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Upper Airway Congestion Implication for Lower Airway Disease

Nasal Congestion: Clinical Assessment to Guide Therapy

Gailen Marshall, MD, PhD, FACAAI, Professor in the Division of Allergy and Clinical Immunology at the University of Texas Medical Center in Houston, TX began the symposium by reminding the audience that the nose has three primary functions: to warm, moisten, and filter inhaled air. If these functions are obstructed, it will also influence lower airway pathophysiology. As stated by Dr. Lichenstein over 20 years ago, “the nose is really the part of the lung that is accessible to the finger.” As will be clear from this symposium, the pathophysiology of both the upper and lower airway are similar and much of what is discussed in regard to nasal congestion is applicable to lower airways diseases such as asthma. With that being said, Dr. Marshall discussed the clinical and laboratory tools to assess nasal congestion and concluded his presentation with an overview of interventions available.

Clinical Assessment
The assessment of nasal congestion in the clinical setting is mostly subjective. Common subjective symptoms include nasal stuffiness, anosmia, snoring, and fatigue. Physical signs that can be assessed include turbinate congestion, mouth breathing, dry mucous membranes, and allergic shiners. In regard to turbinate congestion, it is important to look at both turbinates. Dr. Marshall said, “I’ll look at them at the beginning of the exam then look again at the end of the exam,” adding, “if the normal cycle is about three cycles per hour, which is roughly a normal of turbinate swelling, then over a 5- to 10-minute exam there should be clear differences in the turbinate if you catch them where one side is completely nonoccluded and one side is a maximal.” The condition of allergic shiners is often present as a result of venous blood flow being blocked in the the nasal plexus. This latter condition is most noticeable in children.

Laboratory Assessment
Aside from the above assessments, other options available in laboratory/research settings include rhinometry, nasal inspiratory peak flow, and mucociliary transport time.

Rhinomanometry assesses both nasal resistance and patency which is “the nasal equivalent of FEV1 and peak flow,” according to Dr. Marshall but he cautioned the audience that although this test is useful for examining structural obstructions it is highly variable. As such, repeated measures are necessary to establish an obstruction.

Nasal peak flow assesses both nostrils simultaneously to provide a useful measure of relative patency. It can also be an excellent screening tool to differentiate edema from fixed obstructions. This assessment is dependent on the patient’s breathing effort to breathe in/out and should be correlated with peak expiratory flow (PEF) from the mouth.

The mucous ciliary transport test is a functional test that assesses ciliary function. Its sensitivity is relatively poor since it can be affected by infection and certain medications particularly antihistamines and other anticholinergic drugs. It is, however, a useful test to correlate hyposmia with congestion.

Intervention
There are several approaches to intervention of nasal congestion, including avoidance/environmental control, pharmacotherapy, nasal dilation devices, and surgery. Avoidance and environmental control should be first-line defense to remove any perceived allergens. Since pharmacotherapy will be discussed by Dr. Nathan later in this symposium, Dr. Marshall concluded his presentation with brief descriptions of nasal dilation devices and surgical options available.

Common nasal devices include the breathe-right strip that increases the interior nasal diameter. Dr. Marshall said the nasal strip is very dependent on the size and special care for proper placement on the nose is essential. Another option is to use external nasal diameters or nasal C-PAP machines, which increase the flow of the nose over the congestion. One practical consideration for the nasal C-PAP machine is that it should be avoided in patients with obstruction-induced sleep disturbances. Dr. Marshall said, “older gentlemen who have a nasal C-PAP for their obstructive sleep apnea very often will report waking up the next morning with the C-PAP in their hand because they’ve pulled it off overnight.”

Numerous surgical options are also available, including tubinectomy (laser therapy, linear cautery, submucosal distheramy, somnoplasty, and microdebridement), septoplasty, and nasal valve correction. Dr. Marshall cautioned the audience, however, by saying, “if you’re trimming a turbinate that’s got a big concha bullosa in it or you’re trimming a turbinate that’s got a major amount of scarring in it, there’s probably some value for that,” adding, “but if you’re trimming an inflamed turbinate, you’re cutting it back. They do very well for a year but the next season it starts to come back and now they’ve got a scarred turbinate that’s still just almost as swollen as it was before surgery.”

Dr. Marshall ended his presentation by stating, “I think we can say that nasal congestion is a major morbidity problem that patients with rhinitis suffer from.” Assessment can be both objective and subjective but the objective assessment is rarely performed in clinical practice and generally reserved for measuring nasal patency. The mechanisms of nasal congestion are multifactorial and as such, single effective therapies may have limitations in regard to safety and efficacy.

