The Relation between the Upper and Lower Airways: The United Airway Concept
Summary
Because of its strategic position at the entry of the airway, the nose plays a crucial role in airway homeostasis. The distinction between upper and lower airways is artificial. The upper and lower respiratory tracts are both components of one, united airway.
Rhinitis is an important risk factor for the development of asthma independent of allergy; also, more than half of patients with chronic rhinosinusitis (CRS) have concomitant lower airway disease.
It is therefore important that patients with persistent upper airway disease are evaluated for asthma by history, chest examination, and, if possible and when necessary, assessment of airflow obstruction before and after bronchodilation. It is important to not only assess whether patients have symptoms of lower airway disease but also to check whether those who know that they have asthma are well controlled. In turn, patients with asthma should be appropriately evaluated for rhinitis and/or CRS. Uncontrolled upper airway disease leads to uncontrolled asthma. Adequate treatment of rhinitis and CRS in asthmatics reduces asthma symptoms and improves pulmonary function and the need for asthma medication in a substantial percentage of patients.
Introduction
By warming, humidifying, and filtering incoming air, the nose is essential in the protection and homeostasis of the lower airway.1 The nose and bronchi are linked anatomically, are both lined with a pseudostratified respiratory epithelium, and are equipped with an arsenal of innate and acquired immune defense mechanisms. It is not hard to imagine that nasal conditions causing nasal obstruction may become a trigger for lower airway pathology in susceptible individuals. As early as the second century BC, Galen described a link between sinus problems and asthma, due to leakage of sinus secretions into the lungs (although we now know that this does not happen). In 1871, Voltolini published a case report on the disappearance of asthma after polypectomy.
Since the publication in 2001 of the report Allergic Rhinitis and Its Impact on Asthma (ARIA),1 the relationship between rhinitis and asthma has been the scope of epidemiological surveys, basic research studies, and clinical trials. The relationship between CRS and asthma is less well studied, but there appears to be a very clear relationship in patients with CRS with and without nasal polyps. Also, the united airway concept implies not only asthma but also chronic obstructive pulmonary disease (COPD). Allergic rhinitis and CRS can have a severe impact on social life, sleep, school, and work. The economic impact of allergic rhinitis and CRS is often underestimated because the disease does not induce elevated direct costs. However, the indirect costs are substantial. Rhinitis, CRS, and asthma are systemic inflammatory conditions and are often comorbidities.
Epidemiology
Allergic or Nonallergic
A considerable percentage of patients with rhinitis and asthma are allergic, and most longitudinal studies have explored the development of asthma in individuals suffering from allergic rhinitis. The age of onset of atopy may be an important confounding factor for the development of asthma and rhinitis or rhinitis alone. Atopy acquired at an early age has been shown to be an important predictive factor for the continuation of asthma into late childhood, whereas atopy acquired later in life was only associated with allergic rhinitis but not with asthma. However, rhinitis is an independent risk factor for the development of asthma. The prevalence of nasal symptoms is surprisingly similar in allergic and nonallergic asthmatics even for a symptom typically associated with allergy, namely, sneezing. It is not clear whether allergic rhinitis represents an earlier clinical manifestation of allergic disease in atopic subjects who will later go on to develop asthma, or if the nasal disease itself is causative for asthma.
Association between Rhinitis, Nonspecific Bronchial Hyperreactivity, and Asthma
Many patients with allergic rhinitis have an increased bronchial reactivity to methacholine or histamine, especially during and slightly after the pollen season. Patients with perennial rhinitis have a greater bronchial reactivity than those with seasonal rhinitis. Patients with persistent rhinitis have a greater bronchial hyperreactivity than those with intermittent allergic rhinitis.2 There seems to be an association between the severity of allergic rhinitis and the severity of the bronchial hyperreactivity leading to full-blown asthma in the more severe patients.
Tips and Tricks
The vast majority of patients with CRS have bronchial hyperreactivity, even in the absence of lower airway symptoms.
