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The Impact of Upper Airway Allergic Inflammation on Asthma

The Impact of Sinusitis (Rhinosinusitis) on Asthma

Richard F. Lockey, M.D.
Professor of Medicine, Pediatrics and Public Health Director, Division of Allergy and Immunology
Joy McCann Culverhouse Chair in Allergy and Immunology
University of South Florida College of Medicine of Medicine
James A. Haley Veterans' Medical Center
Tampa, Florida

Roger W. Fox, M.D.
Associate Professor of Medicine and Public Health
University of South Florida College of Medicine
James A. Haley Veterans' Medical Center
Division of Allergy and Immunology
Tampa, Florida

The nasal cavity, paranasal sinuses and lungs are considered separate organs of the respiratory tract. However, a growing body of evidence links the upper and lower airways. For example, the coexistence and impact of allergic and nonallergic rhinitis on asthma is now documented. In addition, inflammation of the nose (rhinitis) commonly is associated with inflammation of sinuses (sinusitis) as reflected in the term rhinosinusitis. This presentation reviews the impact of rhinosinusitis on asthma as related to the links between allergic and nonallergic rhinitis and asthma; viral upper respiratory tract infections and asthma; and allergic and nonallergic rhinosinusitis, allergic and nonallergic hyperplastic rhinosinusitis and asthma; and the aspirin-exacerbated respiratory disease syndrome and asthma.

Introduction
The nasal cavity, paranasal sinuses and lungs are considered separate organs of the respiratory tract with an interaction between the nose and paranasal sinuses serving to protect against noxious agents for the lungs. However, a growing body of scientific evidence and clinical observations now link the upper and lower airways as the “united airway” [1,2,3]. Evidence includes: similar histology and physiology; near identical immune and clinical responses to allergens; the coexistence of allergic and nonallergic rhinitis or rhinosinusitis and asthma; the presence of allergic and nonallergic chronic hyperplastic rhinosinusitis (with or without nasal polyps) and asthma; and the triad of chronic hyperplastic rhinosinusitis with or without nasal polyps, asthma, and aspirin-exacerbated asthma (asthma triad or Samter's Syndrome).

Allergic and nonallergic rhinitis is associated with nasal as well as sinus inflammation. Therefore, the term rhinosinusitis reflects the close relationship between rhinitis and chronic sinusitis, which commonly coexist. [4, 5] These upper airway disorders also share the same prominent symptoms. The term rhinosinusitis will be used in this paper to indicated that an inflammatory process of the nasal cavity, whatever the cause, also affects the sinuses and vice versa.

Studies support a link between rhinosinusitis (rhinitis associated with sinusitis) and asthma. The following information links these two diseases. A similar inflammatory cascade in both the upper and lower airways is initiated by allergens, viral and other kinds of infectious agents (bacterial and fungi) and by aspirin. [6-10]. Many of the cells, mediators, cytokines and neurotransmitters in this inflammatory process are the same for various kinds of rhinosinusitis and asthma [1-3] In addition, the pathophysiology of Churg-Strauss syndrome and allergic fungal rhinosinusitis and allergic bronchopulmonary aspergillosis link the upper and lower airways. Allergic rhinitis is also a risk factor for developing asthma and sinusitis, [11] and allergic rhinitis and asthma are two manifestations of atopy. [12] Severe asthmatics have more prominent abnormalities on computerized tomography scans of the paranasal sinuses, [13] and the treatment of rhinosinusitis benefits asthma clinical outcomes.[14-15]

This review presents evidence that the upper and lower airways are one functional unit and that rhinosinusitis must be appropriately evaluated and treated to achieve optimal clinical outcomes for asthma. The protective role of the nose for the lungs and the nasal pharyngeal bronchial reflexes, which also link these two organ systems, will not be discussed (see Table I).

