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Increase in Urinary Leukotriene LTE4 Levels in Acute Asthma: Correlation with Airflow Limitation S a Green, M-P Malice, W Tanaka, C a Tozzi, T F Reiss

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Increase in Urinary Leukotriene LTE4 Levels in Acute Asthma: Correlation with Airflow Limitation S a Green, M-P Malice, W Tanaka, C a Tozzi, T F Reiss 100 ASTHMA Thorax: first published as 10.1136/thorax.2003.006825 on 3 February 2004. Downloaded from Increase in urinary leukotriene LTE4 levels in acute asthma: correlation with airflow limitation S A Green, M-P Malice, W Tanaka, C A Tozzi, T F Reiss ............................................................................................................................... Thorax 2004;59:100–104. doi: 10.1136/thx.2004.006825 Background: Leukotrienes play a key role in the pathophysiology of chronic asthma. Activation of leukotriene pathways is accompanied by rises in detectable urinary levels of leukotriene E4 (LTE4). The relationship between urinary LTE4 levels and factors associated with acute asthma has not been determined. Methods: Adults aged 15–54 years presenting with moderate to severe acute asthma were evaluated at See end of article for emergency departments in 16 US sites. Forced expiratory volume in 1 second (FEV1) was measured authors’ affiliations during the first 60 minutes after arrival and at specified times until discharge or admission. Urine samples ....................... for measurement of LTE4 levels were obtained either on arrival at the study site and/or before discharge. Correspondence to: Patients were seen 2 weeks later for follow up, at which time repeat FEV1 measurements and urine samples Dr S A Green, Director, for LTE4 were obtained. Respiratory & Allergy, Results: One hundred and eighty four patients were evaluated; LTE4 results from both the acute and follow Merck Research up periods were available for analysis in 146. Urinary LTE levels were increased during asthma Laboratories, 126 East 4 Lincoln Avenue, RY34B- exacerbations compared with levels obtained 2 weeks later (geometric means 111.7 and 75.6 pg/mg 340, Rahway, NJ, USA; creatinine, respectively, mean percentage change 232.3; 95% confidence interval (CI) for the mean [email protected] percentage change 239.6 to 224.3, p,0.001). The correlation between improvement in FEV1 and Received 13 March 2003 decline in LTE4 over the 2 week interval was significant (p,0.001, r = 0.43). Accepted 7 October 2003 Conclusions: Activation of leukotriene pathways in acute asthma is correlated with the degree of airflow ....................... obstruction, and resolution of the asthma exacerbation is associated with a reduction in leukotriene levels. ver the last two decades the incidence of asthma in bation or status asthmaticus,19 20 but the number of patients both children and adults has risen worldwide.12 All available for analysis was small. We have recently conducted Oindividuals with asthma are at risk of an acute a clinical trial comparing the effect of adding intravenous exacerbation of their disease requiring urgent or emergency montelukast 7 or 14 mg or placebo to standard treatment in 3 21 department treatment. While international asthma manage- patients with moderate to severe asthma exacerbations. http://thorax.bmj.com/ ment guidelines have been designed to control asthma This study was undertaken to analyse the activation of symptoms and reduce asthma exacerbations, a recent study leukotrienes in these patients during their treatment in the suggests that 17% of patients with acute asthma experience emergency department and at 14 days follow up, and to relapse attacks within 2 weeks.4 Although the factors under- determine whether the degree of airflow limitation is lying asthma exacerbations and relapses are complex, a better correlated with activation of the leukotriene pathway. understanding of the pathology associated with asthma attacks may lead to improved treatments and reduced METHODS morbidity. Patients on October 6, 2021 by guest. Protected copyright. Cysteinyl leukotrienes (LTC4, LTD4, LTE4) play an impor- Sixteen US sites, primarily emergency departments affiliated tant role in the pathogenesis of asthma. Leukotrienes are with academic medical centres, participated in the study. produced by mast cells, eosinophils, and other airway Adults aged 15–54 years presenting with acute asthma were inflammatory cells and increase vascular permeability, screened for enrolment in the study. Participants were constrict bronchial smooth muscle, and mediate bronchial required to have a history of asthma for at least 1 year, a 5 hyperresponsiveness. Levels of urinary LTE4, the stable history of tobacco use of less than 10 pack years, and no 67 8 metabolite of LTC4 and LTD4, are increased in children concomitant treatment with systemic corticosteroids, leuko- and adults9 with asthma compared with healthy controls and triene modifiers, anticholinergic