Occupational Airway Disease
There is significant evidence that occupational allergic diseases of the upper airway can pose important health problems because they represent an early stage of allergy throughout the respiratory system. Occupational rhinitis is common but less documented than occupational asthma.3
Cross-sectional surveys of workers exposed to sensitizing agents indicate that occupational rhinitis is two to four times more frequent than occupational asthma. Nasal symptoms usually precede those of asthma by 1 to 2 years. Health personnel, cleaners, bakers, apprentices in high-risk occupations, and workers exposed to multiple agents are at increased risk of rhinitis, especially in the very first years of employment. However, how to detect those rhinitic patients who will develop asthma remains unresolved. Also, many patients suffering from work-related airway diseases are exposed to several occupational and nonoccupational risk factors, and it may not be easy to demonstrate the occupational origin of the disease. Diagnosis of occupational asthma and rhinitis should be made precisely and as early as possible to provide accurate and efficient advice.4 Once the diagnosis has been established, complete removal from further exposure to the causative agent should be recommended as the most effective treatment. If diagnosis is made early in the course of the disease, appropriate treatment and avoidance can totally reverse symptoms. Nevertheless, 60% of affected workers retain airway hyperresponsiveness and asthma symptoms requiring antiasthma medication after avoidance of exposure.
Association between Chronic Rhinosinusitis, Asthma, and Chronic Obstructive Pulmonary Disease
Bronchial asthma is considered a comorbid condition of CRS with and without nasal polyps. In some centers, ~50% of patients with CRS have clinical asthma. Interestingly, most patients with CRS who do not report having asthma show bronchial hyperreactivity when given a methacholine challenge test. Others report that 60% of patients with CRS have lower airway involvement, assessed by history, pulmonary function, and histamine provocation tests. Alternatively, sinonasal symptoms are frequently reported in asthmatic patients, ranging up to 80% in some studies. Radiologic imaging of the sinuses has demonstrated mucosal thickening of the sinus mucosa in up to 84% of patients with severe asthma. The majority of patients with late-onset asthma have objective evidence of CRS or nasal polyps. Most of these patients are not allergic.5
Sinonasal involvement in lower airway disease is not restricted to asthma but can also be found in COPD with prevalences of sinonasal symptoms in COPD, ranging from 75 to 88%.6
Does Rhinitis Lead to Asthma? The Role for Prevention
The development and phenotypic expression of (atopic) airway disease depend on a complex interaction between genetic and several environmental factors, such as environmental exposure to inhalant allergens and nonspecific adjuvant factors.
Primary prevention, mainly the prevention of the development of allergy, has been suggested by exclusively breastfeeding preferably for at least 4 months and avoiding exposure to tobacco smoke during pregnancy. In children with a high risk of developing allergic disease, reduced allergen exposure early in life may be beneficial. Secondary prevention to prevent the development of asthma in patients with rhinitis includes avoidance of tobacco smoke and reduction of exposure to the relevant allergens. There are some indications that (sublingual) immunotherapy can prevent the initiation of new sensitizations and the development of asthma.7 Occupational diseases represent an interesting model for studying the relationship between rhinitis and asthma. Rhinitis caused by many occupational agents often develops into occupational asthma, highlighting the importance of cessation of allergen exposure in occupational allergic rhinitis to prevent asthma.
Tips and Tricks
Timely immunotherapy can prevent the development of new sensitizations and asthma.
Can Rhinitis Predict Asthma Exacerbations?
A major part of the burden of asthma is caused by acute exacerbations. Exacerbations have been strongly and consistently associated with respiratory infections and to a lesser degree allergen provocation. Among infectious agents, human rhinoviruses are the most prevalent in regard to asthma exacerbations. The newly identified type C rhinoviruses may prove to be particularly relevant. Respiratory syncytial virus and metapneumovirus are important in infants, and influenza viruses seem to induce severe exacerbations mostly in adults.8 There can be a synergistic interaction between allergy and viral infection that causes increased severity of asthma exacerbations. Optimal treatment of allergic rhinitis may be able to prevent viral infection; however, no conclusive data are available to prove this.
Role of Remodeling
In allergic rhinitis, remodeling is still poorly understood. Inflammation is similar in allergic rhinitis and asthma; however, the pathologic extent of nasal remodeling, as well as its clinical consequences, may be different from those of the bronchi.
