Response profiles to fluticasone and montelukast in mild-to-moderate persistent childhood asthma

BACKGROUND: Outcome data are needed to base recommendations for controller asthma medication use in school-aged children. OBJECTIVE: We sought to determine intraindividual and interindividual response profiles and predictors of response to an inhaled corticosteroid (ICS) and a leukotriene receptor antagonist (LTRA). METHODS: An ICS, fluticasone propionate (100 mug twice daily), and an LTRA, montelukast (5-10 mg nightly, age dependent), were administered to children ages 6 to 17 years with mild-to-moderate persistent asthma using only as-needed bronchodilators in a multicenter, double-masked, 2-sequence, 16-week crossover trial. Clinical, pulmonary, and inflammatory responses to these controllers were evaluated. RESULTS: Improvements in most clinical asthma control measures occurred with both controllers. However, clinical outcomes (asthma control days [ACDs], the validated Asthma Control Questionnaire, and albuterol use), pulmonary responses (FEV(1)/forced vital capacity, peak expiratory flow variability, morning peak expiratory flow, and measures of impedance), and inflammatory biomarkers (exhaled nitric oxide [eNO]) improved significantly more with fluticasone than with montelukast treatment. eNO was both a predictor of ACDs (P = .011) and a response indicator (P = .003) in discriminating the difference in ACD response between fluticasone and montelukast. CONCLUSIONS: The more favorable clinical, pulmonary, and inflammatory responses to an ICS than to an LTRA provide pediatric-based group evidence to support ICSs as the preferred first-line therapy for mild-to-moderate persistent asthma in children. eNO, as a predictor of response, might help to identify individual children not receiving controller medication who achieve a greater improvement in ACDs with an ICS compared with an LTRA.     

Significant variability in response to inhaled corticosteroids for persistent asthma

BACKGROUND: A clinical model is needed to compare inhaled corticosteroids (ICSs) with respect to efficacy. OBJECTIVE: The purpose of this investigation was to compare the relative beneficial and systemic effects in a dose-response relationship for 2 ICSs. METHODS: A 24-week, parallel, open-label, multicenter trial examined the benefit-risk ratio of 2 ICSs in persistent asthma. Benefit was assessed by improvements in FEV(1) and PC(20); risk was assessed by overnight plasma cortisol suppression. Thirty subjects were randomized to either beclomethasone dipropionate (BDP) 168, 672, and 1344 microg/day (n = 15) or fluticasone propionate (FP) 88, 352, and 704 microg/day (n = 15), both administered by means of a metered dose inhaler (MDI) with chlorofluorocarbon propellant via a spacer, in 3 consecutive 6-week intervals; this was followed by 3 weeks of FP dry powder inhaler (DPI) 2000 microg/day. RESULTS: Maximum FEV(1) response occurred with the low dose for FP-MDI and the medium dose for BDP-MDI and was not further increased by treatment with FP-DPI. Near-maximum methacholine PC(20) improvement occurred with the low dose for FP-MDI and the medium dose for BDP-MDI. Both BDP-MDI and FP-MDI caused dose-dependent cortisol suppression. Responsiveness to ICS treatment was found to vary markedly among subjects. Good (>15%) FEV(1) response, in contrast to poor (<5%) response, was found to be associated with high exhaled nitric oxide (median, 17.6 vs 11.1 ppb), high bronchodilator reversibility (25.2% vs 8.8%), and a low FEV(1)/forced vital capacity ratio (0.63 vs 0.73) before treatment. Excellent (>3 doubling dilutions) improvement in PC(20), in contrast to poor (<1 doubling dilution) improvement, was found to be associated with high sputum eosinophil levels (3.4% vs 0.1%) and older age at onset of asthma (age, 20-29 years vs <10 years). CONCLUSIONS: Near-maximal FEV(1) and PC(20) effects occurred with low-medium dose for both ICSs in the subjects studied. High-dose ICS therapy did not significantly increase the efficacy measures that were evaluated, but it did increase the systemic effect measure, overnight cortisol secretion. Significant intersubject variability in response occurred with both ICSs. It is possible that higher doses of ICSs are necessary to manage more severe patients or to achieve goals of therapy not evaluated in this study, such as prevention of asthma exacerbations.     

