Based on considerations of the underlying epidemiology, pathophysiology, histopathology, clinical relationships and treatment outcomes, the links between rhinosinusitis and asthma become evident supporting the unified airway concept.
The interplay between asthma and rhinosinusitis has led a change in ideology from separate disease processes toward development of the unified airway concept. Evaluation of the upper and lower airway demonstrates similar patterns of systemic inflammatory responses. Based on examination of underlying epidemiology, pathophysiology, histopathology, clinical relationships, and treatment outcomes, the links between rhinosinusitis and asthma become evident supporting the one airway, one disease concept. With a change in ideology from local, distinct disease processes to unified airway involvement, otolaryngologists must demonstrate increased awareness of lower airway disease to provide optimal patient care.
Definitions for chronic rhinosinusitis and asthma
A guideline for the definition of rhinosinusitis based on symptoms was published in 1997, “Adult Rhinosinusitis Defined” . Rhinosinusitis is defined as an inflammatory response involving the mucosa of the nasal cavity and paranasal sinuses, fluid within the cavities, and/or involvement of underlying bone. The diagnosis is suggested based on the presence of clinical symptoms and signs, which are divided into major and minor categories as seen in Box 1 . Clinical evaluation by means of anterior rhinoscopy or endoscopy revealing edema, hyperemia, polyps, and most significantly purulence can be indicative of rhinosinusitis. Imaging by means of CT scanning is superior to plain film radiography, and is not indicated routinely, but can be useful in recalcitrant cases. In 2002, the Task Force for Defining Adult Chronic Rhinosinusitis extended the recommendations to include duration of symptoms and the presence of the signs of inflammation as seen by either physical findings and/or radiographic imaging as outlined in Box 2 . Chronic rhinosinusitis (CRS) now is recognized as a spectrum of disease and is defined as “…a group of disorders characterized by inflammation of the mucosa of the nose and paranasal sinuses of at least 12 consecutive weeks’ duration” .
Major
Nasal obstruction
Facial pressure
Nasal discharge/postnasal drainage
Purulence
Anosmia/hyposmia
Minor
Cough
Headache
Dental pain
Ear pressure
Fatigue
Halitosis
Data from Lanza DC, Kennedy DW. Adult rhinosinusitis defined. Otolaryngol Head Neck Surg 1997;117:S1–7.
Duration of symptoms and/or signs of disease for greater than 12 consecutive weeks
Anterior rhinoscopic and/or nasal endoscopic examination findings of signs of inflammation; either
Discolored nasal drainage, polypoid mucosa, nasal polyps, or
Middle meatus edema and/or erythema, or
Localized or generalized erythema or edema or granulation tissue, or
Evidence of disease on radiographic studies,
CT scan or
Plain sinus radiographs with mucosal thickening of greater than 5 mm or complete opacification of one or more sinuses
Data from Benninger MS, Ferguson BJ, Hadley JA, et al. Adult chronic rhinosinusitis: definitions, diagnosis, epidemiology, and pathophysiology. Otolaryngol Head Neck Surg 2003;129(Suppl 3):S1–32.
The definition of rhinosinusitis includes a broad spectrum of causative factors. This is illustrated in Box 3 . Unfortunately, rhinosinusitis is difficult to classify, as many of these conditions occur in overlap and often do not exist in isolation . For this article, it is easiest to think of rhinosinusitis as organized based on inflammatory status—eosinophilic versus neutrophilic . The eosinophilic classification specifically refers to CRS with polyps (CRSwNP), a subset of CRS without polyps (CRSsNP), aspirin-exacerbated respiratory disease, and allergic fungal rhinosinusitis. It is eosinophilic rhinosinusitis that has the most well-delineated relationship with asthma. For the rest of this article, CRSwNP will be used to describe the eosinophilic forms of CRS.
Infectious etiologies
Infectious organisms (eg, bacteria, fungi)
Bacterial superantigens
Biofilms
Osteitis
Noninfectious etiologies
Neurologic dysfunction (eg, trigeminal)
Immunologic disorders
Aspirin sensitivity
Allergies
Extrinsic factors
Infectious inflammation
Noninfectious inflammation
Intrinsic factors
Autonomic dysfunction
Genetic abnormalities
Autoimmune disorder
Inflammatory status
Eosinophilic inflammation
Neutrophilic inflammation
Data from Meltzer EO, Hamilos DL, Hadley JA, et al. Rhinosinusitis: establishing definitions for clinical research and patient care. Otolaryngol Head Neck Surg 2004;131:S1–62.
