**2. The "United airway" concept**

Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. The chronic inflammation is associated with airway hyperresponsiveness

Treatment of Allergic Rhinitis:

various therapy steps.

of publications.

countries.

are shown in Figure 2.

The role of rhinitis in athletes.

ARIA Document, Nasal Lavage, Antihistamines, Cromones and Vasoconstrictors 63

Fig. 1. Classification steps for the severity /persistence of allergic rhinitis symptoms with

a. During the period 2001-2012, knowledge of epidemiology, diagnosis, management and comorbidity of patients with allergic rhinitis broadened due to the considerable number

b. The ARIA Recommendations that were proposed by an expert group must be validated

c. New evidence-based medicine systems will guide and include recommendations for

 Certain aspects of treatment, such as complementary and alternative medicine. Description of the relationship between upper and lower airways in developing

The rhinitis management (algorithm of the ARIA-Update recommendations 2008 and 2010)

The link between rhinitis and asthma in preschool aged children.

The update to the ARIA document is necessary because:

in terms of classification and management.

safety, expenditure and efficacy of various treatments. d. Gaps in the understanding of the first ARIA document:

that leads to recurrent episodes of wheezing, shortness of breath, chest tightness, and coughing. These episodes are associated with widespread and variable airflow obstruction within the lung, which is often reversible either spontaneously or with treatment (Global Initiative for Asthma, Update 2010).

There is increasing evidence that asthma is a complex syndrome made up of a number of disease variants, so-called asthma phenotypes, with different underlying pathophysiologies. Limited knowledge of the mechanisms of these disease subgroups is possibly the greatest obstacle in understanding the causes of asthma and improving treatment, and can explain the failure to identify consistent genetic and environmental correlations to asthma (Lötvall et al, 2011). It has been proposed that the asthma syndrome should be divided into distinct disease entities with specific mechanisms, which have been called "asthma endotypes." An "endotype" is considered to be a subtype of a condition defined by a distinct pathophysiological mechanism (Lötvall et al, 2011).

The ARIA document acknowledged the concept of a "single airway" or "one airway, one disease", in recognition of the indisputable epidemiological and etiopathogenic relationship that exists between asthma and allergic rhinitis (AR). Both are "a single disease whose basis is the chronic inflammatory process of the airway, a premise that must determine the diagnostic and treatment strategy (Bousquet et al, 2008).

The prevalence of allergic rhinitis in developed countries is between 10%-20%, almost three times the prevalence of asthma (Gergen & Turkettaub, 1991; Lester et al, 2001; Mannino et al, 2002). The concept "allergy; systemic disease" with clinical manifestations in various organs makes "one single airway" more accessible. This way, allergic rhinitis, rhinosinusitis, rhinitis with bronchial hyperresponsiveness, asthma, etc., may be reflections of different stages of the same chronic inflammatory disease of the airway.

In our settings, it is important to note that 20.4% of patients visit an allergist for the first time for rhinitis and asthma symptoms, as highlighted by the "2005 Allergological Study" (Spanish Society of Allergology and Clinical Immunology, 2006). Rhinoconjunctivitis (in allergy clinic settings), which was the main reason for visits in the 1992 Allergological Study (2,279 patients who represented the 57.4% of the sample) (Spanish Society of Allergology and Clinical Immunology, 1995), remains so in the 2005 Allergological Study (2,771 patients who represented the 55.5% of the sample) (Spanish Society of Allergology and Clinical Immunology, 2006). These absolute rates and figures reflect the importance of this disorder. In a study of 650 asthmatics from a health area of the Community of Madrid, 50% had an association with allergic rhinitis (Espinosa de los Monteros et al, 1999).