Long-term comparison of 3 controller regimens for mild-moderate persistent childhood asthma: the Pediatric Asthma Controller Trial

BACKGROUND: More evidence is needed on which to base recommendations for treatment of mild-moderate persistent asthma in school-aged children. OBJECTIVE: The Pediatric Asthma Controller Trial (PACT) compared the effectiveness of 3 regimens in achieving asthma control. METHODS: A total of 285 children (ages 6-14 years) with mild-moderate persistent asthma on the basis of symptoms, and with FEV(1) >or= 80% predicted and methacholine FEV(1) PC(20) or= 80% predicted, confirming current guideline recommendations.     

Sputum eosinophil counts predict asthma control after discontinuation of inhaled corticosteroids

BACKGROUND: Although inhaled corticosteroids (ICSs) are effective in preventing deterioration in asthma control, at least half of subjects with mild-to-moderate asthma will remain stable when these agents are discontinued. OBJECTIVE: We sought to determine whether noninvasive markers of inflammation predict which individuals maintain asthma control after discontinuation of ICSs. METHODS: We analyzed data obtained from 164 subjects with mild-to-moderate asthma who participated in a 16-week trial comparing the effects of continued ICS use with the effects of a switch to salmeterol or placebo. RESULTS: In comparison with continued ICS use, a switch to salmeterol or placebo was associated with increased rates of asthma deterioration over 16 weeks (9.3% vs 24.1% and 37.5%, respectively; P = .04 and P < .001, respectively). We found that neither exhaled nitric oxide nor methacholine PC 20 , when measured at randomization or 2 weeks after randomization, were significant predictors of subsequent asthma control in subjects who discontinued ICSs. However, both induced sputum eosinophil counts measured 2 weeks after a switch from ICS to placebo and changes in sputum eosinophil counts from before cessation of ICSs to after a switch to placebo predicted subsequent asthma deterioration (area under the receiver-operating characteristic curve, 0.771 [ P < .001] and 0.825 [ P < .001], respectively). CONCLUSION: On the basis of a model treatment strategy, we estimate that allocating subjects to ICS therapy on the basis of changes in sputum eosinophil counts after a trial discontinuation could allow 48% of subjects with mild-to-moderate asthma to discontinue ICS therapy without an increased risk of asthma deterioration over a period of at least 14 weeks.     

Effect of fluticasone propionate-salmeterol therapy on seasonal changes in airway responsiveness and exhaled nitric oxide levels in patients with pollen-induced asthma.

BACKGROUND: There has been concern that in allergic asthmatic patients there might be an interactive effect on inflammation between regular salmeterol use and exposure to allergens, resulting in increased airway responsiveness. OBJECTIVE: To determine the effects of salmeterol on allergen-induced changes in airway responsiveness and exhaled nitric oxide (ENO) levels in allergic asthmatic patients concomitantly taking inhaled corticosteroids. METHODS: Forty-two asthmatic patients sensitized to pollen allergens were randomly allocated to treatment with fluticasone propionate-salmeterol (n=21) or fluticasone propionate alone (n=21). Spirometry, the methacholine provocation concentration causing a 20% decline in forced expiratory volume in 1 second (PC20), the adenosine 5'-monophosphate (AMP) PC20, and ENO levels were measured before and at the height of the pollen season after 6 weeks of treatment. RESULTS: Changes in the methacholine PC20, the AMP PC20, and ENO levels were not significantly different between treatment groups. No significant changes in the AMP PC20 were observed among the fluticasone propionate-salmeterol and fluticasone propionate groups during natural pollen exposure. However, a significant increase in the methacholine PC20 was observed in the fluticasone propionate-salmeterol group (P = .03) and in the fluticasone propionate group (P = .04); ENO concentrations decreased significantly in both groups during natural allergen exposure (P = .009 and .005). CONCLUSIONS: In patients with pollen-induced asthma, treatment with either fluticasone propionate or fluticasone propionate-salmeterol is associated with significant reductions in methacholine responsiveness and ENO concentrations, even during natural pollen exposure. Furthermore, at least in patients with mild asthma, natural allergen exposure and the regular use of fluticasone propionate-salmeterol are not associated with a greater increase in ENO levels and airway responsiveness than natural allergen exposure and fluticasone propionate use alone.     

