UNIFIED AIRWAY

Patients frequently present to multiple specialties, including their primary care physician, otolaryngologist, and pulmonologist, for workup of respiratory tract complaints. Knowledge and familiarity of the coexistence of upper and lower airway inflammatory conditions are essential in the diagnosis and management of these diseases. Both epidemiologic and pathophysiologic studies have established the connection between the upper and lower airway, supporting the concept of a unified system. The “unified airway model” describes the need for evaluation of the entire respiratory tract from the nose and paranasal sinuses to the trachea and distal bronchioles as one integrated entity. Symptoms arise from the upper airway secondary to allergic and nonallergic rhinitis and from the lower airway as related to asthma. However, one inflammatory condition can initiate a response from another part of the respiratory system, instigating a new response or exacerbating one that is already present. Local and systemic stimuli generate an inflammatory process throughout the upper and lower airway, exacerbating symptoms or creating resistance to treatment if not all systems are addressed. The overall severity of the disease and treatment of each may affect the overall improvement in symptoms and control of the disease process. As such, a thoughtful approach that encompasses and considers the entire airway, including potential extra-airway insult from the alimentary tract, should be taken when evaluating and treating the patient with cough.²

Relationship Between the Upper and Lower Airway: Epidemiologic Evidence

Epidemiologic studies have established the relationship between upper airway diseases, specifically rhinitis and rhinosinusitis, and lower airway illnesses, such as asthma, supporting the unified airway model. Rhinitis and rhinosinusitis confer a significant health burden on the overall population. The prevalence of allergic rhinitis ranges from 15% to 40% and is the fifth most common chronic disease in the United States.^3–5 Rhinosinusitis affects 12% of adults in the US population and is the number one diagnosis leading to an antibiotic prescription.⁶ Research has proven that rhinitis is a primary risk factor in the development of asthma and that there is an increase in bronchial hyperresponsiveness in rhinitis patients. Therefore, otolaryngologists and specialists need to be aware of this association between the upper and lower airway to properly diagnose and manage these illnesses and to optimize treatment outcomes.

Rhinitis and asthma frequently coexist, and upper airway inflammation often precedes lower airway disease. Studies have shown that nasal symptoms occur in up to 78% of patients with asthma. Up to 38% of patients with allergic rhinitis and nonallergic rhinitis also have asthma.7–11 Compared to patients with no history of either disease, there was a two- to fourfold higher incidence of new diagnosis of allergic rhinitis or asthma in patients who previously had one of these diseases.^11–12 There is also a temporal relationship between the development of rhinitis and asthma. It has been shown that 64% of patients had rhinitis before the onset of asthma, and 21% had both upper and lower airway disease at the same time.^{11, 13} In another study, 49% of patients had nasal symptoms first and 25% had both diseases within 1 year of each other.^{9, 11} These findings demonstrate that nasal symptoms of allergic rhinitis precede the development of lower airway symptoms, and patients have an increased risk of developing asthma over time.² Yawn et al found that the association of asthma and allergic rhinitis varied with the age of first diagnosis of asthma, which may demonstrate a relationship between allergic rhinitis and asthma triggers, such as exposure to allergens.¹⁴ Therefore, it is unclear if what causes nasal symptoms leads to the first manifestation of the airway disease process or if the nasal symptoms themselves lead to the development of lower airway disease. Regardless, the association between the two demonstrates the need to evaluate the airway as a unified entity.

Additionally, the presence of allergic rhinitis is a risk factor in the severity of asthma and, conversely, the severity of nasal symptoms has been found to correlate to the severity of asthma.^{2, 15} Total medical care and respiratory care cost was significantly higher when patients had both asthma and allergic rhinitis as compared to asthma alone.¹⁴ Therefore, proper diagnosis and treatment of rhinitis may prevent the development of asthma and improve asthma control.

