Antihistamines and epithelial cells.

Antihistamines have long been utilized in the symptomatic management (antihistaminic effects) of allergic rhinitis and conjunctivitis. Investigation into the nonsedating second-generation antihistamines suggests that they also possess antiinflammatory activity, and may be useful in the management of inflammation associated with allergic airway disease. In vitro studies have shown that these antihistamines decrease the migration and activation of eosinophils and diminish the release of pro-inflammatory mediators from mast cells and basophils after induction by immunological and nonimmunological stimuli. In vivo studies have also demonstrated that these antihistamines decrease inflammatory cell infiltration in allergic airway disease, and mediator release from mast cells and basophils. Epithelial cells, due to their spatial arrangement and predominance in the airways, play a pivotal role in the etiology of airway disease. There is evidence that antihistamines may modulate airway inflammation by influencing the activity of these airway epithelial cells. Studies have shown that expression of adhesion molecules on epithelial cells is decreased by second-generation antihistamines. Collectively, these studies suggest that second-generation H1-histamine receptor antagonists have potential use either as safe antiinflammatory alternatives to corticosteroids or as rescue medication in combination with corticosteroids for the management of severe airway disease.     

Peripheral airways in asthma

The peripheral, or small, airways are usually defined as conducting airways that are less than 2 mm in internal diameter and extend from the noncartilaginous bronchioles to the alveolar ducts. Noninvasively measuring the function of the small airways in isolation is difficult since they make up only about 10% of total airway resistance. Quantitative pathologic studies have shown that both the small and large airways are involved in inflammation and remodeling in asthma. Recent studies also have shown that inflammation involves the alveoli surrounding small airways in asthma and that the distribution of different inflammatory cells across the airway wall varies in both large and small airways. Inhaled treatment that targets the small airways may be more effective than treatment that is deposited more proximally and suggests that treatments in the future need to address the variable distribution of pathology in the bronchial tree in asthma.     

Anti-leukotriene therapy in asthma

There is ample evidence that leukotrienes are important inflammatory mediators of asthma. Anti-leukotriene therapy is a novel, specific anti-asthma strategy providing both reliever and controller effects. Currently, two types of anti-leukotriene drugs are being registered in several countries: leukotriene receptor antagonists and leukotriene biosynthesis inhibitors. Both types of drugs have shown comparable bronchodilator effects, and provided protection against bronchoprovocation tests with cold dry air, exercise, allergen and aspirin. Moreover, beneficial effects have been shown in the treatment of day-to-day asthma resulting in improvement of clinical symptoms, lung function parameters, and a reduction in β₂-agonist- and corticosteroid-use. Furthermore, some studies showed a decrease in the airway eosinophil counts after longterm administration of anti-leukotriene drugs, suggestive of anti-inflammatory effects. Because of these properties in combination with generally mild adverse effects, anti-leukotrienes seem promising in the treatment of patients with various types and severities of asthma, including children. However, their definitive place in the management of asthma will eventually depend on their effectiveness to modulate the chronic airway inflammation, which induces the structural changes within the airways, determining the severity of clinical symptoms of asthma.     

The role of small airway inflammation in asthma.

Although inflammation in the large central airways has been the subject of numerous asthma studies, inflammation in the small distal airways remained largely unexamined because of the relative inaccessibility of these structures. However, fiberoptic bronchoscopy, combining endobronchial and transbronchial biopsy, now allows specimens to be obtained from both proximal and distal areas of the lung. Newly refined morphometric and immunocytochemical techniques have been applied to both autopsy and lung biopsy specimens. Together, these technological changes have had a profound impact on the study of small airway inflammation. Now, it is understood that the asthma-associated inflammation evident in the large airways occurs in the distal airways as well. The inflammatory process in the two regions has related features: infiltrates contain activated T lymphocytes and eosinophils, increased mucus plugging, and smooth muscle hyperplasia can be observed. Although the similarities are pronounced, inflammation in the small airways differs in important ways from large airway inflammation. The eosinophilic infiltration that occurs throughout the asthmatic lung also is active in the small airways. The contribution of small airway inflammation to deficits in pulmonary function has been clarified by thoracic high-resolution computed tomography imaging. Results of such imaging suggest that the distal airways are a major site of airway obstruction in patients with asthma and may play a significant role in airway hyperresponsiveness; both disorders are cardinal features of asthma. In addition, functional bronchoscopic studies of the small airways in asthma patients have found high peripheral airflow resistance, even when lung function appears normal. Current formulations of inhaled anti-inflammatory medications, particularly corticosteroids administered by metered dose inhalers using chlorofluorocarbon propellants, treat the proximal airways more effectively than the distal airways. However, some new formulations of inhaled steroids that utilize hydrofluoroalkane propellants produce aerosols of smaller average particle size, with greater penetration into the peripheral airways. Their potential to treat inflammation at peripheral sites may account for the significant improvements in asthma outcomes that have been reported in clinical trials of these new formulations.     