Responsiveness to montelukast is associated with bronchial hyperresponsiveness and total immunoglobulin E but not polymorphisms in the leukotriene C4 synthase and cysteinyl leukotriene receptor 1 genes in Korean children with exercise-induced asthma (EIA)

BACKGROUND: As previous studies have shown that cysteinyl leukotrienes are important mediators in exercise-induced bronchoconstriction (EIB), and leukotriene receptor antagonists (LTRAs) such as montelukast have been shown to improve post-exercise bronchoconstrictor responses, we herein investigated whether clinical responsiveness to montelukast was associated with polymorphisms in the genes encoding leukotriene C4 synthase (LTC4S) and cysteinyl leukotriene receptor 1 (CysLTR1) and/or clinical parameters in Korean asthmatic children with EIB. METHODS: The study population consisted of 100 asthmatic children with EIB. The individuals studied were given exercise challenge tests before and after receiving montelukast (5 mg/day) for 8 weeks. Responders were defined as children showing>10% post-treatment improvement in forced expiratory volume in 1 s (FEV1). The LTC4S A(-444)C and CysLTR1 T(+927)C polymorphisms were genotyped by PCR-restriction fragment length polymorphism analysis. RESULTS: Of 100 enrolled children, 68 were classified as responders and 32 were classified as non-responders. No significant association was observed between montelukast responsiveness and LTC4S or CysLTR1 genotype, either alone or in combination. In contrast, montelukast-induced improvement in FEV(1) after exercise was correlated with higher pre-treatment PC20 (methacholine) values (r=0.210, P=0.036) and lower total IgE levels (r=-0.216, P=0.031). CONCLUSIONS: The LTC4S A(-444)C and CysLTR1 T(+927)C genotypes do not appear to be useful for predicting clinical responsiveness to montelukast, whereas bronchial hyperresponsiveness and total IgE appear to predict the degree of montelukast responsiveness in Korean asthmatic children with EIB.     

Effect of budesonide and montelukast in asthmatic children exposed to relevant allergens

BACKGROUND: Montelukast has been shown to be effective in controlling the increase in exhaled NO in asthmatic children re-exposed to house dust mite (HDM). This study compared the effect of low dose inhaled budesonide and oral montelukast in preventing the expected relapse of airway inflammation and reactivity in a group of 24 mild asthmatic children allergic to HDM after a brief period of exposure to relevant allergens. METHODS: Lung function, bronchial hyperresponsiveness (BHR) to methacholine (PC(20)), fractional exhaled nitric oxide (FeNO) levels and sputum eosinophilia were evaluated. RESULTS: Pulmonary function remained stable. The BHR was unchanged after exposure in the group treated with budesonide, whereas a significant increase (P = 0.028) was observed in the patients receiving montelukast. No significant difference was observed in FeNO levels after exposure to mite antigen in the two groups. In both the groups of asthmatic children we observed a significant increase in sputum eosinophil % after the exposure to mite antigen. CONCLUSIONS: The significant increase in BHR level observed in the group of children receiving montelukast suggests a more comprehensive effect as disease controller by inhaled steroids than by leukotriene antagonist in allergic asthmatic children re-exposed to relevant allergens.     

Improved refill persistence with fluticasone propionate and salmeterol in a single inhaler compared with other controller therapies

BACKGROUND: Improved adherence to inhaled corticosteroids (ICSs) has also been associated with decreased asthma-associated morbidity and mortality. OBJECTIVE: The purpose of this study was to assess patient medication refill persistence with fluticasone propionate (FP) and salmeterol combination in a single inhaler (FSC), FP and salmeterol in combination from 2 separate inhalers, FP and montelukast in combination, FP as monotherapy, and montelukast as monotherapy. METHODS: We performed a retrospective, observational, 24-month (12-month baseline and 12-month follow-up) database study using medical and pharmacy claims from a large managed care organization. We identified 2511 subjects 12 years of age or older with a claim for asthma (International Classification of Diseases, Ninth Revision: 493.XX): 563 patients receiving FSC, 224 receiving FP plus salmeterol, 75 receiving FP plus montelukast, 798 receiving FP only, and 776 receiving montelukast only. Refill rates of FP, as a measure of adherence, were compared for each FP-containing cohort during the 12-month follow-up period. In addition, refill rates were compared between FSC, an inhaler, and montelukast, an oral medication. RESULTS: Twelve-month baseline asthma medication use and patient demographics were comparable among cohorts. Patients in the FSC cohort obtained significantly more refills compared with the number of FP refills in the other FP-containing cohorts (4.06 for FSC vs 2.35 for FP plus salmeterol, 1.83 for FP plus montelukast, and 2.27 for FP alone) over the 12-month follow-up period. In addition, patients taking FSC had similar refill persistence compared with patients taking the oral leukotriene modifier montelukast (4.51). CONCLUSION: FSC might increase ICS refill persistence compared with FP alone in a single inhaler, FP in combination with salmeterol from 2 separate inhalers, and FP in combination with montelukast. In addition, FSC in a dry powdered inhaler had similar refill rates compared with an oral asthma agent, montelukast. Use of a single inhaler containing both an ICS (FP) and a long-acting bronchodilator (salmeterol) might increase the likelihood that patients are getting more optimal ICS therapy, as well as the benefits from the long-acting bronchodilator, with patient adherence comparable to an oral agent.     

