desloratadine, ebastine, fexofenadine, levocetirizine, loratadine, mizolastine, rupatadine. Cardiotoxic drugs: Astemizole, terfenadine. Mechanism of Action.
2.8 Allergic Rhinitis Joaquim Mullol and Antonio Valero
2.8.1 Introduction Allergic rhinitis is a symptomatic disorder of the nose, induced after allergen exposure by an IgE-mediated inflammation of the nasal mucosa. Allergic rhinitis represents a global health problem. It is a worldwide disease affecting at least 10–25% of the population [1], and its prevalence is increasing. In European countries the prevalence of allergic rhinitis has been estimated from 17 to 29% [2]. An increase in this prevalence has been observed in the past 40 years [3]. Allergic rhinitis is not a severe disease but it alters a patient’s social life, affecting school performance and work productivity [4]; the costs incurred by rhinitis are substantial [5]. Asthma and rhinitis are common comorbidities, suggesting the concept of “one airway, one disease” [6]. Guidelines for the diagnosis and treatment of allergic rhinitis have already been published [7], but some were not predicated on evidence-based medicine and few, if any, considered the patients globally in terms of comorbidities. The ARIA (Allergic Rhinitis and Its Impact on Asthma) initiative [8, 9] has developed a document that is the state of the art, for the specialist as well as for the general practitioner to: • Update his/her knowledge of allergic rhinitis • Highlight the impact of allergic rhinitis on asthma • Provide an evidence-based documented revision on the diagnosis methods and on the treatments available • Propose a stepwise approach to the management of the disease
2.8.2 Definition and Classification Symptoms of allergic rhinitis include rhinorrhea, nasal obstruction, nasal itching, and sneezing, which are reversible spontaneously or with treatment. Allergic rhinitis was previously classified as seasonal and perennial. The new ARIA classification of allergic rhinitis is based on symptoms and quality-of-life parameters. Duration of symptoms is subdivided into “intermittent” or “persistent” disease, while severity is subdivided into “mild” or
Intermittent ≤ 4 days per week or ≤ 4 weeks
Mild
- normal sleep - no impairment of daily activities, sport, leisure - normal work and school - no troublesome symptoms
Persistent > 4 days per week and > 4 weeks
Moderate -severe
one or more items - abnormal sleep - impairment of daily activities, sport, leisure - abnormal work and school - troublesome symptoms
Fig. 2.8.1 Classification of allergic rhinitis (ARIA)
“moderate-severe”, depending on symptoms and quality of life (Fig. 2.8.1). This classification has been recently validated [10, 11].
2.8.3 Aetiology and Triggers 2.8.3.1
Allergens
Aeroallergens are very often involved in allergic rhinitis [12]. The increase in domestic allergens is responsible in part for the increase in the prevalence of rhinitis, asthma and allergic respiratory diseases. In the home, the main allergens are mites, domestic animals, insects or those derived from plant origin. Outdoor allergens include pollens and moulds. Occupational rhinitis is less well documented than occupational asthma is but is often associated with asthma. Latex allergy has become an increasing concern to patients and health professionals, who should be aware of the problem and develop strategies for prevention and treatment. 2.8.3.2
Pollutants
Pollutants are involved in the aggravation of nasal symptoms in patients with allergic and nonallergic rhinitis. The
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interaction between pollutants and rhinitis is suggested by epidemiological evidence, although the mechanism is not well understood. Indoor pollution, including domestic allergens and indoor gas pollutants (tobacco smoke), is of great importance, since in industrialised countries people spend over 80% of their time indoors. Urban-type pollution is in many countries primarily of automobile origin [13], and the principal atmospheric oxidant pollutants include ozone, nitric oxides, and sulphur dioxide. Diesel exhaust fumes may also enhance IgE formation and allergic inflammation. 2.8.3.3
Aspirin and Nonsteroidal Anti-inflammatory Drugs
NSAIDs commonly induce rhinitis and asthma [14].