Chronic rhinosinusitis (CRS) is a significant burden on direct and indirect health care costs with substantial impact on quality of life. It is currently classified by clinical phenotype, although there is a wide spectrum of presentations with overlap in symptoms. CRS is most commonly grouped into CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP), but can also be divided based on the inflammatory state—eosinophilic versus neutrophilic. Eosinophilic rhinosinusitis is the category of upper airway disease most associated with asthma. It presents with thick mucus production, nasal congestion, loss of smell, and acute bacterial exacerbations. The pathophysiology is based on the secretion of cytokines, specifically interleukin-5 (IL-5), which promotes the accumulation of eosinophils in the sinonasal mucosa, causing inflammation and symptoms. Patients with CRS have a 20% prevalence of asthma as compared to 5% to 8% in the general population.¹⁶ In those patients with CRSwNP, the prevalence of asthma increases to 50%.¹⁷ Treatment of CRS with medical therapy and surgical intervention has been shown to improve asthma control and decrease asthma medication usage. Additionally, surgical treatment of nasal polyps has been shown to have long-term improvement in lower airway disease.17 Based on these epidemiologic studies, the coexistence of asthma and CRS, particularly the eosinophilic subtype, has been recognized and further evaluated to prove the connection from histopathologic findings.

NONALLERGIC RHINITIS AND ASTHMA

Most studies have focused on the relationship between allergic rhinitis and asthma; however, nonallergic rhinitis is also strongly associated with asthma. Nonallergic rhinitis can be divided into nonallergic rhinitis without eosinophilia (aka vasomotor rhinitis) or nonallergic rhinitis with eosinophilia (NARES). In a study using a questionnaire, measurement of total and specific immunoglobulin IgE, allergy skin-prick tests, and bronchoprovocation challenges with methacholine, asthma was strongly associated with both allergic and nonallergic rhinitis and remained highly significant when the analysis was limited to nonatopic subjects with relatively low IgE levels.¹⁸ All rhinitis was found to be a significant risk factor for asthma, and increased the risk of developing asthma by threefold.¹⁹

Clinical Relationship Between Rhinitis and Asthma

Airway inflammation in asthma, which leads to the symptomology, is triggered by the activation of eosinophils, mast cells, and T lymphocytes. It has been demonstrated that clinical severity, airway hyperresponsiveness, and lung function are related mainly to eosinophilic inflammation.²⁰ Additionally, the infiltration with T-helper lymphocytes expressing Th2-type cytokines in nasal and bronchial mucosa are well documented in both allergic asthma and rhinitis.^{21, 22} These cytokine mediators are responsible for the vascular engorgement and mucosal edema that cause the symptoms of rhinitis, including nasal obstruction, sneezing, and rhinorrhea. This inflammatory cascade also correlates with the severity of asthma symptoms and degree of bronchial hyperresponsiveness.²¹ Based on this, nasal allergies may induce lower airway responsiveness, despite the lack of a formal diagnosis of asthma, leading to the concept of increased asthma susceptibility in those with rhinitis and suggesting that rhinitis and asthma are one disease process that manifests in different parts of the airway system.

In the presence of severe rhinitis, patients with asthma are associated with a worse prognosis and require more asthma treatment.^{23, 24} Additionally, those patients with allergic rhinitis without a diagnosis of asthma also show bronchospasm and hyperresponsiveness, especially with nasal allergy challenge.²⁵ In a survey from the European Community Respiratory Health Survey, self-reported “nasal allergies” were an independent predictor of bronchial hyperreactivity.²⁶ The difference between perennial allergies and seasonal allergies also alters the degree of hyperresponsiveness. Prieto et al found a lower methacholine threshold value and higher level of plateau on bronchial provocation testing in those with perennial allergies as compared to those with seasonal allergies.4 Nonasthmatics usually reach a maximal response plateau at a mild degree of airway narrowing as compared to patients with asthma, who do not reach a plateau response, leading to increased airway narrowing. In combination with the epidemiologic relationship between rhinitis and asthma, this demonstrates a strong correlation between the two diseases.

As further evidence strengthening the unified airway model, studies have shown therapeutic effects of rhinitis treatment on asthma. Intranasal corticosteroids prevent increases in nonspecific bronchial reactivity and asthma symptoms associated with seasonal pollen exposure.¹¹ Specifically, in a 4-week trial of intranasal budesonide in patients with perennial nasal allergy and asthma, not only was chronic nasal obstruction improved, but daily asthma symptoms and exercise-induced bronchospasm were also reduced.¹¹ Studies have also found more effective improvement in bronchial responsiveness with intranasal delivery of corticosteroid as compared to oral inhalation.²⁷ This demonstrates that intranasal delivery of corticosteroids is effective in managing lower airway symptoms in patients with allergic rhinitis.

