6: Rhinitis and asthma: united airway disease

The nasal and bronchial mucosae consist of pseudostratified, ciliated columnar epithelium resting on a basement membrane. Beneath the basement membrane is the submucosa, containing blood vessels, mucous glands, structural cells, nerves and some inflammatory cells.

The main difference between the upper and lower airways is that upper airway patency is largely influenced by vascular tone, whereas, in the lower airway, airflow is influenced predominantly by smooth muscle function. Direct tests of bronchial hyper-responsiveness (methacholine and histamine challenges) result in smooth muscle constriction and measurable airflow obstruction. In the nose, both agents cause multiple symptoms, including sneezing, anterior rhinorrhoea and nasal obstruction, the latter due to effects on vasculature. However, as there is considerable overlap in the measurable nasal obstruction between people with or without rhinitis, nasal challenges with these agents have little clinical usefulness. Hence it is much easier to demonstrate airway hyper-responsiveness (AHR) in the bronchi than in the nose. The different anatomy also explains the differential effects of drugs such as antihistamines and β2-agonists on the upper and lower airways.1,2

Both the upper and lower airways act as a transport system moving air in and out of the lungs. Both provide defence against inhaled foreign substances, with most particles of 5–10 μm diameter filtered out by the nose, and irritant and soluble gases being extensively removed by dissolution in nasal secretions. The lower airway functions similarly, with smaller inhaled particles that reach the lower airway being trapped and cleared by the mucociliary escalator.

Inspired air is conditioned by the nose so that, by the time it reaches the trachea, the air temperature is about 32°C and the humidity about 98%. Nitric oxide produced by the sinuses (eNO) has a bronchodilatory activity that has been postulated to partially protect the patency of the lower airway.1

Allergic disease is the result of an immune response to external antigens, which leads to production of antibodies that are typically, but not exclusively, IgE antibodies. Allergic airway disease results from hypersensitivity or IgE-mediated reactions when inhaled allergen reacts with cells bearing IgE antibodies (typically mast cells and basophils).3 Cross-linking of allergen-specific IgE molecules bound to cells by allergen particles results in the release of granule-associated mediators (eg, histamine, tryptase), membrane lipid-derived mediators (eg, leukotrienes) and cytokines. The initial reaction, the early allergic response (maximal at 10–20 minutes), is usually followed by a late allergic response (within 2–6 hours) in both the upper and lower airways. The later response is associated with an eosinophilic and T cell (CD4+) tissue infiltrate.

Allergic rhinitis and asthma are common manifestations of the allergic response. It is important to note that non-IgE-mediated disease (eg, hypersensitivity pneumonitis) can also occur in response to inhaled allergens and that non-allergic airway disease (eg, intrinsic asthma and some forms of occupational asthma) is often difficult to distinguish clinically from allergic airway disease.

The symptoms of rhinitis are rhinorrhoea, nasal obstruction, itch and sneeze, while symptoms of asthma are sputum, wheeze, chest tightness and cough. Until recently, allergic rhinitis has been classified as either seasonal or perennial, but, as there is an overlap between these categories in many patients, a new classification of intermittent versus persistent rhinitis has been proposed (Box 1).4 Asthma is currently defined by both histological and functional parameters, with further descriptors relating to disease severity (Box 1).5

Acute and chronic changes in the upper and lower airways in response to an allergic stimulus are summarised in Box 2. Although the nose is usually the first site of exposure to allergens or other noxious substances, the presence of nasal epithelial damage is minimal, whereas, in the bronchi, marked epithelial disruption may be present. Thus, it is postulated that the nasal mucosa has developed protective mechanisms that minimise remodelling and enhance epithelial regeneration.7 In support of this hypothesis, animal models of airway inflammation show that, although the majority of allergen is deposited in the nose, more inflammation occurs in the lower airway.2 Basement membrane thickening, a consistent hallmark of lower airway remodelling in asthma, is present even in children with asthma, and also in atopic patients without asthma and patients with allergic rhinitis; however, it has not been reproducibly demonstrated to occur in the nose.

Inflammatory changes can be detected in both the upper and lower airways without accompanying clinical symptoms. In patients with rhinitis, lower airway inflammation can be demonstrated by increased levels of eNO and by eosinophils found in induced sputum, bronchoalveolar lavage fluid and bronchial biopsies. Similarly, in patients with asthma, nasal biopsies show eosinophilic inflammation, even in those who do not have symptoms of rhinitis.8 After direct allergen challenge in one part of the airway, an inflammatory response can be shown in both the target area and the reciprocal part of the airway within 24–48 hours of the challenge.9,10 These two seminal studies have underpinned further development of the UAD hypothesis.

