Diseases of the upper airway (from nose down to vocal chords) and lower airway (below the vocal chords) have historically been considered separate anatomical and histological entities (the pathophysiology of rhinitis is different from that of asthma) and fall under two different specialties as regards the treatment (otolaryngology for the upper airway, pulmonology for the lower airway). We now know that, notwithstanding different facets of clinical management of these two regions, there is one united airway: Diseases that affect one part of the airway often impact other parts. The united airways disease (UAD) hypothesis, in fact, maintains that upper and lower airway disease are both manifestations of a single inflammatory process within the respiratory tract, and this hypothesis draws support from the growing evidence of a systemic link between the upper and lower airways.1

THE HYPOTHESIS

The UAD hypothesis argues that any disease process that affects the upper airway is likely to affect the lower airway, and vice versa, by both direct and indirect means. Hence, rhinitis and asthma represent the manifestations of one syndrome in two parts of the respiratory tract. At the low end of the severity spectrum, rhinitis may occur alone; in the middle range, rhinitis and airway hyperresponsiveness (AHR) may be present; at the high end of the spectrum, rhinitis and asthma may both be present, with the severity of each condition tracking in parallel.2,3

Disease manifestations in the upper and lower airways may be linked via a systemic inflammatory response. This hypothesis holds not only for allergic but also for nonallergic presentations. Several mechanisms have been proposed to explain the interaction between the upper and lower airways: The most likely is that localized airway inflammation leads to a systemic response, with bone marrow involvement resulting in the release of progenitor cells that are then recruited to tissue sites.4,5 Several observations support the concept of UAD existing outside a purely allergic context. For example, infective inflammation occurring in both the upper and lower airways is often attributed to a direct viral effect at both sites, but the two may also be linked by indirect means.1

The presence of lower AHR without symptoms of clinical asthma has been well documented in population studies, although the relationship between AHR and inflammation is complex, with many studies not supporting a clear link between the two.

As airway inflammation is central to the concept of UAD, it is possible that the upper airway may not be involved in isolated, nonasthmatic AHR. Eosinophilic bronchitis, a newly identified condition of the lower airway associated with persistent cough, is an example of lower airway inflammation without AHR, but, as yet, upper airway disease has not been investigated in association with this condition.6

PREVALENCE ON THE RISE

Atopy, rhinitis, and asthma have all shown increased prevalence worldwide over recent decades.7 In a series of population studies of Australian schoolchildren, hay-fever prevalence increased between 1982 and 2002 from 9.1% to 38.4%, and prevalence of current asthma (defined as recent wheeze and AHR) increased from 4.5% to 11.3%.8 Other studies indicate that rhinitis is a risk factor for later developing asthma (odds ratio, 2.59 to 11.0).8,9 An analysis of the same population showed that the presence of hay fever at the age of 8 to 10 years was predictive of the presence of troublesome asthma by the age of 23 to 25 years (likelihood ratio, 2.14; 95% CI, 1.59–2.89).10

It is well documented that allergic rhinitis is associated with increased AHR, even if there is no diagnosis of asthma.11 People subject to allergic rhinitis have AHR present both outside the pollen season (11% to 73%) and during the pollen season (50%).1 Clinical studies indicate that 80% to 100% of patients with asthma have rhinitis and 50% of patients with rhinitis have asthma and that both the presence and severity of rhinitis are associated with worse asthma outcomes.1

An association between asthma and sinusitis has long been recognized. In a recent study, 100% of subjects with severe asthma (requiring steroid treatment) had abnormal sinus at computed tomography scans versus 77% of subjects with mild to moderate asthma.12 However, perhaps the most direct evidence of the relationship between rhinitis, sinusitis, and asthma comes from studies that show significant improvement in asthma symptoms when sinusitis is appropriately treated.13

TWO RELATIONSHIPS

Under the umbrella term of UAD, two coexistent relationships between the upper (nasal) airway and lower airway have been proposed: a horizontal relationship and a vertical one. The concept of a horizontal relationship is based on evidence of a wide spectrum of disease severity in UAD, with disease manifesting in different parts of the respiratory tract according to the severity, eg, at low severity only in the nasal area versus at high severity in both upper and lower airways with asthma and rhinitis combined.

The concept of a vertical relationship implies that events taking place in the upper airway may negatively affect what happens in the lower airway. For instance, the nose may act as an air conditioner to warm and humidify the air before it reaches the lower airway, but, if the nose is congested, that process is impeded. We also know that patients with asthma who get a sinus infection may often begin to wheeze. This delicate and complex interrelationship between the upper and lower airways, which most likely is at least partially mediated by the autonomic nervous system, is not yet well understood.

Supporting the notion of both a horizontal and vertical relationship between the upper and lower airways is the fact that the vast majority (>80%) of patients with asthma also have concomitant rhinitis or rhinosinusitis. Patients with asthma have more severe rhinitis or rhinosinusitis than patients without asthma. Often in a given patient, several measurable outcomes of rhinitis and asthma show a close correlation. Patients with rhinitis are at higher risk of developing asthma. Patients who have allergen introduced into the nasal airway may show both functional and inflammatory changes in the lower airway. Studies demonstrate also that treatment of nasal symptoms results in beneficial effects for the lower airway.

