Can Rhinitis Treatment Prevent Asthma?

On Monday, November 19th, 2001 three speakers discussed the inter-relationship between allergic rhinitis and asthma, therapeutic strategies for rhinitis that may impact asthma, and concerns about the long-term safety of inhaled corticosteroids.

This program was supported by an unrestricted educational grant from AstraZeneca LP.

The Link Between Rhinitis and Asthma: State of the Art

“Rhinitis and asthma are essentially the manifestations of a single disease in two areas of the respiratory tract,” said Alkis Togias, MD, associate professor of medicine, Divisions of Clinical Immunology and Pulmonary and Critical Care, Johns Hopkins University School of Medicine, Baltimore, MD. This syndrome has a wide spectrum of severity, from patients with clinically evident upper airway disease alone to those who have severe persistent lower airway disease. Even in the absence of clinical evidence of asthma in a patient with rhinitis, some abnormality is present in the lower airways. For example, patients with refractory rhinosinusitis have been shown to have an elevated ratio of respiratory volume to total lung capacity.

This model postulates that all patients with asthma also have allergic rhinitis. Dr. Togias and colleagues investigated the prevalence of symptoms of rhinitis in patients with asthma. When patients from 3 large asthma databases were questioned regarding rhinitis symptoms, 85% to 95% had at least 2 out of 6 symptoms of seasonal or year-round rhinitis, compared with 55% of randomly-selected controls. Only 30% to 33% of controls had 4 of 6 symptoms, however, vs. approximately 85% of patients with asthma. Among patients with asthma without rhinitis, biopsies of nasal airways reveal inflammation similar to that of patients with symptomatic rhinitis.

“According to the model of a spectrum of airway disease, it would be expected that patients with both upper and lower airway disease would have worse upper airway symptoms than those with upper airway disease alone,” said Dr. Togias. It has been demonstrated that these patients have a greater upper airway response to non-specific irritants such as cold, dry air than those with rhinitis alone, both with respect to clinical symptoms and histamine release. 

Additional evidence supports the strong association between upper and lower airway disease. Response to methacholine challenge in adolescent patients with asthma correlates highly with the number of eosinophils in nasal lavage fluids. In addition, presence and degree of small airway dysfunction among patients with or without clinical asthma correlates with presence and degree of olfactory dysfunction associated with rhinitis. Finally, among patients with asthma, the severity of asthma correlates with the presence and severity of rhinitis. 

“An additional aspect of this way of thinking about rhinitis and asthma as manifestations of a single disease is to postulate a causal effect between rhinitis and asthma,” said Dr. Togias. Several studies have demonstrated that nasal allergen provocation in asthmatics and non-asthmatics with rhinitis results in a decline in lung function and an increase in airway hyperresponsiveness. This effect has also been demonstrated in response to a non-specific irritant (cold air). 

Several mechanisms by which this effect occurs have been suggested. Bypassing the nose as a result of nasal obstruction could lead to reduced ability of the respiratory tract to warm and humidify air. This results in exposure of the lower airways to the potential irritant of cold, dry air. Another possibility is that a nasobronchial reflex known to exist in animals, in which stimulation of the nose with chemical or physical agents results in a lower-airway response, may also be present in humans. There is also evidence that the lower airways react to a systemic response provoked by nasal allergen challenge. “I think that there is enough evidence to support that rhinitis and asthma are not only manifestations of a single disease, but that rhinitis is a causal agent with respect to lower airway symptoms,” Dr. Togias said. 
 
 

ARIA: World Health Organization Initiative on Allergic Rhinitis and Asthma

Richard Weber, MD, professor of medicine, National Jewish Medical and Research Center, Denver, CO, talked about the World Health Initiative on Allergic Rhinitis and Asthma. The World Health Organization convened a panel of 30 physicians in 1999 to draft an initiative on the association between asthma and allergic rhinitis. That initiative is entitled Allergic Rhinitis and its Impact on Asthma (ARIA). The resulting document addresses issues related to the pathogenesis, assessment, and management of rhinitis and asthma. Among these are recommendations for a new classification system for allergic rhinitis, an emphasis on evidence-based medicine, and the relationship between rhinitis and asthma. 