Allergic and Nonallergic Rhinitis (Rhinosinusitis) and Asthma
The association between allergic rhinitis and asthma is recognized as a manifestation of atopy [4, 16] The World Health Organization sponsored the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines in 1999 as an evidence-based document linking both allergic and nonallergic rhinitis to asthma. [17] Many patients with allergic rhinitis have concomitant asthma and most asthmatics have coexistent allergic rhinitis [18] often associated with inflammation of the sinuses or rhinosinusitis. [13, 19] The ARIA document recommends that a patient with rhinitis be evaluated for asthma and vice versa since rhinitis occurs in over 75% of allergic asthmatics and 80% of the non-allergic asthmatics. Rhinitis precedes the onset of asthma in 64% of patients, and the onset of rhinitis and asthma occurs concurrently in 21% of the cases. Nineteen to 38% of rhinitis patients present with clinical asthma [20, 21], and many allergic rhinitis patients demonstrate nonspecific bronchial hyperreactivity (BHR), e.g., have a positive methacholine or histamine bronchial challenge study. [22] Allergic rhinitis patients without asthma demonstrate increased bronchial hyperreactivity primarily during a pollen season. [23] Increased bronchial hyperreactivity is more significant in perennial allergic rhinitis patients due to house dust mites and cats versus those with seasonal pollen allergic rhinitis. [24] Subjects with allergic and non-allergic rhinitis are three times more likely to develop adult-onset asthma, and as the duration of rhinitis increases, so too does the risk for developing asthma. [25, 26] In addition, rhinitis and sinusitis together have a stronger predictive value for developing asthma than does rhinitis alone. [27]

Studies, which link the upper and lower airway responses to allergens, support the concept that an allergic stimulus in one organ system, either the nose or lungs, results in a systemic allergic inflammatory response which affects the other. [12] For example, allergen challenge of the nose increases the allergic eosinophilic inflammation of the bronchi, [28, 29] and bronchial allergen challenge enhances the allergic inflammation in the nose. [30] This occurs through the systemic signaling effects of tissue IL-5 on the proliferation and mobilization of eosinophils from the bone marrow. The local allergic reaction in the nose or the lung has a hemapoietic effect resulting in a systemic allergic eosinophilic inflammatory response. (Fig. 1)

The rhinitis (rhinosinusitis) and asthma association is reinforced by the observations that the treatment of one of these respiratory organs benefits the other. For example, not only does intranasal beclomethasone reduce the symptoms of allergic rhinitis, it improves asthma symptoms and BHR and lowers asthma medication requirements and ER visits. [31-33] Likewise, high dose inhaled glucocorticoids given orally for treatment of subclinical asthma also improve allergic rhinitis. [34] Antihistamines benefit rhinitis more than asthma but do benefit both, and leukotriene modifiers are more effective in asthma than rhinitis but benefit both. [35] Likewise, specific allergen immunotherapy [36] and anti-IgE monoclonal antibody (omalizumab) therapy improves both diseases, [37] and specific allergen immunotherapy to treat children with allergic rhinitis without asthma reduces the incidence of new onset of asthma. [38] Environmental control of mites, fungi and animal danders may also benefit both rhinitis and asthma. [39]

Thus, sufficient treatment of asthma or rhinitis blunts the bone marrow response thereby down-regulating the allergic inflammation in the respiratory tissue. Said differently, reducing the local production of IL-5 and thus the eosinophilic infiltration of the upper or lower airway mucosa helps both conditions. [12] Thus, allergic and nonallergic rhinitis and rhinosinusitis and asthma are linked.