Heterogeneity of FeNO response to inhaled steroid in asthmatic children

Background Nitric oxide in exhaled air is regarded as an inflammation marker, and may be used to monitor the anti‐inflammatory control from inhaled corticosteroids (ICSs). However, this response to ICSs exhibits a heterogeneous pattern. Objective The study aimed to describe the independent variables associated with the heterogeneity in the response of exhaled nitric oxide to ICSs. Methods Exhaled nitric oxide (FeNO), lung function, bronchial hyper‐responsiveness (BHR), specific IgE to common inhalant allergens, blood eosinophils, other atopic manifestations and variants in nitric oxide synthethase 1 (NOS1) gene were studied in a double‐blind, placebo‐controlled crossover comparison of budesonide (BUD) Turbohaler 1600 mcg daily vs. placebo in asthmatic schoolchildren. Results Forty children were included in the study from a screening of 184 asthmatic children with moderately persistent asthma, well controlled on regular BUD 400 mcg daily: 20 children with normal FeNO and 20 with raised FeNO. FeNO, BHR and forced expiratory volume in 1 s improved significantly after BUD 1600 mcg (BUD1600). However, FeNO after ICS treatment exhibited a Gaussian distribution and FeNO was significantly raised in 15 children. Allergy and BHR, but none of the other independent variables under study were significantly related to FeNO after BUD1600. Conclusion Exhaled nitric oxide exhibited a heterogeneous response to ICS in asthmatic schoolchildren. Allergy and BHR were driving FeNO level independently of high‐dose steroid treatment. This should be considered when using FeNO for steroid dose titration and monitoring of ICS anti‐inflammatory control in asthmatic children.     

Addition of fexofenadine to inhaled corticosteroid therapy to reduce inflammatory biomarkers in atopic asthma.

BACKGROUND: We previously showed that H1-antihistamines may shift the PC20 (provocation concentration that caused a decrease in forced expiratory volume in 1 second of 20%) threshold to adenosine monophosphate (AMP) challenge but may paradoxically prolong recovery. OBJECTIVES: To measure AMP recovery using a constant predetermined AMP PC20 and to evaluate whether fexofenadine use confers add-on effects to treatment with either fluticasone propionate alone or combined fluticasone propionate-salmeterol. METHODS: Fourteen atopic patients with mild-to-moderate asthma (forced expiratory volume in 1 second of 76%) completed a double-blind, randomized, crossover study consisting of 3-week treatment blocks of either fluticasone propionate-salmeterol, 250 microg twice daily, or fluticasone propionate alone, 250 microg twice daily, in conjunction with either fexofenadine, 180 mg once daily, or matched placebo. Recovery after a predetermined AMP PC20 challenge was measured (primary outcome), along with exhaled nitric oxide levels, plasma eosinophil cationic protein levels, peripheral eosinophil counts, pulmonary function, diary card outcomes, and quality of life (all secondary outcomes). RESULTS: There were no differences in any of the primary or secondary outcomes when fexofenadine was added to treatment with either fluticasone propionate-salmeterol or fluticasone propionate alone. The mean AMP recovery time was 25.0 vs 23.4 minutes for fexofenadine and placebo, respectively, as add-on to fluticasone-salmeterol and 22.5 vs 23.9 minutes, respectively, as add-on to fluticasone alone. CONCLUSION: Fexofenadine did not affect recovery to a fixed dose of AMP challenge or any other surrogate inflammatory markers when given as add-on therapy to corticosteroid-treatedatopic asthmatic patients.     

