The effect of low-dose inhaled fluticasone propionate on exhaled nitric oxide in asthmatic patients and comparison with oral zafirlukast.

BACKGROUND: Exhaled nitric oxide (ENO) is a noninvasive marker of ongoing inflammation in asthmatic patients. Comparison between inhaled and oral anti-inflammatory medications in reduction of ENO in asthmatic patients has not been performed. OBJECTIVE: We measured changes in ENO, spirometry, need for rescue medication, quality of life (QOL), and diary scores (DS) after inhaled and oral anti-inflammatory therapy in adults with moderate asthma. METHODS: A randomized, double-blind, placebo-controlled, crossover design with 4-week washout periods was used. A plateau level of ENO, measured in parts per billion (ppb), was obtained by chemiluminescence with a Sievers 280NOA as per American Thoracic Society recommendations. Eighteen asthmatic adults (15 Hispanic, with a percentage predicted forced expiratory volume in 1 second (FEV1%) of 50% to 85%) on bronchodilators (beta2) only were studied. Subjects used fluticasone propionate (FP) metered-does inhaler (44 microg), two puffs twice daily, and matching placebo (PB) for 4 weeks. Eight of the asthmatic patients (7 Hispanic, FEV1% 50% to 85%) on bronchodilators only then received blinded zafirlukast (ZK) 20 mg and matching PB twice daily for 4 weeks. RESULTS: Low-dose inhaled FP resulted in significant improvements in ENO, spirometry, QOL, DS, and beta2 use. A significant difference in mean ENO was found (P < 0.01) before and after FP from 34+/-7 ppb to 13+/-3 ppb. A significant improvement was found (P < 0.05) with FEV1% from 75+/-3 to 85+/-3 with FP treatment. The other measured parameters, percentage predicted of peak expiratory flow rate, beta2 need, DS, and QOL measurements, were improved with low-dose FP treatment. No significant reduction was found in ENO with oral ZK for 4 weeks. After oral ZK washout and the second extension arm of placebo, ENO significantly increased back to 47+/-14 ppb (P < 0.05), but spirometry measures did not worsen. Significant improvements were found with DS and beta2 use with oral ZK therapy. CONCLUSIONS: These results reveal ENO is reduced with only low-dose inhaled FP in asthmatic patients not on anti-inflammatory medication. In the smaller extension study, ENO was reduced with FP and not with oral ZK treatment, and ENO levels increased back to near prestudy levels after ZK washout and the second extension arm of placebo. As a marker of inflammation, ENO levels reveal an improvement with anti-inflammatory medication and worsening when it is discontinued.

Exhaled nitric oxide before and after montelukast sodium therapy in school-age children with chronic asthma: a preliminary study.

Exhaled nitric oxide (ENO) is a surrogate marker of airway inflammation in asthma. In 12 children aged 6-11 years with mild to moderate persistent asthma, ENO concentrations were measured before and after 4 weeks of treatment with montelukast sodium, a leukotriene receptor antagonist, and 2 weeks after withdrawal of therapy. Baseline ENO levels (mean and 95% confidence interval) were significantly elevated in patients with asthma compared to age-matched nonasthmatic control subjects, with levels of 83 (42-123) vs. 13 (11-15) ppb (P < 0.001). After treatment with montelukast sodium, there was a significant (P < 0.01) reduction in ENO to 58 (27-89) ppb which again rose to 69 (38-99) ppb 2 weeks after treatment was withdrawn. During treatment, the fall in ENO was accompanied by nonsignificant improvements in prebronchodilator forced expiratory volume in 1 s (FEV(1)) from 81-85% predicted or reductions in use of albuterol from a mean of 2.5 to 1.6 puffs/day. Individual ENO measurements and change in ENO concentrations with treatment did not correlate with either pulmonary function changes or use of bronchodilator. These data show that ENO is elevated in children with relatively mild asthma treated with bronchodilator alone, and that treatment with montelukast sodium for 4 weeks results in a significant reduction in ENO concentrations, even in the absence of significant changes in pulmonary function. These findings suggest an anti-inflammatory role for leukotriene D(4) receptor antagonism in the treatment of children with mild to moderate asthma.

Interleukin-4 receptor in moderate atopic asthma. A phase I/II randomized, placebo-controlled trial.