#### **2.1 Why a new "ARIA document Update 2008" (Bousquet et al, 2008) and "Update 2010" (Brozek JL et al, 2010)?**

However, during the period between the first edition in 2001 (Bousquet et al, 2001) and the present (2012), the appearance of numerous studies have caused it to be revised, giving a dynamic and current outlook on the problem both from epidemiologic and therapeutic viewpoints. Thus, the most notable aspect is the inclusion of anti-leukotrienes (Philip G et al, 2004) and the first mention of Omalizumab (Anti-IgE). Successive meetings of experts, along with numerous studies of controlled clinical trials and evidence-based medicine, will produce new up-to-date revisions of this document (Bousquet et al, 2008) (Figure 1).

that leads to recurrent episodes of wheezing, shortness of breath, chest tightness, and coughing. These episodes are associated with widespread and variable airflow obstruction within the lung, which is often reversible either spontaneously or with treatment (Global

There is increasing evidence that asthma is a complex syndrome made up of a number of disease variants, so-called asthma phenotypes, with different underlying pathophysiologies. Limited knowledge of the mechanisms of these disease subgroups is possibly the greatest obstacle in understanding the causes of asthma and improving treatment, and can explain the failure to identify consistent genetic and environmental correlations to asthma (Lötvall et al, 2011). It has been proposed that the asthma syndrome should be divided into distinct disease entities with specific mechanisms, which have been called "asthma endotypes." An "endotype" is considered to be a subtype of a condition defined by a distinct

The ARIA document acknowledged the concept of a "single airway" or "one airway, one disease", in recognition of the indisputable epidemiological and etiopathogenic relationship that exists between asthma and allergic rhinitis (AR). Both are "a single disease whose basis is the chronic inflammatory process of the airway, a premise that must determine the

The prevalence of allergic rhinitis in developed countries is between 10%-20%, almost three times the prevalence of asthma (Gergen & Turkettaub, 1991; Lester et al, 2001; Mannino et al, 2002). The concept "allergy; systemic disease" with clinical manifestations in various organs makes "one single airway" more accessible. This way, allergic rhinitis, rhinosinusitis, rhinitis with bronchial hyperresponsiveness, asthma, etc., may be reflections of different

In our settings, it is important to note that 20.4% of patients visit an allergist for the first time for rhinitis and asthma symptoms, as highlighted by the "2005 Allergological Study" (Spanish Society of Allergology and Clinical Immunology, 2006). Rhinoconjunctivitis (in allergy clinic settings), which was the main reason for visits in the 1992 Allergological Study (2,279 patients who represented the 57.4% of the sample) (Spanish Society of Allergology and Clinical Immunology, 1995), remains so in the 2005 Allergological Study (2,771 patients who represented the 55.5% of the sample) (Spanish Society of Allergology and Clinical Immunology, 2006). These absolute rates and figures reflect the importance of this disorder. In a study of 650 asthmatics from a health area of the Community of Madrid, 50% had an

**2.1 Why a new "ARIA document Update 2008" (Bousquet et al, 2008) and "Update** 

produce new up-to-date revisions of this document (Bousquet et al, 2008) (Figure 1).

However, during the period between the first edition in 2001 (Bousquet et al, 2001) and the present (2012), the appearance of numerous studies have caused it to be revised, giving a dynamic and current outlook on the problem both from epidemiologic and therapeutic viewpoints. Thus, the most notable aspect is the inclusion of anti-leukotrienes (Philip G et al, 2004) and the first mention of Omalizumab (Anti-IgE). Successive meetings of experts, along with numerous studies of controlled clinical trials and evidence-based medicine, will

Initiative for Asthma, Update 2010).

pathophysiological mechanism (Lötvall et al, 2011).

diagnostic and treatment strategy (Bousquet et al, 2008).

stages of the same chronic inflammatory disease of the airway.

association with allergic rhinitis (Espinosa de los Monteros et al, 1999).

**2010" (Brozek JL et al, 2010)?** 

Fig. 1. Classification steps for the severity /persistence of allergic rhinitis symptoms with various therapy steps.

The update to the ARIA document is necessary because:

	- Certain aspects of treatment, such as complementary and alternative medicine.
	- Description of the relationship between upper and lower airways in developing countries.
	- The role of rhinitis in athletes.
	- The link between rhinitis and asthma in preschool aged children.

The rhinitis management (algorithm of the ARIA-Update recommendations 2008 and 2010) are shown in Figure 2.

Treatment of Allergic Rhinitis:

developing countries.