2.8.4 Mechanisms of Action In allergic rhinitis, the understanding of the mechanisms of the disease provides a framework for its rational therapy, based on the complex inflammatory reaction rather than on the symptoms alone. Allergy is classically considered to result from an IgE-mediated allergy associated with nasal inflammation of variable intensity [15]. Allergic rhinitis is characterised by an inflammatory infiltrate made up of different cells, including: • Chemotaxis, activation, differentiation, and survival prolongation of various cell types including eosinophils, T cells, mast cells and epithelial cells • Release of mediators by these activated cells: cytokines, chemokines, histamine and cysteinyl leukotrienes (cys-LT) as the major mediators • Communication with the immune system and the bone marrow Nonspecific nasal hyperreactivity [16] is an important feature of allergic rhinitis and is defined as an increased nasal response to normal stimuli, resulting in sneezing, nasal congestion and/or secretion. Intermittent rhinitis can be mimicked by nasal challenge with pollen allergens, and an inflammatory reaction occurs during the late-phase reaction. In persistent allergic rhinitis, allergic triggers interact with an ongoing inflammatory reaction, and symptoms are due to this complex interaction. The concept of “minimal persistent inflammation” [17] has been confirmed in perennial allergic rhinitis. In patients with persistent allergic rhinitis, allergen exposure varies throughout the year, and there are periods in which there is little exposure. Although symptom free, these patients still present with nasal inflammation.
2.8.5 Comorbidities Allergic inflammation does not limit itself to the nasal airway. Multiple comorbidities have been associated with rhinitis such as asthma [6], rhinosinusitis and conjunctivitis. 2.8.5.1
Asthma
Nasal and bronchial mucosa share many similarities. Epidemiological studies have shown that asthma and rhinitis often coexist in the same patients. Most patients with allergic (80%) and nonallergic (50%) asthma have rhinitis, while many patients with rhinitis (20–30%) have also asthma. Allergic rhinitis constitutes a risk factor for asthma, and many allergic rhinitis patients have bronchial hyperreactivity [18]. Pathophysiological studies also suggest that a strong relationship exists between rhinitis and asthma. Although differences exist between rhinitis and asthma, upper and lower airways may be considered as a unique entity influenced by a common inflammatory process. Since bronchial challenge leads to nasal inflammation and nasal challenge leads to bronchial inflammation, allergic diseases may be considered systemic. Consequently, when considering a diagnosis of rhinitis or asthma, an evaluation of both the lower and upper airways should be made. 2.8.5.2
Other Comorbidities
Other comorbidities include rhinosinusitis and conjunctivitis, and the associations between allergic rhinitis, nasal polyposis, and otitis media are poorly understood.
2.8.6 Diagnosis The diagnosis of allergic rhinitis is based on the coordination between a clinical history (allergic symptoms), nasal examination and diagnostic tests. 2.8.6.1
Clinical History
It is essential for an accurate diagnosis of rhinitis to assess its severity and response to treatment. Although not necessarily of allergic origin, the main nasal symptoms are obstruction, sneezing, itching and rhinorrhea.
2.8.7 Management and Treatment
Table 2.8.1 Diagnostic tests for allergic rhinitis Category of test
Specific test
Routine
History –– Clinical –– Family
2.8.6.3
Diagnostic Tests
In vivo and in vitro tests used to diagnose allergic diseases are directed towards the detection of free or cellbound IgE. The diagnosis of allergy has been improved by allergen standardisation (Table 2.8.1).
General ENT examination (rhinoscopy) Nasal airway assessment –– Peak nasal inspiratory flow (PNIF) Allergy tests –– Skin –– Serum-specific IgE Additional
Endoscopy –– Rigid –– Flexible Radiology –– CT scan
Optional
Nasal challenge –– Allergen –– Lysine aspirin Nasal samples –– Cytology/nasal secretions –– Nasal biopsy –– Nasal swab Radiology –– MRI
2.8.6.3.1 Skin-prick Test
The skin-prick test is used to demonstrate an IgE-mediated allergic reaction and represents a major diagnostic tool in the field of allergy. If properly performed, it gives confirmatory evidence for the diagnosis of a specific allergy. Due to the complexity in performance and interpretation of the test, it is recommended that it be carried out by trained health care professionals [19]. 2.8.6.3.2 Serum-specific IgE
Serum-specific IgE has a similar value to that of skin tests [20]. 2.8.6.3.3 Allergen Nasal Challenge
The allergen nasal challenge is mainly used in research and, to a lesser extent, in clinical practice. It is especially useful in the diagnosis of occupational rhinitis [21].