Urine leukotriene E4 levels are associated with decreased pulmonary function in children with persistent airway obstruction

BACKGROUND: Use of leukotriene receptor antagonists improves disease control in children and adults with asthma. However, the relationship between cysteinyl leukotriene levels and indices of daily asthma control has not been studied directly. OBJECTIVES: We sought to assess the relationship between daily variability in urinary leukotriene E(4) (LTE(4)) levels and daily lung function in children primarily taking inhaled corticosteroids (ICSs) and long-acting beta-agonists (LABAs). METHODS: Fifty children primarily with moderate-to-severe asthma were followed with measurements of urinary LTE(4), monitoring of FEV(1), and albuterol use. RESULTS: Increasing urinary LTE(4) levels were associated with significant (P = .006) decreases in percent predicted FEV(1) (ppFEV(1)) averaging 4.7% per interquartile range increase in LTE(4) and accompanied by increased albuterol use (P = .03). Children with lower FEV(1)/forced vital capacity ratios demonstrated larger LTE(4)-related FEV(1) decreases (6.4%) compared to those with higher ratios (4.2%, P = .009). This association was blunted in children taking montelukast (1.4% ppFEV(1) decrease) compared with that in children not taking this medication (5.4% ppFEV(1) decrease, P = .05). Children with lower lung function ratios demonstrated greater blunting of the LTE(4) effect with montelukast (0.9% ppFEV(1) decrease) compared to those with higher ratios (3.6% ppFEV(1), P = .0002). CONCLUSIONS: Daily variability in LTE(4) levels is associated with clinically significant decreases in pulmonary function. In children who demonstrate a response associated with an increase in urinary LTE(4) levels, leukotriene receptor antagonists protect against daily FEV(1) decreases. This protection might be greatest in those with persistent airway obstruction despite use of ICS and LABA therapy. CLINICAL IMPLICATIONS: Therapies designed to block cysteinyl leukotriene production or function might benefit children receiving ICS and LABA therapy who continue to experience persistent disease.     

Effects of long-term inhaled corticosteroids on adrenal function in patients with asthma.

BACKGROUND: Inhaled corticosteroids (ICSs) are effective asthma controllers, but long-term use could lead to adverse effects. Objective: To examine adrenal responsiveness of patients with persistent asthma treated with long-term ICSs. METHODS: Morning plasma cortisol levels before and 30 minutes after adrenocorticotropic hormone (ACTH) (1 microg intravenously) stimulation were compared. Primary end points included mean prestimulation and poststimulation cortisol levels; secondary end points included morning cortisol level of 5 microg/dL or less, post-ACTH stimulation cortisol level of 18 microg/dL or less, and/or a net change of 7 microg/dL or less from baseline. RESULTS: A total of 103 asthmatic patients (29 in the triamcinolone acetonide group, 18 in the flunisolide group, 45 in the fluticasone propionate group, and 11 in the oral corticosteroids group [positive controls]) completed the study. Mean daily ICS doses and durations were as follows: triamcinolone acetonide: 448 microg for 36 months; flunisolide: 1,181 microg for 41 months; and fluticasone propionate: 745 microg for 19 months. Eleven of 30 patients taking high-dose ICSs (10 of 28 taking fluticasone propionate and 1 of 2 taking flunisolide) had both low morning cortisol levels and abnormal post-ACTH stimulation cortisol levels. Few patients taking lower doses of any ICS had abnormal results. CONCLUSIONS: Patients who require long-term treatment with high-dose ICSs may have abnormal morning plasma cortisol levels and reduced responsiveness to ACTH stimulation. Careful monitoring of adrenal function should be considered in such patients.     

Effects of low dose fluticasone/salmeterol combination on surrogate inflammatory markers in moderate persistent asthma