UNLABELLED: Interleukin-4 mediates important proinflammatory functions in asthma, including induction of the IgE isotype switch, expression of VCAM-1 on endothelium, mucin production, 15-lipoxygenase activity, and Th2 lymphocyte stimulation leading to the secondary synthesis of IL-4, IL-5, and IL-13. Soluble recombinant human IL-4 receptor (IL-4R; Nuvance; altrakincept) inactivates naturally occurring IL-4 without mediating cellular activation. Nebulized IL-4R has a serum half-life of approximately 1 wk. In this double-blind, placebo-controlled trial, 25 patients with moderate asthma requiring inhaled corticosteroids were randomly assigned to receive a single nebulized dose of IL-4R 1,500 microg, IL-4R 500 microg, or placebo after stopping inhaled corticosteroids. No drug-related toxicity was observed. Treatment with IL-4R produced significant improvement in FEV(1) on Day 4 (1,500 microg versus placebo; p < 0.05) and in FEF(25-75) on Days 2 and 4 (1,500 microg versus placebo; p < 0.05). Asthma symptom scores stabilized among patients treated with IL-4R 1, 500 microg, despite abrupt withdrawal of corticosteroids, but not in the IL-4R 500 microg group or the placebo group (p < 0.05). Patients in the IL-4R 1,500 microg group also required significantly less beta(2)-agonist rescue use (p < 0.05). Anti-inflammatory effects were further demonstrated by significantly reduced exhaled nitric oxide (p < 0.05). CONCLUSIONS: A single dose of IL-4R appears safe and effective in moderate asthma. The 1,500 microg dose appears as safe but significantly more effective than the 500 microg dose.

Comparison of exhaled nitric oxide to spirometry during emergency treatment of asthma exacerbations with glucocorticoids in children.

BACKGROUND: Asthma is characterized as a chronic inflammatory process; however, there is no easily measured marker for airway inflammation. Such a marker, particularly in children, would be very helpful in the management of asthma even in the acute setting. OBJECTIVE: The purposes of this study were to determine whether asthmatic children have (1) elevation of exhaled breath nitric oxide (ENO) during acute exacerbations when presenting to the emergency room, (2) reduction of ENO following glucocorticoid treatment, or (3) improvement in spirometry and clinical examination accompanying reduction of ENO levels. METHODS: Peak ENO levels were measured by chemiluminescence during exhalation into the NO analyzer. Ten asthmatic children (mean age 10 years) who presented to the Pediatric Special Care Unit at National Jewish Medical and Research Center in acute respiratory distress with an asthma exacerbation were studied. The subjects were recruited, after informed consent was obtained from the parent, on the basis of specific inclusion/exclusion criteria. Measurements of ENO in parts per billion (ppb) and spirometry, including percentiles of forced expiratory volume in one second (FEV1%) and peak expiratory flow (PEF%), were performed before and after at least 5 days of glucocorticoid therapy. RESULTS: The mean ENO level in the asthmatic children prior to glucocorticoid treatment was 48 +/- 8ppb, and after glucocorticoid treatment the ENO level was 17 +/- 1ppb; (P < .002). Prior to glucocorticoid treatment, the mean FEV1% value was 68 +/- 3% compared with the postglucocorticoid treatment FEV1% value of 100 +/- 5%; (P < .0001). Prior to glucocorticoid treatment, the mean PEF% value was 81 +/- 7%, compared with the postglucocorticoid treatment PEF% value of 105 +/- 6%; (P < .02). CONCLUSIONS: The mean peak ENO level after glucocorticoid therapy was significantly less than that measured before treatment in children with acute asthma exacerbations. Concomitant with the decrease in ENO levels, there was improvement in the spirometry values and physical examination in the asthmatic children; thus, ENO is a sensitive marker for response to anti-inflammatory treatment in children.

Comparison of exhaled nitric oxide, serum eosinophilic cationic protein, and soluble interleukin-2 receptor in exacerbations of pediatric asthma.

The hypotheses tested in this study were that during acute asthma exacerbations (1) exhaled nitric oxide concentrations [eNO] are a more sensitive, noninvasive indicator of asthma disease activity than serum markers of inflammation such as eosinophil cationic protein (ECP) or soluble interleukin 2 receptor (sIL2R), and (2) elevated [eNO] are reduced after treatment with glucocorticoids (GC). Peak eNO levels were measured by chemiluminescence during slow expiration. Seven asthmatic subjects (mean age 11 yrs; mean morning FEV1 65% predicted) receiving inhaled GC, and with no radiographic evidence of acute sinusitis, were studied before and after a course of oral GC. Measurements of [eNO], ECP and sIL2R levels, and FEV1% were obtained before and after a course of GC. Six atopic nonasthmatic subjects (mean age 12 years; mean FEV1 94% predicted) and seven normal subjects (mean age 13 years; mean FEV1 100% predicted) were studied. The mean peak [eNO] level (parts per billion: ppb) for the asthma subjects before treatment (52 +/- 5 ppb SEM) was greater than the value for both nonasthmatic atopic and normal subjects (16 +/- 2 ppb and 14 +/- 2 ppb SEM, respectively; P < 0.0001). There was no significant difference in ECP or sIL2R values between asthmatic subjects and either atopic or normal subjects (P > 0.05). Baseline pre-GC treatment ECP levels in the asthmatic subjects were significantly higher (P < 0.002) than post-GC treatment values. The mean peak [eNO] level in the asthmatic subjects declined after oral GC treatment to 14 +/- 1 ppb (P < 0.0002) and was less than 2 ppb different from either control group (P > 0.75). We conclude that [eNO] is a more sensitive marker of asthma disease activity than ECP and sIL2R levels. In addition, [eNO] appears to be a more useful indicator of the beneficial response to GC therapy than these other measurements in pediatric asthma.