Abstracts

Abstract

The Effect of Montelukast and Fluticasone Propionate on Airway Mucosal Blood Flow in Asthma; Mendes, E.S., Campos, M.A., Hurtado, A., et al. American Journal of Respiratory and Critical Care Medicine 2004; 169:1131–1134.

Background. Inhaled glucocorticoids and leukotriene antagonists are thought to be independent anti-inflammatory modulators. Because tissue inflammation is related to new vascular formation and local vasodilatation leads to increased vascular congestion, the authors deducted that the measurement of airway blood flow could be employed as an index of the severity of airway inflammation and in turn, the effectiveness of anti-inflammatory modulators, fluticasone propionate and montelukast.

Methods. Twelve non-smokers with mild intermittent asthma defined by the Global Initiative for Asthma participated in this double-blinded study.

These subjects were between the ages of 18 and 65 years, and they all had an FEV₁ exceeding 70% of predicted and had not used any controller medication for at least 2 weeks.

Pulmonary function tests were performed, as well as airway blood flow measurements using soluble inert gas uptake. Each subject had four 2-week treatment periods separated by 2-week wash out periods. The four treatment arms were fluticasone via metered dose inhaler (220 µg two puffs twice a day by spacer) plus 10 mg montelukast tablet once a day; fluticasone plus placebo; placebo via metered dose inhaler plus montelukast tablet, and placebo via metered dose inhaler with a placebo tablet.

Results. Fluticasone and montelukast both equally increased airway blood flow by approximately 20%. The combination of fluticasone propionate plus montelukast decreased the mean blood flow by 27% from baseline.

Review of the 2-week treatment period on fluticasone propionate or montelukast at clinically recommended doses causes a decline in airway blood flow. The combination of the two agents was necessary to have a greater effect, although this did not reach statistical significance. The response to fluticasone propionate and montelukast reflected class effects rather than molecule specific outcomes.

Previously, the authors have shown that a 2-week course of fluticasone propionate caused a decrease in blood flow in corticosteroid-naïve patients with asthma with a return of blood flow to pre-treatment level 2 weeks after cessation of fluticasone. Possibly a longer pretreatment period or higher drug dosage would have shown greater effect on blood flow. The authors believe that the pretreatment blood flow decrease is secondary to fluticasone and montelukast. Previous studies have shown that the use of corticosteroids impact on airway remodeling causes a decrease in eosinophilia and reversal of hypervascularity in the vessel wall.

Conclusions. The study demonstrated that a 2-week course of fluticasone without montelukast or fluticasone plus montelukast decreases blood flow in patients with mild asthma. The magnitude of the response is not significantly increased with the combination of the two drugs. The effects of all three active regimens are no longer present after a brief washout period. The authors suggest that blood flow is an index of airway inflammation in asthma that is more sensitive than pulmonary function testing.

Reviewer's Comment. This is a unique paper focusing not on the airway inflammation as such, but rather on the vasculature and blood flow.

Christopher Randolph, M.D.

Waterbury, CT

Causative and Contributive Factors to Asthma Severity and Patterns of Medication Use in Patients Seeking Specialized Asthma Care; Liou, A., Grubb, J.R., Schechtman, K.B., et al. Chest 2003; 124:1781–1788.

Background. The incidence of asthma has increased dramatically in the past decades. The main objective of this investigation was to characterize the presence of specific parameters that were causative or contributive to asthma and may be associated with more severe disease. The authors also sought to determine patterns of medication use in their patients to determine whether failure of inhaled steroid use was a factor in more severe asthma.

Design. The population studied included adult individuals seen in a regional university-based referral center. This was a retrospective chart review of new patients seen in a specialized asthma treatment center over a 2.5-year period with documentation of the prevalence of 14 causative or contributive factors, the severity of asthma, and the intensity of therapy with inhaled corticosteroids in each individual. Individuals were grouped as mild asthma versus moderate/severe asthma, and statistical analysis was done to evaluate whether certain factors were associated with more severe asthma.

Results. Increasing age, male gender, symptomatic gastroesophageal reflux disease, and chronic sinusitis were independently associated with more severe asthma. Suboptimal use of inhaled steroids was more common in individuals with mild persistent asthma, but suboptimal dosing of inhaled corticosteroids was equally common in mild and moderate/severe asthma. There was no association between allergen sensitization combined with exposure to cats, dogs, dust mite, or molds and the more severe asthma.

Conclusions. The authors concluded that this study confirms earlier investigations that demonstrate symptomatic GERD and chronic sinusitis are significant comorbid contributory diagnoses in individuals with asthma, both being related to increasing asthma severity. This investigation further demonstrates that the dose of inhaled steroids used for treatment of asthma fell short of the NHLBI guidelines in the majority of patients. Patients with moderate/severe asthma were 4.2 times more likely to be using cromolyn or nedocromil, 8.9 times more likely to be using theophylline or aminophylline, 4.3 times more likely to be using an oral steroid, 2.6 times more likely to be using salmeterol. In the mild asthma group, 43% of individuals were using inhaled corticosteroids, while in the moderate/severe group 71% of individuals were using them.

