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Measurement of markers of tobacco smoking in patients with coronary heart disease.

591 patients with a history of coronary heart disease had one or more biochemical markers of tobacco smoking measured. 26% were self reported smokers and a further 4% were apparent 'smoking deceivers'. The urinary nicotine metabolite concentration is an excellent marker for tobacco smoking; breath CO would be a suitable alternative for busy clinics. Half the patients were subjected to regular advice on risk factor management but there was no evidence that this contributed effectively to smoking cessation. Overall smoking cessation rate was poor.

Adult↗

Non-invasive assessment of airway inflammation in ship-engine workers.

Smoking is harmful for respiratory function. In young to middle-aged men the damage is insidious and difficult to demonstrate. The respiratory impairment could increase under specific stressful conditions in the professional environment. On the hypothesis that exhaled markers are useful for assessing airway susceptibility to inhaled irritants, we measured exhaled markers and lung function in smoking and non-smoking engine-driver military coastguards before and after a patrol at sea. Eighteen men, mean age 39 yrs (range 23-58 yrs), 8 smokers, underwent spirometry, exhaled and nasal nitric oxide (eNO, nNO), exhaled carbon monoxide (CO) and exhaled breath condensate (EBC) for measures of hydrogen peroxide (H2O2), leukotriene B4 (LTB4), proteins (Prots), 8-isoprostanes (8-IsoPs), nitrite (NO2-) and nitrosothiols (RS-NOs) at baseline and after an 8-hour patrol navigation on board small, high-speed diesel-powered ships. At baseline, the smokers showed higher middle flows and CO levels, lower eNO and nNO than non-smokers, but similar levels of EBC markers; geometric means (95% confidence interval), CO: 23.6 (14.5 to 38.3) vs. 3.5 (2.5 to 5.3) ppm; eNO: 7.9 (4.8 to 12.9) vs. 26.7 (15.7 to 45.5) ppb, p=0.000. After navigation, Prots, 8-IsoPs and RS-NOs (but not lung function variables or other markers) significantly increased only in smokers; baseline vs post-navigation RS-NOs: 0.27 (0.11 to 0.65) vs. 1.30 (0.58 to 2.89) micromol, p=0.012. The respiratory consequences of a stressing environment in engine-driver military coastguards who actively smoke are better assessed by measuring EBC markers than by eNO, nNO or lung function. By increasing airway inflammation from oxidative-stress, tobacco smoking appears to interact with other chemical or physical factors elicited during sea navigation. Precisely what these factors are deserves further investigation.

Adult↗

Markers of lung disease in exhaled breath: nitric oxide.

Management of airway inflammation requires proper monitoring and treatment to improve long-term outcomes. However, achieving this goal is difficult, as current methods have limitations. Although nitric oxide (NO) was first identified 200 years ago, its physiological importance was not recognized until the early 1980s. Many studies have established the role of NO as an essential messenger molecule in body systems. In addition, studies have demonstrated a significant relationship between changes in exhaled NO levels and other markers of airway inflammation. The technique used to measure NO in exhaled breath is noninvasive, reproducible, sensitive, and easy to perform. Consequently, there is growing interest in the use of exhaled NO in the management of asthma and other pulmonary conditions. The purpose of this review is to promote a basic understanding of the physiologic actions of NO, measurement techniques, and ways that research findings might translate to future application in clinical practice. Specifically, the article will review the role of exhaled NO in regard to its historical background, mechanisms of action, measurement techniques, and implications for clinical practice and research.

Asthma↗

The clinical course of acute disseminated encephalomyelitis.

The objective of this review is to describe recent advances in understanding the clinical course of pediatric and adult acute disseminated encephalomyelitis (ADEM), especially the risk of relapse and conversion to multiple sclerosis (MS). The diagnosis of ADEM is reached on clinical grounds, typically in the setting of a post-infectious meningoencephalitic syndrome associated with multifocal neurological symptoms and signs, magnetic resonance imaging (MRI) evidence of white matter lesions and exclusion of other causes. Although typically monophasic, several case series demonstrate 'multiphasic' or 'recurrent' forms of ADEM with clinical relapses occurring within a short interval of disease onset. Furthermore, the estimated risk of developing MS is substantial for both children (0-33%) and adults (approximately 35%). Advances in neuroimaging have identified some MRI features that have predictive value for a relapsing course but they are not accurate enough for therapeutic decision-making; a diagnosis of monophasic ADEM should be made with caution in all cases, especially those presenting in adulthood. Research in ADEM and related disorders remains hampered by lack of prospective studies, specific and reproducible clinical case definitions and variable follow-up methods. Standardization of these variables would facilitate identification of more accurate diagnostic and prognostic variables, discovery and testing of potential objective biomarkers that would, in turn, allow early prediction of a relapsing course and appropriate therapeutic interventions.