BACKGROUND: Noninvasive surrogate markers provide valuable information on the asthmatic inflammatory process. We wished to examine the effects of low dose fluticasone/salmeterol combination on different commonly used inflammatory markers in moderate persistent asthma. METHODS: Twenty-five moderate persistent atopic asthmatics were enrolled of whom 20 completed an open label study. Following an initial 4 week steroid washout period in which patients took salmeterol 50 microg dry powder inhaler 1 puff BD, they received the addition of fluticasone as fluticasone 100 microg/salmeterol 50 microg combination dry powder inhaler 1 puff BD for the next 2 weeks. Exhaled nitric oxide, spirometry, methacholine PD20, sputum/blood eosinophils and sputum/serum eosinophil cationic protein (ECP) were measured following the salmeterol only and fluticasone/salmeterol combination treatment periods. RESULTS: Compared to salmeterol alone (i.e. after the steroid washout), the use of fluticasone/salmeterol combination conferred significant improvements (P < 0.05) in all surrogate markers of inflammation apart from serum ECP. Geometric mean fold changes were 4.3-fold/1.3-fold for sputum/blood eosinophils, 2.2-fold/1.2-fold for sputum/serum ECP, 2.3-fold for methacholine PD20 and 1.8-fold for exhaled nitric oxide. CONCLUSIONS: Surrogate markers apart from serum ECP may be used as a guide to evaluate the anti-inflammatory effects of low dose inhaled corticosteroids. Sputum markers tend to be more sensitive than blood when assessing the anti-inflammatory response.     

Features of severe asthma in school-age children: Atopy and increased exhaled nitric oxide

BACKGROUND: Children with severe asthma have persistent symptoms despite treatment with inhaled corticosteroids (ICSs). The differentiating features of severe asthma in children are poorly defined. OBJECTIVE: To identify features of severe versus mild-to-moderate asthma in school-age children using noninvasive assessments of lung function, atopy, and airway inflammation. METHODS: A total of 75 children (median age, 10 years) with asthma underwent baseline characterization including spirometry and lung volume testing, methacholine bronchoprovocation, allergy evaluation, and offline measurement of exhaled nitric oxide (F(ENO)). Twenty-eight were followed longitudinally over 6 months. Participants were assigned to the severe asthma subgroup if they required high-dose ICS plus 2 or more minor criteria. RESULTS: Children with severe versus mild-to-moderate asthma had more symptoms, greater airway obstruction, more gas trapping, and increased bronchial responsiveness to methacholine. Subjects with severe asthma also had higher concentrations of F(ENO) and significantly greater sensitization to aeroallergens. With long-term study, both the reduction in FEV(1) and increase in F(ENO) persisted in the severe versus mild-to-moderate group. Furthermore, despite adjustments in ICS doses, the frequency of exacerbations was significantly higher in subjects with severe (83%) versus mild-to-moderate asthma (43%). CONCLUSION: Severe asthma in childhood is characterized by poor symptom control despite high-dose ICS treatment and can be differentiated from mild-to-moderate asthma by measurement of lung function and F(ENO). CLINICAL IMPLICATIONS: Clinicians should suspect severe asthma in children with poor response to ICS, airway obstruction, and high F(ENO).     

Add‐on montelukast to inhaled corticosteroids protects against excessive airway narrowing

Rationale Excessive airway narrowing in response to broncho‐active stimuli is a predictor for severe exacerbations in asthma. Leukotriene receptor antagonists (LTRAs) have complementary properties to inhaled corticosteroids (ICS) on asthma control. Objectives The LTRA montelukast may provide an additional protection against excessive airway narrowing. We tested the add‐on effects of montelukast on the maximal response plateau and PD₂₀ to inhaled methacholine in asthmatics on a stable dose of ICS. Methods Thirty‐one patients with allergic asthma [14M/17F, 19–50 years, forced expiratory volume in 1 s (FEV₁) >70% pred., PD₂₀ <3.9 μmol methacholine], with a twice documented response plateau to methacholine, were randomized in a double‐blind (montelukast 10 mg or matching placebo once daily), 12‐week parallel study. Bronchoprovocation tests with methacholine (0.03–256 μmol or 40% decline in FEV₁) were repeated every 4 weeks and after wash‐out. The main study objectives were changes from baseline in maximal FEV₁ decline at the response plateau (i.e. >2 post‐dose FEV₁ values within 5%) and PD₂₀ to methacholine after 12 weeks' treatment. Results Neither treatment affected baseline FEV₁ (P=0.62). Compared with placebo, montelukast significantly decreased the maximal response plateau to methacholine (mean difference 9.4%; 95% confidence interval 3.9–15.7; P<0.005), improved the FEV₁ decline (mean change in FEV₁ decline was 2.1% [montelukast] and ?0.8% [placebo], respectively, P<0.05), and increased PD₂₀ methacholine (mean change in PD₂₀ of 5.3 [montelukast] and 1.4 [placebo] doubling doses, respectively, P<0.001). Conclusion Add‐on montelukast to ICS has disease‐modifying effects in adults with persistent asthma, and hence reduces the risk of excessive airway narrowing (NCT 00913328). Cite this as: C. S. Ulrik and Z. Diamant, Clinical & Experimental Allergy, 2010 (40) 576–581.     

