Asthma and allergic rhinitis as symptoms of the same disease: a paradigm under construction

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1 /02/78-Supl.2/S123 Jornal de Pediatria Copyright 2002 by Sociedade Brasileira de Pediatria Jornal de Pediatria - Vol. 78, Supl.2, 2002 S123 REVIEW ARTICLE Asthma and allergic rhinitis as symptoms of the same disease: a paradigm under construction Paulo A.M. Camargos, 1 Mary Elisabeth Santos Moura Rodrigues, 2 Dirceu Solé, 3 Pierre Scheinmann 4 Abstract Objective: to describe current ideas about the relation between upper and lower respiratory tract and to review the epidemiological, immunological, and pathological aspects that support the paradigm of united airways disease. Sources: literature review using the Medline, MD Consult, HighWire, Medscape and Lilacs databases. We used allergic rhinitis and asthma as keywords, and searched articles published in the past 20 years. Summary of the findings: epidemiological evidence includes prevalence of allergic rhinitis in asthmatic patients and vice-versa, results of cross-sectional studies, bronchial hyperresponsiveness in patients with allergic rhinitis, importance of genetic and environmental factors, and the age of onset of atopic disease. Morphological and physiological aspects show structural differences between the nasal and bronchial mucosa, and the mechanisms that could explain the effect of rhinitis on asthma. Immunological aspects including the participation of bone marrow in the production of inflammatory cells and allergic reactions after allergen challenge are the same in allergic rhinitis and asthma. Finally, the results of the therapy for allergic rhinitis in bronchial hyperresponsiveness and in clinical and functional control of asthma are also reported. Conclusions: epidemiological evidence and immunological and pathological aspects suggest that there is a relation between allergic rhinitis and asthma. The paradigm of united airways disease suggests the implementation of an integrated therapeutic approach. J Pediatr (Rio J) 2002; 78 (Suppl. 2)S123-S128: asthma, allergic rhinitis, epidemiology, immunology, pathology, therapy. Literature has recorded empirical observations of the existing interrelations between upper and lower airways for approximately fifty years, but the concept of united airway disease has become, especially over the last ten years, a 1. Associate Professor, Department of Pediatrics, School of Medicine, Universidade Federal de Minas Gerais (UFMG); Head, Pediatric Pulmonology Department, Hospital das Clínicas, teaching hospital of the Universidade Federal de Minas Gerais (UFMG). 2. Master s Degree. Assistant Professor, Department of Pediatrics, School of Medicine, Universidade Federal de Minas Gerais. 3. Professor, Department of Pediatrics, School of Medicine, Universidade Federal de São Paulo. 4. Professor, Head of the Service de Pneumologie et d Allergologie Pédiatriques, Hôpital Necker-Enfants Malades, Paris. specific object of experimental research and of a few clinical therapeutic studies. In pediatrics, for instance, clinical experience has long observed that asthma crises are preceded or provoked by rhinitis, either of viral etiology, as it occurs in infants, or secondary to allergic stimuli in older children. Nonetheless, the real importance of rhinitis, and even the sinusitis that usually follows it, has remained relatively underestimated, not having been considered, for instance, as a compromising factor of asthmatic patients quality of life. 1 One airway, one disease, 2 allergic rhinobronchitis, 3 united airways disease 3 and combined allergic rhinitis and asthma syndrome (CARAS) 4 are more recently coined S123

2 S124 Jornal de Pediatria - Vol. 78, Supl.2, 2002 expressions due to, among other reasons, the elevation of prevalence rates and the existing interaction between allergic rhinitis and asthma. These entities frequently coexist. Rhinitis is, nowadays, a recognized risk factor for the development and intensification of asthma. Daily clinical observation demonstrates very clearly that clinical and functional control of an asthmatic patient with associated allergic rhinitis is not satisfactory if the manifestations of the upper airways are not considered under the adequate therapeutic approach. The understanding that asthma and allergic rhinitis are manifestations of the same inflammatory process, replacing the idea of two distinct entities, each one confined to a specific organ, has considerably developed, and literature presents a robust and attractive body of evidence that reinforces this new paradigm, which has resulted, for example, in a document published in cooperation with the World Health Organization, called ARIA - Allergic Rhinitis and its Impact on Asthma. 1 The purpose of this review is to present epidemiological, morphological, physiological, immunological, pathophysiologic aspects and the therapeutic implications of these concepts. Epidemiological evidence Epidemiological evidence strongly suggests that the links between allergic rhinitis and asthma do not occur at random; there is much evidence of this comorbidity. 