Encephalomyelitis, Acute Disseminated↗

Non-invasive biomarkers of oxidative stress: reproducibility and methodological issues.

Oxidative stress is the hallmark of various chronic inflammatory lung diseases. Increased concentrations of reactive oxygen species (ROS) in the lungs of such patients are reflected by elevated concentrations of oxidative stress markers in the breath, airways, lung tissue and blood. Traditionally, the measurement of these biomarkers has involved invasive procedures to procure the samples or to examine the affected compartments, to the patient's discomfort. As a consequence, there is a need for less or non-invasive approaches to measure oxidative stress. The collection of exhaled breath condensate (EBC) has recently emerged as a non-invasive sampling method for real-time analysis and evaluation of oxidative stress biomarkers in the lower respiratory tract airways. The biomarkers of oxidative stress such as H2O2, F2-isoprostanes, malondialdehyde, 4-hydroxy-2-nonenal, antioxidants, glutathione and nitrosative stress such as nitrate/nitrite and nitrosated species have been successfully measured in EBC. The reproducibility, sensitivity and specificity of the methodologies used in the measurements of EBC oxidative stress biomarkers are discussed. Oxidative stress biomarkers also have been measured for various antioxidants in disease prognosis. EBC is currently used as a research and diagnostic tool in free radical research, yielding information on redox disturbance and the degree and type of inflammation in the lung. It is expected that EBC can be exploited to detect specific levels of biomarkers and monitor disease severity in response to appropriate prescribed therapy/treatment.

Antioxidants↗

Exhaled nitric oxide measurement in workers in a microwave popcorn production plant.

Airways obstruction in microwave-popcorn workers has been attributed to inhalation of flavoring agents. Two former workers at a microwave-popcorn plant were found by lung biopsy to have bronchiolitis obliterans. The study's aim was to determine whether exhaled nitric oxide (FENO) levels were associated with exposure levels, respiratory symptoms, or airways obstruction. A questionnaire, spirometry, and FENO measurements were completed by 135 workers. The FENO levels of workers with high flavoring exposures (n = 107) were compared with those of workers with low exposures (n = 28) and healthy external controls (n = 31). FENO levels were significantly lower in the high-exposure group (p < 0.05). There is no indication that FENO is useful as a marker of lung injury in a flavoring-exposed worker population with a substantial lung disease burden, but the finding of low FENO in the high-exposure group should not be dismissed.

Adolescent↗

"Haemoxygenase-1 induction and exhaled markers of oxidative stress in lung diseases", summary of the ERS Research Seminar in Budapest, Hungary, September, 1999.

In recent years, there has been increasing interest in noninvasive monitoring of airway inflammation and oxidative stress. Several volatile and nonvolatile substances can be measured in exhaled breath and have been suggested as potential biomarkers of these events. Exhaled gases, including carbon monoxide (CO), alkanes (ethane, pentane), and substances measured in breath condensate, such as hydrogen peroxide (H2O2) and isoprostanes were all suggested as potential markers of oxidative stress in the lung. A European Respiratory Society (ERS) International Research Seminar entitled "Haemoxygenase-1 induction and exhaled markers of oxidative stress in lung diseases" was organized by the Airway Regulation and Provocation Group of the Clinical Allergy and Immunology Assembly in Budapest, Hungary in September, 1999 to integrate the latest knowledge on these issues and accelerate further improvement in this area. During this 2-day event several issues were raised about: the use and standardization of measurements in exhaled breath; problems of measuring expired H2O2 and other mediators in breath condensate; role and regulation of haemoxygenase (HO)-1 in the lung; and conditions and factors influencing exhaled CO. This report is a summary of the main presentations at the seminar, together with the current areas of research in this rapidly expanding field.

Antioxidants↗

Elevated nitrite in breath condensates of children with respiratory disease.

The aim of the study was to determine the differences in nitrite, in the exhaled breath condensates of healthy children and those children with asthma, cystic fibrosis (CF) and nonasthmatic, episodic cough. Breath condensates were obtained from 66 children (43 males:23 females, 3.1-16 yrs) and included 29 asthmatics, 12 clinically stable CF patients, 12 children with cough but not asthma and 13 healthy volunteers. The collected condensate was assayed colourimetrically using the Griess reaction to determine nitrite concentrations. Patients with CF (median: 5-95% percentiles; 2.02: 0.43-6.37 microM) or asthma (2.10: 0.63-5.45 microM) had significantly higher levels of nitrite compared to healthy subjects (0.41: 0.13-1.83 microM; p<0.05) or subjects with cough (0.75: 0.03-1.75 microM; p<0.05). Airway inflammation, as assessed by the nitrite in breath condensates, is present in children with asthma and cystic fibrosis, but not those children with nonasthmatic, episodic cough. Nitrite can be conveniently, cheaply and rapidly measured in breath condensates of children as young as 3 yrs of age, and may prove useful for the assessment of airway inflammation in children with respiratory disease.