Viral Upper Respiratory Tract Infections and Asthma
Viral upper respiratory tract infections, otherwise known as the “common cold”, can cause uncomplicated rhinosinusitis. Patients with any type of rhinitis may be more susceptible to upper respiratory tract infections and their secondary complications. Some viral upper respiratory tract infections, in particular, rhinovirus, in spite of the fact that they infect the nose and not the lungs, exacerbate asthma. Also, the combination of allergen and rhinovirus in an allergic subject enhances the inflammatory response. This provides a second link between rhinitis and rhinosinusitis and asthma. [40]

Allergic or Nonallergic Infectious/Inflammatory and Allergic or Nonallergic Chronic Hyperplastic Rhinosinusitis
When the paranasal sinuses are diseased, so too is the nasal cavity. [41]

Acute or chronic sinusitis is usually defined as inflammation of one or more of the paranasal sinuses. However, it more accurately should be referred to as acute or chronic infectious rhinosinusitis. Acute infectious rhinosinusitis usually is caused by a viral upper respiratory tract infection and persists for several weeks or less, depending on whether or not a secondary bacterial infection complicates the clinical course. Chronic infectious rhinosinusitis is usually characterized by persistent inflammation complicated by a bacterial infection lasting for 6 weeks or longer.

Acute and chronic infectious rhinosinusitis exacerbate asthma, and appropriate medical treatment improves both upper and lower airway symptoms. Likewise, successful medical or surgical treatment of chronic infectious rhinosinusitis improves asthma and reduces medication requirements. [14, 15]

The concept of chronic infectious rhinosinusitis, although certainly true for many subjects, has undergone change since some of these patients have, or go on to have, noninfectious chronic hyperplastic rhinosinusitis, a persistent inflammatory disease of the nose and sinuses associated with certain inflammatory cells and cytokines, with an allergic or nonallergic etiology. Patients with chronic hyperplastic rhinosinusitis often have the typical symptoms of chronic infectious rhinosinusitis. These symptoms may include post-nasal drip, rhinorrhea (often clear but sometimes suppurative), nasal obstruction, facial discomfort and even pain, fatigue and cough. Likewise, they also can have nasal polyposis and abnormal mucosal thickening, not only in their nasal cavity, but throughout their sinuses.

Chronic infectious rhinosinusitis is characterized by an inflammatory infiltrate with B and T lymphocytes, mononuclear phagocytes and neutrophils. It is not as commonly associated with persistent asthma as is chronic hyperplastic rhinosinusitis, which is often preceded by non-allergic or allergic responses and/or infection and possibly other unknown factors. This section discusses chronic hyperplastic rhinosinusitis and its relationship to asthma.

Rhinitis often precedes the onset of rhinosinusitis and allergic rhinitis coexists with chronic rhinosinusitis in 67% of patients. [42] Over 50% of perennial allergic rhinitis patients have abnormal sinus radiographs, and during a pollen season, allergic rhinitis patients have sinus mucosal radiographic abnormalities. [43-46] Some of these patients also develop chronic hyperplastic rhinosinusitis, which occurs more commonly in severe asthma. [27, 47]

When adult asthmatic patients are evaluated by computed tomographic scanning, approximately 74-90% have some degree of mucosal hyperplasia. [51] Over 50% of patients with chronic hyperplastic rhinosinusitis have asthma and 50% of patients with aspirin intolerance [13] have chronic hyperplastic rhinosinusitis with sputum eosinophilia. These patients may have more severe asthma. [47] While associated with asthma, there is no association of chronic hyperplastic rhinosinusitis with chronic obstructive pulmonary disease. [13]

Forty to 75% of patients with chronic hyperplastic rhinosinusitis with nasal polyps are atopic. This persistent inflammatory disorder is characterized by increased and activated eosinophils, fibroblasts, mast cells, and goblet cells in the nasal and sinus mucosa and submucosa, the primary hallmark of this condition. Eosinophils and TH2 cell mucosal infiltration is present in most subjects with either allergic or nonallergic chronic hyperplastic rhinosinusitis. [48, 49] Allergic chronic hyperplastic rhinosinusitis is characterized by TH2- like lymphocytes and the presence of IL-3, IL-4, IL-5, IL-13, TNF-alpha, eotaxin, growth factors and GM-CSF. In contrast, the nonallergic chronic hyperplastic rhinosinusitis cytokine profile consists of IL-5, IL-13, TNF-alpha, IFN-gamma and growth factors. [50]