5 Literature reports that 28 to 50% of asthmatic patients have associated allergic rhinitis, while isolated allergic rhinitis is found in 20% of the general population. On the other hand, asthma coexists in 13 to 38% of the patients with allergic rhinitis, whereas in the general population this rate varies between 5 and 15%. These percentages are probably underestimated, considering that in recent studies, using standardized and validated questionnaires, rhinitis was reported in 98.9% of the asthmatic patients with evidence of atopic disease, while this rate decreased to 78.4% among asthmatic patients who did not present this evidence. 3 On average, 75% of the patients with asthma followed by markers of atopic disease have associated rhinitis, and up to 20% of the patients with allergic rhinitis, especially those with the perennial or persistent types, suffer from asthma in a concomitant fashion. 3 Similar figures were obtained in a study carried out in a clinic of pediatric pneumology in Belo Horizonte, which showed that among 560 children and adolescents with persistent, moderate or severe asthma recorded by the service and selected at random between 1996 and 2000, the diagnosis of allergic rhinitis was confirmed in 65% of the cases. (Profeta SC, Camargos PAM, unpublished data). On the other hand, the presence of rhinitis in patients with asthma has been confirmed as a marker of asthma severity. A significantly higher frequency of cases was observed among school children who reported at least four wheezing episodes in the last year, as well as sleep disorders due to acute episodes and exercise-induced Asthma and allergic rhinitis as symptoms... - Camargos PAM et alii bronchospasm. These children were evaluated by the written questionnaire of the International Study of Asthma and Allergies in Childhood (ISAAC), and they presented both diseases associated (Solé D, Camelo Nunes IC, Wandalsen G, unpublished data). It is widely known that perennial (or persistent, according to the nomenclature proposed by ARIA1) allergic rhinitis is followed by a high degree of bronchial hyperresponsiveness, especially when allergic phenomena related to acarids and to the fur of domestic animals are involved. Furthermore, it is known that, during pollination, growing but transient, or with no clinical expression, bronchial hyperresponsiveness is detectable in susceptible individuals. It seems to be likely that allergic rhinitis consists of a previous phase of a journey towards allergy and that, in the ample and complex allergy context, allergic rhinitis, with or without bronchial hyperresponsiveness, and asthma, may combine and interact in a variable way according to the individual, the genetic predisposition, the season of the year, exposure to allergens, and age. 1,6,7 Bucca, when evaluating nonasthmatic patients with respiratory symptoms, carried out histamine bronchoprovocation monitored by a flow-volume curve. These patients were not asthmatic, or had been treated for asthma once in their lives. The presence of bronchial hyperresponsiveness was documented in 52% of the cases, in 71% in case of extrathoracic airways, and occurred simultaneously in 41%. According to the author, the dysfunction of extrathoracic airways was the main factor related to the respiratory symptoms presented by these patients. 8 Therefore, the analysis of risk factors and the determinants of the association between the upper and lower airway diseases help us understand the mechanisms involved in this association; in fact, there are unmistakable demonstrations that the presence of atopic disease is the most important factor to reinforce the interrelation between allergic rhinitis and asthma. In addition, genetic factors and the hyperresponsiveness of the airways are other determinants of this association. For example, adults with a family history of asthma and rhinitis present a risk three to four times as high for asthma, and two to six times as high for rhinitis compared to adults who do not present these antecedents Likewise, the age of onset of atopic disease seems to be a determining factor of asthma or rhinitis, since its acquisition before six years of age was considered an important positive predictive factor for the persistence of asthma, while the atopic disease acquired later was associated with seasonal allergic rhinitis. 12 Among environmental factors, pollution and smoking significantly increase the risk of asthma and rhinitis. Smoking, for instance, is more frequently observed in adolescents with asthma and rhinitis than in adolescents with no asthma or rhinitis, an association also observed in passive smokers. 13 Other potential determinants that still have to be confirmed are listed in Table 1. 13