Pathophysiology of Congestion

William Busse, MD, Professor of Medicine and Chief of the Allergy Immunology Division at the University of Wisconsin in Madison, WI, began his presentation with a list of the pathological features of air congestion, which include: airway inflammation, mucous gland hyperplasia and hypertrophy, goblet cell hyperplasia and metaplasia, sub-basement membrane, hypertrophy of the airway smooth muscle, increased vascular proliferation, and airway edema.

There are several models to study this process. One of the classical models is the inhaled antigen provocation test. “What one does in this situation is take an individual with allergic disease, primarily allergic asthma, have them inhale antigens to which they are sensitive and then look at some of the allergic reactions in the lung,” said Dr. Busse. Using this method, the sequence of physiological events leading to obstruction can be observed. These methods have noted the classic cascade of events beginning with acute bronchoconstriction to late phase inflammation and have noted the numerous mediators involved in the process (e.g., histamine, prostaglandins, leukotrienes, and chemokines). How these mediators affect, or are affected by, vascular tissue was the focus of Dr. Busse’s presentation.

Vascular Tissue Changes
Mediators interact with the vascular tissue throughout the pathophysiologic process. For example, histamine can affect epithelial and endothelial permeability, cytokines facilitate movement of cells across the airway, growth factors (e.g., VEGF) stimulate vascular cell proliferation and tissue remodeling, . metalloproteases can stimulate cell migration, and prostanoids can change vasopermeability. All of these mediators significantly change the size and permeability of the vascular tissue and Dr. Busse said, “we need to consider the vascular response as a contributor to the airflow obstruction.”

One model that can be used to examine how the vascular bed is playing a role in this airway congestion is exercise- induced bronchospasm. In 1992, Drs. Jarjour and Calhoun showed that after intense exercise (FEV1 decreased 40%) there is very little change in histamine or tryptase concentrations (JACI 1992;89: 60). Subsequent studies have shown exercise- induced asthma to be blocked by salmeterol and Dr. Busse said, “most of us feel that to a large extent this is due to its action upon the airway smooth muscle.” In a more recent study Edelman et al showed that the antileukotriene, montelukast, was able to partially block airflow obstruction in the post-exercise period (Ann Inter Med 2000;18:97) and Dr. Busse speculated, “some of the protective effect that one sees in these situations is due not only to actions upon the airway smooth muscle but possibly on the vasodilating activity of these medications.” Inflammatory mediators can also affect the vascular tissues and studies have shown TNF-alpha and IL-1-beta to enhance inflammatory cell movement.

Concluding Remarks
The classical view of nasal obstruction involves the allergic inflammatory response, mast cells, lymphocytes, and eosinophils. According to Dr. Busse, it is much more complicated and an additional component that interacts with all of the above factors is the vascular tissue.

 

Targeting Airway Congestion

It is apparent that there is a strong pathologic connection between the upper and lower airways. Clinically, this can be observed in asthma patients who represent about 40% of allergic rhinitis patients (and allergic rhinitis affects up to 80% asthmatic patients). Furthermore, “when you treat allergic rhinitis you can improve asthma in a large proportion of patients,” stated Robert Nathan, MD, Clinical Professor of Medicine at the University of Colorado Health Center in Denver, CO and a member of the Asthma and Allergy Associates and Research Center in Colorado Springs, adding “allergic rhinitis patients with no asthma often have bronchial hyperreactivity.”

As discussed by the previous two speakers, there are numerous links between the upper and lower airways. These links are also reflected in treatment efficacy. As early as 1978, the connection between the two systems was beginning to emerge when Dr. Shturman-Ellstein and colleagues (ARRD 1978; 118:65) showed that breathing through your nose could block exercise- induced asthma. This was followed by several pharmacological studies showing treatment of asthma could improve upper airway congestion and treatment of upper airway obstruction could improve asthma and other lower airway conditions (AARD 1984;130:1014, May Clin Proc 1987;62:125, JACI 1992;90:250, JACI 1993;91:97).

Intranasal Corticosteroids
Intranasal corticosteroids are highly efficacious in treating allergic rhinitis. In a study by Welsh et al. (May Clinic Proc 1987;62:125), asthmatics with seasonal allergic rhinitis were given inhaled corticosteroids (beclomethasone or flunisolide) or a mast cell stabilizer (cromolyn) during three periods (pre-peak, peak, post-peak) of ragweed pollenosis. They found that only the inhaled corticosteroids were effective in all seasons while cromolyn was only effect during pre- and peak periods.

Using the methacholine-induced bronchial hyperactivity model, an inhaled steroid (beclomethasone) was found to reduce bronchiohyperactivity (JACI 1992;90:250) in patients with both seasonal rhinitis + mild asthma. In children with perennial allergic rhinitis, the inhaled steroid beclomethasone was also shown to be effective (JACI 1993; 91:97).

