Consideration of the unified airway model when managing patients with rhinitis and or asthma allows a more comprehensive care plan and therefore improved patient outcomes. Asthma is linked to rhinitis both epidemiologically and biologically, and this association is even stronger in individuals with atopy. Rhinitis is not only associated with but is a risk factor for the development of asthma. Management of rhinitis improves asthma control. Early and aggressive treatment of allergic rhinitis may prevent the development of asthma. In patients with allergic rhinitis that is not sufficiently controlled by allergy medication, allergen-directed immunotherapy should be considered.
Key points
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In the unified airway model, the nose and the paranasal sinuses through the respiratory bronchi are considered as components of 1 functional unit.
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Rhinitis and asthma are linked epidemiologically and pathophysiologically.
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Rhinitis is not only associated with but is a risk factor for the development of asthma.
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Atopy/allergy and disease severity are important factors affecting the association between rhinitis and asthma.
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Hygiene hypothesis suggests that a lack of microbial exposures as a child may result in modification of immunity toward T helper 2 (Th 2 ) skewing and the increased risk for asthma and other atopic diseases.
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Proper management of allergic rhinitis can concomitantly allow better asthma control.
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In evaluating and treating patients with rhinitis, the diagnosis of asthma should be considered.
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It is important that physicians managing rhinitis/rhinosinusitis become familiar with the diagnosis and management of asthma.
Introduction
Although rhinitis and asthma are frequently comorbid conditions, physicians managing patients with rhinitis and or rhinosinusitis have traditionally not taken part in the diagnosis or management of asthma. Rhinitis, sinusitis, and asthma are linked both epidemiologically and pathophysiologically and thus the nose through the paranasal sinuses to the distal bronchioles should not be thought of as separate entities but rather constituents of 1 functional unit. This unit is referred to as the unified airway model. Rhinitis is not only associated with but is a risk factor for the development of asthma. Although both allergic and nonallergic forms of rhinitis are associated with asthma, the association between asthma and allergic rhinitis (AR) is even stronger. The use of allergen-directed immunotherapy in young children with allergic rhinitis has been shown to prevent the development of asthma in later life. Irritants and allergens presented at one portion of the airway have distal effects. It is thought that the upper and lower airways communicate through a complex interaction of inflammatory mediators and the autonomic system. Furthermore, disease severities in rhinitis and asthma often parallel each other. Adequate treatment of allergic rhinitis can allow better asthma control and, in some situations, may even prevent the development of asthma. With the substantial evidence to support the link between upper and lower airway disease it is imperative that physicians who manage patients with rhinitis and sinusitis become familiar with the diagnosis and management of asthma.
| AR | Allergic rhinitis |
| BHR | Bronchial hyperresponsiveness |
| CGRP | Calcitonin gene-related peptide |
| ICS | Inhaled corticosteroids |
| LABA | Long-acting β2-agonists |
| RSV | Respiratory syncytial virus |
| SABAs | Short-acting bronchodilators |
Introduction
Although rhinitis and asthma are frequently comorbid conditions, physicians managing patients with rhinitis and or rhinosinusitis have traditionally not taken part in the diagnosis or management of asthma. Rhinitis, sinusitis, and asthma are linked both epidemiologically and pathophysiologically and thus the nose through the paranasal sinuses to the distal bronchioles should not be thought of as separate entities but rather constituents of 1 functional unit. This unit is referred to as the unified airway model. Rhinitis is not only associated with but is a risk factor for the development of asthma. Although both allergic and nonallergic forms of rhinitis are associated with asthma, the association between asthma and allergic rhinitis (AR) is even stronger. The use of allergen-directed immunotherapy in young children with allergic rhinitis has been shown to prevent the development of asthma in later life. Irritants and allergens presented at one portion of the airway have distal effects. It is thought that the upper and lower airways communicate through a complex interaction of inflammatory mediators and the autonomic system. Furthermore, disease severities in rhinitis and asthma often parallel each other. Adequate treatment of allergic rhinitis can allow better asthma control and, in some situations, may even prevent the development of asthma. With the substantial evidence to support the link between upper and lower airway disease it is imperative that physicians who manage patients with rhinitis and sinusitis become familiar with the diagnosis and management of asthma.
