Andrew D. Smith

Factors affecting exhaled nitric oxide measurements: the effect of sex

BackgroundExhaled nitric oxide (FENO) measurements are used as a surrogate marker for eosinophilic airway inflammation. However, many constitutional and environmental factors affect FENO, making it difficult to devise reference values. Our aim was to evaluate the relative importance of factors affecting FENO in a well characterised adult population.MethodsData were obtained from 895 members of the Dunedin Multidisciplinary Health and Development Study at age 32. The effects of sex, height, weight, lung function indices, smoking, atopy, asthma and rhinitis on FENO were explored by unadjusted and adjusted linear regression analyses.ResultsThe effect of sex on FENO was both statistically and clinically significant, with FENO levels approximately 25% less in females. Overall, current smoking reduced FENO up to 50%, but this effect occurred predominantly in those who smoked on the day of the FENO measurement. Atopy increased FENO by 60%. The sex-related differences in FENO remained significant (p < 0.001) after controlling for all other significant factors affecting FENO.ConclusionEven after adjustment, FENO values are significantly different in males and females. The derivation of reference values and the interpretation of FENO in the clinical setting should be stratified by sex. Other common factors such as current smoking and atopy also require to be taken into account.

Predicting corticosteroid response in chronic obstructive pulmonary disease using exhaled nitric oxide.

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 (FEV(1)), and St. Georges Respiratory Questionnaire (SGRQ) were calculated. MEASUREMENTS AND MAIN RESULTS A total of 65 patients (mean FEV(1) = 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 FEV(1) (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 FEV(1) 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. FE(NO) 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 FEV(1). Clinical trial registered with www.anzctr.org.au (ACTRN12605000683639).

Is exhaled nitric oxide measurement a useful clinical test in asthma

Purpose of reviewExhaled nitric oxide measurements (FENO) are easy to perform and are repeatable. Given the strong correlations between FENO and bronchial biopsy and induced sputum eosinophilia, as well as airway hyper-responsiveness, FENO may now be advocated as a surrogate for these tests in certain circumstances. They provide the opportunity to assess pathological rather than physiological changes in asthma. This review highlights recent advances in applying this technology to the diagnosis and ongoing assessment of asthma in the clinical and epidemiological settings. Recent findingsEpidemiological data confirm that whereas FENO measurements reflect the presence and severity of airway inflammation, levels do not correlate strongly with symptoms or lung function abnormalities. Although reference values and thresholds for an abnormal test still need to be agreed internationally, there are now sufficient data for clinicians to use the test meaningfully in clinical practice. Studies confirm the relatively high diagnostic accuracy of FENO measurements compared with conventional tests to distinguish asthma from nonasthma. Further, dose–response relationships for changes in FENO with inhaled steroids have been confirmed, and provide the basis for using FENO to assess asthma control and, potentially, to determine antiinflammatory treatment requirements. SummaryThe measurement of FENO is evolving to provide a complementary role alongside existing pulmonary function tests. Further work is required to establish reference values and possibly prediction equations in relation to age and height. Its role in determining optimum steroid requirements in chronic asthma and to identify steroid responsiveness in chronic obstructive pulmonary disease are two important areas for future research. Abbreviations AHR: airway hyper-responsiveness; COPD: chronic obstructive pulmonary disease; FENO: fraction of NO in expired air; FEV1: forced expiratory volume in 1 s; ICS: inhaled corticosteroid; NO: nitric oxide.

The role of sleep-disordered breathing, daytime sleepiness, and impaired performance in motor vehicle crashes-a case control study.

Study Objective: To examine levels of sleep-disordered breathing, daytime sleepiness, and impaired performance in 60 motor vehicle crash drivers and 60 controls matched for age, gender, and body mass index. Measurements and Results: All participants underwent polysomnography and daytime function assessments. Cases reported significantly higher levels of driver sleepiness (% sleepiness: mean ± SD; cases: 26 ± 17% controls: 16 ± 12% p= 0.003) and demonstrated slower reaction times on a sustained attention task (p= 0.02). There was a trend for more objective sleepiness in cases (maintenance of wakefulness test: cases: 17 ± 4 minutes; controls: 18 ± 3 minutes, p= 0.06) despite no differences in general subjective sleepiness (Epworth score: cases: 8 ± 4; controls: 8 ± 4; p= 0.93). There were no significant differences in polysomnography measures between groups (apneas + hypopneas per hour slept: cases: 8 ± 9; controls: 9 ± 16; p= 0.89; arousals per hour slept: cases: 18 ± 8; controls: 21 ± 12; p= 0.11). Conclusion: Crash drivers demonstrated significantly more driver sleepiness, slower reaction times and a trend for greater objective sleepiness compared with well-matched controls. However, the findings in crash drivers were independent of medical causes of sleep fragmentation, with both cases and controls showing moderate levels of unrecognized mild sleep-disordered breathing. Crash prevention strategies should focus on increasing personal awareness of the risks of sleepiness behind the wheel in all individuals.