The definition of asthma has evolved through the years. In 1991, the National Heart, Lung, and Blood Institute defined asthma as a lung disease with airway obstruction that is reversible, airway inflammation, and hyper-responsiveness to various stimuli. In 1997, the National Asthma Education Prevention Program highlighted the chronic nature of asthma emphasizing the interplay of inflammatory cells and mediators leading to symptomatology .
The triad of wheezing, chest tightness, and shortness of breath, although nonspecific, is present in most patients in asthma exacerbation. Diagnostic strategies in adults include pulmonary function tests, specifically forced expiratory volume in 1 second (FEV 1 ), FEV 25-75 , and provocative stimuli such as methacholine to test hyper-responsiveness. In the ambulatory setting, peak expiratory flow also can be considered.
Epidemiology
For over 70 years, there has been a recognized coexistence and association between asthma and sinusitis . Asthma and rhinosinusitis coexist at a higher frequency than would be expected from the prevalence of each alone in the general population . The prevalence of asthma in the general population is 5% to 8%. The prevalence of rhinosinusitis has been estimated to be 10% to 30%, but objective measures and newer definitions need to be applied to ascertain more definitive prevalence rates. Patients who have CRS have a 20% prevalence of asthma, approximately three to four times greater than the general population . On the other hand, patients who have asthma have an 85% to 90% prevalence of nasal symptoms. Ninety percent of mild-to-moderate asthmatics have abnormal findings on CT scans of the sinuses . From an epidemiologic standpoint, asthma and rhinosinusitis share similarity greater than would be expected for their consideration as separate entities. Adoption of newer definitions to establish diagnoses of rhinosinusitis and asthma can provide additional epidemiologic support of coexistence.
Economically, the 1998 US National Health interview reported a 16% prevalence of sinusitis with estimated costs of $5.8 billion annually, of which $3.4 billion were health care costs. Indirect costs were related to the time and resources spent going to the doctor and in obtaining medications, with lost time from work accounting for the remainder of expenditure .
Fiscally, asthma accounts for $16.1 billion in expenditures annually, of which $11.5 billion are direct costs. Prescription drugs account for $5 billion of these direct costs. The largest indirect cost is because of lost productivity caused by death, accounting for $1.7 billion annually .
Epidemiology
For over 70 years, there has been a recognized coexistence and association between asthma and sinusitis . Asthma and rhinosinusitis coexist at a higher frequency than would be expected from the prevalence of each alone in the general population . The prevalence of asthma in the general population is 5% to 8%. The prevalence of rhinosinusitis has been estimated to be 10% to 30%, but objective measures and newer definitions need to be applied to ascertain more definitive prevalence rates. Patients who have CRS have a 20% prevalence of asthma, approximately three to four times greater than the general population . On the other hand, patients who have asthma have an 85% to 90% prevalence of nasal symptoms. Ninety percent of mild-to-moderate asthmatics have abnormal findings on CT scans of the sinuses . From an epidemiologic standpoint, asthma and rhinosinusitis share similarity greater than would be expected for their consideration as separate entities. Adoption of newer definitions to establish diagnoses of rhinosinusitis and asthma can provide additional epidemiologic support of coexistence.
Economically, the 1998 US National Health interview reported a 16% prevalence of sinusitis with estimated costs of $5.8 billion annually, of which $3.4 billion were health care costs. Indirect costs were related to the time and resources spent going to the doctor and in obtaining medications, with lost time from work accounting for the remainder of expenditure .
Fiscally, asthma accounts for $16.1 billion in expenditures annually, of which $11.5 billion are direct costs. Prescription drugs account for $5 billion of these direct costs. The largest indirect cost is because of lost productivity caused by death, accounting for $1.7 billion annually .
Proposed mechanisms
Proposed mechanisms of interplay between the upper and lower airway include nasobronchial and pharyngobronchial reflex, and posterior nasal drainage of inflammatory mediators. Additionally, systemic inflammatory response and mucosal susceptibility along the entire airway secondary to either rhinosinusitis or asthma are discussed in the following sections.
Local reaction in one portion of the airway with a subsequent effect on distant airway sites has been proposed through multiple routes. The nasobronchial reflex is mediated by afferent pathways involving the trigeminal nerve and efferent fibers causing bronchoconstriction by means of the vagus nerve. Multiple studies have demonstrated that placement of an irritant in the nasal cavity has led to efferent bronchoconstriction. The nasobronchial reflex exhibits tachyphylaxis, lacks precision, and cannot account for the chronic symptoms associated with sinusitis and asthma. The pharyngobronchial reflex has afferent and efferent pathways involving the vagus nerve. Irritation of the hypopharynx with sinus secretions leads to bronchoconstriction and reduction in airflow rates. There is little evidence that drainage from the sinonasal cavity leads to direct bronchial irritation. Overall, the putative nasobronchial and pharyngobronchial reflexes, and lower airway response to posterior sinonasal drainage do not provide a complete explanation of the interplay between rhinosinusitis and asthma . A review of more recent research on systemic signaling and investigations of histopathologic changes in upper and lower airway in conjunction with the systemic inflammatory response provides insight into the unified airway concept.