| AR | Allergic rhinitis |
| BHR | Bronchial hyperresponsiveness |
| CGRP | Calcitonin gene-related peptide |
| ICS | Inhaled corticosteroids |
| LABA | Long-acting β2-agonists |
| RSV | Respiratory syncytial virus |
| SABAs | Short-acting bronchodilators |
AR and asthma defined
AR is defined as a symptomatic immunoglobulin E (IgE)–mediated inflammation of the nasal mucosa. Symptoms of rhinitis are reversible and include nasal congestion/obstruction, rhinorrhea, sneezing, pruritus, postnasal drip, chronic cough, throat clearing, and conjunctivitis. Rhinitis is categorized, based on duration of symptoms and by the disease’s impact on quality of life, as intermittent or persistent mild or moderate to severe ( Table 1 ).
| Intermittent |
|
| Persistent |
|
| Mild |
|
| Moderate to severe |
|
Asthma is a chronic inflammatory disorder of the airways that results in reversible airway obstruction and bronchial hyperresponsiveness (BHR) to a variety of stimuli. Inflammatory mediators and mainly mast cells, eosinophils, T lymphocytes, neutrophils, and epithelial cells are known to play an important role in this process. In advanced cases, airway remodeling can occur, with irreversible injury to the pulmonary mucosa. The airway inflammation and subsequent airway obstruction experienced by these individuals can result in symptoms of wheezing, breathlessness, chest tightness, and coughing.
Although the focus of asthma pathophysiology was once on the hyperresponsiveness of the airways, it is now known that inflammation is the driving mechanism, with the increased bronchial reactivity being caused by this inflammatory state. This concept is important to understanding the pathophysiology and treatment of asthmatics.
Epidemiology
Asthma-Rhinitis Link
AR and asthma affect about 30% and 7% to 8% of people respectively. Between 75% and 80% of atopic and nonatopic individuals with asthma have rhinitis. Between 10% and 40% of individuals with rhinitis have asthma. Not only are rhinitis and asthma associated but rhinitis is a risk factor for the development of asthma. Twenty percent of individuals with rhinitis go on to develop asthma later in life. Studies suggest that individuals with rhinitis have a 3-fold increased risk for the development of asthma. Rhinitis often precedes the development of asthma.
This association is influenced by a variety of factors. The development of atopy in early childhood, before 6 years of age, is an important risk factor for the development of BHR in late childhood. However, although early sensitization to inhalant allergens is a known risk factor for the development of atopic disease later in life, only about 25% of individuals sensitized to one or more inhalant allergen go on to develop asthma. Among individuals with AR and atopy the type of protein to which the individual is sensitized correlates with differing propensities for development of asthma. Individuals sensitized to perennial allergens have a significantly higher likelihood for developing asthma than individuals sensitized to seasonal allergens. In a study by Linneberg and colleagues, compared with their nonallergic counterparts, individuals sensitized to pollen, a seasonal allergen, had a 10-fold increased risk for developing asthma, whereas those who were sensitized to dust mite, a perennial allergen, had a 50-fold increased risk for developing asthma.
Genetics
In addition, there seems to be a genetic predilection to the development of these diseases. In a study in northern Sweden, a family history of atopic rhinitis and atopic asthma increased the risk of developing those conditions up to 6-fold and 4-fold respectively.
Geography
Significant geographic variability exists in reference to the prevalence of allergic respiratory diseases. Dahl and colleagues performed a study looking at the prevalence of patient-reported allergic respiratory disorders in 10 European countries. Spain had a significantly lower prevalence and Italy a significantly higher prevalence of allergic respiratory disorder compared with other European countries: 11.7% and 33.6%, respectively ( Table 2 ).
| Country | Prevalence (%) a |
|---|---|
| Italy | 33.6 |
| Norway | 26.8 |
| Sweden | 26.8 |
| United Kingdom | 26.2 |
| Finland | 26.0 |
| The Netherlands | 24.2 |
| Germany | 23.5 |
| Denmark | 20.6 |
| Austria | 15.9 |
| Spain | 11.7 |
a Nationally balanced prevalence % weighted against size of national population.
Disease Severity
Disease severity also has an important influence on this association. Individuals with severe, persistent forms of rhinitis are more likely to have symptomatic asthma than individuals with intermittent forms of rhinitis. Patients with asthma and severe rhinitis experience a higher rate of nighttime awakenings and increased absences from work than asthmatics with less severe rhinitis.
Environmental Factors Beyond Allergens
In addition to allergens, there are a variety of environmental factors that have been implicated in the development of asthma. As an example, there is a known association between respiratory symptoms such as dyspnea on exertion, breathlessness, and cough with air pollution. Furthermore, exposure to moisture damage at work or at home and other causes of occupational rhinitis are well-studied risk factors. The risk of asthma has been shown to be as high as 7 times that of controls among farmers with occupational rhinitis. Although further studies need to be performed, reduced exposure to known occupational triggers for rhinitis is important not only for symptom management but also for the potential prevention of occupational asthma. Furthermore, tobacco smoke, drugs such as aspirin, obesity, and viral infections such as respiratory syncytial virus are known risk factors for the development of asthma.