Safety and application of induced sputum analysis in childhood asthma

BACKGROUND: The value of sputum induction in pediatric asthma lies in its potential to directly and noninvasively assess airway inflammation in children, because bronchoscopy and biopsy carry some risk. The Childhood Asthma Management Program (CAMP) study was designed to evaluate the long-term effects of budesonide and nedocromil compared with placebo in children with mild to moderate asthma across 8 centers. OBJECTIVE: At the Denver CAMP site, we sought to evaluate the safety of sputum induction, to determine differences in airway inflammation between treatment groups by using induced sputum analysis, and to examine correlations between other biomarkers and sputum eosinophils. METHODS: Sputum induction was performed, and exhaled nitric oxide, circulating eosinophil counts, and serum eosinophil cationic protein were obtained at treatment discontinuation and after washout. Spirometry and a methacholine challenge were also performed according to the CAMP protocol. RESULTS: Ninety of 117 children provided an adequate sputum sample for analysis. In 9 subjects (3 nedocromil and 6 placebo), sputum induction resulted in bronchospasm. These subjects had greater disease severity, as measured by a lower median prebronchodilator FEV 1 percentage predicted (85.0% vs 96.0%; P =.024) and FEV 1 /FVC ratio (70.0% vs 79.0%; P =.0008); greater bronchodilator reversibility (16.5% vs 6.8%; P =.004); higher serum IgE (1390.0 vs 495.0 ng/mL; P =.017) and circulating eosinophil count (757.0 vs 282.0/mm 3; P =.04); greater use of prednisone (1.9 vs 0.9 courses per 100 person-years; P =.05); and greater supplemental inhaled steroid doses (85.3 vs 0 mg; P =.016). At treatment discontinuation, budesonide-treated patients had a lower median (1st, 3rd quartile) sputum percentage eosinophil (SPEos) (0.2% [0%, 1.2%] vs 0.8% [0.2%, 4.6%]; P =.03) compared with those treated with placebo; no significant difference was noted between nedocromil- and placebo-treated patients. Higher SPEos at the time of treatment discontinuation was associated with asthma worsening that required rescue prednisone (n = 23) during the washout period compared with patients who remained stable (3.6% [0.4%, 6.4%] vs 0.6% [0.2%, 3.2%] SPEos; P =.023). Finally, greater SPEos was associated with atopy, higher bronchodilator reversibility, lower FEV 1 /FVC ratio, higher exhaled nitric oxide levels, circulating eosinophils, sputum and serum eosinophil cationic protein, more prednisone courses during the treatment period, and greater asthma severity. CONCLUSIONS: Sputum induction is a relatively noninvasive and safe procedure that can provide information on eosinophilic inflammation and treatment response and is also associated with several measures of asthma control. However, this procedure still remains a research tool in asthma because of its requirements for technical expertise.     

Magnitude of late asthmatic response to allergen in relation to baseline and allergen-induced sputum eosinophilia in mild asthmatic patients.

BACKGROUND: Late asthmatic response (LAR) to allergen challenge is a validated method for studying the pathogenesis of and new treatments for asthma in the laboratory. OBJECTIVE: To evaluate the relationship between the magnitude of allergen-induced LAR and clinical and biological determinants, including sputum and blood eosinophil percentages and eosinophil cationic protein concentrations. METHODS: Thirty-eight untreated mild asthmatic patients (mean age, 21.2 years) were selected for the presence of allergen-induced early asthmatic response (EAR) and LAR. Each patient measured methacholine responsiveness (provocation dose that caused a decrease in forced expiratory volume in 1 second of 20% [PD20FEV1]) at baseline, differential blood cell counts and eosinophil cationic protein levels in blood and induced sputum, and serum neutrophil chemotactic activity at baseline and 24 hours after allergen challenge. RESULTS: A correlation was found between LAR (as area under the curve [AUC]) and sputum eosinophil percentages at baseline (r = 0.51; P = .001) and 24 hours after allergen challenge (r = 0.44; P < .007). Furthermore, we found significant correlations between AUC LAR and AUC EAR, baseline methacholine PD20FEV1, baseline blood eosinophil percentages, and baseline serum neutrophil chemotactic activity. A stepwise multiple regression analysis showed that the stronger determinants of AUC LAR were baseline sputum eosinophilia and AUC EAR. CONCLUSION: Baseline sputum eosinophilia and functional findings are determinants of the magnitude of allergen-induced LAR.     