Reviewer's Comments. This study is in agreement with earlier studies by Erwin et al. and Field et al. indicating that the overall impact of GERD on asthma is significant, particularly if asymptomatic reflux had been included. This was not done in this study. In at least one study by Harting et al., appropriate treatment of GERD resulted in significant improvement in asthma.

Chronic sinusitis has been associated with more severe asthma independently; however, studies have been conflicting in terms of the relationship between chronic sinusitis and severe asthma. The most compelling evidence supports a pharyngobronchial reflex mechanism. Further studies indicate that the inflammatory process of sinusitis and rhinitis is systemically amplified in the lung and vice versa, i.e., cross-talk between the upper and lower airways.

Sixty-five percent of individuals in this study were using a dose of inhaled corticosteroids below that recommended by the guidelines. The authors surmise that both patients and physicians underestimate asthma severity and physicians may under-dose inhaled steroids for fear of adverse side effects and may underrate inhaled corticosteroids due to lack of awareness or disagreement with the guidelines. There is clearly need for further education regarding inhaled corticosteroids and their utility in asthma as the front-line therapy, and for better management in GERD and chronic sinusitis as potential conditions further contributing to the severity of asthma.

Christopher Randolph, M.D.

Waterbury, CT

Trends in Emergency Department Asthma Care in Metropolitan Chicago, Results in the Chicago Asthma Surveillance Initiatives; Lenhardt, R., Malone, A., Grant, E.N., et al. Chest 2003; 124:1774–1780.

Background. Asthma accounted for approximately 1.9 million emergency room visits in 1995 with an increasing yearly rate of asthma visits from 1992 to 1999 from 5.8 to 7.4 patients per 1,000 population. Asthma care in the emergency room has been influenced by 1) increasing utilization and overcrowding of emergency rooms, 2) greater asthma prevalence, 3) publication of national guidelines regarding management of asthma.

The purpose of this study was to evaluate trends in emergency department asthma care in a single large community, Chicago, and to address how these trends meet national guidelines for asthma care. The clinical population included 51 emergency departments in the Chicago area responding to both the 1996–1997 and 2000 surveys, which provided the database for this investigation.

Design and Setting. The design and setting of this study was a repeated cross-sectional, self-administered survey of ED directors or designees in the Chicago area.

Results. The outcome of the study was that there were areas of significant improvement from 1996–1997 to 2000 including decline in the use of theophylline (10.1% to 3.1%), increased use of systemic steroid prescriptions at discharge (57.7% vs. 77.2%), and documenting progress after therapy (18.8% vs. 8.9%) with increasing use of pulse oximetry as part of the initial patient assessment (95.1% vs. 98.1%). Areas that represented a decline in asthma care from 1996–1997 to 2000 included a decline in the use of arterial blood gas analyses in the evaluation of severe cases (71.5% vs. 47.5%), decreased use of written instructions to inform patients what to do when they are unable to attend their follow-up appointment (94.4% vs. 38.9%), and decline in the use of peak flow measurements to report improvement after therapy (82.7% vs. 78.6%).

Conclusions. From 1996–1997 to 2000, emergency department asthma care in metropolitan Chicago has declined in some areas but improved in others. However, asthma care, in general, failed to meet national asthma guidelines. The lack of overall progress, even in the face of well-publicized national guidelines, suggests that the current strategy of medical education by itself is not adequate to improve emergency department asthma care.

Reviewer's Comments. The study has limitations in that 1) only half of the emergency departments in the study used written protocols or guidelines, 2) the physicians' self-report may not provide the accuracy of directly observed care, 3) although 70% of hospitals responded to the survey, these results may not be generalizable, and 4) more time may be necessary for dissemination of changes in guidelines to reach clinical practice. Although the study suggests that adherence to asthma care continues to fall short in many areas in 2000, as it did in 1996 to 1997, this may reflect overcrowding and areas of improvement in the surveys tended to be less physician time dependent, i.e., increase in prescription writing for steroids requires less time than patient education. Overall, the results of this study suggest that different pathways to education, such as house staff education, ongoing asthma care audits, and asthma care pathways may be more meaningful than dissemination of guidelines in improving asthma care in the emergency room.

Christopher Randolph, M.D.

Waterbury, CT

Comparison of Racemic Albuterol and Levalbuterol for Treatment of Acute Asthma; Carl, J.C., Myers, T.R., Kirchner, L., et al. Journal of Pediatrics 2003; 143:731–736.

Background. Inhaled beta-agonists are widely used to treat bronchospasm and acute asthma exacerbations. Recently, a more potent and purified form of levalbuterol, which is the R isomer, has been demonstrated to have 100-fold more potent beta-2 receptor binding activity than the S albuterol. The S albuterol has been demonstrated to have proinflammatory effects, and pediatric levalbuterol studies have demonstrated improvement in forced expiratory flow at 1 second at less than ½ the dose of racemic albuterol and a lower adverse effect profile. These previous studies, however, have been conducted in stable pediatric individuals. The present study was conducted in an acute setting.