Increased levels of cysteinyl leukotrienes (CysLTs) are present whether or not chronic hyperplastic rhinosinusitis is allergic or nonallergic. [52] These findings appear to be irrespective of whether the initial insult results from either allergic or non-allergic stimuli, such as a respiratory tract infection. Chronic hyperplastic rhinosinusitis is less responsive to surgical intervention than is chronic rhinosinusitis associated with a chronic bacterial infection. As previously stated, it frequently is associated with asthma, reflecting the shared pathophysiology of both the upper and lower airways. Both chronic hyperplastic rhinosinusitis and asthma are associated with a TH2 paradigm. [53, 54, 55] Eosinophils, an additional source of cytokines, and the up-regulated eosinophils, have an autocrine-like function resulting in chronic mucosal inflammation.

A direct relationship between sinus mucosal thickness on computerized tomography scan and bronchial inflammation (peripheral eosinophilia, induced sputum eosinophilia and increased exhaled NO) in severe adult asthmatics has been reported, but whether the sinus disease directly affects the intensity of bronchial inflammation is not completely understood. [13] It's possible that chronic hyperplastic rhinosinusitis represents a remodeling process of the upper airways as described in some patients with asthma. Thus, infectious/inflammatory rhinosinusitis and chronic hyperplastic rhinosinusitis, both of which can be allergic or nonallergic, and their relationship with asthma provide a third link between these diseases of the upper and lower airways.

Aspirin-Exacerbated Respiratory Disease
Aspirin-exacerbated respiratory disease is a chronic inflammatory disease of both the upper (chronic hyperplastic rhinosinusitis, usually with nasal polyps) and lower (usually nonallergic asthma) airways. Severe exacerbations of asthma and rhinosinusitis occur following the ingestion of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs). However, these patients can tolerate the Cox 2 selective analgesic, celecoxib. [56] This syndrome provides for the fourth link between rhinosinusitis and asthma.

The aspirin exacerbated respiratory disease is a unique phenotype of asthma, accounting for up to 10-15% of asthmatic patients in some populations, based on challenge studies. [9] The diagnosis should be suspected in asthmatic cases presenting with a) a history of asthma associated with the ingestion of aspirin or any other NSAID, b) chronic and intractable nasal congestion and watery rhinorrhea, c) nasal polyposis, d) pansinusitis demonstrated by computed tomography scanning, and e) severe attacks of asthma without apparent cause requiring emergency care or hospitalization.

The pharmacological action of aspirin is to inhibit COX-1 and to accelerate the depletion of the protective prostaglandin E2 (PGE2) [57]. Cysteinyl leukotrienes (Cys-LTs) are the principle mediators of aspirin-exacerbated respiratory disease. Baseline levels of leukotriene E 4 (LTE 4 ) in urine and in exhaled air are elevated in these patients. [57, 58] After an aspirin challenge, all 3 cysteinyl leukotrienes levels ( C4, D4 and E4) rise significantly above the baseline values. The biosynthesis of cysteinyl leukotrienes is up-regulated in these patients by the over-expression of the enzyme, leukotriene C4 synthase (LTC4S), found in the bronchial and nasal mucosa and circulating eosinophils. [59]