Several factors may account for this interrelationship: for example, when the nose is congested, patients often breathe through the mouth. When this occurs, the warming, filtering, and humidification of inspired air does not take place as it does when they breathe through the nose. With mouth breathing, the air may also have a higher concentration of inspired particulates and gaseous irritants. Second, patients with rhinitis who have increased responsiveness to irritants, presumably occurring via sensory nerves in the nasal membranes, may manifest bronchoconstriction via parasympathetic nerve pathways.14 Sensorineural stimulation of the nasal airway may also stimulate increased bronchial responsiveness via the central nervous system to receptors actually present in the lower airway. This phenomenon is called the bronchial reflex. This falls under the concept of central sensitization, first noted by researchers studying pain medicine.14

Upper airway inflammation may also propagate systemically and affect the lower airway. Experimentally, there is evidence for this concept. For example, intranasal allergen challenge has been found to result in increased expression of adhesion molecules in the pulmonary vasculature and lower airway eosinophilia.

From a treatment point of view, two main aspects should be emphasized:

  • the unity of the respiratory airways and the influence exerted by the nose on the bronchi;
  • the fact that both symptoms and allergic inflammation should be targets for treatment.

SYNERGY

Indeed, there is evidence suggesting that optimal control of rhinitis has a beneficial effect on asthma in terms of reduction of bronchial responsiveness during natural exposure to the offending allergens. Thus, one of the new clues to the treatment of UAD is the evidence of a synergistic effect of drugs used in both rhinitis and asthma. This aspect is relevant, since it would allow treatment to be harmonized, possibly reducing the dosage of each drug. Ultimately, this may result in better control of the disease(s) and fewer side effects.15 The existence of persistent airway inflammation suggests the need for continuous rather than on-demand treatment. Studies have demonstrated a decrease in exacerbation rate in asthmatic patients treated to control airway hyperresponsiveness or eosinophilia compared with those treated to control clinical parameters only.16,17 There is also evidence that airway hyperresponsiveness continues to improve in response to long-term anti-inflammatory therapy, emphasizing the importance of continuing regular controller treatment even when clinical endpoints have been normalized.

Another lower airway inflammatory disease, chronic obstructive pulmonary disease (COPD), may also be an example of UAD. COPD is associated with elevated levels of intranasal interleukin (IL)-8, which correlate with sputum levels, indicating concomitant upper and lower airway inflammation.18 In COPD exacerbation, there is, as well as a pan-airway response, evidence of a systemic response as determined by elevated serum levels of IL-6 and C-reactive protein. With a predominantly infective stimulus, however, it is more difficult to separate site-specific effects of the provoking agent from underlying systemic processes.19

Our traditional understanding of COPD has focused on the presence of chronic airflow obstruction and, accordingly, therapy has been mainly directed to relieve this. More recently, it has been demonstrated that airflow limitation is associated with an abnormal inflammatory response and that the latter appears to be responsible for specific effects on mucociliary function, structural changes in the airways and lung parenchyma, and extrapulmonary effects (the systemic effects of COPD, including impairments of metabolism and inflammation, that lead to comorbid conditions).20,21 Optimal therapeutic targeting of COPD depends on a clear understanding of the precise mechanisms of these complex processes and on early and correct evaluation of disease severity.

At present, a combination of pharmacological and nonpharmacological approaches seems the most effective strategy for confronting this multicomponent disease. As regards pharmacotherapy, bronchodilators and inhaled corticosteroids have shown complementary mechanisms of action, targeting different arms of the vicious cycle of COPD: A combination of the two types of drugs has the potential to address several major components of the disease, including airflow limitation, mucociliary dysfunction, and airway inflammation.22 This translates into improvement of several clinical outcomes, such as dyspnea, exacerbations, and quality of life. Furthermore, since COPD is a progressive disease, with lung function worsening over time, a major target of the therapy is to modify its clinical course, in other words, slow down the evolution of lung damage to respiratory failure and improve survival. Recent evidence suggests that appropriate pharmacological therapy can reduce the long-term decline of FEV1 in patients with moderate-to-severe COPD, thus slowing disease progression, and this has a favorable trend on survival.23, 24

CONCLUSION

The current shift in the approach to respiratory diseases favors the hypothesis of a united airways disease, supported by the growing evidence of a systemic link between the upper and lower airways. Diseases that affect one part of the airway often impact other parts. The united airways disease hypothesis, in fact, maintains that upper and lower airways disease are both manifestations of a single inflammatory process within the respiratory tract, and a unified diagnostic approach to upper and lower airways disease will constitute a solid basis for a common therapeutic management.

Claudio F. Donner, MD, is medical director, Mondo Medico, Multidisciplinary and Rehabilitation Outpatient Clinic, Borgomanero (NO), Italy. For further information, contact [email protected].

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