Clinical Relationship Between Chronic Rhinosinusitis and Asthma

Eosinophilic-mediated or T-helper (Th) 2 type inflammation leading to CRSwNP is the subtype most commonly associated with asthma, particularly late-onset asthma.²⁸ Based on histopathologic findings, eosinophil infiltration and similar airway remodeling are found throughout the upper and lower airway. Basement membrane thickening, goblet cell hyperplasia, subepithelial edema, mucus hypersecretion, and epithelial damage are among the common findings in both the upper and lower airways in CRS and asthma.^28–32 Th2 lymphocytes trigger the release of cytokines IL-4, IL-5, and IL-13, which are inflammatory mediators that drive the cascade leading to both upper airway symptoms and lower-airway inflammation.

Clinical studies have used symptoms and computed tomography (CT) imaging to identify the correlation between CRS and asthma. There is a highly significant correlation between extent of sinus involvement based on CT imaging and the severity of asthma.³³ Eosinophil count in peripheral blood was also directly correlated with symptom scores and sinus CT imaging scores in those with mild to moderate asthma. Therefore, this leads to the conclusion that rhinosinusitis and asthma are the manifestations of eosinophilic inflammatory process in the upper and lower airways. Brinke et al also found CT imaging abnormalities in those with severe asthma, even in the absence of nasal symptoms. These findings were more frequently associated with adult-onset asthma, indicating the eosinophil mediated inflammatory process is the driver of both upper and lower airway diseases.28, 34 The medical and surgical treatment of CRS is associated with improvement in asthma, which further supports the hypothesis that inflammation of the upper airway has direct effects on the lower airway through inflammatory mediators and cytokines.

Clinical Relationship Between Chronic Rhinosinusitis and Laryngopharyngeal Reflux

GERD or laryngopharyngeal reflux (LPR) has been linked to multiple disease processes in the upper airway and middle ear.^35–40 In the pediatric population, LPR has been implicated as a reason for failure of CRS to respond to appropriate medical therapy.^35–37 In adults, CRS has been found to occur in greater frequency in patients with LPR than in those without, and those with medically refractory CRS have been found to be associated with higher likelihood of LPR.^{38, 41–43} Additionally, patients with persistent CRS after endoscopic sinus surgery were found to have more reflux at the distal and proximal aerodigestive tract, specifically the nasopharynx, representing a causative factor of refractory CRS that needs to be addressed.⁴⁴ GERD has also been found to be a significant predictor of poor symptomatic outcome after endoscopic sinus surgery for CRS.⁴⁵ Recent systematic review and meta-analysis also supported a significant association between GERD and CRS, and CRS patients were found to have a greater prevalence of intranasal Helicobacter pylori and acid reflux than those without CRS.⁴⁰ Although the exact pathophysiology of how LPR contributes to CRS is unknown, there is sufficient evidence supporting the effects of reflux on CRS, and consideration for treatment of both is recommended.

Pathophysiology of Upper and Lower Airway Interrelationship

The unified airway model is well supported; however, the pathophysiology connecting the upper and lower airway is poorly understood. There are several theories that explain the relationship between the upper and lower airway.¹¹ The first is the nasal–bronchial reflex, which describes trigeminal afferent nerves originating in the nose (afferent limb) causing efferent bronchoconstriction of the lower airway. Nasal stimulus with allergens has been shown to cause lower airway resistance, such as with silica,⁴ nasal petrolatum packing,⁴⁷ and cold air.⁴⁸ Between 11% and 32% of patients with rhinitis have positive bronchoconstrictor responses to histamine, methacholine, or carbachol in the range of responses consistent with patients with asthma.^{11, 49–51} It has also been shown that exposure of cold air to the nasal mucosa induces a positive bronchoconstrictor response in normal individuals.⁵² The effect is attributed to the cholinergic reflex because the systemic administration of atropine⁴⁶ and resection of the trigeminal nerve⁵³ have been shown to prevent this bronchospasm (efferent limb).

The second theory describes the shift from nasal to mouth breathing with nasal obstruction, leading to bronchospasm. Improvement in lower airway symptoms may be the result of better humidification and warming of the air with nasal breathing, preventing lower airway constriction.

The third theory is the aspiration of sinonasal drainage. Several animal studies have identified upper respiratory tract substances in the tracheobronchial tree, and the blockage of this has prevented nonspecific bronchial responsiveness.54–56 Nelson et al performed a prospective study evaluating pulmonary aspirates and identified aspiration of sinonasal secretions into the lungs of both patients with cystic fibrosis and healthy adults in the recumbent position.⁵⁷

The theory of systemic amplification has also been used to explain the linkage between CRS and asthma. This describes that one airway compartment can impact disease in another through inflammatory mediators and the recruitment of these inflammatory progenitors from the peripheral blood to the airway.¹⁵ Thus, control of one airway compartment leads to the improvement of symptoms in another airway compartment, such as with control of CRS and associated improvement in asthma.

