Bradley F. Marple, MD, is Professor and Vice-Chairman of the Department of Otolaryngology-Head and Neck Surgery at University of Texas Southwestern Medical Center in Dallas.
Explore This IssueAugust 2007
I have found that it is not uncommon during the course of an office visit for a patient to offer an opinion pertaining to the role that nasal troubles play in his or her general health. Specifically, these individuals point out the fact that exacerbations of their chronic rhinosinusitis or allergic rhinitis gives rise to a worsening of asthma symptoms, decreases in exercise tolerance, and need for more frequent use of rescue medications. The coexistence and seeming interdependence of these maladies resonate with the sufferers to the point that when asked, many patients will often happily describe their personal theory of the pathophysiology of this phenomenon. And even though in many instances the explanation may be a little off the scientific mark, I am generally impressed with the consistency of these observations from patient to patient. Truth be known, when the premise of this argument is subjected to current peer-reviewed medical literature, it appears that these patient observations are reasonably close to the current conventional wisdom as it relates to respiratory diseases.
Concept of the Unified Airway
Over the course of the past two decades, the concept of inflammation involving both the upper and lower airways has become increasingly recognized and studied. When examined, asthma, allergy, and rhinosinusitis appear to behave similarly and in conjunction with one another in many cases, suggestive of an integration of the involved areas of the airway. This pattern of similarities has given rise to the concept of the unified airway model, which, simply stated, considers the entire respiratory system to represent a functional unit that consists of the nose, paranasal sinuses, larynx, trachea, and distal lung.1 The broad number of inflammatory diseases that occur within this functional unit present to a variety of specialties, including otolaryngology, pulmonology, primary care, and allergy. Similarly, literature related to this concept is distributed among the literature of each of these specialties.
Initial associations among these diseases were noted due to the concurrence of these disease processes and were later more objectively established by way of epidemiologic studies. The simple coexistence of rhinitis and asthma, as an example, was demonstrated by Corren,2 who noted that nasal symptoms were suffered by approximately 78% of a large group of patients with asthma. In another classic paper, the Finnish Twin Cohort Study,3 more than 11,000 patients were followed longitudinally to assess whether the presence of allergic rhinitis was associated with the development of other respiratory diseases over time. Questionnaires were administered in 1975, 1981, and 1990 and revealed a fourfold increase in asthma reporting at the end of the study in subjects with hay fever over normal control subjects. In 2002, Guerra et al. corroborated these findings after following 1655 patients with allergic rhinitis and 2177 normal controls over a 20-year period. As in the previous study, sufferers of allergic rhinitis were approximately three times more likely to develop asthma than were the controls.4
Similar relationships have been identified among other allergic and nonallergic respiratory diseases. Anecdotal associations between asthma and rhinosinusitis have been reported for more than 70 years.5 The prevalence of asthma, for instance, in patients with chronic rhinosinusitis (approximately 20%) is consistently noted to be much greater than that observed in the general population (5-8%),6 and in those patients who undergo endoscopic sinus surgery the prevalence climbs even higher, to approximately 42%.7 This same association exists between chronic rhinitis and allergic rhinitis, as shown by a cohort of patients with the diagnosis of recurrent acute or chronic rhinosinusitis who were followed within a major health care system. In this study, patients diagnosed with chronic rhinosinusitis demonstrated a 57% prevalence of positive in vitro or allergy skin testing.8
The overlap and interrelationship of these respiratory diseases become less surprising as definitions of disease and underlying pathophysiologies come into better focus. The concept of asthma as a chronic inflammatory disease emerged in 1991 as a result of a report by the National Institute of Health and the National Heart, Lung, and Blood Institute.9 With this report, the pathophysiological focus of asthma shifted from bronchospasm to one of inflammation that is mediated at the cellular level. The implications of this report were monumental and resulted in a major shift in treatment strategy for the disease. It was not until later that similar observations resulted in refinements in the definition of chronic rhinosinusitis. In 2003, a definition of chronic rhinosinusitis was introduced that emphasized the pathogenic role of inflammation in the disease.10
Inflammation as a common theme underlying the definitions of both chronic upper and lower respiratory disease makes sense for several reasons. The respiratory epithelium that lines the nose, sinuses, and lower airways is composed of the same pseudostratified, ciliated, columnar epithelium. Functionally, these respiratory surfaces share many similarities. In the case of chronic inflammation, mucosa of upper and lower air passages demonstrate similar patterns of inflammatory cellular infiltrate and eventual basement membrane thickening.11 Histopathology consistently points to the eosinophil as the primary effector cell common to all these diseases. Eosinophilic inflammation, thought originally to represent evidence of allergic stimulation, is now recognized as important to Th2-mediated inflammation independent of allergy. Other common inflammatory cells include CD4 T-lymphocytes and other mononuclear cells.1
Perhaps even more intriguing evidence of the overlap and potential interplay of asthma, allergy, and rhinosinusitis are commonalities in cytokines expressed by CD4 lymphocytes within inflamed respiratory tissue and the resulting cascade of local and regional events. Lemanske and Busse12 described cytokines released from patients with asthma. Cytokines such as interleukin (IL)-4, IL-5, and IL-13 are produced by Th2 lymphocytes in conjunction with chemokines such as RANTES and eostaxin. This soup of mediators leads to activation of cellular adhesion molecules, ICAM-1 and VCAM-1, essential for chemotaxis and activation of eosinophils to the site of inflammation. Evidence suggests that this signaling is not confined to one compartment of the respiratory tract. Inflammatory triggers from any one of these respiratory diseases appears capable of initiating inflammation at distant sites within the respiratory system. In fact, this characteristic of the unified airway theory is referred to as the concept of systemic amplification.
