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Comorbidities of Allergic Rhinitis and Its Impact on Treatment

Sinusitis

Raymond Slavin, MD, Professor of Medicine at St. Louis University School of Medicine in St. Louis, MO, began
the symposium with a few sobering statistics regarding rhino-sinusitis.

For example, it is reported in 15% of Americans, and accounts for 11.5 million office visits and for over $2 billion in direct medical costs.

Many factors can contribute to rhino-sinusitis, including:
• Ostial patency
• Gas exchange
• Mucociliary action
• Enzymatic defense
• Immunoglobulins

Dr. Slavin said that allergic rhinitis is NOT rhino-sinusitis. CT scans of sinuses of patients with allergic rhinitis are normal whereas in rhino-sinusitis they are not (J Allergy Clin Immunol 1996; 98:1130). However, allergic rhinitis can lead to rhino-sinusitis and there are several experimental and clinical studies illustrating this transition (Allergy 1989; 44:116, JACI 1991; 87:219, Pediatrics 1991; 87:311, Adv Otolaryngol 1961; 10:1, Allergy 1999; 54:242, Otolaryngol Head Neck Surg. 2000; 123:687, JACI 2000; 150-S70, JACI 2001; 108:424). “One can conclude from a whole raft of studies that there’s a minimum concordance of allergy and sinusitis of 25% with a maximum of 70% and that’s clearly above the general prevalence of allergy and it supports the impression that allergy is an important associated, and a probable predisposing, factor in the causation of rhinosinusitis,” stated Dr. Slavin.

Treatment
Glucocorticoids reduce the ability of bacteria to attach to and invade epithelium. They also enhance the ability of macrophages to kill bacteria. In an experimental model of sinusitis (rabbit), nasal steroids reduce polyp formation and systemic steroids improve healing (Acta Otolaryngol 1994; suppl. 515:1-64). In the clinical setting, “the usefulness of intranasal corticosteroids in chronic rhino-sinusitis would be in the reduction of the inflammatory reaction leading to a decrease in nasal mucosal swelling, that in turn, results in increased aeration, better drainage, and elimination of infectious organisms,” stated Dr. Slavin. The clinical trials that support this theory are numerous. For example, Qvarnberg et al (Rhinology 1992; 30:103) showed adjunctive budesonide (200 mg bid for 3 months) in patients with recurrent chronic rhino-sinusitis reduced nasal symptoms, facial pain, cough, and mucosal thickening (Rhinology 1992; 30:103). Budesonide is also effective in children (Ann AAI 1997; 78:598). Other intranasal cortico-steroids have shown similar results including, flunisolide (JACI 1993; 92:812), mometasone (JACI 2000; 106:630), and fluticasone (JACI 2000; Jan. S206).


Concluding Remarks
Rhino-sinusitis is often a comorbid effect of allergic rhinitis. There is an abundance of clinical and experimental evidence to indicate that acute allergic rhinitis does predispose the development of rhino-sinusitis. Fortunately, intranasal corticosteroids are proving to be safe and effective treatment for acute, chronic, and recurrent rhino-sinusitis.

Nasal Abnormalities and Sleep The Impact of Nasal Pathology on Sleep

Jonathan Schwartz, MD, Clinical Professor of Medicine at the University of Oklahoma and Medical Director of the Integris Sleep Disorders Research Center in Oklahoma City, OK, introduced his presentation by stating it would be a “review of some thoughts and ideas regarding sleep and sleep medicine as well as the importance of recognizing the nasal component of sleep and how much nasal abnormalities can affect sleep.”

There are a number of diseases that affect sleep. For example, patients with rhinitis, asthma, and COPD may have significant sleep disturbances. In a large study by the University of Wisconsin (Wisconsin Sleep Cohort Study), 4916 patients were analyzed and it was shown that nasal congestion was independently associated with snoring frequency (adjusted for age, sex, weight, BMI, and smoking) (Arch Intern Med 2001;161: 1514-1519).

“Basically, anything that leads to narrowing of the upper airway, including the nose, nasopharynx, oropharynx, or hypopharynx, and typically it’s a combination of these, can lead to obstructive sleep apnea. Many patients with neuromuscular disorders (i.e., Parkinson’s, muscular dystrophy) have unstable upper airways and an increased incidence of obstructive sleep apnea,” said Dr. Schwartz.

Sleep apnea is often associated with several cardiovascular diseases. For example, 35%-50% of patients with high blood pressure have significant sleep- disordered breathing and obstructive sleep apnea syndrome ( Am J Respir Crit Care Med 2001;164:2147-2165). Furthermore, sleep- disordered breathing occurs in 50% of patients with
coronary artery disease, myocardial infarction, or congestive heart failure, and up to 70% of patients with cerebral vascular disease (Am J Respir Crit Care Med 2002;165:677-682).