The unified airway model considers multiple facets of airway disease to elucidate the connection between upper airway disease, such as rhinitis and rhinosinusitis, and asthma. The evidence behind this model supports the need to consider the upper and lower airway together, both for diagnosis and for treatment to optimize outcome. The prevalence of rhinitis and rhinosinusitis in asthmatic patients demonstrate that these are different manifestations of respiratory disease within one system.¹⁵ The exact pathogenesis of how upper airway disease leads to lower airway disease is unknown; however, this review of the literature supporting the unified airway model highlights the importance of being familiar with these common conditions for diagnosis and management of the symptom chronic cough.

WHEN IT ISN’T SINONASAL DISEASE

When smoking and angiotensin converting enzyme (ACE) inhibitor use are ruled out as a cause for chronic cough, three diagnoses account for more than 90% of all chronic cough symptoms: cough-variant asthma (CVA), GERD or LPR, or postnasal drip (PND).^{58, 59} In 2006, the American College of Chest Physicians updated its evidence-based guidelines on cough and replaced the diagnosis of postnasal drip syndrome (PNDS) with upper airway cough syndrome (UACS). Although a significant amount of idiopathic chronic cough is attributed to postnasal drip, the diagnosis of PND lacks objective diagnostic measures and is based on highly variable symptoms as described by patients. UACS can be caused by various types of rhinitis, as described below. The mechanism of how PND induces cough is controversial and largely unproven. The pharyngobronchial reflex hypothesizes that the mechanical drainage of secretions from the sinonasal tract into the hypopharynx causes pharyngeal constriction, and ultimately bronchoconstriction and cough symptoms.19 PND is described as the drainage of secretions from the nose and paranasal sinuses into the pharynx that is eventually swallowed.⁵⁹ This is reported by patients as a sensation of “something dripping down the back of the throat,” sore throat in the morning, and frequent spitting of mucus. The direct visualization of mucus or secretions in the posterior pharynx is unreliable and there may not be evidence of nasal secretions, termed “silent PND.”⁵⁸ Other signs on physical examination include cobblestoning of the posterior pharyngeal mucosa or swollen mucous glands. Pratter et al demonstrated that 20% of the chronic cough patients diagnosed with PND were asymptomatic from the drainage, such as throat clearing and sensation of PND, and 59% of these patients had negative physical exam findings, such as nasal secretions and cobblestoning of the posterior pharynx.⁶⁰ Therefore, this leads to the controversy of the pathogenesis of chronic cough from UACS.

One explanation of cough from UACS is the direct irritation by nasal secretions in the larynx and pharynx. However, O’Hara and Jones demonstrated that only 8% of patients with purulent nasal drainage had cough with no other pathology, thereby putting the hypothesis of direct irritation by secretions in question.⁶¹ More recent work has explored the phenomenon of increased sensitivity of cough reflex secondary to an insult, causing hyperresponsiveness of cough receptors. Studies looking at the effects of capsaicin has suggested that chronic cough may be secondary to decreased threshold of the cough reflex in those with UACS as compared to those with rhinitis/sinusitis without cough and healthy patients.⁶² Additionally, cough reflex sensitivity has been shown to have transient hyperresponsiveness induced by upper respiratory infection, leading to the concept of hypersensitivity as an explanation for chronic cough.⁶³ Allergens and irritants stimulate the afferent limb of the cough reflex peripherally, leading to central reactivity that manifests as cough.⁵⁹ In the setting of chronic cough without evidence of PND or allergic symptoms with a normal intranasal exam, GERD and LPR are presumed the etiology of chronic cough until proven otherwise.

Allergic rhinitis (AR) affects between 10% and 30% of the United States adult population, and 40% of children, making it the fifth most common chronic disease.⁶⁴ It is an inflammatory, IgE-mediated process characterized by nasal congestion, rhinorrhea, sneezing, and/or nasal itching with findings of sinonasal mucosal inflammation with exposure to specific allergens.⁵ AR can be seasonal or perennial, and diagnosed with skin testing. The allergic response can be divided into early- and late-phase symptoms, with early-phase symptoms including sneezing, pruritus, and rhinorrhea, while congestion is predominantly a late-phase reaction. If an allergic reaction to specific antigens is identified on skin testing, a positive treatment response may lead to the diagnosis of AR as the cause for UACS.