Adolescent↗

Exhaled nitric oxide and bronchial responsiveness in healthy subjects exposed to organic dust.

Inhalation of organic dust from swine houses causes an intense inflammatory reaction in the respiratory tract, and increased bronchial responsiveness to methacholine in healthy subjects. The aims of the present study were to investigate whether exhaled nitric oxide (NO) is a marker of the inflammation caused by exposure to organic dust (swine dust), whether there is a relationship between an increase in exhaled NO and bronchial responsiveness, and also whether wearing a half-mask influences the airway reaction (assessed by exhaled NO) and the increased bronchial responsiveness. Thirty-three healthy nonatopic, nonsmoking subjects were exposed during 3 h of light work in a swine confinement building. Eleven of the subjects were wearing a half-mask and 22 were unprotected. Lung function, bronchial responsiveness and exhaled NO were measured before and after exposure. The provocative concentration causing a 20% fall in forced expiratory volume in one second fell by 2.7 (2.1-4.1) (median (25th-75th percentiles)) doubling concentration steps in subjects without a half-mask and by 1.5 (0.9-2.9) doubling concentration steps in subject wearing a mask. Exhaled NO increased from 7.5 (5.7-13.7) parts per billion (ppb) before to 13.4 (10.5-17.5) ppb after exposure in the unprotected group and was unaltered (8.3 (6.1-14.1) to 8.6 (6.6-14.6) ppb) in the group wearing a half-mask. There was no correlation between NO increase and provocative dose causing a 20% fall in the forced expiratory volume in one second decrease. In conclusion, bronchial responsiveness and exhaled nitric oxide increased after exposure to a swine confinement facility. Half-mask abolished the increase in exhaled nitric oxide levels, but influenced the increase in bronchial responsiveness to a minor extent. These results indicate that these two outcome measures reflect different aspects of airway inflammation induced by exposure to a farming environment.

Adult↗

Exhaled breath condensate pH is a robust and reproducible assay of airway acidity.

Exhaled breath condensate (EBC) pH is low in several lung diseases and it normalises with therapy. The current study examined factors relevant to EBC pH monitoring. Intraday and intraweek variability were studied in 76 subjects. The pH of EBC collected orally and from isolated lower airways was compared in an additional 32 subjects. Effects of ventilatory pattern (hyperventilation/hypoventilation), airway obstruction after methacholine, temperature (-44 to +13 degrees C) and duration of collection (2-7 min), and duration of sample storage (up to 2 yrs) were examined. All samples were collected with a disposable condensing device, and de-aerated with argon until pH measurement stabilised. Mean EBC pH (n=76 subjects, total samples=741) was 7.7+/-0.49 (mean+/-SD). Mean intraweek and intraday coefficients of variation were 4.5% and 3.5%. Control of EBC pH appears to be at the level of the lower airway. Temperature of collection, duration of collection and storage, acute airway obstruction, subject age, saliva pH, and profound hyperventilation and hypoventilation had no effect on EBC pH. The current authors conclude that in health, exhaled breath condensate pH is slightly alkaline, held in a narrow range, and is controlled by lower airway source fluid. Measurement of exhaled breath condensate pH is a simple, robust, reproducible and relevant marker of disease.

Acid-Base Equilibrium↗

Prevalence of asthma and exhaled nitric oxide are increased in bleachery workers exposed to ozone.

The aims of the present study were to determine whether exposure to high peaks of ozone resulted in an increased prevalence of asthma or respiratory symptoms among bleachery workers and whether nitric oxide (NO) was elevated in the exhaled air of these workers. Bleachery workers (n=228) from three Swedish pulp mills who had been exposed to ozone, together with 63 unexposed control subjects, were investigated by means of spirometry, Phadiatop, exhaled and nasal NO and answers to a questionnaire concerning respiratory symptoms and exposure. Exposure to an ozone peak that gave rise to respiratory symptoms was defined as a "gassing". Bleachery workers reporting four or more gassings involving ozone had an increased prevalence of adult-onset asthma, wheeze, and current asthma symptoms. They also had a higher median concentration of exhaled NO in comparison with those who reported no such gassings (19.2 versus 15.7 parts per billion). No such associations were found in respect of nasal NO. The results from this study show that bleachery workers who have been repeatedly exposed to ozone gassings have an increased prevalence of adult-onset asthma. The results also indicate exhaled nitric oxide may be a marker of airway inflammation in bleachery workers who have been exposed to high peaks of ozone.