In a recent study (Am J Resp Crit Care Med 2002;165:1395-1399), it was found that children with more than 10 apnea events per hour had increased right ventricular dimension and left ventricular mass index. Abnormal left ventricular geometry was also observed in these children as well as in children with snoring symptoms but no sleep apnea. These changes in cardiac morphology may be occurring as the heart adjusts to nocturnal spikes in the sympathetic nervous system due to hypoxic states caused by airway obstructions. As an example of how the respiratory and cardiac pathophysiology can affect each other, a study involving 24 children with seasonal allergic rhinitis or perennial allergic rhinitis showed that treatment with the nasal steroid budesonide improved both rhinitis symptoms and pulmonary arterial pressure (Int J Pediatr Otorhinolaryng-ology 2001;60:21-27).

Some treatment options for sleep apnea or snoring are nonpharmacologic such as diet, exercise, and allergen avoidance. In addition, upper airway relaxants such as alcohol, sleeping pills, and other benzodiazepines should be avoided in patients with sleep apnea. Pharma-cologic treatments such as nasal steroids and non-sedating antihistamines can also improve snoring.

Another option is nasal CPAP (continuous positive airway pressure), which has become the gold standard of treatment for moderate to severe obstructive sleep apnea. When using nasal CPAP, Dr. Schwartz stressed the importance of using a heated humidifier for those patients who complain of CPAP-associated nasal congestion or dryness.

If the above treatments fail, then the final option is surgery. “You’ve heard about patients having a throat surgery or uvulopalatopharyngoplasty. Unfortunately, this is not very effective nor is somnoplasty,” said Dr. Schwartz. Maxillofacial surgery may be effective but should be restricted to severe cases such as patients with micrognathia or retrognathia.


Concluding Remarks
“There have been several reports of patients with asthma who, despite treatment of other comorbid conditions like rhinitis and gastroesophageal reflux, continue to have ongoing asthma symptoms, and have obstructive sleep apnea,” said Dr. Schwartz, adding “when the obstructive sleep apnea is treated, their asthma is better controlled.”
Both nasal obstruction and obstructive sleep apnea can have significant multi-system ramifications. Fortunately, therapy can have a significant impact. With proper therapy of obstructive sleep apnea, improvements in quality of life, as well as decreased cardiovascular risk and improved survival can result.

Impact of Nasal Steroid Therapy on Rhinitis

William Storms, MD, Clinical Professor of Medicine at the University of Colorado Health Science Center in Colorado Springs, CO, began his presentation with a list of common comorbidities of rhinitis. They include asthma, sinusitis, and bronchial hyperresponsiveness. In addition, there are controversial associations, including otitis media, nasal polyps, and craniofacial abnormalities. The focus of Dr. Storms’ presentation was on asthma and sinusitis and how treatment with nasal cortico-steroids can be beneficial.

Asthma and Rhinitis
Asthma is a very common comorbidity. It has been well documented that rhinitis is a risk factor for the development of asthma and upwards of 85%-94% of asthma patients have rhinitis (JACI 2000;105:S599-S604). In a famous study by Dr. Settipane et al. (Allergy Proc 1994;15:21-25), college students with or without allergic rhinitis were followed for 23 years and it was concluded that college students with allergic rhinitis had a 10.5% risk of developing asthma over the next 23 years while college students without allergic rhinitis had only a 3.6% risk. Dr. Storms speculated, “if you extrapolate that to a younger age group, my feeling is you would probably have a larger differential because this already excluded patients with asthma.”

The physiological mechanisms that link asthma and rhinitis are likely multifactorial, including the nasobronchial reflex, the rhinovirus adhesion theory (i.e., susceptibility to allergic inflammation and ICAM-1 expression increased), postnasal drip, and migration of inflammatory cells (i.e., eosinophil) to other tissues after initial sensitization.

The ARIA Guidelines address the rhinitis/asthma link by recommending that patients with persistent allergic rhinitis should be evaluated for asthma and asthma patients should be evaluated for rhinitis. Furthermore, the guidelines stress the importance of developing a strategy to treat both the upper and lower airways.

Sinusitis and Rhinitis
Atopy is a frequent finding in patients with sinusitis. Furthermore, up to 70% of children with allergy and chronic rhinitis have abnormal sinus x-rays. The mechanisms linking rhinitis and sinusitis are not known but may involve narrowing/closure of the sinus ostia due to nasal mucosal swelling in rhinitis.