Passalacqua et al, 2006; Passalacqua & Durham, 2007).

ARIA Document, Nasal Lavage, Antihistamines, Cromones and Vasoconstrictors 65

Provide an initial view of the magnitude of the problem with the first strategies in

The following Figure 3 presents the degrees of evidence of the various studies in terms of each type of treatment (Shekelle et al, 1999; Custovic & Wijk, 2005; Bousquet et al, 2006;

Fig. 3. Level of evidence of different interventions in allergic rhinitis (AR) (Bousquet et al, 2008).

Fig. 2. Rhinitis management (algorithm of the ARIA-Update recommendations 2008 and 2010) (Bousquet et al, 2008; Brozek et al, 2010).

The **initial primary goal** of "education and implementation of the handling of allergic rhinitis based on the dissemination of information that exists about it, its relationship with asthma, as well as allowing scientific evidence (increasingly up-to-date) to be used for control, which results in the benefiting of more than 600 million patients who suffer from this pathology" has been supplemented by the following news:

Developments of the 2008- and 2010-ARIA document (Brozek et al, 2010):


Fig. 2. Rhinitis management (algorithm of the ARIA-Update recommendations 2008 and

The **initial primary goal** of "education and implementation of the handling of allergic rhinitis based on the dissemination of information that exists about it, its relationship with asthma, as well as allowing scientific evidence (increasingly up-to-date) to be used for control, which results in the benefiting of more than 600 million patients who suffer from

Better understand the impact of allergic rhinitis on patient quality of life starting with

Perform a review based on the scientific evidence of all available treatments (published

Suggest a plan for implementing the recommendations in Europe (in collaboration with

Emphasize studies that highlight the relationship between rhinitis and asthma.

2010) (Bousquet et al, 2008; Brozek et al, 2010).

the management of rhinitis.

the EAACI).

this pathology" has been supplemented by the following news:

trials), including anti-leukotrienes and omalizumab.

Developments of the 2008- and 2010-ARIA document (Brozek et al, 2010): Confirm the clinical validity of the new allergic rhinitis classification.  Provide an initial view of the magnitude of the problem with the first strategies in developing countries.

The following Figure 3 presents the degrees of evidence of the various studies in terms of each type of treatment (Shekelle et al, 1999; Custovic & Wijk, 2005; Bousquet et al, 2006; Passalacqua et al, 2006; Passalacqua & Durham, 2007).


Fig. 3. Level of evidence of different interventions in allergic rhinitis (AR) (Bousquet et al, 2008).

Treatment of Allergic Rhinitis:

the elimination of the antigen.

given to the intranasal route.

**2.3 Allergen avoidance** 

only be administered systemically.

Drugs Generic names Mechanism of

Beclomethason e dipropionate Budesonide Ciclesonide Flunisolide Fluticasone

Azelastine Levocabastine Olopatadine

use (Table 1).

Local H1 antihistamines (intranasal, intraocular)

Intranasal glucocorticoster

oids

ARIA Document, Nasal Lavage, Antihistamines, Cromones and Vasoconstrictors 67

quality of life is assessed through the use of questionnaires. The recommendations for treatment depend on symptom severity along with repercussions on patient quality of life.

For the first time, therapy is approached using evidence-based medical criteria, reviewing controlled randomised studies, and performed according to the prior classification of seasonal and perennial rhinitis. These recommendations are based on meta-analysis studies regarding drug treatment and immunotherapy, and on a clinical practice guideline drawn up after an analysis of evidence available to date, based on the opinion of experts regarding

Of note are considerations regarding drug administration routes, and their advantages/disadvantages and indications/contraindications. There is special attention

In 1995, the first manual portable controlled-dose inhaler, called the "Medihaler", was introduced, which was the result of studies carried out in the Richer Co. laboratories (British Society for Allergy and Clinical Immunology, 2000). In the USA, a smaller inhaler was developed that was easier to handle than nebulizers and avoided the use of sedative antihistamines, which alter cognitive and motor functions. The inhaler was developed for the asthmatic daughter of Dr. G. Maison, chairman of the laboratories. The inhaler had a pressurized canister and metering valve. The use of topical medication in rhinitis has been

Although there is disagreement as to the efficacy of eliminating the antigen, it must always

Although there is disagreement as to the efficacy of eliminating the antigen, it must always be carried. In recent years, the pharmaceutical industry has researched new administration routes. It appears that the nose is a magnificent channel for drugs that until recently could

There are eight major therapeutic groups in the "ARIA-pharmaceutical market" available

Side effects Comments

Rapidly effective (minor than 30 minutes) on nasal or ocular symptoms.