Adult↗

Comparison between exhaled and sputum oxidative stress biomarkers in chronic airway inflammation.

The aim of the present study was to compare aldehyde levels resulting from lipid peroxidation in exhaled breath condensate (EBC) and induced sputum (IS) supernatant of subjects with asthma and chronic obstructive pulmonary disease (COPD). Aldehydes (malondialdehyde (MDA), acrolein, n-hexanal (C6), n-heptanal (C7), n-nonanal (C9), 4-hydroxynonenal (HNE) and 4-hydroxyhexenal (HHE)) in both biological fluids were measured by liquid chromatography-tandem mass spectrometry. MDA concentrations in sputum were 132.5 nM (82.5-268.8) and 23.7 nM (9-53.7) in EBC. Similarly, C6, C7 and C9 concentrations in IS were 1.5-4.7-fold higher than in EBC. Acrolein levels were 131.1 nM (55.6-264.6) in IS and 45.3 nM (14.4-127.1) in EBC. The concentrations of HNE and HHE in IS were not significantly different from the levels in EBC. Aldehyde levels in EBC did not show any correlation with aldehyde levels in IS or with differential sputum cellular count. In COPD, MDA in EBC, but not its IS counterpart, was negatively correlated with the severity of disease. In conclusion, the data presented here show that aldehydes can be detected in both exhaled breath condensate and supernatant of induced sputum, but that their relative concentrations are different and not correlated with each other. Therefore, with regard to lipid peroxidation products, exhaled breath condensate and induced sputum must be considered as independent techniques.

Adult↗

Exhaled breath condensate: methodological recommendations and unresolved questions.

Collection of exhaled breath condensate (EBC) is a noninvasive method for obtaining samples from the lungs. EBC contains large number of mediators including adenosine, ammonia, hydrogen peroxide, isoprostanes, leukotrienes, nitrogen oxides, peptides and cytokines. Concentrations of these mediators are influenced by lung diseases and modulated by therapeutic interventions. Similarly EBC pH also changes in respiratory diseases. The aim of the American Thoracic Society/European Respiratory Society Task Force on EBC was to identify the important methodological issues surrounding EBC collection and assay, to provide recommendations for the measurements and to highlight areas where further research is required. Based on the currently available evidence and the consensus of the expert panel for EBC collection, the following general recommendations were put together for oral sample collection: collect during tidal breathing using a noseclip and a saliva trap; define cooling temperature and collection time (10 min is generally sufficient to obtain 1-2 mL of sample and well tolerated by patients); use inert material for condenser; do not use resistor and do not use filter between the subject and the condenser. These are only general recommendations and certain circumstances may dictate variation from them. Important areas for future research involve: ascertaining mechanisms and site of exhaled breath condensate particle formation; determination of dilution markers; improving reproducibility; employment of EBC in longitudinal studies; and determining the utility of exhaled breath condensate measures for the management of individual patients. These studies are required before recommending this technique for use in clinical practice.

Biomarkers↗

Effects of exacerbations and seasonality on exhaled nitric oxide in COPD.

Exhaled nitric oxide (eNO) appears to be associated with airway inflammation seen in chronic obstructive pulmonary disease (COPD). The present authors studied the effects of exacerbation, season, temperature and pollution on eNO. eNO was measured seasonally and at exacerbations in 79 outpatients suffering from COPD (mean forced expiratory volume in one second=42%). The effects of exacerbation symptoms, physiological and environmental parameters were analysed. Stable eNO levels were correlated positively with arterial oxygen tension. Median levels were found to be lower in smokers (5.3 ppb) than in ex- or nonsmokers (6.8 ppb). Levels were higher during October to December (6.9 ppb) than in April to June (4.6 ppb). Levels were also higher during 68 exacerbations in 38 patients (7.4 ppb) than in stable conditions (5.4 ppb), independent of the effects of smoking. The rise in eNO was greater in exacerbations that were associated with colds, a sore throat or dyspnoea combined with a cold. In conclusion, exhaled nitric oxide levels were higher in colder weather and in the autumn, perhaps related to the increased prevalence of viral infection at this time of year. The levels were lower in more severe chronic obstructive pulmonary disease. Exhaled nitric oxide levels were raised at the onset of exacerbation, particularly in the presence of a cold.

Age Distribution↗