Several mechanisms to explain the interaction between the upper and lower airways have been proposed (Box 3). The most likely mechanism is that localised 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 (Box 4).11

Are there possible exceptions to the UAD hypothesis, and is it purely an allergic phenomenon?

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 (Box 3).1

Intrinsic asthma, such as aspirin-exacerbated respiratory disease (Samter’s triad of aspirin sensitivity, nasal polyposis and asthma), demonstrates that upper and lower airway inflammation can sometimes be found in the absence of atopy (Box 5).1 A study by Gaga et al8 assessed nasal biopsies in 19 non-atopic subjects with asthma, with or without nasal symptoms. Both study groups showed similarly high nasal eosinophil counts compared with normal patients. Given that lower airway inflammation is accepted as universal in asthma (Box 1), this finding supports the coexistence of upper and lower airway inflammation in non-atopic subjects. However, a larger number of subjects would need to be studied to establish whether this finding can be generalised.

The presence of lower AHR without symptoms of clinical asthma has been well documented in population studies. In addition, the relationship between AHR and inflammation is complex, with many studies not supporting a relationship 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, non-asthmatic 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 looked for in association with this condition.15

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-8 (IL-8), which correlates with sputum levels, indicating concomitant upper and lower airway inflammation.16 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. But again, with a predominantly infective stimulus, it is more difficult to separate site-specific effects of the provoking agent from underlying systemic processes.17

The prevalence of atopy, rhinitis and asthma have all increased worldwide over recent decades.18 In a series of population studies of Australian schoolchildren in Belmont, New South Wales, 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%.19 Other studies indicate that rhinitis is a risk factor for later developing asthma (odds ratio, 2.5919 to 11.020).

An analysis of the same Belmont population showed that the presence of hayfever at the age of 8–10 years was predictive of the presence of troublesome asthma by the age of 23–25 years (likelihood ratio, 2.14; 95% CI, 1.59–2.89).21

It is well documented that allergic rhinitis is associated with increased AHR, even if there is no diagnosis of asthma. People subject to allergic rhinitis have demonstrable AHR both outside the pollen season (11%–73%) and during the pollen season (50%).1 Clinical studies indicate that 80%–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 recognised. In a recent study, 100% of subjects with severe asthma (requiring steroid treatment) had abnormal sinus computed tomo-graphy scans versus 77% of subjects with mild to moderate asthma.22 However, perhaps the most direct evidence of the relationship between sinusitis and asthma is provided by studies that show significant improvement in asthma symptoms when sinusitis is appropriately treated.23

Topical corticosteroids. Topical corticosteroids are frequently used to treat disease in each segment of the airway and are the most effective therapy for most patients with rhinitis or asthma. They also provide an ideal opportunity for treating one airway segment and observing the effect on the other segment.

A Cochrane database meta-analysis suggests that intranasal corticosteroids are generally effective in controlling asthma, but studies refuting this finding do exist.24 The effect of inhaled corticosteroids on allergic rhinitis has rarely been studied, but Grieff et al demonstrated reduced nasal and blood eosinophilia and reduced seasonal nasal symptoms with the use of inhaled budesonide.25 Stelmach et al, in a double-blind, parallel, three-group study comparing the use of intranasal budesonide (400 μg), inhaled budesonide (1000 μg), or both, showed that intranasal therapy alone improved asthma symptoms (although it did not increase lung function), and that this effect was as good as the inhaled therapy or the combination of inhaled and intranasal therapy.26 Adams et al,27 in a retrospective study of 13 844 patients with asthma, showed that intranasal corticosteroid therapy reduced the risk of emergency department visits (overall relative risk, 0.70; 95% CI, 0.59–0.94), independently of whether or not patients used inhaled corticosteroids.

Antihistamines. Oral antihistamines are generally believed to have little effect on asthma. However, when used to treat seasonal allergic rhinitis, they have been shown to reduce the symptoms of asthma during the pollen season, although they had no effect on lung function.28 In the Early Treatment of the Atopic Child study,29 children aged 12–24 months with atopic dermatitis and a high risk of asthma (because of their parental history) were given cetirizine or placebo for 18 months and followed up for a further 6 months. Infants with evidence of sensitivity to house dust mite, grass pollen or both who were treated with cetirizine were significantly less likely to have developed asthma (50% reduction) compared with those treated with placebo over the 18 months. This study is being followed by the Early Prevention of Asthma in Atopic Children study, but results are not yet published. At present, the prophylactic use of cetirizine to prevent asthma at at-risk children cannot be recommended. There is no study examining the effect of intranasal antihistamines on asthma.