3 Asthma and allergic rhinitis as symptoms... - Camargos PAM et alii Table 1 - Relation between asthma and rhinitis: determinants and risk factors Determinants and risk factors Evidence Related to the patient Genetical factors + Family history of allergy + Atopy + Bronchial hyperresponsiveness Immunological factors + Related to the environment Smoking and polution + Passive smoking + Cold air Humidity Seasonal variations Nutrition Life style Socioeconomical conditions Infections (+) there is direct and indirect evidence (-) there is not direct or indirect evidence Morphological and physiological aspects The respiratory tract can be seen as a morphofunctional unit. The nasal and bronchial mucosa has a similar architecture, characterized by a pseudostratified epithelium, with ciliated columnar cells which rest on the basement membrane. On practically all of its extension, the respiratory tract mucosa is rich in mast cells and lymphoid tissue, constituting the so-called lymphoid tissue associated with the mucosa or the bronchus. On the submucosa, blood vessels, mucous glands, nerves and inflammatory cells, namely monocytes, lymphocytes, mast cells and eosinophils can be found. Parallel to these common characteristics there are also differences. The nose, in addition to being a rigid compartment, presents an ample vascular network consisting of branches of the posterior lateral nasal and septonasal arteries, and branches of the ophthalmic artery and subepithelial capillaries. This rich vascularization is the origin of the nasal obstruction, a primordial manifestation in inflammatory processes of the nose. The lower airway is characterized by its plasticity and by the presence of lean muscle of the trachea and bronchiole, which explains the bronchoconstriction that affects asthmatic patients. The innervation of the nasal mucosa consists of adrenergic fibers, cholinergic fibers and, finally, even though their definition has not clearly been established, noncholinergic adrenergic fibers. Neurotransmitters and neuropeptides - the former ones are also identifiable in bronchial tissue - in the autonomous nervous system are responsible for homeostasis control, i.e., they regulate Jornal de Pediatria - Vol. 78, Supl.2, 2002 S125 vascular permeability and secretion releasing processes. Cholinergic innervation is the most important bronchoconstriction effector mechanism. Adrenergic control is made in the nose and bronchiole by different mechanisms; -adrenergic agonists are powerful nasal vasoconstrictors, while ß 2 -adrenergic are powerful bronchodilators. Several mechanisms were suggested to explain how uncontrolled allergic rhinitis is supposed to act as a triggering and intensifying factor of asthma 1, such as: nasobronchial reflex: the evidence for its existence is still a paradox, because arguments in favor of this hypothesis come from experiments in animal models in which the use of atropine inhibited bronchial hyperresponsiveness after nasal provocation; what contradicts this hypothesis is the observation that the intranasal application of topical lidocaine did not alter the degree of bronchial reactivity; in case of nasal obstruction - an ordinary fact in allergic rhinitis - there are deficiencies in the heating and humidification of the air inhaled as well as in the nasal filtering function. Oral respiration, which is secondary to this function, allows aeroallergens to reach lower airways, provoking bronchial hyperresponsiveness and exercise-induced asthma; inflammatory mediators produced in the nose would reach the respiratory tract systemically and/or through the aspiration of nasopharyngeal secretions, provoking the contraction of the lean muscles, or inducing an inflammatory process in the lower airways, but, on the other hand, aspiration is of difficult occurrence and even impossible in healthy individuals; the activation of the bone marrow and the production of inflammatory cells after stimulus from the nasal mucosa; viral infections of upper airways contribute to elevate the degree of bronchial inflammation and hyperresponsiveness in asthmatic subjects; the hypothetical role played by nitric oxide (NO) is still discussed. It is produced by the nose in a large scale and it is an important mediator in nasonasal reflex, resulting in vasodilation, and, therefore, improving pulmonary vascularization and oxygenation. Immunological and pathophysiologic evidence Nasal inflammatory processes, as it is the case of allergic rhinitis, reflect negatively on asthmatic patients. Even though nasal provocation tests do not result in bronchospasm, they are able to determine bronchial hyperresponsiveness. However, it is illustrative to observe that, in asthmatic patients, a nasal provocation test can be positive in children without any clinical manifestation of rhinitis. 15 Inflammation plays a critical role in the pathogenesis of asthma and rhinitis and, as it has been said, some factors that trigger the local inflammatory reaction are common to both.

