Allergic rhinitis: the nose and beyond
Authors: G. Passalacqua
Journal: Allergy (2006)

Over the past 15 years, the general pathogenic interpretation of allergic rhinitis (AR) has rapidly changed and evolved. At least three main aspects of this evolution deserve special consideration: (i) the more detailed knowledge of immunological mechanisms, (ii) the pathogenic unification of the upper and lower airways and (iii) the extension of clinical investigation regarding paranasal sinuses, which has gradually introduced the term ‘upper respiratory disease’ into our common language to encompass rhinitis, chronic rhinosinusitis (CRS), nasal polyposis (NP) and related disorders. In parallel, investigation has commenced in many other clinical aspects of respiratory allergy in addition to nasal symptoms. These facts have reinforced the status of allergology as a ‘cross-sectional specialty’ that has increasingly more contact points with pulmonology, ENT, clinical immunology and internal medicine. The pathogenic unity of the upper and lower respiratory tract in allergy was first envisaged about 10 years ago and was gradually elucidated and confirmed. The relationship which existed between the nose and the bronchi could be hypothesized on the basis of epidemiological observations, showing the frequent co-existence of rhinitis and asthma (1, 2), and also as a consequence of the structural similarity of the nasal and bronchial mucosa. Subsequently, it was shown that allergic inflammatory responses are identical in the two compartments, that there is a bi-directional link between the nose and the bronchi, and that a systemic signalling pathway (3) is probably involved. The hypothesis of the ‘united airways disease’ led to the comparative study of the inflammatory features in the nose and bronchi. In this regard, the phenomenon of ‘remodelling’ (epithelial shedding, collagen deposition, basement membrane thickening, smooth muscle hyperplasia) was clearly shown to be a distinctive feature of bronchial asthma. Moreover, it was demonstrated that remodelling is, at least in part, constitutive and genetically controlled (4). Nonetheless, despite the apparent structural similarity of the nose and the bronchi, remodelling is not always clearly detectable in rhinitis and its features in the nose are somewhat less defined than in the bronchi (5). This different and peculiar behaviour of the nose can be explained either by the different embryological origin of the nasal mucosa or by the absence of smooth muscle cells (6), as a source of specific cytokines that may favour remodelling (7–9). In this issue of Allergy, these challenging aspects of remodelling in rhinitis are discussed in detail in an extensive review by Watelet et al. (10). It is important to note that the article reviews the pathogenesis of remodelling as a repairing process, not only in the nasal mucosa but also in paranasal sinuses and in nasal polyposis (11). Even though we have an impressive amount of experimental data available on nasal and bronchial mucosa in allergic diseases, little is known about the eye that, in turn, is a frequent target organ of allergy. Hughes et al. (12) used biopsies to study the structural features of conjunctiva in seasonal allergic conjunctivitis. They found that out of the pollen season, in symptom-free subjects, the expression of E-cadherin and ICAM-1 adhesion molecules as well as some keratins was significantly reduced in comparison with normal subjects. As E-cadherin and ICAM-1 are involved in the maintenance of epithelial integrity as well as in the repairing processes, the authors hypothesize that allergic conjunctiva has a constitutionally weak structure and can be easily penetrated by allergens. Over the past decade, as previously mentioned, paranasal sinuses and their diseases (nasal polyps and chronic rhinosinusitis) (13) have been extensively investigated as far as their relationships with rhinitis are concerned. Nasal polyposis is relatively common (14) and affects quality of life (15). The article by Pohlzel et al. (16) published in this issue tries to elucidate a special pathogenic aspect of rhinosinusal diseases. The authors used mucosal biopsies to study comparatively subjects with chronic rhinosinusitis but no nasal polyps as well as subjects with polyps at early stages. They found a substantial histochemical difference between the two groups: plasma cells, macrophages and eosinophils were more represented in the patients with polyps. There was no difference in IgE+ cells and mast cells. These aspects were also addressed, from a partially different point of view, in another related article (17). In this study, the authors compared the histochemical and immunological aspects of four groups of subjects (nasal polyps, chronic rhinosinusitis, cystic fibrosis and healthy) and found that nasal polyposis is clearly a distinct disease with prominent eosinophil and plasma-cell infiltration and with an overall Th2 polarization. On the other hand, chronic rhinosinusitis without polyposis had a Th1 profile. Other important aspects of the upper–lower airways link concern the possible functional