Second-Generation Antihistamines in Asthma Therapy

Second-generation histamine H₁ receptor antagonists are recognized as being highly effective treatments for allergic-based disease and are among the most frequently prescribed drugs in the world. The newer antihistamines represent a heterogeneous group of compounds with markedly different chemical structures, a spectrum of antihistaminic properties, adverse effects, half-life, tissue distribution, metabolism and varying degrees of anti-inflammatory effects. Histamine is an important mast cell- and basophil-derived mediator that has been implicated in the pathogenesis of asthma, resulting in smooth muscle contraction, mucus hypersecretion, and increased vascular permeability leading to mucosal edema. Antihistamines should never be used as monotherapy for asthma but there is evidence that these drugs give a measure of protection in histamine-induced bronchoconstriction. Furthermore, several studies have demonstrated that the use of second-generation antihistamines, as adjunct therapy, may benefit those patients whose allergic asthma co-exists with allergic rhinitis. Indeed, many patients present with both allergic rhinitis and asthma. The link between the upper and lower respiratory airways is now well established and there is increasing evidence that allergic rhinitis is a risk factor for the development of asthma. More recently, a number of novel antihistamines have been developed which are either metabolites of active drugs or enantiomers and there is emerging evidence that at least one of these drugs, desloratadine, may give significant symptomatic benefit in some types of asthma. It is of interest to note that cetirizine provides a primary pharmacological intervention strategy to prevent the development of asthma in specifically-sensitized high risk groups of infants. Moreover, the documented anti-inflammatory activities of antihistamines may provide a novel mechanism of action for the therapeutic control of virus-induced asthma exacerbations by inhibiting the expression of intercellular adhesion molecule-1 (ICAM-1) by airway epithelial cells. Finally, several well-conducted studies suggest that combination therapy with antihistamines and anti-leukotrienes may be as effective as corticosteroid use in patients with allergic asthma and seasonal allergic rhinitis.     

Second-generation antihistamines in asthma therapy: is there a protective effect?

Second-generation histamine H(1) receptor antagonists are recognized as being highly effective treatments for allergic-based disease and are among the most frequently prescribed drugs in the world. The newer antihistamines represent a heterogeneous group of compounds with markedly different chemical structures, a spectrum of antihistaminic properties, adverse effects, half-life, tissue distribution, metabolism and varying degrees of anti-inflammatory effects. Histamine is an important mast cell- and basophil-derived mediator that has been implicated in the pathogenesis of asthma, resulting in smooth muscle contraction, mucus hypersecretion, and increased vascular permeability leading to mucosal edema. Antihistamines should never be used as monotherapy for asthma but there is evidence that these drugs give a measure of protection in histamine-induced bronchoconstriction. Furthermore, several studies have demonstrated that the use of second-generation antihistamines, as adjunct therapy, may benefit those patients whose allergic asthma co-exists with allergic rhinitis. Indeed, many patients present with both allergic rhinitis and asthma. The link between the upper and lower respiratory airways is now well established and there is increasing evidence that allergic rhinitis is a risk factor for the development of asthma. More recently, a number of novel antihistamines have been developed which are either metabolites of active drugs or enantiomers and there is emerging evidence that at least one of these drugs, desloratadine, may give significant symptomatic benefit in some types of asthma. It is of interest to note that cetirizine provides a primary pharmacological intervention strategy to prevent the development of asthma in specifically-sensitized high risk groups of infants. Moreover, the documented anti-inflammatory activities of antihistamines may provide a novel mechanism of action for the therapeutic control of virus-induced asthma exacerbations by inhibiting the expression of intercellular adhesion molecule-1 (ICAM-1) by airway epithelial cells. Finally, several well-conducted studies suggest that combination therapy with antihistamines and antileukotrienes may be as effective as corticosteroid use in patients with allergic asthma and seasonal allergic rhinitis.     

