Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

16th Annual Congress of the European Respiratory Society

Munich, Germany / September 2-6, 2006

According to Dr. Leif Bjermer, Department of Clinical Medicine, Division of Lung Medicine, University Hospital, Lund, Sweden, “There is a distinct pathophysiologic link between upper and lower airways and having rhinitis is a risk factor for the development of asthma. Allergic rhinitis is also frequently associated with bronchial hyperresponsiveness [BHR] and BHR should be regarded as an intermediate stage between pure rhinitis and asthma.”

Since cysteinyl leukotrienes are major mediators of both asthma and rhinitis, they are distinct targets for therapy, Dr. Bjermer noted. Leukotriene receptor antagonist (LTRA) treatment has the advantage of treating both the nose and lungs concomitantly to improve asthma and rhinitis simultaneously, he explained, adding that leukotrienes also seem to play an important role in small airway inflammation. He believes the transition from rhinitis to asthma depends on the degree of small airways involvement. While patients with seasonal rhinitis seem to improve their BHR off-season, those with perennial rhinitis have persistent BHR and evidence of more pronounced lower airway inflammation, so strategies for rhinitis and asthma should also aim to control inflammation in the small airways.

Dr. Bjermer discussed findings from the COMPACT (Clinical Outcomes with Montelukast as a Partner Agent to Corticosteroid Therapy) trial, which analyzed budesonide 1600 µg/day and budesonide 800 µg/montelukast 10 mg. “In our study of patients with asthma and seasonal rhinitis, the LTRA montelukast reduced both day and nighttime nasal symptoms,” Dr. Bjermer reported. “However, when the asthma patients were stratified by degree of severity, it became apparent that those with more active asthma disease benefited most from LTRA treatment. This indicated that those with involvement of the upper and lower airways, including the small airways, benefit the most from LTRA treatment.” In addition, he said that among patients with symptomatic asthma, the addition of the LTRA to the corticosteroid demonstrated increased efficacy at improving lung function and asthma control in those who had concomitant rhinitis.

Dr. Bjermer concluded that the link between lower and upper airways should always be considered as a year-round problem, with the need for systemic treatment not only in the central airways and the nose but also in the small airways.

Improving Baseline Scores

In his double-blind, placebo-controlled evaluation of montelukast 10 mg/day for a month to treat concomitant persistent allergic rhinitis and asthma, Dr. Giuseppe Lombardo, University of Messina, Italy, found that improvements from baseline in daytime and nighttime nasal symptom scores were significantly greater in the active-treatment group of 56 patients than among 28 given placebo. He said the LTRA improved asthma total symptoms and reduced beta2-agonist use for asthma control while maintaining FEV1.

Findings from a Swiss study were reported by Dr. Jörg Leuppi, University Hospital, Basel, Switzerland, whose aim was to document asthma treatment and control. He found that when outpatients at 281 clinics were switched from their existing treatment of either fixed combinations of inhaled corticosteroids and long-acting bronchodilators or monotherapy with a selection of agents to a different fixed combination or single-agent regimen, asthma control increased from 15.7% to 69.9% overall. When one of those fixed-combination or single-agent modalities included montelukast, asthma control increased from 9.8% to 58.1%. Dr. Leuppi noted that before the switch, 49% of patients were taking a fixed combination, which increased to 63% after the switch, of which 78.6% included the LTRA.

Dr. Terufumi Shimoda, Fukuoka National Hospital, Japan, compared the benefit of adding montelukast 10 mg/day or salmeterol 100 mg/day to budesonide 400 to 800 mg/day in 29 patients with bronchial asthma in a month-long trial. He reported that whereas FEV1 improved significantly in both groups (P=0.002 and P=0.04, respectively), expiratory flow at 50% of vital capacity (V50) improved significantly only in LTRA-treated patients (P=0.02). Eosinophil percentage decreased significantly (P=0.001 and P=0.013, respectively) in both treatment arms. Exhaled nitric oxide decrease reached significance with the LTRA (P=0.02) but not in the salmeterol group.

Researchers concluded, “Although both agents combined with budesonide were effective on central airway dilation, only the montelukast/steroid combination exhibited a pronounced anti-inflammatory effect and an effect on peripheral airway dilation in patients not responding to steroid monotherapy.”

Asthma and the Epithelium

Dr. Stephen Holgate, University of Southampton, UK, argued that asthma is more than an inflammatory disease and may well be a genetic or acquired primary disorder of airway epithelium, which creates a kind of chronic wound situation that leads to characteristic structural changes. It appears that these changes in the epithelium occur when asthma starts, not many years later.

“We are coming around to the view that this barrier between the external and internal environments is really where the action is in asthma if we are thinking about the origins of the disease,” he told delegates. “It raises the possibility that new forms of anti-asthma therapy might be directed more toward reducing tissue injury and promoting repair, similar to the management of other chronic epithelial wounds.”

According to Dr. Holgate, inflammatory diseases like ulcerative colitis and atopic dermatitis may be kinds of chronic wounds in which there is inflammation, but the real mechanism is more like a poor ability to repair epithelial lesions. In moderate asthma, basal cells in bronchial biopsies express epidermal growth factor receptor which is linked to the repair response indicating that the cells are stressed, injured and undergoing change in an attempt to repair ongoing environmental wounding by viruses (most frequently the common cold rhinovirus), allergens or pollutants in a wound situation.

Dr. Holgate explained that the asthmatic epithelium is deficient in its ability to generate interferon-beta, which acts as the first step in the immune response that destroys the virus, consequently ensuring the survival of the virus in an asthmatic population. The early propensity for asthma to develop may be due to a defect in immunity.

“We believe now with evidence coming from other longitudinal studies that this defect in innate immunity is critical to the early onset of asthma,” he remarked. “Involvement of viruses in the origins of asthma also raises the possibility that impaired epithelial defences could be the reason why asthma develops in one person and not another, and why only a minority of [individuals with atopic dermatitis] develop lower airways disease. This concept raises the possibility that new forms of anti-asthma therapy might one day be more directed toward reducing tissue injury and promoting repair than toward dampening inflammation once it has developed.”

Real-world Results

In a real-life, open-label, non-placebo-controlled study, researchers evaluated the clinical benefit of adding montelukast to the treatment of 2452 asthma patients, 42% of whom were symptomatic for allergic rhinitis who had remained symptomatic, despite regular treatment with a fixed combination of inhaled corticosteroid and long acting beta2-agonist. The primary end point at two months was a mean asthma control score of six items of the Juniper questionnaire: asthma-driven nocturnal awakenings, symptoms upon awakening in the morning, limitation of daily activity, shortness of breath, wheezing and the use of short-acting beta2-agonist rescue medication.

Dr. Rudi Peché, Centre hospitalier universitaire André Vésale, Montigny-le-Tilleul, Belgium, reported that the Juniper score improved significantly (P<0.001) from 11.5 to 5.7 among the subgroup with allergic rhinitis, which was significantly more important than in the patients without rhinitis. “Amelioration of rhinitis was observed in 82% of asthma patients with concomitant allergic rhinitis and their Juniper score improved significantly from 11.5 to 5.3. Of the patients with improved allergic rhinitis, 97.1% reported global improvement in asthma control, compared to 87.2% of patients without allergic rhinitis,” he noted.

Dr. Peché concluded that treating rhinitis improved global asthma control and that treating an airway inflammation pathway distinct from that of corticosteroids seems to confer additional benefit by acting both on nasal and bronchial inflammation.