Mucociliary function –– Nasal mucociliary clearance (NMCC) –– Ciliary beat frequency (CBF) –– Electron microscopy
2.8.6.3.4 Imaging
Nasal airway assessment –– Rhinomanometry (anterior, posterior) –– Acoustic rhinometry Smell test (University of Pennsylvania smell identification test [UPSIT], ZOST, Barcelona smell test [BAST]-24) Nitric oxide measurement
Guidelines for recognising and diagnosing asthma have been published by the Global Initiative for Asthma (GINA) [22] and are recommended. Measurement of lung function and confirmation of the reversibility of airflow obstruction are essential steps in the diagnosis of asthma.
Imaging is not usually necessary. 2.8.6.3.5 Diagnosis of Asthma
2.8.7 Management and Treatment
2.8.6.2
Nasal Examination
In patients with mild, intermittent allergic rhinitis, a nasal examination is optimal, but all patients with persistent allergic rhinitis need a nasal examination. Anterior rhinoscopy, using a speculum and mirror, gives limited information. Nasal endoscopy, which can be performed only by specialists, is more useful.
The management of allergic rhinitis is based on allergen avoidance, pharmacological treatment, specific immunotherapy, and, when possible, patient education [8, 9, 23]. 2.8.7.1
Allergen Avoidance
Most allergen-avoidance studies have dealt with asthma symptoms, and very few have studied rhinitis symp-
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H 1-antihistamines oral intranasal intraocular Corticosteroids intranasal Chromones intranasal intraocular Decongestants intranasal oral Anti-cholinergics Anti-leukotrienes
sneezing
rhinorrhea
nasal obstruction
nasal itch
eye symptoms
+++ ++ 0
+++ +++ 0
0 to + + 0
+++ ++ 0
++ 0 +++
+++
+++
++
++
+
+ 0
+ 0
+ 0
+ 0
0 ++
0 0 0 0
0 0 +++ +
++ + 0 ++
0 0 0 0
0 0 0 ++
toms. A single intervention may be insufficient to control symptoms of rhinitis or asthma. Although more data are needed to appreciate fully the clinical value of allergens, allergen avoidance, including house dust mites, should be an integral part of a management strategy [24, 25]. 2.8.7.2
Pharmacological Treatment
Pharmacological management for treatment of allergic rhinitis involves several classes of drugs (Figs. 2.8.2 and 2.8.3).
intervention
SAR SAR adult adult children children
PAR adult adult children children
anti -H11 oral anti-H
A
A
A
A
intranasal anti-H anti -H11
A
A
A
A
intranasal CS
A
A
A
A
intranasal chromone chromone
A
A
A
A
subcutaneous SIT
A
A
A
A
sublingual
A
A
nasal SIT
A
A
A
allergen avoidance
D
D
D
2.8.7.2.1 H 1 -Antihistamines Drugs Old generation:
Chlorpheniramine, clemastine, diphenhydramine, hydroxyzine, ketotifen, mequitazine, oxatomide
New generation:
Acrivastine, azelastine, cetirizine, desloratadine, ebastine, fexofenadine, levocetirizine, loratadine, mizolastine, rupatadine
Cardiotoxic drugs:
Astemizole, terfenadine
Mechanism of Action
The mechanism of action is via blockage of H1 receptor and some anti-allergic activity. New generation drugs can be used once daily. There is no development of tachyphylaxis is usually noted. Side Effects Old generation:
Sedation and/or anticholinergic effect is common
New generation:
No sedation for most drugs, no anticholinergic effect, no cardiotoxicity. Acrivastine has sedative effects, mequitazine has anticholinergic effects, and oral azelastine may induce sedation and has a bitter taste
D
Fig. 2.8.3 Strength of evidence for the treatment of allergic rhinitis. Recommendations are evidence-based on randomisedcontrolled trials (RCT) carried out on studies performed with the previous classification of rhinitis: seasonal (SAR) and perennial (PAR) allergic rhinitis. Strength of recommendation: A based on RCT or meta-analysis, D based on the clinical experience of experts
Fig. 2.8.2 Pharmacological management and drug effects on the symptoms of allergic rhinitis. 0 no effect, + mild, ++ moderate, +++ intense
2.8.7 Management and Treatment
Comments
New generation oral H1-antihistamines should be prefer red for their favourable efficacy/safety ratio and pharmacokinetics. They are rapidly effective (less than 1 h) on nasal and ocular symptoms and poorly effective on nasal congestion. Cardiotoxic drugs should be avoided [23, 26].