Targeting small airways in asthma: improvement in clinical benefit?

Background and Aim: Disease control is not achieved in a substantial proportion of patients with asthma. Recent advances in aerosol formulations and delivery devices may offer more effective therapy. This review will focus on the importance and potential clinical benefit of targeting the lung periphery in adult asthma by means of ultra‐fine aerosols. Results: Ultra‐fine formulations of inhaled corticosteroids (ICS) have improved lung deposition up to at least 50%, primarily in the peripheral airways. Ultra‐fine formulations of ICS provide equivalent asthma control to non‐ultra‐fine ICS at approximately half the daily dose, with no increased risk of systemic effects. Clinical studies of adults with asthma have shown a greater effect of ultra‐fine ICS, compared with non‐ultra‐fine ICS, on quality of life, small airway patency, and markers of pulmonary and systemic inflammation, but no difference with regard to conventional clinical indices of lung function and asthma control. Conclusions: Asthma patients treated with ultra‐fine ICS, compared with non‐ultra‐fine ICS, have at least similar chance of achieving asthma control at a lower daily dose. Further clinical studies are needed to explore whether treatment with ultra‐fine formulations of ICS will change the natural history of asthma and prevent airway remodelling in both the large and small airways. Please cite this paper as: Ulrik CS, Lange P. Targeting small airways in asthma: Improvement in clinical benefit? Clin Respir J 2011; 5: 125–130.     

Small airways disease in asthma

A mounting body of physiologic and pathologic evidence indicates that asthma involves the central and the more distal airways. In patients with asthma, the peripheral lung accounts for a significant portion of airway resistance and, similar to the large airways, the small airways have been shown to be hyperresponsive to nonspecific stimuli, such as methacholine. Cellular inflammation, consisting of an infiltrate rich with lymphocytes and eosinophils, is present in the small airways of patients with asthma and may be more intense than that observed in the large airways. Clinical assessment of the peripheral airways continues to be a challenge, and new techniques, such as quantitative analysis of chest CT images, have proven to be useful research tools. The recognition of small airways involvement in asthma has clinical relevance, as new formulations of inhaled corticosteroids with smaller particle aerosols may be more effective in addressing this component of asthma.     

New immunological approaches and cytokine targets in asthma and allergy.

The aims of current asthma treatment are to suppress airway inflammation and control symptoms, and corticosteroids maintain a commanding position in this role. Steroids effectively suppress inflammation in the majority of patients but have little impact on the natural history of this disease. In severe asthmatics, corticosteroids may have relatively less beneficial effects. Recent advances in understanding the inflammatory and immunological mechanisms of asthma have indicated many potential therapeutic avenues that may prevent or reverse abnormalities that underlie asthma. As the roles of effector cells, and of signalling and adhesion molecules are better understood, the opportunities to inhibit or prevent the inflammatory cascade have increased. In addition, there have been advances in the synthesis of proteins, monoclonal antibodies and new small molecule chemical entities, which may provide valuable flexibility in the therapeutic approach to asthma. The novel immunological approaches include the prevention of T-cell activation, attempts to influence the balance of T-helper cell (Th) populations to inhibit or prevent Th2-derived cytokine expression, and the inhibition or blockade of the downstream actions of these cytokines such as effects on immunoglobulin-E and eosinophils. These approaches provide broad as well as highly specific targeting, and also prospects for prevention and reversal of immunological and inflammatory abnormalities associated with asthma. Hopefully, the development of effective antiasthma agents with effects beyond those provided by current therapies coupled with lesser side-effects will further address the unmet needs of asthma.     

Exhaled nitric oxide in persistent rhinitis with or without lower airway involvement: a review of the literature

The link between upper and lower respiratory airways has been investigated in the past decade leading to the concept of united airways disease. This hypothesis was suggested by several epidemiological observations, which had shown the high prevalence of rhinitis and sinusitis in patients with asthma, and indirectly, by observing the effects of drugs used for rhinitis on asthma symptoms. A broad spectrum of airway involvement severity can be associated with rhinitis or rhinosinusitis: from a subclinical/asymptomatic inflammatory involvement with an increase in eosinophils in induced sputum cell count, to asthma-like symptoms without functional features of asthma with or without extrathoracic airway hyperresponsiveness, to respiratory symptoms with clinical and functional criteria of asthma. The aim of this paper is to review the literature about the role of breath analysis in the relationship between nose and lung, focusing on exhaled nitric oxide (FE(NO)) measurement, a non-invasive marker of inflammation, in rhinitis and in chronic rhinosinusitis in patients complaining or not of asthma symptoms.     