Exhaled nitric oxide levels in asthma: Personal best versus reference values

BACKGROUND Factors affecting the fraction of nitric oxide in exhaled air (FE(NO)) are multiple. Interpreting values when assessing airways disease may be problematic. Clinically optimum levels have not been defined. OBJECTIVES We aimed to establish the relationship between predicted values for FE(NO) obtained from equations by Olin et al, Travers et al, and Dressel et al, and normalized levels after oral prednisone. We also compared postprednisone FE(NO) levels with those obtained during optimized treatment with inhaled fluticasone. METHODS Data were obtained before and after a trial of oral prednisone (30mg/d for 14 days), and also from a previously published study in which patients had their dose of inhaled corticosteroid adjusted using either FE(NO) or symptoms/lung function to optimize treatment. RESULTS Seventy-three patients completed the study. The geometric mean FE(NO) after prednisone (17.7 parts per billion [ppb]; 95% CI, 15.5-20.2) was significantly lower than mean FE(NO) at the optimized fluticasone dose (20.2 ppb; 95% CI, 17.1-23.8; P=.04) and at loss of control (27.6 ppb; 95% CI, 22.8-33.4; P < .001). FE(NO) levels after prednisone did not differ significantly from the predicted values of Olin et al (16.8 ppb, 95% CI, 16.0-17.5; P=.44), but were significantly lower than values of Travers et al (predicted, 21.5 ppb; 95% CI, 20.9-22.2; P=.005) and Dressel et al (predicted, 27.8 ppb; 95% CI, 26.7-28.9; P < .001). CONCLUSIONS Optimum FE(NO) levels are best established by using oral rather than inhaled steroid treatment, and these approximate to predicted values from the reference equation by Olin et al. However, at optimized doses of inhaled corticosteroid, although FE(NO) levels were higher than predicted, asthma was well controlled. Targeting FE(NO) on reference values is not justified.

Serial Exhaled Nitric Oxide Measurements in the Assessment of Laboratory Animal Allergy

Background. Laboratory animal allergy (LAA) may cause eosinophilic airway inflammation, for which exhaled nitric oxide (FENO) measurements are sensitive and specific. Our objective was to assess whether serial FENO measurements might detect exposure-related inflammation in laboratory animal workers. Methods. Fifty laboratory animal workers participated. Measurements of FENO and spirometry were obtained at baseline (Friday) and twice-daily following a weekend with no animal contact. Results. Eleven of 50 subjects had work-related symptoms, and 2 of 11 had positive serology for LAA. Baseline FENO was high (> 150 ppb) in the two seropositive subjects and increased progressively during the working week in one subject, confirming exposure-driven airway inflammation. In seronegative subjects, mean FENO levels were 19.8 (standard deviation [SD], 20.1) and 21.7 (SD, 20.8) in the symptomatic and nonsymptomatic groups, respectively, with no significant changes in FENO over time. Conclusion. Serial FENO measurements may provide complementary information in the assessment of possible occupational sensitisation. The sensitivity and specificity of this approach to diagnosing occupational asthma requires further evaluation.

Adverse effects of short‐acting beta‐agonists: Potential impact when anti‐inflammatory therapy is inadequate

Background:  Short‐acting beta‐agonists (SABAs) are associated with reduced lung function and increased bronchial hyper‐responsiveness. Earlier studies have failed to show that these changes are clinically important when SABAs are taken regularly in modest doses. However, some patients use SABAs to excess, especially with deteriorating asthma. Our aim was to establish whether adverse effects of SABAs are greater at higher than normal doses and after withdrawing inhaled corticosteroid (ICS) therapy.

Predicted versus absolute values in the application of exhaled nitric oxide measurements

BACKGROUND Constitutional factors such as age, sex and height, and acquired factors such as atopy and smoking, influence exhaled nitric oxide (F(E)NO) levels. The utility of predicted values based on reference equations which account for these factors has not been evaluated. AIM To compare the performance characteristics of absolute versus % predicted values for F(E)NO as predictors of diagnosed asthma and steroid response. METHODS We compared the sensitivities, specificities and likelihood ratios using F(E)NO (% predicted) with absolute values for F(E)NO (ppb) in 52 steroid-naive subjects with non-specific respiratory symptoms. The reference equations of Olin et al. (Chest, 2007) and Dressel et al. (Resp. Med., 2008) were used to derive predicted values. Receiver operating curve analyses were performed and the areas under the curve (AUC) were calculated for two outcomes: diagnosed asthma (yes/no), and steroid response after fluticasone for 4 weeks (defined as ≥ 12% increase in FEV(1); increase in mean morning PEF ≥ 15%; reduction in symptoms ≥ 1 point; increase in PC(20)AMP of ≥ 2 doubling doses). RESULTS The AUCs for diagnosed asthma were: F(E)NO (absolute) 0.770; F(E)NO (% pred.): 0.758 (Olin) and 0.775 (Dressel) (NS). The AUCs for F(E)NO (abs.) and F(E)NO (% pred.) with respect to the four indices of steroid response were likewise not significantly different. CONCLUSION Correcting F(E)NO for combinations of age, sex, height, smoking and atopy using reference equations did not enhance the performance characteristics of F(E)NO as a predictor of either the diagnosis of asthma or steroid responsiveness in patients with chronic airways-related symptoms.

Low Cost Remote Evaluation for Interface Prototyping

The increasing incidence of distributed information systems has led to the requirement for remote usability evaluations. The development of network systems and the Internet has created both the necessity and the opportunity to involve remote users much earlier in the development cycle. This paper describes the application of remote evaluation methods to the rapid prototyping development of a software product. The methods used include critical incident reporting, electronic questionnaires and written current protocols for asynchronous remote evaluation used in a context centred manner.