The most effective pharmacologic treatment of allergic

Effective on nasal congestion.

rhinitis.

Minor local side effects. Azelastine: bitter taste.

Minor local side effects. Wide margin for systemic side effects. Growth concerns with

BDP only. In young children

developed to reduce systemic side effects as much as possible.

be carried out using environmental control measures.

**2.4 Therapeutics groups in the "ARIA-pharmaceutical"** 

action

nasal inflammation. Reduce nasal hyperactivity.

Blockage of H1 receptor. Some antiallergic activity for azelastine.

Potently reduce

The recommendations follow criteria which may differ from country to country, and in Europe and at WHO another Shekelle method was commonly used (Shekelle et al, 1999) (Figure 3).

Strength of recommendation:

A: Category I evidence (meta-analysis of randomized-controlled trials (RCT); or at least one RCT).

B: Category II evidence (at least one controlled study without randomization; or at least one other type of study) or extrapolated recommendation from category I evidence

C: Category III evidence (nonexperimental descriptive studies) or extrapolated recommendation from category I or II evidence.

D: Category IV evidence (expert committee reports or opinions or clinical experience of respected authorities) or extrapolated recommendation from category I, II or III evidence.

#### **2.3 Controversy in the treatment of allergic rhinitis**

Rhinitis, or inflammation of the nasal mucosa, is currently recognised as a major cause of morbidity, which significantly deteriorates quality of life (ISAAC Steering Committee, 1998). Although the prevalence of rhinitis is highly variable, we can conclude that between 15% and 20% of the population suffers from rhinitis, based on various studies that are influenced by the questionnaires used and the geographical area in which they are carried out (Broder et al, 1974a; Broder et al, 1974b; Sibbald & Rink, 1991; Spanish Society of Allergology and Clinical Immunology, 1995; Spanish Society of Allergology and Clinical Immunology, 2006). Early intervention with appropriate treatment may improve patient quality of life and productivity, as well as prevent its evolution to asthma (European Academy of Allergology and Clinical Immunology, 1998). A few years ago, the goal of rhinitis treatment was to improve symptoms. Currently, the goal is to block pathophysiological mechanisms that cause chronic inflammation and that leave patients vulnerable to respiratory airway infections.

The therapeutic approach to allergic rhinitis (AR) entails comprehensive treatment of the allergic inflammation of the airways (ARIA). The selection and combination of the therapeutic arsenal is achieved by taking into account current clinical practice guidelines, and by individualising the treatment for each patient, depending on the frequency of discomfort (intermittent or persistent AR) and its repercussion on the quality of life (mild or moderate/severe AR) (Bousquet et al, 2001). Treatment cost-effectiveness must also be assessed, as well as safety and the fact that we are dealing with a chronic disease.

The protocol for managing rhinitis, according to the 1994 Consensus (International Rhinitis Management Working Group, 1994), proposes a phased approach for the treatment of both allergic and non-allergic rhinitis. The above protocol is not very clear about the indications for immunotherapy, which in the final summary is indicated exclusively for seasonal AR. The European Academy of Allergy and Clinical Immunology (EAACI) Position Paper for treatment of AR published in 2000 and created from consensus between experts of the Academy (van Cauwenberge et al, 2000), reviewed 185 articles on rhinitis, focusing exclusively on therapeutic issues. The proposed treatment guidelines in this review, differentiated for seasonal and perennial AR in children and adults, are too rigid. The indication for immunotherapy is envisioned in very advanced phases of the therapeutic range, and also in an undefined manner. The therapeutic approach in ARIA (Bousquet et al, 2001) is phased and not as rigid as in other consensus. Treatment guidelines are open and do not list directives, and quality of life is assessed through the use of questionnaires. The recommendations for treatment depend on symptom severity along with repercussions on patient quality of life.