Elastin in asthma

Extracellular matrix is generally increased in asthma, causing thickening of the airways which may either increase or decrease airway responsiveness, depending on the mechanical requirements of the deposited matrix. However, in vitro studies have shown that the altered extracellular matrix produced by asthmatic airway smooth muscle cells is able to induce increased proliferation of non-asthmatic smooth muscle cells, which is a process believed to contribute to airway hyper-responsiveness in asthma. Elastin is an extracellular matrix protein that is altered in asthmatic airways, but there has been no systematic investigation of the functional effect of these changes. This review reveals divergent reports of the state of elastin in the airway wall in asthma. In some layers of the airway it has been described as increased, decreased and/or fragmented, or unchanged. There is also considerable evidence for an imbalance of matrix metalloproteinases, which degrade elastin, and their respective inhibitors the tissue inhibitors of metalloproteinases, which collectively help to explain observations of both increased elastin and elastin fragments. A loss of lung elastic recoil in asthma suggests a mechanical role for disordered elastin in the aetiology of the disease, but extensive studies of elastin in other tissues show that elastin fragments elicit cellular effects such as increased proliferation and inflammation. This review summarises the current understanding of the role of elastin in the asthmatic airway.     

Asthma attack associated with oxidative stress by exposure to ETS and PAH.

Asthma is primarily an airways inflammatory disease, and the bronchial airways have been shown to be particularly susceptible to oxidant-induced tissue damage. OBJECTIVE: The purpose of this study was to investigate whether pulmonary inflammation in asthma is associated with exposure to environmental oxidants such as polycyclic aromatic hydrocarbon (PAH) and environmental tobacco smoke (ETS). METHOD: We assessed the exposure level of PAH and ETS by using urinary 1-hydroxypyrene glucuronide (1-OHPG) and cotinine. We estimated oxidative damage and inflammatory cytokine levels from 16 asthma patients and 16 patients in stable conditions 1 to 2 months later. RESULTS: Our study showed that the levels of oxidative damage, as measured by malondialdehyde (MDA), were significantly increased (p = 0.006) during the asthma attacks. Proinflammatory and anti-inflammatory cytokines were both increased during the asthma attacks compared to the stable conditions at follow-up. Interleukin (IL-6) and IL-10 were especially increased significantly (p = 0.015 and p < 0.001, respectively). Correlations were observed between inflammatory cytokines such as IL-6 and IL-1beta (p = 0.034). CONCLUSION: This study supports the results of in vitro studies that oxidative stress, specifically lipid peroxidation, contributes to the pathophysiology of asthma. Therefore, environmental interventions based on this better understanding are needed to significantly reduce oxidant stress and prevent or minimize the development of asthmatic symptoms.     

History and future perspectives of treating asthma as a systemic and small airways disease

Asthma is an inflammatory disorder in which the small airways of the lung play an important role. There is also evidence for the systemic nature of asthma. No current method adequately measures small airways function alone. Therefore, a combination of functional and clinical parameters should be used to ensure that patients with asthma are adequately treated with due consideration of the small airways. Previously therapeutic strategies have focused on bronchodilation and attenuation of airway inflammation.While early oral therapies had the advantage of reaching the small airways and treating the systemic aspect of asthma, they were associated with serious side-effects. Inhaled therapies were therefore developed to limit these effects. However, inhaled therapies have the disadvantage of limited penetration into the peripheral airways and an inability to treat the systemic component of asthma. They are also associated with local and systemic side-effects. The future for asthma treatment is likely to be a systemically administered medication with few side-effects targeting disease-specific mediators. The leukotriene receptor antagonists and anti-IgE monoclonal antibodies are examples of such therapies and the emergence of other new strategies is awaited.     

