The ‘united airways’ require an holistic approach to management

Authors


Prof. Á. A. Cruz
Centro de Enfermidades Respiratórias
HUPES
Faculdade de Medicina da Bahia
UFBA
Rua Augusto Viana
s/n – 3° andar
40110-160 Salvador BA
Brazil

We live an era of fragmentation of knowledge in the context of an extraordinary analysis of nature. This has lead to an understanding of biological phenomena down to the molecular level. Unfortunately, one does not see as much progress in the desirable synthesis of the knowledge generated. In a recent publication, Togias has declared the respiratory system a victim of fragmented medical science (1). It is surprising that it took so long for the concept that nose and bronchi are both parts of one whole airway (2), in terms of the pathophysiology of asthma and rhinitis, to be widely accepted. Furthermore, a straightforward benefit of this new paradigm is not yet established for the management of these extremely common chronic illnesses.

We have learned the epidemiological association between asthma and rhinitis is far stronger than previously thought (3). Patients with asthma and allergic rhinitis have greater costs and morbidity than those with symptoms of asthma alone (4). On the other hand, asthmatics with symptoms of rhinitis have worse quality of life (5). Rhinitis and asthma share common genetic and environmental risk factors, but rhinitis is a remarkable risk factor for asthma regardless of atopy (6, 7). We know now that the immunopathology of asthma and rhinitis is virtually the same and there is convincing imaging and histopathological evidence that chronic rhinitis is closely related to chronic sinusitis, and both of them are related to asthma (8–12). We have nowadays various options of intervention available, which may control symptoms of rhinosinusitis as well as those of asthma. Nevertheless, the practical consequences of the understanding that rhinitis, sinusitis and asthma are not different diseases, in general, but different manifestations of one only syndrome affecting the entire airway, seems to be far from satisfactory. This is true for the diagnostic approach as much as for the treatment.

Several studies, performed among patients with allergic rhinitis and asthma, have demonstrated some degree of improvement or protection against asthma manifestations by the use of nasal corticosteroids, either in small clinical trials (13, 14) or in retrospective analysis of databases (15–17). However, a systematic review on the matter published recently did not demonstrate indisputable benefits from the intervention in question (18). Therefore, we should not be very surprised with the negative results published in this issue of Allergy by Dahl et al. (19). Their paper present a double-blind placebo-controlled study of 262 patients divided into four groups, to evaluate the effects of a nasal corticosteroid in protecting subjects with seasonal rhinitis and asthma from developing asthma symptoms. Their conclusion is that, in such patients, the combination of intranasal and inhaled corticosteroids is needed to control the seasonal increase in symptoms from the upper and lower airways.

Why did three large database studies (15–17) find a marked reduction of asthma morbidity associated with rhinitis treatment? The three large retrospective studies were performed in the USA and demonstrated reduction in emergency visits and admissions among asthmatic subjects treated for their rhinitis, when compared with asthmatics not taking any rhinitis medication. We should remember that Dahl et al.'s trial meets the criteria for the best level of evidence: double-blind placebo-controlled randomized study with enough power, whereas all three studies demonstrating morbidity reduction are less reliable evidence because they were retrospective, and therefore more likely to be biased. For instance, patients suffering from asthma and rhinitis might have search medical assistance for dyspnoea related to nasal obstruction, which is not easily differentiated from dyspnoea of bronchial origin. Obviously, patients without treatment for rhinitis would more likely be at risk for this misclassification, when lack of control of rhinitis could be taken as lack of control of asthma, leading to emergency visits or even admissions. It is noteworthy calling attention to a recent publication by Sazonov Kocevar et al. (20) that demonstrates a striking higher risk of recurrent admissions in children with asthma and rhinitis, when compared to those with asthma and no diagnosis of rhinitis, in a broad population database in Norway.

The negative results reported by Dahl et al. (19) should not be taken as definitive, however. Studies of efficacy of topical corticosteroids in allergic rhinitis do not demonstrate control of symptoms in 100% of subjects (21). Therefore, there is a case for subgroup post hoc analysis to be performed, in which only those subjects with nasal symptoms significant improvement would be considered for the benefit of the nasal corticosteroids in controlling asthma. A different conclusion might be reached.