Effect of Treatment of the Respiratory Tract as a Functional Unit
The impact of these findings is only now starting to bear fruit from a clinical point of view. Increasingly, studies are beginning to show the beneficial impact of treating the respiratory tract as a whole. Multiple studies have shown the impact that controlling chronic sinusitis has on the management of asthma. When taken in aggregate, successful management of chronic rhinosinusitis results in decreased asthma medication, improved pulmonary function, and fewer exacerbations.13 Similarly, treatment of allergic rhinitis has an impact on asthma, as demonstrated in a cohort of patients with concurrent allergic rhinitis and asthma. As an example of this observation, patients in this study who were treated with nasal steroids enjoyed an improvement in pulmonary symptoms after 12 weeks of therapy over disease-matched controls.14
Some of the treatment modalities currently available to patients may even possess the capability to alter host cellular responses to inflammatory triggers responsible for some aspects of chronic respiratory disease. In 1999, Durham et al.15 demonstrated the effect of antigen-specific immunotherapy on CD4 function. Over the course of therapy, cutaneous CD4 lymphocytes obtained from patients treated with subcutaneous immunotherapy for a period of at least three years revealed a change in cytokine expression suggestive of a shift from Th2 to Th1 compartmentalization. Findings such as these illustrate the potential impact of treatments such as allergen-specific immunotherapy to reach beyond simply that of symptomatic control of allergic rhinitis.
Impact on the Practice of Otolaryngology
So while the exact mechanism by which a patient may describe the relationship among asthma, allergy, and rhinosinusitis may remain in question, the general observation appears reasonably sound and supportable by current literature. The notion of the unified airway concept offers both a challenge and an opportunity to the practice of otolaryngology. On one hand, common and interrelated inflammatory disease of the respiratory tract requires treating physicians to be aware of common comorbidities. Successful treatment of nasal polyposis fails to matter if an unrecognized asthma threatens a patient’s activity or life. On the other hand, this concept offers hope that comprehensive recognition and management may lead to improved overall patient outcomes.
The relevance of the unified airway concept is now becoming increasingly recognized by professional organizations within otolaryngology. Otolaryngologists treating patients with allergic rhinitis are beginning to identify, monitor, and manage patients with concurrent asthma. Otolaryngologists who treat chronic rhinosinusitis are beginning to incorporate allergy evaluation and treatment into their operative and nonoperative management schemes. The end result is the potential for improved patient care.
Given the importance of these issues, the American Academy of Otolaryngology-Head and Neck Surgery, the American Academy of Otolaryngic Allergy, and the American Rhinologic Society have organized a half-day seminar focusing on the unified airway concept as it affects the practice and direction of otolaryngology. A series of panels, case presentations, and lectures will be presented focusing on the comprehensive treatment of patients with respiratory disease. Topics have been selected to focus on surgical rhinology, medical rhinology, allergy, and asthma, highlighting the interdependency of involved treatment modalities. The session will be held on Monday, September 17, 2007, and will be available to anyone who has registered for any of the participating professional society meetings. It is our collective hope that this will set the stage for advances in the field of rhinology and allergy, and will lead to increasing improvements in patient care.
- Krouse JH, Brown RW, Fineman SM, et al. Asthma and the unified airway. Otolaryngol Head Neck Surg 2007;136:S75-S106.
- Corren J. Allergic rhinitis and asthma: how important is the link. J Allergy Clin Immunol 1997;99:S781-S786.
- Huovinen E, Kaprio J, Laitinen LA, et al. Incidence and prevalence of asthma amon adult Finnish men and women of the Finnish twin cohort from 1975 to 1990, and their relation to hay fever and chronic bronchitis. Chest 1999;115:928-36.
- Guerra S, Sherrill DL, Martinez FD, et al. Rhinitis as an independent risk factor for adult-onset asthma. J Allergy Clin Immunol 2002;109;419-25.
- Annesi-Maesaano I. Epidemiological evidence of the occurance of rhinitis and sinusitis in asthmatics. Allergy 1999;54:7-13.
- Hamilos D. Chronic sinusitis. J Allergy Clin Immunol 2000;106:213-27.
- Senior B, Kennedy DW, Tanabodee J. Long-term impact of functional endoscopic sinus surgery on asthma. Allergy 1999;57:136-40.
- Gutman M, Torres A, Keen KJ, et al. Prevalence of allergy in patients with chronic rhinosinusitis. Otolaryngol Head Neck Surg 2004;130:545-52.
- National Asthma Education and Prevention Program (NAEPP). Guidelines for the diagnosis and management of asthma. National Heart, Lung, and Blood Institute. National Asthma Education Program. Expert Panel Report. J Allergy Clin Immunol 1991;88:425-534.
- Benninger MS, Ferguson BJ, Hadley JA, et al. Adult chronic rhinosinusitis: definitions, diagnosis, epidemiology, and pathophysiology. Otolaryngol Head Neck Surg 2003;129(3 Suppl):S1-S32.
- Bachert C, Vignola M, Gavaert P, et al. Allergic rhinitis, rhinosinusitis, and asthma: one airway disease. Immunol Allergy Clin N Am 2004;24:19-43.
- Lemanske RF, Busse WW. Asthma. J Allergy Clin Immunol 2003;111:S502-S519.
- Batra P, Kern R. Tripathi A, et al. Outcome analysis of endoscopic sinus surfery in patients with nasal polyps and asthma. Laryngoscope 2003;113:1703-6.
- Stelmach R, do Patrocinio T, Nunes M, et al. Effect of treating allergic rhinitis with corticosteroids in patients with mild to moderate persistent asthma. Chest 2005;128:3140-7.
- Durham SR, Walker SM, Varga EM, et al. Long-term clinical efficacy of grass-pollen immunotherapy. N Engl J Med 1999;341:468-75.
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