“We’re all aware that the prevalence of allergic disease, including allergic rhinitis, asthma, and atopic eczema has been increasing over the past 75 years. Prevalence of allergic rhinitis in adolescents is between 10% and 20% in many countries, and may be 25% to 33% in some adult populations. The presence of indoor allergens has also increased during that time.
The ARIA panel developed a new classification system for rhinitis that is similar to that used for asthma (Figure 1). The concepts of persistent or intermittent rhinitis are used rather than seasonal and perennial rhinitis. Persistent rhinitis suggests that chronic inflammation is present even when a patient is asymptomatic. Using the classification of mild or moderate/severe takes into account the impact of symptoms on sleep and daily activities.

Good quality data, such as that from controlled trials, supports the use of most types of agents for treatment of symptoms of allergic rhinitis, including antihistamines, decongestants, topical cromolyn sodium or steroids, and oral immunotherapy. “There is evidence that certain therapeutic agents are more effective for certain symptoms, and some agents do not work at all,” said Dr. Weber. Recommendations for appropriate medications for mild rhinitis are antihistamines, antihistamine/decongestant combinations, or intranasal cromolyn sodium. Moderate/severe disease may be treated with intranasal corticosteroids, antihistamine/decongestant combinations, and/or immunotherapy. 

The preferred approach for mild intermittent rhinitis is oral or intranasal antihistamines or intranasal decongestants. For moderate/severe intermittent or mild persistent rhinitis, intranasal corticosteroids are recommended as first-line therapy. A stepwise approach may be used for moderate/severe persistent rhinitis, with oral corticosteroids or decongestants, anticholinergics, or topical antihistamines added as required. Patients should be re-evaluated in a timely fashion to assess efficacy of therapy.

Patients with persistent rhinitis should be evaluated for asthma at least by physical examination, and preferably by pulmonary function studies as well; conversely, patients with asthma should be evaluated for rhinitis. “We need a strategy that combines the treatment of both upper and lower airway disease,” said Dr. Weber. 

Evaluation of Strategies for Controlling Rhinitis: Effects on Asthma

“Allergic rhinitis is a cause of considerable morbidity, including reduced quality of life, impaired school and work performance, and increased risk of asthma,” said William Storms, MD, clinical professor, University of Colorado, Colorado Springs. The concomitant occurrence of asthma and rhinitis can also result in high medical costs.

The link between rhinitis and asthma is not one that is recognized commonly in the primary care community. Rhinitis is an independent risk factor for asthma, with non-allergic rhinitis increasing asthma risk to approximately 8 times that of patients without rhinitis, and allergic rhinitis associated with approximately 11 times the risk. When rhinitis symptoms are present, asthma symptoms are also more likely to be present: both clinical asthma symptoms and increase in bronchial inflammatory mediators have been demonstrated in response to nasal allergen challenge.

“There is currently enough evidence to support the assertion that strategies that effectively control rhinitis can improve asthma control,” said Dr. Storms. A study by Corren et al (J Allergy Clin Immunol 1997 100:81-88) demonstrated that treatment of patients with allergic rhinitis and mild asthma with loratadine 5 mg plus pseudoephedrine 120 mg BID improved morning peak expiratory flow rates and FEV-₁. 

Nasal corticosteroids have also been demonstrated to have a beneficial effect on asthma in several studies. A study by Watson and colleagues (J Allergy Clin Immunol 1993;91:97-101) showed that intranasal beclomethasone BID improved mean PC20 in response to methacholine challenge in patients with rhinitis and mild asthma. The effect on clinical symptoms was demonstrated in a study of children with nasal obstruction by Henriksen et al (Am Rev Respir Dis 1984;130; 1014-1018), in which a significant decrease in cough and asthma symptom severity and a trend toward decrease in wheezing occurred in response to nasal budesdonide. Another study by Foresi and colleagues (J Allergy Clin Immunol 1996; 151:315-320) demonstrated a protection against worsening of response to methacholine challenge in patients treated with intranasal fluticasone. 

Additional studies by Wilson and colleagues (Clin Exper Allergy 2001; 316:616-624) have compared the effects of montelukast and inhaled plus intranasal budesonide in patients with rhinitis and asthma on total seasonal allergic rhinitis symptoms, nasal nitric oxide, and airway response to AMP challenge. Budesonide and montelukast showed comparable efficacy in improving pulmonary function, asthma symptoms, and use of rescue medication. Budesonide significantly improved the bronchial hyperresponsive-ness compared to montelukast. Greater efficacy in reducing nasal nitric oxide, improving nasal peak flow, and improving nasal symptoms was demonstrated with inhaled plus nasal budesonide than with montelukast.