The absence of clear protection against seasonal asthma by use of nasal corticosteroids, in subjects with concomitant rhinitis, is not evidence contrary to the ‘united airway’ theory. It does not argue against the identity of the respiratory system pathophysiology. But it demonstrates that the causal hypothesis (rhinitis provoke asthma) should not be accepted as the most important determinant of the association between the two of them. A diagram representative of the evolution of the understanding of the interrelationship between rhinitis and asthma is presented in Fig. 1.

Figure 1.

Three different phases of the evolution of understanding of the interrelationship between rhinitis and asthma.

If we want to take advantage of the new paradigm in clinical practice, we need first to make sure we rationalize our decisions based upon the ‘identity’ concept. Secondly, we should influence nonspecialists with our evidence-based rational approach, which might benefit patients and the health system with a more efficient track to control of asthma and rhinitis, improving effectiveness, and possibly lowering costs and risks. This has been the mission of ARIA Initiative, which seems to be a nongovernmental organization (NGO) that could be taken as a model for worldwide dissemination of new medical knowledge, which is relevant to clinical practice and may change the management of a disease.

Although some evidence of direct nose–lung interaction exists, indicating that an exacerbation of rhinitis may precipitate asthma symptoms, and therefore control of rhinitis could protect subjects from asthma, it is likely that the strong association between asthma and rhinitis results from the fact they are both manifestations of the same systemic disease. Moreover, finding rhinitis as a risk factor for asthma does not necessarily imply causality. Being a risk factor could also be explained in the context of sequential manifestations of one systemic disease, in which symptoms of rhinitis often precede those from asthma. It might be easier to envisage rhinitis and asthma as a systemic illness if we take the vascular consequences of hypertension, diabetes of dyslipidaemia in many different organs for analogy. Therefore, if this is the case for asthma and rhinitis, we should pursue therapeutical options with systemic actions such as immunotherapy (22), antihistamines (23), antileucotrienes (24), anti-immunoglobulin E (IgE) (25) or to provide agents concomitantly to the nose and to the bronchi, if we want to have upper and lower airway symptoms under control. A rational approach to diagnosis and therapy according to different phases of understanding of the interrelationship between rhinitis and asthma is proposed in Table 1.

Table 1.  Rational approach to diagnosis and therapy according to different phases of understanding of the interrelationship between rhinitis and asthma
 Dissociation or causality phase (rhinitis and asthma are distinct illnesses)Identity phase (rhinitis and asthma are manifestations of one disease)
DiagnosisEmphasis in investigating sinus infections among asthmatics by using imaging techniques, assuming that sinus thickening was likely to represent infection and that antibiotics would favour asthma controlQuestions about symptoms of upper and lower airways in asthmatics or rhinitics, accepting that rhinitis and sinusitis may be present in the majority of asthmatics and that mucosal thickening is likely due to allergic inflammation
TreatmentUse of topical medication in the nose and by mouth inhalation when necessary, often associated with antibiotics for presumed sinusitisUse of topical medication in the nose and by mouth inhalation when necessary, considering the possibility of holistic airway therapy (immunotherapy, antihistamine, antileucotriene, anti-immunoglobulin E (IgE), nasal inhalation of corticosteroids)

A creative practical immediate solution would be providing topical corticosteroids by nasal inhalation (26–28), which has been shown to treat rhinitis while maintaining asthma under control. This option might not be the ideal, because it has no systemical action, but could reduce costs and risks while improving compliance to treatment, which would be very welcome in developing countries. Fine particle aerosols of corticosteroids with hydrofluoroalkane (HFA) as a propellant, delivered through a spacer, may allow an adequate distribution between upper and lower airways (29). The idea may not be attractive to pharmaceutical industry, but needs to be better analysed in further pharmacokinetics, efficacy and safety studies, to support recommendations for clinical practice.

Switching the way we see someone may take us some time. So it may happen with a disease. It has taken me 25 years of clinical practice and scientific curiosity to get rid of old beliefs and reach the views expressed in this editorial. I hope it will not take so long for you to improve the efficiency of your practice when caring for patients with asthma and rhinitis.

Conflict of interest statement

I am a member of the Executive Committee of ARIA Initiative, and I have received research funds from NIH-USA, Welcome Trust, CNPq and FAPESB – Brazil, and grants for clinical trials, honoraria as a speaker or payment as a consultant from the following companies: AstraZeneca, Aventis Pharma, Altana, Novartis Pharma, Merck, Sharp and Dohme, GSK, Schering Plough, Boehringer Ingelheim, LIBBS, Chiesi, Sankyo.

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