For the first time, therapy is approached using evidence-based medical criteria, reviewing controlled randomised studies, and performed according to the prior classification of seasonal and perennial rhinitis. These recommendations are based on meta-analysis studies regarding drug treatment and immunotherapy, and on a clinical practice guideline drawn up after an analysis of evidence available to date, based on the opinion of experts regarding the elimination of the antigen.

Of note are considerations regarding drug administration routes, and their advantages/disadvantages and indications/contraindications. There is special attention given to the intranasal route.

In 1995, the first manual portable controlled-dose inhaler, called the "Medihaler", was introduced, which was the result of studies carried out in the Richer Co. laboratories (British Society for Allergy and Clinical Immunology, 2000). In the USA, a smaller inhaler was developed that was easier to handle than nebulizers and avoided the use of sedative antihistamines, which alter cognitive and motor functions. The inhaler was developed for the asthmatic daughter of Dr. G. Maison, chairman of the laboratories. The inhaler had a pressurized canister and metering valve. The use of topical medication in rhinitis has been developed to reduce systemic side effects as much as possible.

## **2.3 Allergen avoidance**

66 Otolaryngology

The recommendations follow criteria which may differ from country to country, and in Europe and at WHO another Shekelle method was commonly used (Shekelle et al, 1999) (Figure 3).

A: Category I evidence (meta-analysis of randomized-controlled trials (RCT); or at least one

B: Category II evidence (at least one controlled study without randomization; or at least one

C: Category III evidence (nonexperimental descriptive studies) or extrapolated

D: Category IV evidence (expert committee reports or opinions or clinical experience of respected authorities) or extrapolated recommendation from category I, II or III evidence.

Rhinitis, or inflammation of the nasal mucosa, is currently recognised as a major cause of morbidity, which significantly deteriorates quality of life (ISAAC Steering Committee, 1998). Although the prevalence of rhinitis is highly variable, we can conclude that between 15% and 20% of the population suffers from rhinitis, based on various studies that are influenced by the questionnaires used and the geographical area in which they are carried out (Broder et al, 1974a; Broder et al, 1974b; Sibbald & Rink, 1991; Spanish Society of Allergology and Clinical Immunology, 1995; Spanish Society of Allergology and Clinical Immunology, 2006). Early intervention with appropriate treatment may improve patient quality of life and productivity, as well as prevent its evolution to asthma (European Academy of Allergology and Clinical Immunology, 1998). A few years ago, the goal of rhinitis treatment was to improve symptoms. Currently, the goal is to block pathophysiological mechanisms that cause chronic

The therapeutic approach to allergic rhinitis (AR) entails comprehensive treatment of the allergic inflammation of the airways (ARIA). The selection and combination of the therapeutic arsenal is achieved by taking into account current clinical practice guidelines, and by individualising the treatment for each patient, depending on the frequency of discomfort (intermittent or persistent AR) and its repercussion on the quality of life (mild or moderate/severe AR) (Bousquet et al, 2001). Treatment cost-effectiveness must also be

The protocol for managing rhinitis, according to the 1994 Consensus (International Rhinitis Management Working Group, 1994), proposes a phased approach for the treatment of both allergic and non-allergic rhinitis. The above protocol is not very clear about the indications for immunotherapy, which in the final summary is indicated exclusively for seasonal AR. The European Academy of Allergy and Clinical Immunology (EAACI) Position Paper for treatment of AR published in 2000 and created from consensus between experts of the Academy (van Cauwenberge et al, 2000), reviewed 185 articles on rhinitis, focusing exclusively on therapeutic issues. The proposed treatment guidelines in this review, differentiated for seasonal and perennial AR in children and adults, are too rigid. The indication for immunotherapy is envisioned in very advanced phases of the therapeutic range, and also in an undefined manner. The therapeutic approach in ARIA (Bousquet et al, 2001) is phased and not as rigid as in other consensus. Treatment guidelines are open and do not list directives, and

other type of study) or extrapolated recommendation from category I evidence

inflammation and that leave patients vulnerable to respiratory airway infections.

assessed, as well as safety and the fact that we are dealing with a chronic disease.

