The fractional concentration of exhaled nitric oxide (Feno) has been proposed as a noninvasive marker of airway inflammation, a primary process in the pathogenesis of asthma. Nitric oxide (NO) synthesized by constitutive NO synthases mediates physiologic responses such as vasorelaxation, while inducible NO synthase (iNOS) is expressed in pathologic states and is involved in host defense and the inflammatory response.
Exhaled NO is increased in some subjects with asthma, falls after treatment with corticosteroids, and this effect is both rapid in onset and resolves rapidly on steroid therapy withdrawal. iNOS is increasingly expressed in the respiratory epithelium in asthma, in response to cytokines secreted from macrophages and lymphocytes. This expression has also been shown to be reduced after inhaled bude-sonide dipropionate (iBDP). Corticosteroids modulate the expression of iNOS via binding with nuclear factor kB in the cytosol and possibly by inhibiting cytokine synthesis.
Standard efficacy measures in asthma include symptom scores, home pulmonary function monitoring, rescue medication use, and pulmonary function testing including assessment of airway reactivity. These efficacy measures mainly assess airway obstruction rather than airway inflammation. Use of standard efficacy measures to determine a dose response for inhaled corticosteroids has not been easy,- probably because of the variability in response between individuals, as well as lack of adequate sensitivity. The lack of a dose response has made it difficult to use standard efficacy measures to determine the optimal dose of inhaled corticosteroids.
Due to potential systemic effects, it is preferable to prescribe the minimal dose of inhaled steroids that will achieve adequate asthma control. This requires a sensitive and specific method for assessing airway inflammation. Using a standardized Feno measurement technique together with other standard outcomes, we examined the dose response of iBDP on the decrease in Feno. In a second study, we determined if the effect on Feno of repeated administration of the same dose of iBDP, with washout in between, was reproducible over a short time period.
Materials and Methods
Study A: Dose Response of the Fall in Feno After iBDP
Subjects: We recruited 15 asthmatic patients (8 male patients; age range, 17 to 40 years) with baseline Feno > 60 parts per billion (ppb; a value > 2 SD above mean values for healthy control subjects in our laboratory), in order to select subjects with increased baseline Feno. Asthma was diagnosed according to American Thoracic Society recommendations (1986). Exclusion criteria included the use of oral or inhaled corticosteroids, other anti-inflammatory agents, of long-acting p2 agonists in the 4 weeks prior to the study; smoking within the previous 3 years or > 5 pack-year smoking history; upper respiratory tract infection in the previous 4 weeks; pregnancy; and any other significant chronic medical disease. The study was approved by the Toronto Hospital Ethics Committee; subjects signed an informed consent form.
Study Design: This was a single-cohort, prospective study with five visits over 4 weeks. Each subject served as his or her own control on placebo and active medications. The baseline visit (visit 1) included history and physical examination, Feno, spirometry, and determination of the provocative concentration of methacholine resulting in a 20% fall in FEV1 (PC20) according to American Thoracic Society guidelines. For four 1-week periods (periods 1 to 4), the following were administered twice daily via metered-dose inhaler to the 15 subjects: period 1, placebo; period 2, 100|j,g/d of iBDP; period 3, 400 ^g/d of iBDP; and period 4, 800 ^g/d of iBDP. After 1 week at each dose level, the subjects came to the laboratory for measurement of Feno, spirometry, and PC20.