Oral:
When possible, intranasal corticosteroids should replace oral or IM drugs. A short course of oral corticosteroids may be needed with severe symptoms [23]
Local Antihistamines
Local antihistamines include Azelastine and levocabastine. They are rapidly effective (less than 30 min) on nasal or ocular symptoms. Minor local side effects: azelastine has a bitter taste.
2.8.7.2.3 Chromones (Intranasal, Ocular) Drugs
Drugs used include cromoglycate and nedocromil. Mechanism of Action
2.8.7.2.2 Corticosteroids
The mechanism of action is not well known.
Drugs
Side Effects
Intranasal:
Side effects are minor and local in nature. Beclomethasone, budesonide, flunisolide, fluticasone, momethasone, triamcinolone
Oral/intramuscular Dexamethasone, hydrocortisone, (IM): methylprednisolone, prednisolone, prednisone, triamcinolone, betamethasone, deflazacort
Comments
Intraocular chromones are very effective. Intranasal chromones are less effective, and their effect is short lasting. Overall they have an excellent safety record. 2.8.7.2.4. Nasal Decongestants Drugs
Mechanism of Action
The mechanism of action is via potent reduction of nasal inflammation and nasal hyperreactivity.
Oral:
Ephedrine, phenylephrine, phenylpropanolamine, pseudoephedrine
Side Effects
Intranasal:
Oxymethazoline, naphazoline, xylometazoline, and others
Intranasal:
Oral/IM:
Minor local side effects, wide margin for systemic side effects, growth concerns with some molecules only. In young children the combination of intranasal and inhaled drugs should be considered Systemic side effects common in particular for IM drugs. Depot injections may cause local tissue atrophy
Mechanism of Action
Sympathomimetic drugs relieve symptoms of nasal congestion by acting on alpha-adrenergic receptors. Side Effects Oral:
Hypertension, palpitations, restlessness, agitation, tremor, insomnia, headache, dry mucous membranes, urinary retention, exacerbation of glaucoma or thyrotoxicosis
Intranasal:
Same side effects as oral decongestants but less intense. Rhinitis medicamentosa is a rebound phenomenon occurring with prolonged use (over 10 days)
Comments Intranasal:
The most effective pharmacological treatment of allergic rhinitis. Effective on nasal congestion and loss of smell. Effect observed after 12 h but maximal effect after a few days
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2.8.7.3
Comments Oral:
Oral decongestants should be used with caution in patients with heart disease. Oral H1-antihistamine combined with decongestant may be more effective than either product alone, but side effects are combined
Intranasal:
Act more rapidly and more effectively than oral decongestants. Limit duration of treatment to less than 10 days to avoid rhinitis medicamentosa [27]
2.8.7.2.5 Anticholinergics Drug
Ipratropium is the drug of choice. Mechanism of Action
Anticholinergic drugs block almost exclusively rhinorrhea.