Strength of recommendation:

recommendation from category I or II evidence.

**2.3 Controversy in the treatment of allergic rhinitis** 

RCT).

Although there is disagreement as to the efficacy of eliminating the antigen, it must always be carried out using environmental control measures.

#### **2.4 Therapeutics groups in the "ARIA-pharmaceutical"**

Although there is disagreement as to the efficacy of eliminating the antigen, it must always be carried. In recent years, the pharmaceutical industry has researched new administration routes. It appears that the nose is a magnificent channel for drugs that until recently could only be administered systemically.

There are eight major therapeutic groups in the "ARIA-pharmaceutical market" available use (Table 1).


Treatment of Allergic Rhinitis:

abundant.

**3. Nasal lavage** 

**3.1 Efficacy in AR** 

well-tolerated, effective and inexpensive treatment.

important in the treatment of allergic rhinosinusitis.

IgE response to grass pollen (Subiza et al, 1999).

administered lavages and were used as controls.

**3.2 Usefulness in sinusitis and chronic rhinitis** 

performance of these lavages for rhinitis.

ARIA Document, Nasal Lavage, Antihistamines, Cromones and Vasoconstrictors 69

Topical nasal drugs acts as both a preventive and a curative medication for rhinitis. It is very important that the application be performed appropriately, with the goal of achieving uniform distribution of the drug throughout the nasal mucosa, especially if rhinorrhoea is

Nasal lavage is a non-pharmacological treatment of rhinitis. Most authors agree that this is a

Georgitis showed that the use of saline solution in nasal irrigation reduces inflammatory mediators (nasal histamine, prostaglandin D2 and leukotriene C4), while at the same time decreasing nasal symptoms (Georgitis, 1994). It observed that performing nasal lavage is

Subiza et al, published one of the best and most complete articles in the JACI, which indicated that the action of nasal lavages is simple and known: cleaning of nasal secretions, with anti-inflammatory effect and reduction in basophils and other anti-inflammatory cells. It is a complementary technique for intranasal corticosteroids, but is effective and convenient. Saline irrigation of the nose and sinuses during the pollen season inhibits the

According to Tomooka et al, patients who use nasal lavage twice a day for 3-6 week periods have statistically significant improvement (23 of the 30 symptoms on The Quality of Well

Garavello et al state that the use of nasal irrigation with hypertonic saline serum (3 times a day) decreases the consumption of antihistamines and significantly improves rhinitis, starting from the third week of treatment, and clearly in the fourth and fifth, with a significant reduction in the use of oral antihistamines (Garavello et al, 2003). The study was performed on 20 children, whose ages were not reported, with seasonal AR and sensitisation to *Parietaria judaica*. Irrigation with hypertonic serum was performed on 10 of the children 3 times at day during the entire pollen season (6 weeks). The other 10 were not

Degirmencioglu et al showed that saline irrigation with isotonic or hypertonic solutions

Lavages with isotonic and hypertonic saline serum are one of the mainstays of treatment of rhinosinusal disease, as they are safe, inexpensive and effective. The weight of evidence is such that the Allergy Foundation published an International Consensus article in *Allergy* (International Rhinitis Management Working Group, 1994) recommending the routine

Different clinicians confirmed that nasal irrigations with a saline solution along with nasal steroids are the basis of treatment for chronic sinusitis (Aukema & Fokkens, 2004).

Being scale questionnaires improve or disappear) (Tomooka et al, 2000).

improve symptoms during the pollen season (Degirmencioglu et al, 2004).


Table 1. Therapeutic groups in the "ARIA-pharmaceutical market" (Bousquet et al, 2008).

Topical nasal drugs acts as both a preventive and a curative medication for rhinitis. It is very important that the application be performed appropriately, with the goal of achieving uniform distribution of the drug throughout the nasal mucosa, especially if rhinorrhoea is abundant.