The genetic polymorphism of the LTC4S promoter gene transcription which upregulates the biosynthesis of Cys-LTs partially explains this syndrome. [60] This single polymorphism at nucleotide –444C of the LTC4S promoter gene is a marker of the severe glucocorticoid-dependent phenotype of aspirin-induced asthma. [61] In addition, patients with aspirin sensitivity appear to generate more Cys-LT receptors, enhancing their ability to respond to available Cys-LTs. [62] Another explanation for the increased pharmacodynamic action of Cys-LTs in aspirin sensitive patients may be due to the diminished capacity of lipoxin biosynthesis. The absence of the protective role of lipoxins, an anti-inflammatory derivative of arachidonic acid metabolism, against the Cys-LTs may be a factor in the self-perpetuating and protracted course of inflammation in the upper and lower airways of the aspirin sensitive patient. [63] There is also growing evidence that mast cell activation occurs not only after ASA provocation but also as a continuous process in stable aspirin-exacerbated respiratory disease. The baseline prostaglandin D2 metabolite and tryptase have been reported to be elevated in aspirin-exacerbated respiratory disease patients. The persistent eosinophilic inflammation of the sinuses and bronchi in aspirin-exacerbated respiratory disease patients may be due to the continuous and enhanced PGD2 release and mast cell activation. (Brochenek. J Allergy Clin Immunol, in press)

Any or all of the following treatments may be required to control aspirin-exacerbated respiratory disease: inhaled and systemic corticosteroids, Cys-LT modifiers, aspirin desensitization and polypectomy/sinus surgery. [9] Inhaled and systemic glucocorticosteroids are the mainstay for treating asthma, particularly, severe asthma, and in this case, aspirin-exacerbated respiratory disease. Cys-LT inhibitors and modifiers improve aspirin-exacerbated respiratory disease. With aspirin desensitization and the use of daily aspirin, 650 mg twice daily for 5 months, LTB4 synthesis in peripheral monocytes declined to normal control levels. Also, urine LTE4 levels decreased to near baseline, and the absolute number of nasal inflammatory cells expressing Cys-LT1 receptors declined to non-aspirin-sensitive asthma levels. [64] Aspirin desensitization probably interferes with Cys-LT1 receptors and/or some intracellular signaling mechanism to override the concentrations of Cys-LTs. Likewise, surgical intervention also has been shown to benefit some patients with chronic hyperplastic rhinosinusitis, but aspirin-exacerbated respiratory disease patients with chronic hyperplastic rhinosinusitis may be more refractory to such treatment. Thus, the aspirin triad of nasal polyps, chronic rhinosinusitis and persistent asthma is another example of the “united airway” response to a common pathogenic mechanism.

In conclusion, not only is allergic and nonallergic rhinitis linked to sinusitis (rhinosinusitis) and asthma, so too are allergic and nonallergic infectious rhinosinusitis and allergic and nonallergic chronic hyperplastic rhinosinusitis. Treatment of these upper airway diseases is necessary for the well-being of the patient and for optimal asthma outcomes.

 

Table I

Classification of Rhinitis and Rhinosinusitis

  1. Rhinitis
    1. Allergic
      1. Seasonal (intermittent)
      2. Perennial (persistent)
    2. Nonallergic
      1. Intermittent
      2. Persistent
  2. Allergic Rhinosinusitis
    1. Seasonal (intermittent)
    2. Perennial (persistent)
    3. Acute (intermittent) infectious/inflammatory (associated with asthma flares)
    4. Chronic (persistent)
      1. Infectious/inflammatory
        1. may be associated with chronic asthma
        2. contributing factors: anatomical abnormalities, immunodeficiency, cystic fibrosis, etc.
        3. non-eosinophilic
        4. more responsive to surgery
      2. Hyperplastic*
        1. often associated with asthma (extensive sinus disease), typically more severe asthma phenotype
        2. Frequently associated with aspirin-exacerbated respiratory disease
        3. polyps are common
        4. eosinophilic
        5. less responsive to surgery
  3. Nonallergic Rhinosinusitis
    1. Intermittent or persistent
    2. Acute (intermittent) infectious/inflammatory (associated with asthma flares)
    3. Chronic (persistent) - same as II c.

* The role of chronic bacterial infection uncertain. Bacterial infection alone is insufficient to produce chronic hyperplastic rhinosinusitis in most patients. Other host factors and other cofactors are required. Mucosal damage, inflammation and sinus obstruction are required.

 

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