Rationale: Predicting corticosteroid response in COPD is important but difficult. Response is more likely to occur in association with eosinophilic airway inflammation, for which the fraction of exhaled nitric oxide (Fe NO) is a good surrogate marker. Objectives: We aimed to establish whether Fe NO levels would predict the clinical response to oral corticosteroid in COPD. Methods: We performed a double-blind, crossover trial of steroid in patients with COPD. After a 4-week washout of inhaled steroids, patients received prednisone 30 mg/d or matching placebo, in random order, with an intervening 4-week washout. The predictive values of Fe NO for clinically significant changes in 6-minute-walk distance (6MWD), spirometry (FEV1), and St. George's Respiratory Questionnaire (SGRQ) were calculated. Measurements and Main Results: A total of 65 patients (mean FEV1 = 57% predicted) were randomized. With prednisone, there was a net increase of 13 m in 6MWD (P = 0.02) and 0.06 L in postbronchodilator FEV1 (P = 0.02) compared with placebo. The change in SGRQ was not significant. Using receiver operator characteristic analysis, the area under the curve for an increase of 0.2 L in FEV1 was 0.69 (P = 0.04) with an optimum Fe NO cut-point of 50 ppb. The positive and negative predictive values were 67 and 82%, respectively. FENO was not a significant predictor for changes in 6MWD or SGRQ. Conclusions: Fe NO is a weak predictor of short-term response to oral corticosteroid in COPD, its usefulness being limited to predicting increase in FEV1. Clinical trial registered with www.anzctr.org.au (ACTRN12605000683639).

Selected ion flow tube-mass spectrometry (SIFT-MS) can measure volatile compounds in breath on-line in real time and has the potential to provide accurate breath tests for a number of inflammatory, infectious and metabolic diseases, including diabetes. Breath concentrations of acetone in type 2 diabetic subjects undertaking a long-term dietary modification programme were studied. Acetone concentrations in the breath of 38 subjects with type 2 diabetes were determined by SIFT-MS. Anthropomorphic measurements, dietary intake and medication use were recorded. Blood was analysed for beta hydroxybutyrate (a ketone body), HbA1c (glycated haemoglobin) and glucose using point-of-care capillary (fingerprick) testing. All subjects were able to undertake breath manoeuvres suitable for analysis. Breath acetone varied between 160 and 862 ppb (median 337 ppb) and was significantly higher in men (median 480 ppb versus 296 ppb, p = 0.01). In this cross-sectional study, no association was observed between breath acetone and either dietary macronutrients or point-of-care capillary blood tests. Breath analysis by SIFT-MS offers a rapid, reproducible and easily performed measurement of acetone concentration in ambulatory patients with type 2 diabetes. The high inter-individual variability in breath acetone concentration may limit its usefulness in cross-sectional studies. Breath acetone may nevertheless be useful for monitoring metabolic changes in longitudinal metabolic studies, in a variety of clinical and research settings.

Using selected ion flow tube-mass spectrometry (SIFT-MS) for on-line analysis, we aimed to define the optimal single-exhalation breathing manoeuvre from which a measure of expired acetone concentration could be obtained. Using known acetone concentrations in vitro, we determined the instrument's accuracy, inter-measurement variability and dynamic response time. Further, we determined the effects of expiratory flow and volume on acetone concentration in the breath of 12 volunteers and calculated intra-individual coefficients of variation (CVs). At acetone concentrations of 600–3000 ppb on 30 days over 2 months there was an instrument measurement bias of 8% that did not change over time, inter-day and intra-day CVs were 5.6% and 0.0%, respectively, and the 10–90% response time was 500 ± 50 ms (mean ± SE). Acetone concentrations at exhalation flows of 193 ± 18 (mean ± SD) and 313 ± 32 ml s−1 were 619 ± 1.83 (geometric mean ± logSD) and 618 ± 1.82 ppb in the fraction 70–85% by volume of exhaled vital capacity (V70−85%) and 636 ± 1.82 (geometric mean ± logSD) and 631 ± 1.83 ppb in V85−100%. A difference was observed between acetone concentrations in the V70−85% and V85−100% fractions (p < 0.01), but flow had no effect. Median intra-individual CVs were 1.6–2.6%. On-line SIFT-MS measurement of acetone concentration in a single exhalation requires control of exhaled volume but not flow, and yields low intra-individual CVs and is potentially useful in approximating blood glucose and monitoring metabolic stress.