Specific Immunotherapy
Specific immunotherapy is effective when optimally administered. Standardised therapeutic vaccines are favoured when available. Subcutaneous immunotherapy raises contrasting efficacy and safety issues [29, 30]. The use of optimal doses of vaccines either labelled in biological units or labelled in mass of major allergens has been proposed. Doses of 5–20 µg of the major allergen are optimal doses for most allergen vaccines. 2.8.7.3.1 Subcutaneous Immunotherapy
Subcutaneous immunotherapy (SIT) alters the natural course of allergic diseases [31]. SIT should be performed by trained personnel, and patients should be monitored for 30 min after injection. SIT is indicated in patients insufficiently controlled by conventional pharmacotherapy, in whom oral H1-antihistamines and intranasal pharmacotherapy insufficiently control symptoms, who do not wish to be on pharmacotherapy, in whom pharmacotherapy produces undesirable side effects and who do not want to receive long-term pharmacological treatment.
Side Effects
There are minor, local side effects; there is virtually no systemic anticholinergic activity. Comments
Ipratropium is effective in allergic and nonallergic patients with rhinorrhea.
2.8.7.3.2 Nasal and Sublingual-swallow Specific Immunotherapy
Nasal and sublingual-swallow specific immunotherapy may be used with doses at least 20–100 times greater than those used for SIT, or in patients who had side effects or refused SIT. The indications follow those of subcutaneous injections.
2.8.7.2.6 Leukotriene-receptor Antagonists 2.8.7.3.3 Immunotherapy in Children Drugs
This class of drugs includes montelukast, pranlukast and zafirlukast.
Specific immunotherapy is effective. It is recommended to start this treatment after the child reaches 5 years of age.
Mechanism of Action
This class of drugs works by way of blockage of cys-LT receptor. Side Effects
Patients are found to have excellent tolerance of these drugs. Comments
These drugs are promising used alone or in combination with oral H1-antihistamines, but more data are needed to categorize better these drugs [28].
2.8.7.4
Education
When possible, education is always recommended. 2.8.7.5
Surgery
Surgical intervention may be used as an adjunctive intervention in few and selected patients (e. g. turbinate hypertrophy, septal deviation).
2.8.8 Special Considerations
2.8.7.6
Selection of Medications
Medications have no long-lasting effect when stopped. Therefore, in persistent disease, maintenance treatment is required (Fig. 2.8.4). • Tachyphylaxis does not usually occur with prolonged treatment. • Medications used for rhinitis are most commonly administered intranasally or orally. • Some studies have compared the relative efficacy of these medications, of which intranasal corticosteroids are the most effective. However, the choice of treatment also depends on many other criteria. • The use of alternative care (e. g. homeopathy, herbalism, acupuncture) for the treatment of rhinitis is increasing. Scientific and clinical supports are lacking for these therapies. There is an urgent need for large, randomised and controlled clinical trials for alternative therapies of allergic diseases and rhinitis. • IM injection of glucocorticosteroids is not usually recommended due to the possible occurrence of systemic side effects. • Intranasal injection of glucocorticosteroids is not usually recommended due to the possible occurrence of severe side effects.
more studies are needed, optimal management of rhinitis may improve coexisting asthma [32]. Drugs administered by the oral route may affect both nasal and bronchial symptoms. The safety of intranasal glucocorticoids is well established. Large doses of inhaled (intrabronchial) glucocorticoids can induce side effects [33]. One of the problems of dual administration may be the possible additive side effects. Although the addition of intranasal formulations to inhaled formulations does not produce any further significant suppression, more data are needed. It has been proposed that the prevention or early treatment of allergic rhinitis may help to prevent the occurrence of asthma or the severity of bronchial symptoms but more data are also needed. 2.8.7.8
The options of treatment are oral and/or ocular H1-antihistamines, ocular chromones and saline. Administration of ocular corticosteroids is not recommended.
2.8.8 Special Considerations 2.8.8.1
2.8.7.7
Treatment of Concomitant Rhinitis and Asthma
Treatment of asthma should follow the GINA guidelines [22]. Some drugs are effective in the treatment of both rhinitis and asthma (e. g. glucocorticoids, antileukotrienes), while others are only effective in the treatment of either rhinitis or asthma (e. g. α- and β-adrenergic agonists, respectively). Some drugs are more effective in rhinitis than in asthma (e. g. H1-antihistamines). Although
mild intermittent
moderate severe intermittent
mild persistent
moderate severe persistent
intranasal steroid local chromone oral or local non-sedative H 1-blocker oral / topical (