NARES is also a diagnosis of exclusion with similar but more intense symptoms, including perennial sneezing, pruritus of nasal and ocular mucosa, and excessive lacrimation. The diagnosis is based on negative skin testing, absence of serum IgE antibodies to allergens, and elevated eosinophils in nasal secretions.59

Vasomotor rhinitis accounts for most of NAR and is described as the overactive nose involving an autonomic nervous system dysfunction, characterized by predominance of the parasympathetic system, leading to nasal secretions, vasodilation, and edema of the sinonasal mucosa.^{59, 64, 65} Symptoms of rhinorrhea (e.g., nasal congestion and postnasal drip) leading to UACS and cough can be triggered by various stimuli, such as change in temperature, strong odors, respiratory irritants, emotional stress, spicy foods, and alcoholic beverages.⁶⁵

Postinfectious UACS, also known as postviral vagal neuropathy (PVVN), is diagnosed based on the symptoms of chronic cough preceded by a recent history of viral or bacterial upper respiratory tract infection when the cough is present 8 weeks or more after resolution of other symptoms. Hypersensitivity of the cough reflex is a well-known phenomenon; however, in a subset of patients, this hypersensitivity persists and becomes a chronic cough. Studies have shown that cough reflex sensitivity is transiently enhanced during acute viral URI compared with the postrecovery state.⁶⁶ Based on similar findings, the newly proposed cough hypersensitivity syndrome has been suggested as a concept explaining chronic cough. It is based on the mechanism of dysregulated sensory neural functions triggered by low-level stimuli.^{67, 68} Viral infections, such as herpes simplex virus and influenza virus, and other irritants can cause local inflammation and injury of vagal nerves, leading to central pathway dysfunction and cough hypersensitivity.⁶⁸ See Chapter 6 for more information on neurogenic cough.

Rhinitis medicamentosa is described as severe rebound swelling of the nasal mucosa secondary to chronic use of nasal decongestants. Patients become dependent on the use of the topical decongestants to relieve nasal congestion and, over time, require more frequent application in larger doses. Treatment requires discontinuing the use of the nasal decongestant, which may be difficult for patients because of the rebound nasal blockage ensuing from the chronic use. The use of nasal steroid spray has been used to help patients wean off of the topical decongestant.

Rhinitis of pregnancy, or hormonal rhinitis, is nasal congestion from mucosal swelling resulting from increased circulating blood volume and vasodilation caused by hormones, leading to vascular pooling and edema, secondary to leakage of plasma from the vascular bed into the stroma.69 There are limited clinical trials in the use of intranasal corticosteroid spray in pregnancy. However, based on the current literature, fluticasone, mometasone, and budesonide are safe when used at the recommended dosage.⁷⁰

Rhinitis due to chemical or environmental irritants and occupational rhinitis is described as noninflammatory rhinitis with symptoms of nasal congestion, rhinorrhea, sneezing, and itching following exposure to irritants in the environment. Diagnosis depends on a thorough history with a temporal relationship between exposure and onset of symptoms. Treatment includes avoidance and reduction in exposure of the irritant.

Anatomic abnormalities including deviated nasal septum, concha bullosa, and Haller cells have been implicated in the development of chronic rhinosinusitis^71–74 (Figure 3–1).

Alkire and Bhattacharyya identified that only Haller cells were related to the occurrence of recurrent acute rhinosinusitis.⁷⁵ Calhoun et al compared CT findings between those with sinus disease and healthy patients and found that septal deviation was associated with osteomeatal complex disease, anterior ethmoid, and posterior ethmoid disease.⁷⁶ Furthermore, the presence of concha bullosa was associated with anterior ethmoid disease. Dental pathology has also been associated with postnasal drainage and cough. One study showed a significant correlation between number of missing posterior teeth and postnasal drip and nasal congestion.7 Additionally, obstruction of the maxillary sinus meatus and thickening of the maxillary sinus mucosa was associated with the complaint of cough.⁷⁷ Nasopharyngitis, adenoiditis, adenoid hypertrophy, Thornwaldt’s cyst, and iatrogenic disease, such as maxillary sinus accessories causing mucous recirculation, can also contribute to postnasal drainage^78–81 (Figures 3–2 and 3–3).

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