Determining economic feasibility of fluticasone propionate-salmeterol vs montelukast in the treatment of persistent asthma using a net benefit approach and cost-effectiveness acceptability curves.

BACKGROUND: The choice of treatment can have a major impact on the total costs associated with asthma care. OBJECTIVE: To determine the relative cost-effectiveness of twice-daily treatment with inhaled fluticasone propionate-salmeterol via Diskus, 100/50 microg, with that of once-daily treatment with oral montelukast as initial maintenance therapy in patients with persistent asthma uncontrolled with a short-acting beta2-agonist alone. METHODS: Data from a randomized, double-blind, double-dummy, 12-week clinical trial were analyzed. Efficacy end points included (1) symptom-free days (SFDs) during the 12-week period and (2) a 12% or greater increase in forced expiratory volume in 1 second (FEV1) from baseline. The economic analysis was performed from a payer's perspective, and hence only direct costs were included in the analysis. The incremental cost-effectiveness ratio (ICER), which is the mean difference in average costs divided by the mean difference in average effectiveness, was calculated for both effectiveness outcomes (SFDs and FEV1). RESULTS: For the SFDs end point, the ICER for fluticasone propionate-salmeterol vs montelukast was $2.87 (95% confidence interval, -$1.08 to $6.65), indicating that it costs, on average, an extra $2.87 per day for an additional SFD with fluticasone propionate-salmeterol than with montelukast. With regard to FEV1, the ICER was $1.79 (95% confidence interval, -$0.72 to $3.86), indicating that it costs, on average, an extra $1.79 per day to achieve a lung function improvement of 12% or greater from baseline with fluticasone propionate-salmeterol than with montelukast. At a widely acceptable ceiling ratio of $9.95 per day, the probability of fluticasone propionate-salmeterol being more cost-effective than montelukast was 99.8% for SFDs and was almost 100% for an FEV1 improvement of 12% of greater. CONCLUSIONS: Treating 2 main components of asthma, inflammation and smooth muscle dysfunction, using fluticasone propionate-salmeterol is more cost-effective than using a single mediator antagonist alone, such as montelukast, as initial maintenance therapy for persistent asthma in patients treated with a short-acting beta2-agonist only.     

激素治疗对运动诱发性哮喘患者痰嗜酸性粒细胞计数的影响

目的探讨气道嗜酸性粒细胞性炎症和运动诱发的支气管痉挛（EIB）之间的关系,及其对吸入糖皮质激素（ICS）治疗的反应。方法本研究为随机、双盲、二阶段交叉试验,将26例有运动诱发性支气管痉挛发作史且从未接受过激素治疗的哮喘患者随机分为两组,每组分别给予两个剂量水平的布地奈德吸入：①100μg/d与400μg/d对比;②200μg/d与800μg/d对比。每一阶段为3周,洗脱期3～8周。治疗前及开始治疗后每隔1周进行1次运动激发试验并留取痰液标本行嗜酸性粒细胞计数。结果高剂量ICS治疗（400μg/d和800μg/d）可显著减少痰嗜酸性粒细胞比例。痰嗜酸性粒细胞百分比与运动诱发性支气管痉挛严重程度相关,且对EIB的严重程度有预测作用;高剂量ICS治疗时,尚可预测EIB对激素治疗有效,而对低剂量ICS组（100μg/d和200μg/d）则无预测作用。低剂量ICS治疗,不管基线痰嗜酸性粒细胞计数是否增多,EIB在第1周末发作显著减轻,尔后几无改善。而高剂量ICS治疗对EIB的改善作用在痰嗜酸性粒细胞增多的患者中显著优于嗜酸性粒细胞计数小于5%者,这种明显的差异在开始治疗1周后即显现,且随时间的推移而继续加大。结论气道嗜酸性粒细胞性炎症可能在EIB的发生及其对ICS治疗有效的调节机制中起重要的作用。测定痰嗜酸性粒细胞计数在预测EIB的严重程度及其对不同剂量ICS治疗的反应具有一定的临床应用价值。