In general, the nasal mucosa of patients with allergic rhinitis shows far less damage than the bronchial epithelium. Remodeling in lower airway disease has been extensively studied and reviewed. It includes changes in the airway epithelium, lamina propria, and submucosa, resulting in airway wall thickening. In CRS with and without nasal polyps, significant remodeling is found. However, the remodeling is very different in these two groups. Transforming growth factor (TGF)-β has been implicated as an important factor in remodeling processes involved in chronic sinus disease.9
Interaction between the Upper and Lower Airways
Pathophysiologic Mechanisms
Several mechanisms have been suggested as playing a role in the mutually reciprocal interaction between inflammatory processes in the upper and lower respiratory tracts.10 First, the upper and lower airways are lined with the same respiratory mucosa, along with both ciliated cells and mucus-producing cells and glands ( Fig. 12.1 ). The only difference is the presence of smooth muscle tissue around the mucosal lining in the lower airway, whereas the mucosa in the upper airway is more abundant. In both the upper and lower airways, the mucociliary clearance system is the most important defense mechanism. Inflammatory reactions in the upper and lower airways are rather similar, with deposition of collagen and remodeling present only in the lower airway.
Nasobronchial Reflex
In 1903, Dixon described an immediate bronchoconstriction after electrical or mechanical stimulation of the nasal mucosa in cats, which could be prevented by cutting the vagal nerve.
Sluder published a study in 1919 titled “Asthma as a Nasal Reflex,” in which exacerbation of asthma symptoms occurred in eight patients after stimulation of the sphenopalatine ganglion, which could be prevented by local application of cocaine.
Neuropeptides such as substance P and calcitonin gene-related peptide, capable of inducing inflammatory reactions, have been found to be present in connection with the trigeminal and vagal nerves. Nasal provocation with cold air causes immediate bronchoconstriction in patients with asthma, prevented by local anesthesia of the nasal mucosa. Nasal provocation with allergens results in immediate bronchoconstriction and bronchial hyperreactivity in allergic patients with asthma and without asthma.11 Control studies with radioactive particles showed that these allergens remained in the upper airway and did not reach the lower airway.
However, after several hours bronchial hyperreactivity is still increased. Furthermore, the peak expiratory flow starts to decline after 4 to 6 hours, suggesting other mechanisms than a nasobronchial reflex.
Direct Contamination of the Lower Airway by Inflammatory Products from the Upper Airway
This has mainly been suggested in animal experiments, in which an artificially induced sinusitis resulted in increased bronchial hyperreactivity, though only in the upright position. Some silent aspiration may occur during sleep. However, in patients with sinusitis and asthma, radioactivity instilled in the sinuses could not be detected in the lower airway.12
Impaired Air Conditioning in the Upper Airway
Mouth breathing, with inhalation of cold, dry air, is a well-known inducer of bronchoconstriction and hyperreactivity. Improving nose breathing during sleep in patients with asthma reduced nocturnal asthma symptoms and the need for asthma medication.13 By some, the improvement of lung function after medical or surgical treatment of upper airway inflammation has been attributed to better nose breathing. However, in several studies a direct correlation between the degree of nasal obstruction and lung function has not been found.
Blockade of β-adrenergic Responsiveness
Viral infections of the upper airway in asthmatic patients result in an increase in bronchial hyperreactivity and a diminished response to sympathicomimetics. Adequate treatment of sinusitis in children with therapy-resistant asthma gives a better response to inhalation sympathicomimetics.14 In vitro, granulocytes of asthmatic patients release more histamine when incubated with influenza virus, pointing to a diminished-adrenergic responsiveness. However, as the evidence from clinical studies is more or less circumstantial, other mechanisms could also be involved.
Dissemination of Inflammation-related Substances via the Systemic Circulation
Nasal allergen challenge can induce bronchial inflammation10 ( Fig. 12.2 ). Endobronchial allergen challenge can induce nasal and bronchial symptoms, as well as reductions in pulmonary and nasal function.15,16 In this study,16 the number of eosinophils increased in the challenged bronchial mucosa, in the blood, and in the nasal mucosa 24 hour after bronchial challenge. Moreover, eotaxin-positive cells in the nasal lamina propria and enhanced expression of interleukin 5 (IL-5) in the nasal epithelium were found 24 hours after bronchial challenge.
In patients with allergic diseases, allergen provocation can activate a systemic response that provokes inflammatory cell production by the bone marrow.17 After release and differentiation of progenitor cells, eosinophils, basophils, and mast cells are typically recruited to tissues in atopic individuals.