Two recent double-blind placebo-controlled studies investigated the effect of nasally administered budesonide inhaled deeply into the lungs in children and adults with rhinitis and mild asthma. Budesonide was effective in controlling global symptoms in both patient groups. 

Immunotherapy has also been shown in several studies to reduce not only nasal symptoms but asthma symptoms in patients with rhinitis, and also may prevent or modify progression from allergic rhinitis to asthma. “It is clear that therapies that include antihistamines, decongestants, nasal steroids, and/or immunotherapy also are effective in controlling symptoms of asthma,” said Dr. Storms. 


 

Safety Concerns in Inhaled Corticosteroid Therapy

“The data regarding safety of long-term inhaled corticosteroid therapy are contradictory,” said Phillip Lieberman, MD, clinical professor of medicine and pediatrics, University of Tennessee College of Medicine, Memphis. These data lead to safety concerns such as growth suppression in children, ocular complications, changes in bone mineral density, and hypothalamic-pituitary-adrenal (HPA) axis suppression. 

Among reasons for confusion in the interpretation of these studies are the large number of confounding variables that exist. Among these are the potential influence of the disease itself on growth in children, qualitative differences among brands of steroids, differences in delivery systems, intermittent use of systemic corticosteroids in some patients, paucity of long-term controlled studies, and difficulty in determining the clinical relevance of observed effects. “ I do not believe that there is a study that has been published yet that definitively resolves these questions,” said Dr. Lieberman.

It is now known that inhaled corticosteroids exert a dose-dependent effect on the HPA axis. This effect has been demonstrated for beclomethasone, budesonide, fluticasone, and triamcinolone. Controlled studies have not demonstrated signs or symptoms of adrenal failure, however, bringing into question the clinical significance of these findings. A study of budesonide, momestasone furoate, and triamcinolone acetonide administered intranasally demonstrated that there is no effect on overnight plasma cortisol when these agents are administered via this route.

“The effect of orally inhaled corticosteroids on the eye is perhaps the most controversial; the data are clearly contradictory,” said Dr. Lieberman. In one study of exposure of elderly patients for 3 months to inhaled corticosteroids, high doses were associated with increased risk of ocular hypertension, while low or moderate doses were not. This was contradicted by 4 prospective, randomized, double-blind placebo-controlled trials of inhaled budesonide 200 mcg to1600 mcg for 12 to 20 weeks that demonstrated no effect on intraocular pressure. Intranasal administration of corticosteroids has not been associated with increased intraocular pressure in clinical studies.

The majority of studies have demonstrated no increased risk of posterior subcapsular cataracts in children; however, there have been studies that suggest that there is an increase in risk of posterior subcapsular cataracts in elderly patients following prolonged administration of high-dose inhaled corticosteroids. Large, long-term studies of inhaled or nebulized budesonide, and post-marketing surveillance of nebulized budesonide corresponding to 184 million treatment days have demonstrated no evidence of increased risk of cataracts in children.

“Because the development of osteoporosis is a major concern with oral corticosteroid therapy, the long-term effects of high-dose inhaled corticosteroid therapy on bone mineral density are currently under investigation,” said Dr. Lieberman. Studies in adults have demonstrated contradictory results, although a dose-dependent effect on bone-mineral density may occur at the hip. No effect on bone mineral density has been demonstrated in children.

It is well accepted that significant growth velocity reduction occurs associated with oral and intranasal inhaled steroids during the first year of administration. This effect varies with dose, delivery device, and time of day of administration. Reductions in growth velocity appear similar between intranasal and oral inhalation routes. Longer-term studies of budesonide, however, reveal that despite early, transient reductions in growth velocity, children receiving long-term inhaled corticosteroid therapy attain normal adult height. Although little is known regarding the potential for additive effects of intranasal and inhaled corticosteroids on growth, one 24-month study of combined intranasal and inhaled budesonide also demonstrated no significant effect on final adult height. “Despite evidence demonstrating no effect of long-term inhaled corticosteroid therapy on growth in children, the potential for growth suppression in selected patients warrants careful monitoring of growth in all children receiving inhaled corticosteroid therapy,” said Dr. Lieberman.

“The risks of low-dose inhaled and intranasal corticosteroid therapy are low, and in patients who require high doses, benefits must be weighed against risks,” said Dr. Lieberman. “These drugs probably represent the most significant advance in care for rhinitis and asthma patients in the last 30 to 40 years.” 

All contents Copyright © 1999 - 2002 Medical Association Communications