agents, or long acting b in asthmatics after bronchial challenge with antigen,10 11 after agonist bronchodilators. Patients with pneumonia, conges- oral challenge with aspirin in aspirin sensitive asthmatic tive heart failure, or other clinical explanations for dyspnoea subjects,12 and during exercise induced bronchospasm.13 The were excluded, as were patients with significant co-morbid importance of leukotrienes in the pathology of asthma has disorders requiring acute management. The study protocol been further demonstrated in large clinical trials with agents was approved by each investigator’s respective Institutional that block the actions of leukotrienes. For example, mon- Review Board and all patients gave written informed consent telukast, a potent leukotriene receptor antagonist taken to participate. orally once daily, significantly improves asthma control in both children (aged 2–14 years)14 15 and adults16 and Study design attenuates exercise induced bronchoconstriction.17 18 The primary study examined the benefit of adding intrave- While leukotrienes play an important role in chronic nous montelukast to standard treatment for adults with asthma, activation of the leukotriene pathway in acute moderate to severe acute asthma; the benefit of intravenous 21 asthma is less well defined. Raised levels of LTE4 have been montelukast in this setting has been reported elsewhere. detected in the urine of patients during an asthma exacer- Briefly, the study consisted of a screening period, active www.thoraxjnl.com Increase in urinary leukotriene LTE4 levels in acute asthma 101 treatment period, and a 2 week follow up after discharge. The Table 1 Demographic data and baseline Thorax: first published as 10.1136/thorax.2003.006825 on 3 February 2004. Downloaded from screening period began when the patient arrived in the characteristics of patients emergency department and lasted up to 60 minutes. During the screening period patients were treated with short acting b Mean (SD) agonists (albuterol (salbutamol) 2.5 mg by nebuliser) and Number of patients 184 oxygen. Patients also underwent an initial spirometric test Age (years) 35.4 (10.3) (Puritan Bennett model PB-100) followed by albuterol Duration of asthma (years) 19.1 (12.8) nebulisation (a total of two albuterol nebulisations were Current smokers (%) 29.9 allowed during the screening period) and a second spiro- Allergic rhinitis (%) 56.6 * metric test. Each spirometric test was performed and Baseline FEV1 (l) 1.6 (0.6) Baseline FEV1 (% predicted) 46.7 (15.8) interpreted in accordance with the reproducibility and 22 acceptability criteria of the American Thoracic Society. FEV1 = forced expiratory volume in 1 second. Patients whose forced expiratory volume in 1 second *Baseline FEV1 was defined as the measurement made (FEV ) was more than 70% of the predicted value23 on either before enrolment in the study, following initial treatment with 1 oxygen and b agonists. spirometric test were excluded. In addition, patients were excluded if the FEV1 (expressed as a percentage of the predicted value) increased or decreased by >20 percentage points between the two measurements. Baseline characteristics of the patients are presented in Patients included in the study received blinded treatment table 1. Most patients enrolled in the study had moderate to (intravenous montelukast or placebo) and, in addition, severe asthma exacerbations (FEV1 ,50–60% of the predicted 25 continued treatment with b agonists at the investigator’s value). The mean FEV1 before the start of the study was discretion. When indicated, corticosteroids were adminis- 1.6 l, corresponding to 47% of the predicted value. It should tered at a standard dose (prednisone 60 mg orally). Serial be noted that the baseline value was determined after spirometric tests were performed at selected times for up to patients had received initial treatment with b agonists and/ 6 hours or until a decision was made for discharge or or oxygen, so the pre-study baseline value most probably admission, whichever occurred first. All patients successfully overestimated the FEV1 upon arrival at the study site, which discharged from the emergency setting were given a standard was not measured at that time. course of oral prednisone (50 mg/day for 5 days) and were LTE4 levels during the acute exacerbation or at the 2 week scheduled for a follow up visit 14 (SD 3) days later, at which follow up visit were not significantly different between the time the FEV1 measurement was repeated. group which received the single dose of intravenous montelukast (n = 123) and those who received placebo Urinary LTE4 measurements (n = 61; p = 0.36), a result that was not unexpected given As an exploratory objective of the main study, spot urine that montelukast is a receptor antagonist and has no effect samples were obtained during the acute treatment period and on leukotriene synthesis. Subsequent analyses were thus at the follow
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