The concept of systemic amplification by means of systemic interaction is a logical explanation for the idea that upper airway disease can affect lower airway disease. A local inflammatory reaction in one portion of the airway can reach the systemic circulation and potentially affect distant airway sites . Support for a systemic link in airway inflammation has been demonstrated by nasal challenge studies. For example, Braunstahl and colleagues have shown that nasal provocation with grass pollen stimulated the influx of eosinophils and inflammatory mediators in the bronchial mucosa and decreases in peak expiratory flow. In a demonstration of a systemic inflammatory linkage between CRS and asthma, patients who have severe asthma and extensive sinus disease as seen by CT scan have been shown to have a correlation between: sputum eosinophil counts and the extent of sinus disease and serum eosinophil counts .
This ability of one airway compartment to impact disease in another (remote) airway compartment seems to occur at the cellular level with involvement by eosinophils, T lymphocytes, and their inflammatory mediators . One suggested mechanism for this amplification is signaling through the bone marrow with release of inflammatory progenitors, such as mast cell and eosinophil–basophil progenitors into the peripheral blood and recruitment to the upper and lower airways . Through his research, Denburg has shown that the airway has the capacity to produce hematopoietic growth factors that drive the maturation of such inflammatory cell progenitors.
Histopathophysiology
The same cells, mediators, and evidence of chronic inflammation are found in the upper and lower airway inflammation seen in rhinosinusitis and asthma—T lymphocytes, eosinophils and mast cells with histamine, cytokines, granulocyte macrophage colony-stimulating factor (GM-CSF), and the presence of adhesion molecules. This histopathophysiologic association has been well-studied and confirmed in chronic hyperplastic sinusitis with nasal polyps (CHS/NP) and chronic asthma.
CHS/NP is a subset of CRS. This is an eosinophilic form of CRS that has been studied extensively and has some distinguishing characteristics. First, it has characteristic pathologic findings, with very thick mucosa with the infiltration of inflammatory cells, expanded epithelium, and fibrotic changes in the underlying connective tissue. Secondly, infection likely does not play a significant role in the perpetuated inflammation in CHS/NP as compared with some other forms of CRS. Thirdly, CHS/NP is the form of CRS that is most commonly epidemiologically, clinically, and pathologically linked to asthma . Among those patients who have CHS/NP, at least 50% have asthma, and 30% to 40% have associated aspirin intolerance . One-half to two thirds of patients who have CHS/NP are nonallergic .
Although there is an abundance of Th-2 lymphocytes seen, the role of allergies in eosinophilic CRS is unclear. Allergies and atopy may or may not be found in the eosinophilic form of CRS. Similar inflammatory responses are seen in both allergic and nonallergic forms of rhinosinusitis with the elaboration of Th-2 lymphocytes and the production of interleukin (IL)-4, IL-5, and IL-13 along with an influx of eosinophils . In fact, the level of eosinophilia can be equal in both allergic and nonallergic chronic hyperplastic sinusitis with polyps . Both the allergic and nonallergic forms of CHS/NP also have the same histopathologic findings . Furthermore, no studies exist to show that the treatment of allergies has a benefit in the management of CHS/NP . As such, there is little to distinguish allergic and nonallergic forms of eosinophilic rhinosinusitis. The same can be said of the eosinophilic-associated inflammatory reaction seen in allergic and nonallergic asthma, and this is supported by clinical outcomes as discussed later .
The histopathologic similarities between CRS and asthma are underscored by the fact that the respiratory lining from the nasal cavity and paranasal sinuses down through the larynx, trachea, and primary and secondary bronchi consists of a pseudostratified, ciliated columnar epithelium. The findings of airway remodeling seen in asthma involve mucus hypersecretion, goblet cell hyperplasia, submucosal gland formation, polymorphonuclear leukocyte cell infiltration, subepithelial edema, and basement membrane thickening. Increase in smooth muscle also is seen. Aside from the presence of smooth muscle, these identical histopathologic findings of chronic inflammation are seen in CRSwNP . These similarities are summarized in Box 4 .