Studies that support the critical involvement of the bone marrow in the development of eosinophilic inflammation of the airways point out the systemic nature of these conditions. It is clear that this mechanism, dissemination of inflammation-related substances and cells via the systemic circulation, plays the most important role in the relation between the upper and lower airways.
Diagnosis and Assessment of Severity
Quality of Life
Quality of life has been found to be impaired both in patients with asthma and in patients with allergic rhinitis and CRS, and the relative burden of these diseases has been recently studied using the generic SF-36 (Short Form) questionnaire in the European Community Respiratory Health Survey (ECRHS), a population-based study of young adults. Patients with both asthma and allergic rhinitis experienced more physical limitations than patients with allergic rhinitis alone, but no difference was found between these two groups for concepts related to social/mental health. Subjects with asthma but without rhinitis could not be studied, as their number was too low. However, it seems that impairment in social life in asthmatics may be attributable to nasal symptoms. CRS patients have a significantly impaired quality of life.18 They experience worse quality of life than patients with asthma, COPD, or coronary artery disease. Asthma has an additional negative impact on the quality of life of patients with nasal polyps.19 It is not known whether CRS has a negative impact on the quality of life of patients with asthma, but it has been shown that it has a negative impact on patients with bronchiectasis.20
Severe Chronic Upper Airway Disease and the Relation to Asthma
Many patients suffer from severe chronic upper airway disease (SCUAD).21 SCUAD defines those patients who are inadequately controlled despite effective, safe, and acceptable pharmacological treatment based on guidelines. These patients have impaired quality of life, social functioning, sleep, school, and/or work performances. Severe uncontrolled allergic rhinitis, nonallergic rhinitis, CRS, aspirin-exacerbated respiratory diseases, and occupational airway diseases are defined as SCUAD. It has been shown that ~50% of patients with rhinitis in a general practice and otorhinolaryngological setting had poor to partial control using local corticosteroids or a combination of local corticosteroids and antihistamines. For CRS, these data are unknown, but the number of patients needing surgery after aggressive medical treatment, the number needing revision surgery (20%), and the number still having significant symptoms based on the SNOT-22 (Sinonasal Outcome Test) after surgery (mean 26 in CRS with nasal polyps to 33 in CRS without nasal polyps compared with a score of 7 in the SNOT-22 in healthy adults) point to significant uncontrolled disease.22 Uncontrolled upper airway disease leads to uncontrolled asthma.
Diagnostics of the Lower Airway in Patients with Rhinitis or Rhinosinusitis
According to the ARIA guidelines,1,2,23 patients with persistent allergic rhinitis should be evaluated for asthma by history, chest examination, and, if possible and when necessary, assessment of airflow obstruction before and after bronchodilation. It is important to not only assess whether patients have symptoms of lower airway disease (see Table 12.1 for examples of questions to ask) but also to check whether those who know that they have asthma are well controlled. An effective way to assess lower airway disease is the asthma control test ( Fig. 12.3 ).
Diagnostics of the Upper Airway in Patients with Asthma
Patients with asthma should be appropriately evaluated (history and physical examination) for rhinitis. A very helpful article was published by Dixon at el24 showing that a set of questions developed by them was highly sensitive and specific for chronic sinonasal disease (CRS or rhinitis). These five questions (called the SNQ by the authors) were found to be superior to endoscopy and computed tomography (CT) scan assessment in these circumstances.
The authors stated that endoscopy and CT scans provide important anatomical data in patients who require surgery or a similar intervention, but they are not necessary to make the initial diagnosis of chronic rhinitis or CRS in patients with asthma. The SNQ questions ask about symptoms over the past 3 months: runny nose, postnasal drip, need to blow the nose, facial pain/pressure, and nasal obstruction. The scores range from 0 to 3 (never, 1–4 times per month, 2–6 times per week, daily). A cutpoint of 1 (experiencing each symptom an average of 1–4 times per month) was highly sensitive and specific for diagnosing chronic sinonasal disease.
Tips and Tricks
Every patient with asthma should be evaluated for rhinitis and CRS. Every patient with rhinitis or CRS should be evaluated for asthma.
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