Systemic Cross-talk between the Lung and the Nose

Alkis Togias, M.D.

Divisions of Clinical Immunology and Respiratory and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, Maryland

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Many practitioners, even among those with specialization in respiratory disease, fail to recognize that the nasal passages are an integral part of the airways. As a consequence, they also fail to recognize the strong relationship between rhinitis and lower airways inflammatory disease, particularly the relationship between allergic rhinitis and asthma. This relationship has two major aspects: the primary aspect is that rhinitis and asthma are the manifestations of one syndrome in two parts of the respiratory tract. The second aspect is that the nasal airways and the intrathoracic airways are in cross-talk. As a result, rhinitis and asthma are interdependent. Understanding this interdependence not only has significant therapeutic implications, but is also a challenge in pathophysiology for the purists among us with primary interest in the mechanisms of disease (1).

Most patients with allergic rhinitis do not suffer from asthma. Yet, there is ample evidence that their lower airways are inflamed (2). In other words, they have a condition that affects the entire respiratory tract, but only the nasal airways produce symptoms. Perhaps, in these individuals the overall severity of the respiratory ailment is low and that is why the lower airway component does not manifest itself clinically. It is quite natural that the nasal element of the disease becomes symptomatic first: the majority of allergen-containing inhaled particles deposit in the nasal passages.

In patients with symptomatic asthma and atopy, the presence of allergic rhinitis is almost ubiquitous (3). It is possible that these patients are affected by a more severe form of the allergic inflammatory airway syndrome. Alternatively, the development of symptoms from the lower airways represents a more advanced stage of a progressively worsening condition. In fact, most patients with asthma start experiencing rhinitis before or simultaneously with their lower airway ailment (4). In cross-sectional studies, having rhinitis raises the risk of having asthma at least 10-fold, compared with a population that has no nasal symptoms. Young adults with rhinitis have a 3-fold higher chance of developing asthma over the next two decades, compared with healthy control subjects (5). Some patients with rhinitis who have no asthma symptoms have concomitant lower airways hyperresponsiveness. These individuals are at even higher risk for developing asthma.

The allergic inflammatory airway syndrome is further complicated by the fact that allergy is a systemic illness. Allergic reactions that occur in any part of the respiratory tract are not just episodes of local anaphylaxis. It has long been shown that after an allergic airway reaction, regardless of whether the site is in the nasal or the lower airways, peripheral eosinophilia and other systemic cytologic changes occur. Denburg and colleagues have convincingly shown that the bone marrow is involved in this process (6). The fact that, after a localized reaction in the airways, leukocytic infiltration occurs at the same site indicates that the systemic element of the reaction feeds back to a peripheral target. In the current issue of the journal (pp. 858-865), Braunstahl and colleagues provide evidence that the final target site of the systemic allergic response is the entire airway and not only the airway area where the original localized reaction took place (7). This work is part of a recent series of studies on this theme by the same group of investigators, including a highly complementary publication which described the reverse experiment: in that study, a nasal allergic reaction induced inflammation of the lower airways as well as bronchoconstriction (8).

Braunstahl's work supports various concepts, raises new questions, and provides a potential fascinating model for the study of allergic disease and, more broadly, human immune responses. The evidence presented in the current and in the previous publications from this group of investigators supports the concept of the oneness of the human airways, from the nose to the lungs. This concept would become even stronger if we knew that the target specificity of the systemic allergic response is confined to the airways. In other words, if biopsies from a cutaneous or an intestinal site were to be obtained simultaneously with those from the airway mucosa, would basophilia and eosinophilia also be observed in these tissues after a segmental allergen bronchoprovocation? If airway specificity of an airway-generated systemic allergic reaction can be further established, the nose-lung or lung-nose inflammatory cross-talk becomes a model to study the mechanisms of such specificity. The scientific field of immune cell homing is rapidly expanding (9). A human airway model has the potential to offer very valuable knowledge related not only to allergic airway disease, but also to other inflammatory illnesses of the airways.

Braunstahl's work also offers a potential explanation to the clinical experience and the experimental findings of several investigators indicating that allergic rhinitis and asthma follow parallel lines with respect to clinical activity. Several mechanisms have been proposed to explain nose-lung interaction (1); now, we are presented with the possibility of lung-nose interaction that may have important clinical implications. There is evidence that treating allergic inflammation in the nose and sinuses improves asthma and even some evidence that treating inflammation in the lower airways improves rhinitis (10). In both cases, the findings are under debate. Realization of the bidirectional cross-talk between these two parts of the respiratory tract should emphasize the importance of simultaneously treating both manifestations of the allergic inflammatory airway syndrome. From the perspective of ease of management and even efficacy, we may have to start revisiting our established paradigm/dogma: is topical treatment the optimal approach or would a systemic strategy be more beneficial?

It may now be time to view the airways from a more "holistic" angle. Splitting them into small parts has provided us with detailed understanding of structure and function and with a good deal of pathophysiology. In the next phase of our quest to conquer airway inflammatory disease, we will benefit enormously from returning to the forest. We should not, however, forget what the tree has taught us.

	References

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