relationship between rhinosinusal disorders and asthma. This link is well defined, for instance, in the special case of NP and aspirin-induced asthma (18–20), but little is known in other conditions. A group of researchers (21) experimentally approached this problem by measuring free radicals and trying to correlate them with bronchial hyperresponsiveness (BHR) and asthma. Free radicals are reactive species that are produced during an inflammatory process and that are believed to play a relevant role in tissue injury (22). Cheng et al. found that free radicals are largely more abundant in nasal polyps and that their level correlates well with the degree of BHR, thus providing a possible pathogenic link between NP and lower airways. Neurogenic mechanisms may be of importance in nasal polyposis (23). Moving on to the clinical features of allergic rhinitis, these are quite well known from many points of view and the new pathogenic classification of AR proposed in the ARIA guidelines (24) has only recently been validated (25, 26). Nonetheless, there are still several aspects that have been poorly studied. One of these aspects is the natural course of allergic rhinitis over a period of time (27). We know that AR is a risk factor for and frequently evolves towards asthma (28, 29), but there is little or no information, for instance, on the spontaneous remission rate of AR. This problem was addressed by Nihlen et al. (30) in a questionnaire-based survey, which considered the prevalence, incidence and spontaneous remission rate over an 8-year period. This study confirmed on the one hand the increase of prevalence of AR, but on the other hand it also proved that in about 20% of subjects, a spontaneous disappearance of the disease occurs, especially in older ages. Another clinical aspect that has deserved increasing attention in recent years is the possible relationship among physical activities, e.g. sports, exercise and rhinitis as testified by the recent ARIA update on respiratory allergy in athletes (31). From the ARIA update, it has clearly emerged that the prevalence of AR is influenced by physical exercise and that some types of sport are more strictly related to upper airway diseases either because of the immunological effects of exercise per se or because of the particular environments where certain sports are performed. In this issue of Allergy, two epidemiological articles focus on certain aspects of the problem. The first one (32) confirms that early swimming pool attendance in infancy is a risk factor for the onset of rhinitis later in life. The authors attribute this effect to the prolonged exposure to chlorine. Another study (33) suggests that physical inactivity is also significantly associated with a greater incidence of rhinitis. These two apparently unrelated observations, although yet to be confirmed, open new research perspectives within the interesting model of physical exercise. Finally, it is well known from the literature that AR significantly affects the QoL of patients (34) and that among QoL aspects, sleep may be heavily impaired by rhinitis symptoms (35). Baiardini et al. (36), in their intriguing review article, examine the complex relationships among sleep disturbances, quality of life, allergic disorders and sleep apnoeas, with details on the practical aspects and diagnosis of sleep alterations. Within the broad spectrum of approaches to upper respiratory allergy (including pathophysiology, clinical aspects, diagnosis and epidemiology), special attention has been devoted to the treatment. The ARIA document (24), with its recent updates (37–39), provides evidence-based guidelines for the management and therapy of AR. Novel therapeutic options have also been proposed in recent years. In addition to leukotriene modifiers and anti-IgE (40) that were included in the ARIA update (37), there are new molecules currently undergoing clinical investigation (41, 42). In parallel to conventional drugs, the use of complementary/alternative medicines to treat allergic disorders is continuing to increase in all countries (28). Regarding this fact, this issue contains an article by Kung et al. (43) reporting that Chinese herbs for AR are used by more than 35% of allergic subjects in Taiwan. Among complementary medicines, herbal remedies are the most scientifically credible, as our conventional drugs are largely based on herb-derived substances. There are rigorous studies confirming the beneficial effects of some herbal preparations in AR (44). Finally, sublingual immunotherapy, thanks to recent experimental evidence (45–47), is achieving a position of importance in the therapy of respiratory allergy. In conclusion, it is nowadays clear that nasal allergy is much more prevalent than the well-known symptoms of allergic rhinitis and that we are moving ‘beyond the nose’, with a rapidly expanding knowledge of the pathogenic, immunological and clinical aspects. In this regard, the investigation on the complex links among the nose, the paranasal sinuses and the bronchi represents a major field of interest, which also has potential for the development of relevant therapeutic advances.