4 S126 Jornal de Pediatria - Vol. 78, Supl.2, 2002 It begins after exposure to the allergen on the entire respiratory mucosa, and induces both rhinitis and asthma. It can be detected even in the absence of florid symptomatology; it is referred to as minimal persistent inflammation. (MPI) MPI is associated with the expression of CD54 adhesion molecule (ICAM-1), which is the main rhinovirus receptor. Both in asthma and in rhinitis, the same cell infiltrate is observed, composed of eosinophils, mast cells, T lymphocytes, and monocytic lineage cells. 12 Adhesion molecules and inflammatory mediators are also identical: histamine, cysteine leukotrienes, Th2 cytosine, among which interleukins 4, 5 and 13, in addition to GMC- SF and RANTES. Even though the immunological mechanism is similar, histopathological differences on the nasal and bronchial mucosa are observed. In allergic rhinitis, the integrity of the epithelium is preserved in a general way or there is a slight desquamation and no important thickening of the basement membrane is observed, contrary to what happens in asthma. When asthma and rhinitis coexist, the desquamation and the continuity solution of the epithelium are also more intense in the bronchiole than in the nose. The intensity of inflammation is variable in patients with moderate and severe persistent asthma; eosinophilic inflammation is more pronounced in the lower airways. 16 In mild persistent asthma, nasal and bronchial inflammations seem to have the same intensity. 12 An interesting finding is that nasal eosinophilic inflammation occurs in asthmatic patients with no nasal symptoms and it still has not been revealed in other pulmonary diseases. 12 Inversely, in atopic patients or in those with rhinitis, but without asthma, the bronchial mucosa presents thickening of the basement membrane and moderate eosinophilic inflammation. 12 Although there are immunopathologic differences, the reactions that occur after antigenic exposure are the same for asthma and allergic rhinitis. They are characterized by an immediate, type I, allergic reaction and by the type IVa2 delayed reaction, the inflammation of the epithelium and the submucosa in the classification by Gell and Coombs. Epithelial cells, Langerhans cells, dendritic cells and other antigen-producing cells are involved in the process. The bone marrow actively takes part in the production of inflammatory cells, eosinophils, basophiles and mast cells through the increase of the number of precursor cells when facing antigen provocation. 17 The involvement of the bone marrow in this process also reveals the systemic character of asthma and the asthma-allergic rhinitis binomial. The recruitment and activation of CD4+ Th2 lymphocytes and effector cells, such as eosinophils, basophiles and mast cells also occurs. Moreover, the expression of cytosines also increases, especially that of IL- 4 and IL-13, which act in the local production of IgE and play an undeniable role in this process. The expression of other cytosines is also increased, as is the case of GM-CSF, RANTES, IL-3 and IL-5, which acts by lengthening the Asthma and allergic rhinitis as symptoms... - Camargos PAM et alii half-life of eosinophils. The production of preformed inflammatory mediators, such as histamine, tryptase, kinases, and preformed proteases (e.g. prostaglandins, leukotrienes, platelet aggregation factor, and neurotransmitters), has a similar profile in the upper and lower airways, although the action of each one in the target organ seems to have a different nature. The late phase reaction develops after antigen provocation, depending on the degree of exposure and individual sensitivity. It is responsible for the persistence of symptomatology, and the recruitment of inflammatory cells decreases the threshold of response to antigenic stimuli, causing the continuous exposure to low concentrations of aeroallergens to provoke a persistent inflammation of the nasal and/or bronchial mucosa. This ample array of evidence that brings molecular and cellular bases consistently with them point to the unicity of responses and behavior of the respiratory tract in asthma and allergic rhinitis. Allergen provocation tests The most promising indications referring to the interrelations between allergic rhinitis and asthma come from the information provided by the studies based on tests of nasal and bronchoprovocation with allergens. In essence, these papers alert to the fact that the allergic reactions that take place in the nose and in the bronchiole are the translation of the same immunoallergic mechanisms, both in the cytological, and in the humoral plane. 1,7 These tests can be classified into natural or observational, because they result from records that follow spontaneous exposure to pollens, or experimental, which are obtained in a laboratory by nasal or bronchoprovocation. Chakir et al., for example, studied eight individuals before and during the pollination season, all of them with manifested allergy to pollen, even though they were neither asthmatic nor produced evidence of bronchial hyperresponsiveness. During pollination, an increased bronchial reactivity was verified because the biopsies of bronchial tissue revealed an elevation of CD4+, CD8+ and CD45RO+ lymphocytes, EG1 cells and 5+ interleukin. Degranulation of eosinophils, but not of mast cells, was observed, which is the reason why those individuals were safe from typical asthmatic manifestations. Furthermore, the authors succeeded in identifying a moderate bronchial remodeling in patients with allergic rhinitis, but with no asthma, and have postulated that the bronchial inflammation would predispose to asthma. 18 Under a similar perspective, Braunstahl et al. Equally studied eight other patients with allergic rhinitis to grass plants, but without asthma or bronchial hyperresponsiveness, from whom specimens of nasal and bronchial biopsies were obtained before and after segmental bronchoprovocation tests. After allergenic stimulation, the authors observed eosinophilic infiltration, which even extended to other segments, bronchial obstruction, and clinical alterations.