Objective. To determine whether levalbuterol was associated with fewer hospital admissions than racemic albuterol when used for treatment of acute asthma.

Study Design. A randomized, double-blind, controlled trial conducted in the emergency room and inpatient asthma care unit of a children's hospital. Children 1 to 18 years of age (n = 482) were followed. Patients received either a nebulized solution of 2.5 mg racemic albuterol or 1.25 mg levalbuterol every 20 minutes for a maximum of six doses. Children subsequently admitted to the asthma care unit were treated in a standardized fashion with continuation of the same blinded drugs assigned in the emergency room. The primary parameter for outcome was hospitalization rate.

Results. The results of the study indicate that hospitalization rate was significantly less in the levalbuterol group (36%) than in the racemic albuterol group (45%). The adjusted relative risk of admission in the racemic group compared with the levalbuterol group was 1.25 with a 95% confidence interval. There was no difference in hospital length of stay and there were no significant adverse events in either group.

Conclusions. Substituting levalbuterol for racemic albuterol in the management of emergency room acute asthma significantly reduced the number of hospitalizations.

Reviewer's Comments. While the authors demonstrated impact of levalbuterol in reduction of admissions to hospital versus racemic albuterol, they did not demonstrate any change in hospital length of stay possibly because the levalbuterol group that was hospitalized after those discharged in the emergency room may have been sicker than the albuterol group. They also did not demonstrate any difference in mean number of aerosols used and oxygen saturation, and no attempt was made to measure pulmonary function, as the hospital stays were generally quite brief, and more than half the patients were too young to apparently perform pulmonary function testing. Furthermore, there was no economic analysis.

Christopher Randolph, M.D.

Waterbury, CT

High Doses of Inhaled Fluticasone Reduces High Levels of Urinary Leukotriene E4 in Early Morning and Moderate Nocturnal Asthma; Tanaka, S., Tanaka, H., Abe, S. Chest 2003; 124:768–773.

Background. Cysteinyl leukotriene and thromboxane 2 are known metabolites of arachidonic acid with significant bronchoconstrictive potency as much as 1,000 times that of histamine. Nocturnal exacerbations of asthma are well known, but the role of leukotriene modifiers remains controversial with some studies finding a significant linear correlation between morning dip and peak expiratory flow and urinary LTE₄ levels. Urinary leukotriene E₄ excretion rates are increased during severe asthma attacks, and measurement of urinary stable metabolites LTE₄ and TXB₂ [thromboxane B(2)] may be useful markers for evaluating asthmatic status.

Methods. The study population included 20 patients with nocturnal asthma, 8 men and 12 women, chosen at random from a larger group of non-aspirin–sensitive asthmatics at a university center.

The authors measured peak expiratory flows, urinary LTE₄, TXB₂, and creatinine levels six times, every 4 hours for 24 hours in two groups: patients with mild-to-moderate, steroid-naïve nocturnal asthma (n = 10, group A), and individuals with severe nocturnal asthma that was treated with high-dose inhaled corticosteroids (n = 10, group B). High-dose inhaled corticosteroids was regarded as 800 µg per day of inhaled fluticasone propionate and compared the measured parameters before and after therapy.

Clinical Findings. There was no difference in peak flow before and during the studies using patient diaries. Group A patients had significantly higher (p < .01) peripheral blood eosinophils than Group B. There was no significant difference in pulmonary function. In Group A the circadian rhythm in urinary LTE₄ with peak levels at approximately 4 AM was associated with reduced peak flows. The high dose of fluticasone in Group A significantly reduced LTE₄ levels, abolished the circadian rhythm, and produced improvement in peak flow.

Conclusions. Leukotrienes may make a greater contribution in nocturnal exacerbations in individuals with mild to moderate steroid naïve asthma than in those treated with high-dose inhaled corticosteroids. High-dose inhaled corticosteroids reduced urinary LTE₄ levels and eliminated their circadian variation in individuals with asthma, suggesting the role of leukotrienes in the mechanism of nocturnal asthma. The authors speculate that the morning dip in individuals with severe asthma with high-dose inhaled corticosteroids might occur due to the leukotrienes and other bronchoconstrictive agents.

Reviewer's Comments. The authors speculate the direct suppression of the activity of leukotriene producing inflammatory cells and indirect reduction of eosinophils, lymphocytes, and other inflammatory cells in the airway with down regulation of cytokines and chemokines that might be the mechanism by which inhaled steroids lead to decline in inflammation. This is an excellent study that indicates that high-dose inhaled corticosteroids may diminish urinary leukotriene E₄ levels and abolish urinary LTE₄ circadian rhythmicity in individuals with asthma, leading to changes in nocturnal asthma.

Christopher Randolph, M.D.

Waterbury, CT