Calcium-channel blockers in prophylaxis and treatment of asthma

Calcium-channel blocking drugs do not induce bronchoconstriction in susceptible persons with cardiac disease and concomitant hyperreactive airways (such as asthma or chronic bronchitis). The ways in which calcium blockers might in fact play a beneficial role in preventing bronchoconstriction or inducing bronchodilation in asthma are explored. Nifedipine and verapamil have been shown to inhibit the bronchoconstriction provoked by exercise, histamine, methacholine and antigen. The potential mechanisms by which this protective effect is mediated--whether by direct action on tracheobronchial smooth muscle, inhibition of release of mediators from activated mast cells or both--are examined by reviewing in vitro studies of both cell systems. Calcium blockers also exhibit some bronchodilating activity in vitro. Early clinical trials of these drugs in ambulatory asthmatic patients have shown little, if any, therapeutic benefit, but results must be considered preliminary in view of the nature of the short-term, small-scale trials performed to date. Regardless of their therapeutic potential in obstructive lung diseases, the calcium-channel blockers offer a powerful probe into the role of calcium in the physiologic make-up of airways and, in particular, the pathophysiologic features of airway hyperreactivity.     

Diving: what to tell the patient with asthma and why?

Until a decade ago, divers with asthma were uniformly barred from diving with compressed air. This prohibition was based more on theoretical concerns for barotrauma than on actual data. Follow-up studies, although retrospective, do not support a ban on recreational or commercial diving for divers with stable asthma. These studies have noted that, despite the prohibition on diving, many divers with asthma have logged multiple dives without negative consequences. When those who have suffered diving-related barotrauma have undergone physiologic testing, measurements of small airways dysfunction (maximal mid-expiratory flow rates) have been lower than measurements for comparable divers who have never suffered diving accidents. Follow-up studies with long-term commercial divers have shown that a small percentage of individuals who have sufferred diving-related barotrauma also develop abnormal maximal mid-expiratory flow rates and even some airway hyperreactivity. These latter findings correlate with the changes that occur in chronic asthmatic patients, especially those who are not well treated. The decision as to whether an asthmatic patient should be allowed to dive rests on the individual's physiologic function, maturity, and insight into the consequences of poorly managed airway inflammation and bronchospasm.     

Neurogenic inflammation in the airways

Release of neuropeptides, including tachykinins and calcitonin gene-related peptide, from sensory nerves via an axon or local reflex may have inflammatory effects in the airways. This neurogenic inflammation may be initiated by activation of sensory nerves by inflammatory mediators and irritants. Neurogenic inflammation is well developed in rodents and may contribute to the inflammatory response to allergens, infections and irritants in animal models. However, the role of neurogenic inflammation in airway inflammatory diseases, such as asthma and COPD is still uncertain as there is little direct evidence for the involvement of sensory neuropeptides in human airways. Initial clinical studies using strategies to block neurogenic inflammation have not been encouraging, but it is important to study more severe forms of airway disease in more prolonged studies in the future to explore the role of neurogenic inflammation.     

Step Care Therapy: A Logical Approach to Asthma Management

In the decade of the 1980s, physicians have significantly changed their approach to both their understanding and treatment of asthma. It is not clear if this is related to the increasing rates of morbidity and mortality worldwide with asthma or if it has simply been a function of a better understanding of the pathophysiologic events associated with this disease. Until recently, asthma was primarily thought of as a disease in which the airways had an obstructive process which caused the individuals to have wheezing and shortness of breath. This oversimplified concept has been expanded dramatically, and it is now recognized that inflammation leading to increased bronchial reactivity is the basis for which airways react and become obstructed. The role of inflammation in asthma has been so emphasized that one leading investigator has recently described asthma as “chronic desquamative eosinophilic bronchitis” (1). This terminology takes the asthmatic one step further in understanding the pathophysiologic relationship between airways inflammation and airways reactivity. Secondary bronchospasm and obstruction occur and that this inflammation may be a chronic process.     