Intranasal Corticosteroid: Affects on Rhinitis Comorbidities
“It’s well accepted that intranasal steroids are the most effective treatment for the symptoms of allergic rhinitis including typical sneezing, itching, rhinorrhea and congestion,” said Dr. Storms (J Allergy Clin Immunol 2000;105:489-494).

The effect of intranasal cortico-steoids on treating rhinitis in patients with asthma has also been studied. Watson and colleagues performed an 8-week, randomized, double-blind, crossover study in 21 patients who had perennial allergic rhinitis and asthma treated with intranasal beclomethasone or placebo (JACI 1993;91:97-101). They observed that treatment with the nasal cortico-steroid-reduced symptoms scores for both rhinitis and asthma, although only the rhinitis scores were significantly different. In another study, children with asthma and rhinitis (n = 26) were treated with intranasal budesonide and it significantly reduced cough and asthma severity (Ann Rev Respir Dis 1984; 130:1014-1018). Adams and colleagues examined the effects of intranasal steroid therapy on asthma-related emergency room visits and found that it reduced the number of visits (JACI 2002;109:636-642).

In contrast to asthma-rhinitis studies, the effects of intranasal cortico-steroids on patients with rhinitis and sinusitis has not been as well studied but a study by Meltzer et al (JACI 1993;92;812-823) showed antibiotic plus flunisolide was superior to antibiotic alone in reducing turbinate swelling/obstruction, facial pain, headache severity, discharge, and percussion tenderness. In a recent study by Lund and colleagues, a comparison of intranasal budesonide and placebo in patients with rhinosinusitis (n = 167) found significant improvements in peak nasal inspiratory flow, as well as improvements in morning and evening symptoms scores, and quality of life (JACI 2002; 109:S290).

“How does intranasal steroid treatment affect nasal polyps?” asked Dr. Storms, adding, “this is difficult to study because nasal polyps are not easy to quantitate.” However, Dr. Storms said, “there was a review article (Drugs 2001;61:573-578) indicating that if we look at all the studies, we can say that nasal steroids will reduce polyp size and they will control symptoms,” adding, “for maintenance therapy, there is data showing that you can delay the recurrence of polyps following surgery.” Studies with fluticasone and beclo-methasone nasal sprays have shown some improvement in severe polyposis (Arch Otolaryngol Head Neck Surg 1998;124:513-518) but intranasal corticosteroids appear to be most effective in mild to moderate cases of nasal polyps (Arch Otolaryngol Head Neck Surg 2001;127:447-452).

Patient Preference
Dr. Storms said, “in general, adherence with pulmonary inhaled medicines is very poor and we know that poor adherence leads to treatment failure.” For example, quite a few asthma studies show that inhaled therapy is less effective in some patients than oral therapy due to poor compliance with the inhalers. Therefore, Dr. Storms asked, “What are the nasal steroid attributes that may lead to good or bad adherence?” The answer involves the patient’s perceptions of efficacy, safety, dosing, and formulation. For example, the patients will likely not take the medication regularly if they feel it is not working, causes nasal irritation, requires several squirts per day, or if it tastes/ smells bad. Often the manufacturers of an inhalant have to balance these attributes. For example, aqueous formulations are more efficient than dry powders but tend to cause postnasal drip and taste bad. In contrast, dry powders tend to dry up the mucosa. Balancing these attributes have led most manufacturers therefore to favor aqueous formulations.

Another safety concern, especially in children, is the effect of intranasal steroids on growth. In a recent study involving 40 children who received long- term use of inhaled and intranasal corticosteroids, it was found that these treatments did not significantly affect adult height (NEJM 2000;343:1064-1069).

Looking at some of the different attributes and patients’ preferences for different nasal sprays, a recent study presented at the AAAAI meeting (Shah et al., AAAAI 2002, New York, NY) compared budesonide aqueous nasal spray and fluticasone propionate nasal spray and found budesonide to be superior in regard to patients’ perceptions of sensory attributes. As shown in Figure 1 “comparing budesonide (blue) and fluticasone (gray), you can see that the difference was that for budesonide there wasn’t much smell, there wasn’t much taste, there wasn’t much aftertaste, and there wasn’t much run down the throat or out the front of the nose,” stated Dr. Storms.

Concluding Remarks
Intranasal steroids are the most effective treatment for allergic rhinitis and play an important role in treatment of rhinitis comorbidities such as asthma,sinusitis, and nasal polyps.

While clinical trials are essential to determine safety and efficacy of a drug, if the patient does not like the drug, they will likely not comply to treatment. New developments in drug delivery that adhere to patient preference will likely lead to improved efficacy.

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