The β‐adrenoceptor agonist, isoprenaline, inhibited the IgE‐mediated release of histamine from human lung mast cells (HLMC) in a dose‐dependent manner. Maximal inhibitory effects were obtained with 0.1 μM isoprenaline. However, the inhibition of histamine release from HLMC by isoprenaline (0.1 μM) was highly variable ranging from 33 to 97% inhibition (mean, 59±3%, n=27). Long‐term (24 h) incubation of HLMC with isoprenaline led to a subsequent reduction in the ability of a second exposure of isoprenaline to inhibit IgE‐mediated histamine release from HLMC. The impairment in the ability of isoprenaline (0.1 μM) to inhibit histamine release following desensitizing conditions (1 μM isoprenaline for 24 h) was highly variable amongst HLMC preparations ranging from essentially negligible levels of desensitization in some preparations to complete abrogation of the inhibitory response in others (mean, 65±6% desensitization, n=27). The ability of HLMC to recover from desensitization was investigated. Following desensitizing conditions (1 μM isoprenaline for 24 h), HLMC were washed and incubated for 24 h in buffer and the effectiveness of isoprenaline (0.1 μM) to inhibit IgE‐mediated histamine release from HLMC was assessed. The extent of recovery was highly variable with some HLMC preparations failing to recover and others displaying a complete restoration of responsiveness to isoprenaline (mean, 40±6% recovery, n=23). The effects of the glucocorticoid, dexamethasone, were also investigated. Long‐term (24–72 h) treatments with dexamethasone (0.1 μM) had no effect on IgE‐mediated histamine release from HLMC. Additionally, long‐term (24–72 h) treatments with dexamethasone (0.1 μM) had no effect on the effectiveness of isoprenaline to inhibit histamine release. However, long‐term (24–72 h) treatments with dexamethasone (0.1 μM) protected against the functional desensitization induced by incubation (24 h) of HLMC with isoprenaline (1 μM). The protective effect was time‐dependent and pretreatment of HLMC with dexamethasone for either 24, 48 or 72 h prevented desensitization by either 15±7, 19±5 or 51±10%, respectively (n=5–7). HLMC preparations which were relatively refractory to isoprenaline even after withdrawal (24 h) from desensitizing conditions responded more effectively to isoprenaline (0.1 μM) if dexamethasone (0.1 μM) was also included during the recovery period (19±9% recovery after 24 h in buffer; 50±8% recovery after 24 h with dexamethasone, n=5). These data indicate that the responses of different HLMC preparations to isoprenaline, the susceptibility of HLMC to desensitization and the ability of HLMC to recover from desensitizing conditions varies markedly. Dexamethasone, which itself has no direct effects on IgE‐mediated histamine release from HLMC, protected HLMC from the functional desensitization to β‐adrenoceptor agonists. Because β₂‐adrenoceptor agonists and glucocorticoids are important in the therapeutic management of asthma and as the HLMC is probably important in certain types of asthma, these findings may have wider clinical implications. British Journal of Pharmacology (1997) 121, 717–722; doi:10.1038/sj.bjp.0701185

Hydrogen cyanide (HCN) in exhaled breath has been proposed as a biomarker for airway inflammation, and also a marker of the presence in the airways of specific organisms, especially Pseudomonas aeruginosa. However the production of HCN by salivary peroxidase in the oral cavity increases orally exhaled concentrations, and may not reflect the condition of the lower airways. Using SIFT-MS we aimed to determine an appropriate single-exhalation breathing maneuver which avoids the interference of HCN produced in the oral cavity. We have established that the SIFT-MS Voice200™ is suitable for the online measurement of HCN in exhaled breath. In healthy volunteers a significantly higher end exhaled HCN concentration was measured in oral exhalations compared to nasal exhalations (mean ± SD) 4.5 ± 0.6 ppb versus 2.4 ± 0.3 ppb, p < 0.01. For the accurate and reproducible quantification of end exhaled HCN in breath a nasal inhalation to full vital capacity and nasal exhalation at controlled flow is recommended. This technique was subsequently used to measure exhaled HCN in a group of patients with chronic suppurative lung disease (CSLD) and known microbiological colonization status to determine utility of HCN measurement to detect P. aeruginosa. Median nasal end exhaled HCN concentrations were higher in patients with CSLD (3.7 ppb) than normal subjects (2.0 ppb). However no differences between exhaled HCN concentrations of subjects colonized with P. aeruginosa and other organisms were identified, indicating that breath HCN is not a suitable biomarker of P. aeruginosa colonization.