Diagnosis of asthma – new theories

Introduction: Recent studies have shown a remarkably high frequency of poorly controlled asthma. Several reasons for this treatment failure have been discussed, however, the basic question of whether the diagnosis is always correct has not been considered. Follow-up studies have shown that in many patients asthma cannot be verified despite ongoing symptoms. Mechanisms other than bronchial obstruction may therefore be responsible. The current definition of asthma may also include symptoms that are related to mechanisms other than bronchial obstruction, the clinical hallmark of asthma. Aim: Based on a review of the four cornerstones of asthma – inflammation, hyperresponsiveness, bronchial obstruction and symptoms – the aim was to present some new aspects and suggestions related to the diagnosis of adult non-allergic asthma. Conclusion: Recent studies have indicated that “classic” asthma may sometimes be confused with asthma-like disorders such as airway sensory hyperreactivity, small airways disease, dysfunctional breathing, non-obstructive dyspnea, hyperventilation and vocal cord dysfunction. This confusion may be one explanation for the high proportion of misdiagnosis and treatment failure. The current diagnosis, focusing on bronchial obstruction, may be too “narrow”. As there may be common mechanisms a broadening to include also non-obstructive disorders, forming an asthma syndrome, is suggested. Such broadening requires additional diagnostic steps, such as qualitative studies with analysis of reported symptoms, non-effort demanding methods for determining lung function, capsaicin test for revealing airway sensory hyperreactivity, careful evaluation of the therapeutic as well as diagnostic effect of corticosteroids and testing of suggested theories.     

Bronchial hyper-responsiveness and exhaled nitric oxide in chronic obstructive pulmonary disease

Several lung diseases including asthma and chronic obstructive pulmonary disease (COPD) involve chronic inflammation of the airways. Therefore, there is great interest in non-invasive methods assessing airway inflammation. Measurement of bronchial hyper-responsiveness (BHR) and exhaled nitric oxide (NO) are such indirect markers of airway inflammation. Additional information about severity of disease, prognosis and possible response to anti-inflammatory treatment with inhaled corticosteroids can be gained by these methods. However, they are not yet established in assessing patients with COPD in clinical routine. BHR has long been recognised as a hallmark of asthma. Less is known about prevalence and clinical relevance of BHR in the general population and in COPD patients. Longitudinal studies have shown that BHR in healthy persons is a risk factor for development of respiratory symptoms, asthma and COPD. BHR has also been shown to increase the detrimental effect of cigarette smoke and is associated with a decline in lung function. Furthermore, studies indicate that the presence of BHR is a prognostic factor in COPD. Increased BHR to histamine has been shown to be a predictor for mortality in COPD patients. Based on current guidelines, treatment of patients with severe COPD (GOLD stage III and IV) and regular exacerbations includes therapy with inhaled corticosteroids. Inhaled corticosteroids have been shown to reduce frequency of exacerbations but they have not been shown to modify long-term decline in FEV1. However, one small study found that BHR to inhaled mannitol could possibly predict responsiveness to inhaled corticosteroids in patients with moderately severe COPD and identify a subgroup of patients that is likely to benefit from this treatment. Exhaled NO has been shown to correlate with other inflammatory markers and to be elevated in asthma. In COPD patients, data is inconsistent. However, measuring exhaled NO may have a role in the identification of patients with severe, unstable COPD who were shown to have higher NO levels compared to patients with stable COPD. This suggests that exhaled NO might be a method to assess and monitor disease activity in COPD. Possible explanations for the contradictory results are different measurement techniques of exhaled NO and different smoking histories of patients in various studies. Smoking has been found to be a confounding factor by reducing NO levels significantly, an effect which might counteract the potentially increased exhaled NO due to airway inflammation. In conclusion, measuring BHR and exhaled NO in patients with COPD might provide additional information about disease severity, prognosis and possible response to anti-inflammatory medical treatment. However, to establish these methods in clinical routine in COPD patients, more data is clearly needed.     

Rhinitis-asthma connection: epidemiologic and pathophysiologic basis.

Over the last several years, important research has demonstrated the link between the upper airways disease, rhinitis, and lower airways disease, asthma. In fact, it appears that asthma and rhinitis represent components of a single inflammatory airways disease. With the use of epidemiologic data and pathophysiologic studies, the connection between these inflammatory conditions becomes clear. Numerous population studies show the high rate of asthma in patients with allergic rhinitis compared to the general population. Several surveys suggest the rate of rhinitis in asthma patients to be as high as 100%. Recent studies in humans demonstrate that local allergen exposure in the nose of patients with allergic rhinitis can quickly lead to significant allergic inflammation in the lungs, even without a previous history of asthma or airways bronchial hyperreactivity. It is important for the clinician to understand the connection between these disorders so that all patients with rhinitis are evaluated for lower airways disease, and all patients with asthma be screened for upper airways conditions.