Immunotherapy interferes with the basic mechanism ofallergy and alters the natural course of allergic diseases,

which therefore offers a long-lasting and preventive

effect. Subcutaneous specific immunotherapy (SIT) has

been shown to be a causal treatment with long-term

efficacy for allergic rhinoconjunctivitis and asthma and

a preventive measure against the development of

asthma and new sensitisations. Sublingual

immunotherapy (SLIT) is now officially accepted as a

viable alternative to the traditional subcutaneous route,

and is particularly widely used in European countries.

Recent data confirmed SLIT safety in very young

children and its efficacy in preventing asthma onset inpaediatric rhinitis patients. Recent data confirm the

clinical value of this treatment and show that it is

comparable with subcutaneous immunotherapy from

several points of view. Specific immunotherapy should

Histamines sustain inflammation through the

upregulation of adhesion molecules and the release of

pro-inflammatory cytokines.

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not be considered an ultimate treatment but an

additional tool to pharmacotherapy. Future approaches

are related to novel therapeutic interventions against

events characterising the inflammatory and

remodelling responses that may occur in the nose.

Further research into the pathogenesis of AR, with

particular emphasis on the previously mentioned areas

raised, is therefore needed.

Al le rg ic Rhini t i s

Fu r th e r R ead i n g

1. Consensus Statement on the Treatment of Allergic Rhinitis, European Academy of Allergology and Clinical Immunology

(EAACI), Van Cauwenberge P, Bachert C, Bousquet J et al., Allergy (2000);55: pp, 116134.

2. Kaplan A, Van Cauwenberge P and GLORIA advisory board, Global Resources in Allergy (GLORIA): Allergic rhinitis

and allergic conjunctivitis (World Allergy Organization), WAO (2001).

3. Bousquet J, Van Cauwenberge P, Khaltaev N, Allergic rhinitis and its impact on asthma (ARIA),J. Allergy Clin.

Immunol. (2001);108 (suppl. 5):S147334.

4. Bousquet J, Cauwenberge P V, Requirements for medications commonly used in the treatment of allergic rhinitis, Allergy

(March 2003);58(3): pp. 192197.

5. Canonica G W, Compalati E, Fumagalli F, Passalacqua G, Sublingual and oral immunotherapy, Immunol. Allergy

Clin. North Am. (November 2004);24(4): pp. 685704.

6. Passalacqua G, Pasquali M, Guerra L, Lombardi C, Canonica G W, Efficacy and safety of sublingual immunotherapy,Ann. Allergy Asthma Immunol. (July 2004);93(1): pp. 312.

7. Custovic A, Wijk R G, The effectiveness of measures to change the indoor environment in the treatment of allergic rhinitis

and asthma: ARIA update (in collaboration with GA(2)LEN), Allergy (September 2005);60(9): pp. 1,1121,115.

8. Bousquet J, Annesi-Maesano I, Carat F, Characteristics of intermittent and persistent allergic rhinitis: DREAMS study

group, Clin. Exp. Allergy. (June 2005);35(6): pp. 728732.

9. Milanese M, Ricca V, Canonica G W, Ciprandi G, Eosinophils, specific hyper-reactivity and occurrence of late phase

reaction in allergic rhinitis, Allerg. Immunol. (Paris) (January 2005);37(1): pp. 710.

10. Ciprandi G, Cirillo I, Vizzaccaro A et al., Seasonal and perennial allergic rhinitis: is this classification adherent to real

life?, Allergy (July 2005);60(7): pp. 882887.

11. Bachert C, Bousquet J, Canonica G W et al., XPERT Study Group, Levocetirizine improves quality of life and reduces

costs in long-term management of persistent allergic rhinitis, J. Allergy Clin. Immunol. (October 2004);114(4): pp.

838844.12. Canonica G W, Compalati E, Fumagalli F, Passalacqua G, Sublingual and oral immunotherapy, Immunol. Allergy

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13. Asher I, Baena-Cagnani C, Boner A, World Allergy Organization, World Allergy Organization guidelines for

prevention of allergy and allergic asthma, Int. Arch. Allergy Immunol. (September 2004);135(1): pp. 8392.

14. Passalacqua G, Guerra L, Pasquali M, Lombardi C, Canonica G W, Efficacy and safety of sublingual immunotherapy,

Ann. Allergy Asthma Immunol. (July 2004);93(1): pp. 312.

15. Bousquet J, Bindslev-Jensen C, Canonica G W, The ARIA/EAACI criteria for antihistamines: an assessment of the

efficacy, safety and pharmacology of desloratadine, Allergy (2004);59(suppl. 77): pp. 416.

16. Passalacqua G, Ciprandi G, Pasquali M, Guerra L, Canonica G W, An update on the asthma-rhinitis link, Curr.

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17. Passalacqua G, Guerra L, Compalati E, Sublingual immunotherapy, Rev. Al. Mex. (NovemberDecember

2003);50(6): pp. 220225.18. Majani G, Baiardini I, Giardini A et al., Health-related quality of life assessment in young adults with seasonal allergic

rhinitis, Allergy (April 2001);56(4): pp. 313317.

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20. Vissers J L, van Esch B C, Hofman G A, Allergen immunotherapy induces a suppressive memory response mediated by

IL-10 in a mouse asthma model,J. Allergy Clin. Immunol. (June 2004);113(6): pp. 1,2041,210.

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Opin. Allergy Clin. Immunol. (June 2004);4(3): pp. 177183.24. Pawankar R, Allergic rhinitis and asthma: the link, the new ARIA classification and global approaches to treatment,

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