5 Asthma and allergic rhinitis as symptoms... - Camargos PAM et alii Similarly, on the nasal mucosa an increase of eosinophilic infiltration, eotaxin and interleukin 5 was observed, which was detected, concomitantly with GM-CSF, in higher concentrations in peripheral blood. Furthermore, there was an expressive correlation among the clinical nasal and bronchial scores. Such results suggest a systemic activation of the eosinophils concerning their migrations along the mucosa of the upper and lower tract. 19 One year later, the group led by Braunstahl showed that, in those very same patients, the bronchoprovocation test triggered, in peripheral blood, a decrease of circulating basophiles and an increase in interleukin 5, whereas, in the lower airways, a basophile increment occurred. In the nose, on the other hand, mast cell degranulation and basophile increase occurred, supposedly coming from peripheral blood. Since the allergen dose used in the experiment was superior to that found in usual exposure conditions, it is not very likely that these allergens have passed through the bronchial mucosa. The most plausible hypothesis is admitted to be that the local inflammatory reaction is followed by another one involving the group of airways, and that this reaction would be facilitated by the transportation of cells and mediators through the bloodstream, i.e., by a systemic phenomenon. 20 Finally, a test of nasal allergic provocation induces eosinophilia both in the nose and in the bronchi, which has a direct correlation with the expression of inflammatory mediators, among which are ICAM-1, VCAM-1 and E- selectin. Hence, a hypothesis is made: the absorption of proinflammatory mediators, starting from the spot of the allergic provocation, may release bone marrow eosinophils and, through the bloodstream, these cells could reach the nasal and bronchial mucosa thanks to the increase in the expression of adhesion molecules by the vascular endothelium. 21 Clinical evidence Indirect therapeutic evidence of the interrelations between allergic rhinitis and asthma were provided by studies that were carried out on the last ten years in which, basically, topic corticoids, antihistamines, associated or not with sympathomimetic drugs and the association between antileukotrienes with antihistamines were used. Several studies demonstrated that, in asthmatic patients, intranasal corticoids reduce a preexisting bronchial hyperresponsiveness provoked in a laboratory environment by inhaling of metacholine or carbachol. 10,11,22,23 Besides, in a retrospective study, Adams et al. documented that the treatment with intranasal corticosteroid is a protection factor against asthma of greater severity. 24 In addition, the association of loratadine - which, as an antihistamine is not, by itself, effective against asthma - to pseudoephedrine, a drug that acts on the nasal alphaadrenergic receptors, produced a clinical and functional Jornal de Pediatria - Vol. 78, Supl.2, 2002 S127 improvement and reduced the consumption of beta-agonists in patients with allergic rhinitis and moderate persistent asthma. This synergic effect was also observed by aggregating antihistamines to antileukotrienes. 25,26 Another reinforcement to these indirect evidence was provided by the study known as ETAC (Early Treatment of Atopic Child), which involved an expressive number of children whose encouraging results indicated that the continuous use of antihistamines was able to reduce subsequent development of asthma. 27 Finally, in a study carried out with 3,500 patients between 12 and 60 years of age, 20% of whom were teenagers, all of them with allergic rhinitis and asthma, the risk of hospitalization, or visits to the ER due to acute asthma was 50% lower in the group of patients that received simultaneous treatment for both disorders when compared with the untreated group. Final comments The concept of united airway disease in patients with allergic rhinitis and asthma is a reality, and the impact on the quality of life determined by rhinitis is widely known. In spite of the need for incorporation of new knowledge that ratifies this comorbidity and its consequences to patients and their families, there is a consensus in the literature that the treatment should contemplate both diseases. Even if it is absolute necessary to take into consideration the differences between nasal and bronchial mucosae (rich nasal vascular system and bronchial lean muscles), the effectiveness of nasal and inhaled corticoids is widely recognized in these conditions. However, due to the limitations on the use of these drugs in children, controlled studies have to be carried out. These studies should be based on the paradigm of united airway disease and should evaluate therapeutic schemes that can offer advantageous risk-benefit and costeffectiveness. Furthermore, clinical assays that evaluate the effectiveness of systemic drugs, as is the case of antileukotrienes, will provide useful information about their comparative effectiveness with topic steroids associated or not with antihistamines. It is a good opportunity to observe that the specific immunotherapy may, at least in cases of allergic rhinitis, help with the reduction of nonspecific bronchial hyperresponsiveness, or even eliminate the development of asthma When financial and material resources are limited - a reality that Brazil and other developing countries are confronted with - pharmacological treatment is of paramount importance. Antihistamines are recognizably effective in allergic rhinitis and, depending on the intensity of symptoms and severity of the clinical scenario, it is recommendable to replace them or associate them with topic corticoids such as beclomethasone. However, in cases in which rhinitis and asthma coexist, the treatment of the latter is a clinical priority. 1

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Federal de Minas Gerais Avenida Alfredo Balena, 190/4061 CEP Belo Horizonte, MG, Brazil Phone: +55 (31) Fax: +55 (31) pcamargs@medicina.ufmg.br