Allergens and/or irritants cause local inflammation in the nasal mucosa that leads to an increased ability for inhaled irritants to get to the distal bronchioles by disrupting the filtering capabilities of the nose, which results in the inhalation of unfiltered irritants into the distal airways and subsequently pulmonary symptoms. However, even in the absence of a local response, allergens/irritants presented to an isolated portion of the respiratory system exert distal effects.
Pathophysiology
Two mechanisms have been proposed to explain the communication between the nasal and bronchial mucosa:
- 1.
Inflammatory crosstalk in which local irritation leads to upregulation of a variety of inflammatory mediators at a distal site within the respiratory tract
- 2.
Neurogenic reflexes, in which neuronal stimulation in the nose can result in the release of cholinergic neurotransmitters and subsequent contraction of the bronchial smooth muscle
Inflammatory Response
A series of studies were performed by Braunstahl and colleagues in which antigen placed in the nose resulted in upregulation of inflammatory mediators at the distal bronchi, and inoculation of an antigen into the bronchi using a bronchoscope resulted in upregulation of inflammatory mediators in the nose. The upregulation of inflammatory mediators at a site distal to inoculation suggests an inflammatory crosstalk between the upper and lower airway systems. Bronchoconstriction results from the interaction between resident inflammatory cells, such as mast cells and alveolar macrophages, with upregulated inflammatory mediators such as eosinophils, lymphocytes, neutrophils, and basophils. Mediators such as histamine, leukotrienes, prostaglandin D 2 , and platelet-activating factor, are subsequently released and act on bronchial smooth muscle to cause muscle contraction.
Autonomic Response
Either by direct activation of the vagus nerve or via secondary activation of the parasympathetic system, neuroregulatory mechanisms act at the level of the bronchial smooth muscle to result in bronchoconstriction. Neuromediators such as substance P and calcitonin gene-related peptide, affect the release of histamine and bradykinin. These mediators work at the vascular epithelium to cause an unrestricted passage of proteins and fluid. In addition, cholinergic neurotransmitters cause contraction of the bronchial smooth muscle. Moreover, mucus plugging from excessive mucus production further contributes to airflow obstruction.
Histopathology
The nose, paranasal sinuses, trachea, and primary and secondary bronchi are all lined by a pseudostratified ciliated columnar epithelium. The inflammatory cell profile in the nasal mucosa of patients with AR is similar to that seen in the bronchial mucosa of patients with atopic asthma, with both having an increased infiltration of mainly eosinophils, as well as a variety of other cytokines.
Unlike the lower respiratory tract, the nasal passages have an extensive vascular system with subepithelial capillaries, arteries, and venous and cavernous sinusoids. Vessel engorgement results in symptomatic nasal obstruction, which is one of the characteristic features of rhinitis. In contrast, the trachea through the respiratory bronchi is lined by smooth muscle. It is the contraction of this smooth muscle system either through the inflammatory or neuroregulatory mechanisms discussed earlier that causes the acute, reversible airway obstruction that is the pathognomonic feature of asthma.
T helper 2 (Th 2 ) cells are responsible for allergic inflammation. Interleukin (IL)-4, IL-5, and IL-13, along with other inflammatory mediators and chemokines, result in the transendothelial migration and activation of eosinophils. In addition, endothelial adhesion proteins intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 assist in the migration of neutrophils, lymphocytes, and eosinophils from the intravascular space into the airway. Mast cell degranulation and histamine release lead to the production of leukotrienes. Eosinophils present in the inflamed tissue causes the release of toxic basic proteins, which leads to epithelial damage and airflow obstruction. This processes results in the characteristic histologic features of mucosal edema, submucosal gland and bronchial smooth muscle hypertrophy, mucus hypersecretion, and basement membrane thickening and fibrosis seen in asthma.
Chronic inflammation in asthmatics can result in airway remodeling. Remodeling is a process in which tissue injury and subsequent repair leads to mucosal edema, submucosal gland and bronchial smooth muscle hypertrophy, mucus gland and goblet cell hyperplasia, angiogenesis, collagen deposition, basement membrane thickening, and subepithelial fibrosis in the lamina reticularis. Although similar finding are seen in patients with chronic rhinosinusitis, remodeling has not been well shown in patients with allergic rhinitis. Further, the reticular basement membrane thickening is not as pronounced in nasal epithelium in rhinitis as it is in the bronchial epithelium in patients with asthma.
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