Newer systemic therapies. Newer systemic therapies include the use of oral leukotriene receptor antagonists (eg, montelukast) and subcutaneous anti-IgE monoclonal antibody therapy (omalizumab). These therapies target specific parts of the inflammatory process and provide evidence for the concept that leukotriene mediators and the downstream effects of IgE–allergen interactions play a part in the pathophysiology of the allergic immune response. It is likely that a range of other, similar therapies will be developed, but these are not always predictably successful, as has been illustrated by the lack of effect of anti-IL-5 in asthma trials.30

Leukotriene receptor antagonists cause bronchodilation and can block the acute effects of allergen exposure in both the upper and lower respiratory tract, as well as controlling chronic airway disease.31,32 Although not as effective as topical corticosteroids for controlling asthma (montelukast 10 mg/day is said to be equivalent to 400 μg/day of inhaled steroids),32 leukotriene receptor antagonists have an important role to play in childhood asthma, mainly because of their better safety profile. If patients have concurrent symptoms of rhinitis and asthma, there is the potential advantage of using a single oral therapy for both diseases.

Omalizumab is used to treat allergic disease, showing benefit in patients with moderate to severe allergic asthma and in those with seasonal and perennial allergic rhinitis.33 Omalizumab reduces serum levels of IgE and down-regulates the number of IgE receptors. It also reduces the number of tissue eosinophils (both nasal and bronchial), bronchial IgE positive cells (mast cells), T cells and B cells. Moreover, it is of benefit to patients who have poorly controlled asthma despite using high-dose inhaled corticosteroids. Indeed, patients who are the best “responders” to anti-IgE treatment are those with asthma at the more severe end of the spectrum.

Systemic anti-IgE therapy with omalizumab has been shown to improve symptoms, quality of life and disease control (asthma exacerbations) in patients with concomitant asthma and persistent allergic rhinitis.33 However, as it is an expensive drug with consequent limited availability, it does not have a significant role in treating asthma and rhinitis at the present time.34

Allergen immunotherapy delivered by subcutaneous injection has been used successfully to treat both allergic rhinitis and asthma (Box 7).35,36 A meta-analysis of allergen immunotherapy that included 75 prospective, randomised controlled trials of immunotherapy for asthma showed a reduction in the need for medication, a reduction in bronchial hyper-responsiveness, and improvement in forced expiratory volume in 1 second (FEV1).36 Studies in children have shown that immunotherapy reduces the likelihood of developing asthma37,38 and the risk of developing new allergies.37

In a European study, 205 children aged 6–14 years with seasonal rhinoconjunctivitis were treated for 3 years with allergen immunotherapy.38 Before the start of the study, all subjects had moderate to severe hayfever symptoms and 20% had mild seasonal asthma. Active therapy resulted in a statistically significant reduction in rhinitis, conjunctivitis and bronchial reactivity compared with the control group. Further, active therapy led to a 50% reduction in the development of newly diagnosed asthma.

Allergen immunotherapy can also prevent the development of sensitisation to new allergens. A group of 134 children who had intermittent asthma (with or without rhinitis) and who were singly sensitised to dust mite were enrolled into active treatment and placebo groups. Specific dust mite immunotherapy was given for 3 years and subjects were followed up for a further 3 years. Only 24.6% of children in the immunotherapy group developed new sensitisation (most commonly to pollens), compared with 66.7% in the control group (P < 0.001).37

Sublingual/oral immunotherapy (SLIT), which is easier to administer to children than injection therapy and also has the advantage of carrying minimal or no risk of anaphylaxis, leads to improvement in symptoms of rhinitis. There is limited evidence that SLIT may prevent the development of allergic disease in childhood.39

The value of allergen avoidance as a therapeutic measure for rhinitis or asthma, or both, has long been controversial. Avoidance studies can be categorised according to the specific allergen avoided and the outcome measures: relief of current symptoms or the primary prevention of allergic disease. In the case of occupational asthma, allergen avoidance is highly recommended and often successful.3

Although a meta-analysis of all avoidance studies of ubiquitous allergens such as dust mite allergen provided little evidence of benefit,40 some of the studies included in the analysis did not show evidence of reduced allergen exposure. Allergen avoidance directed at a particular allergen to which the patient is allergic (eg, cat allergen) may be more effective, but the data are conflicting.41 Early childhood interventional studies in which there have been measurable reductions in allergen levels (eg, in dust mite exposure) have provided little evidence of disease prevention.42

These results are perplexing and have led to the realisation that the relationship between the level of allergen exposure and the degree of sensitisation is complex, with immunological tolerance occurring in some cases (eg, to cat allergen). However, the increase in prevalence of allergic diseases, particularly in affluent societies, implicates environmental factors that need to be identified before adequate preventive measures can be undertaken. Current recommendations for allergen avoidance for patients are summarised at <http://www.allergy.org.au>.