Ratio of leukotriene e(4) to exhaled nitric oxide and the therapeutic response in children with exercise-induced bronchoconstriction

Abstract

Purpose: This study assessed the association between the ratio of leukotriene E(4) (LTE(4)) to fractional exhaled nitric oxide (FE(NO)) in the response of children with exercise-induced bronchoconstriction (EIB) enrolled in a therapeutic trial with montelukast or inhaled corticosteroid (fluticasone propionate [FP]).

Methods: Children aged 6 to 18 years with EIB were randomized in a 4-week, placebo-controlled, double-blinded trial with montelukast or FP. Before and after treatment, treadmill exercise challenges were performed. The LTE(4) levels in the induced sputum and urine and the FE(NO) levels were measured in subjects before and 30 minutes after the exercise challenges. The same tests were conducted after treatment.

Results: A total of 24 patients completed the study: 12 in the montelukast group and 12 in FP group. Both study groups displayed a similar postexercise maximum decrease in forced expiratory volume in one second (FEV1) before treatment as well as after treatment. However, there were significant differences in the magnitude of change between the two (Δ; -18.38±14.53% vs. -4.67±8.12% for the montelukast and FP groups, respectively; P=0.021). The Δ logarithmic sputum baseline and postexercise LTE(4)/FE(NO) ratio were significantly lower in the montelukast group than in the FP group (baseline; -0.09±0.21 vs. -0.024±0.03, P=0.045; postexercise, -0.61±0.33 vs. -0.11±0.28, P=0.023).

Conclusions: These data indicate that the efficacy of montelukast for preventing a maximum decrease in FEV1 after exercise is significantly higher than that of FP, and the high LTE(4)/FE(NO) ratio is associated with a greater response to montelukast than to FP for EIB therapy. These results suggest that LTE(4) may play an important role in EIB.

Keywords: Exercise-induced bronchoconstriction; fractional exhaled nitric oxide; inhaled corticosteroid; leukotriene E4; montelukast.

Fig. 1

Sputum and urinary LTE₄/FE_NO, baseline and postexercise, before and after treatment in the two study groups of asthma. There were significant differences in the sputum LTE₄/FE_NO ratio at baseline and postexercise after treatment compared to those before treatment in the montelukast group (baseline, 25.66±23.47 vs. 8.42±8.01, P=0.008; postexercise, 45.72±52.94 vs. 16.63±15.26, P=0.001) (A) and in the FP group (baseline, 25.24±17.58 vs. 20.41±17.54, P=0.048; postexercise, 51.10±47.91 vs. 45.79±39.86, P=0.044) (B). There were significant differences in the urine LTE₄/FE_NO ratio at baseline and postexercise between treatments in the montelukast group (baseline, 2.36±2.37 vs. 0.88±0.38, P=0.012; postexercise, 2.53±1.64 vs. 1.04±0.68) (C) and in the FP group (baseline, 2.23±2.01 vs. 1.60±1.48, P=0.038; postexercise, 2.28±1.75 vs. 1.71±1.39, P=0.043) (D).

Fig. 2

Mean±SE changes in percent decrease FEV1 after exercise challenge before treatment (A) and after 4 weeks of asthma treatment (B) with montelukast (n=12) or FP (n=12). No significant differences were observed in the postexercise maximum decrease in FEV1 and area under the FEV1 curve over the first 20 min after exercise (AUC₂₀) before treatment between two groups (A). Postexercise maximum decrease in FEV1 and AUC₂₀ in the montelukast group were significantly lower compared to those of the FP group after treatment (8.83±7.74% vs. 16.54±7.71%, P=0.024; 232.1±187.9 vs. 374.9±145.0, P=0.035) (B).

Fig. 3

Difference between two measurements after and before treatment for the montelukast and FP groups. There were significant differences in the Δpostexercise maximum decrease in FEV1 between the montelukast group and the FP group (-18.38±14.53% vs. -4.67±8.12%, P=0.021) (A). There were significant differences in the ΔAUC₂₀ between the montelukast group and the FP group (-21.23±17.53 vs. -3.72±3.81, P=0.028) (B). The Δ logarithmic sputum baseline and postexercise LTE₄/FE_NO ratio were significantly lower in the montelukast group compared to the FP group [baseline, -0.09±0.21 vs. -0.024±0.03, P=0.045 (C); postexercise, -0.61±0.33 vs. -0.11±0.28, P=0.023 (D)]. The Δ logarithmic urinary baseline and postexercise LTE₄/FE_NO ratio were significantly lower in the montelukast group compared to the FP group [baseline, -0.60±0.21 vs. -0.084±0.14, P=0.046 (E); postexercise, -0.30±0.25 vs. -0.16±0.16, P=0.038 (F)]. Δ, measurement_{after treatment} - measurement_{before treatment}; FP, fluticasone propionate. ^*P<0.05 Montelukast vs. FP, analyzed by a Mann-Whitney test.