Inhaled steroids may also improve late phase reactions. In a study by Foresi and colleagues, another inhaled steroid (fluticasone) attenuated the reduction in mean PD20 methacholine associated with seasonal pollen exposure and reduced peripheral blood eosinophilia (JACI 1996;98:274).

In summary, intranasal steroids “reduce asthma symptoms, reduce bronchial hyperreactivity, and improve exercise-induced asthma in patients with concomitant allergic rhinitis and mild intermittent asthma,” said Dr. Nathan. These actions may be indirect via improved nasal symptoms, change from mouth to nasal breathing, and reduction in inflammatory cells and mediators. Dr. Nathan cautioned the audience by stating the effects of inhaled steroids on pulmonary function are inconsistent; they may not be effective in patients with more severe asthma.

Antihistamines
Nonsedating antihistamines do not have the anticholinergic effects that earlier antihistamines had (i.e., increased mucus thickening) and their efficacy was discussed by Dr. Nathan using two examples. In the first study, Grant et al. compared cetirizine with placebo in patients with seasonal allergy rhinitis + asthma and found cetirizine to reduce nasal symptoms and asthma scores but had no affect on peak flows, FEV1, or albuterol use (JACI 1995;95:923). In another study, Corren et al. compared the combination of loratadine + pseudoepinephrine (antihistamine + decongestant) with placebo in patients with seasonal allergy rhinitis + asthma and found this combination to improve nasal symptoms and lung functions (e.g., morning PEFR, FEV) (JACI 1997;100:781).
In a post-marketing study involving 48,000 people with seasonal allergic rhinitis, the new antihistamine desloratadine reduced asthma symptom scores by 72% (Plenker & Bachert ACAAI 2002).

Dr. Nathan concluded by saying “antihistamines +/- decongestants reduces asthma symptoms in patients with allergic rhinitis and mild intermittent asthma,” adding, “the actions may be indirect via improved nasal symptoms, reduction in postnasal drip, and/or change from mouth to nasal breathing.” As with inhaled steroids, the effects of antihistamines on pulmonary functions are inconsistent and further studies are needed.

Leukotriene Antagonists
Cystinyl leukotrienes are the most potent constrictors of bronchial smooth muscle and include leukotriene C4 (LTC4), leukotriene D4 (LTD4), and leukotriene E4 (LTE4). Furthermore, LTD4 challenge produces significant increases in nasal blood flow and nasal airway resistance, and is significantly more potent at producing nasal congestion compared to histamine (i.e., 3000-fold). Recently, leukotriene antagonists have been examined to determine if they can safely and effectively reduce congestions. In a study by Wilson and colleagues, 14 patients with seasonal allergic rhinitis + asthma were part of a single blind, double dummy, crossover study that compared inhaled budesonide + intranasal budesonide with montelukast + cetirizine (AJRCCM 2000;162:1297). Primary assessment included PEF, symptoms, daily activity, AMP challenge, and exhaled nitrous oxide. The authors found montelukast + cetirizine to be significantly superior in the AMP bronchial challenge compared to either placebo or budesonide. When they looked at exhaled nitrous oxide, however, which is an indirect measurement of mucosal blood flow, only budesonide showed significant differences. In younger patients, a comparison of montelukast with placebo in children with cat-induced asthma found that after 1 week of treatment, the montelukast-treated children had reduced lower airway symptoms but showed no change in upper airway symptoms.

Dr. Nathan hypothesized while leukotriene antagonist act effectively on the lower airways, topical steroids appear to act more effectively on both the upper and lower airways. Further studies examining possible combination therapies are warranted.


The Cost Effectiveness of Pharmacotherapy
“If we can control the upper airway and have an impact on lower airway we can certainly reduce urgent care visits and hospitalizations,” stated Dr. Nathan. To illustrate this point, Dr. Nathan discussed two recent studies examining asthma treatment and hospital care. In the first study of nearly 5000 patients with allergic rhinitis and asthma (73% of whom were treated for allergic rhinitis) found that the patients treated for allergic rhinitius had less than half the risk of developing an asthma-related urgent care event (JACI 2002;109:57) (Figure 1). In a second study, the frequency of asthma-related ED visits were examined in 1031 asthmatics and found significant reduced risks in patients given either intranasal steroids or antihistamines compared to untreated patients (JACI 2002;109:636).

Concluding Remarks
Dr. Nathan concluded the symposium by stating that the evidence clearly indicates that upper and lower airway disease do overlap. “The extent to which the pathophysiology of the two diseases overlaps and whether treating one will affect the other still remains to be clarified,” said Dr. Nathan, adding, “management approaches that consider the association between asthma and allergic rhinitis should improve all outcomes in patients with concomitant disease.”


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