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.     

Nitric oxide but not carbon monoxide is continuously released in the human nasal airways.

Results from different laboratories indicate that nitric oxide (NO) and carbon monoxide (CO) coexist in the human airways both in health and disease. These gases are present in exhaled human breath and high concentrations of NO as well as CO have been reported in the nasal airways. In addition, exhaled CO and NO are increased in patients with airways inflammation. NO and CO were measured simultaneously in orally exhaled air and in air sampled from the nose in 18 healthy subjects using chemiluminescence (for NO) and infrared (for CO) techniques at different fixed flow rates. The acute effects of smoking on airway release of NO and CO were also studied. Nasal NO was detected in all subjects and the concentrations were highly flow-dependent (mean+/-SEM: 236+/-23 and 527+/-49 parts per billion (ppb), at 2 and 0.5 L x min(-1), respectively). In contrast, no evidence of CO release in the nasal airways regardless of sample flow rate was found. In fact, additional experiments indicated a net absorption of CO when low levels of this gas were flushed through the nasal cavity. Nasal CO also remained undetectable after smoking. Both NO (22+/-2 ppb) and CO (1.1+/-0.1 parts per million) were consistently found in orally exhaled air. CO, but not NO, levels increased acutely after smoking a cigarette. The authors conclude that the patterns of nitric oxide and carbon monoxide release in the airways seem to differ profoundly in healthy subjects. Orally exhaled air contains both nitric oxide and carbon dioxide whereas nasal air contains nitric oxide only.     

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.     

Exhaled nitric oxide in specific challenge tests to assess occupational asthma.

Exhaled nitric oxide (NO) is a marker of eosinophilic inflammation of the airway mucosa accompanying changes in the clinical condition of asthma. Allergen exposure has been associated with delayed elevation of exhaled NO. The aim of this study was to assess the asthmatic airway inflammation with exhaled NO measurements during specific bronchial challenge tests with occupational agents. Forty patients with suspected occupational asthma were investigated. Specific bronchial challenge tests were performed with forced expiratory volume in one second or peak expiratory flow follow-up, supplemented by exhaled NO measurements before and 24 h after challenge tests. In active challenges, which induced bronchoconstriction, a significant mean increase of exhaled NO concentration was noted. In patients with a normal or slightly increased (<14.5 parts per billion (ppb)) basal NO level and a late bronchoconstriction, a significant increase in exhaled NO was seen. Patients with a high basal NO level (>14.5 ppb) and a significant bronchoconstriction did not show a significant NO elevation. Challenge tests without bronchoconstriction were not associated with a significant elevation of exhaled NO. Exhaled nitric oxide measurements can be used to indicate the development of airway inflammation accompanying late asthmatic reaction after bronchial challenge tests in patients with a normal or slightly increased basal nitric oxide concentration.     

Reference values of exhaled nitric oxide for healthy children 6-15 years old

Nitric oxide (NO) can be detected in human exhaled air, and its endogenous production is increased in patients with asthma. It may provide a noninvasive means for measuring airway inflammation. The aim of this study was to establish reference values for exhaled NO concentrations in a large number of healthy school-age children. We measured exhaled NO levels in 159 white healthy children (88 girls, 71 boys, age range 6-15 years) recruited from two public schools of Padua, Italy. Exhaled NO levels in exhaled gas were measured by a tidal breathing method with a chemiluminescence analyzer, and NO steady-state levels were recorded. Nasal NO levels were measured by direct sampling from the nose during mouth breathing. The mean concentration of endogenous NO in orally exhaled gas was 8.7 parts per billion (ppb) (95% confidence interval (C.I.), 8.1-9.2 ppb) and sampled data followed a log-normal distribution (Kolmogorov-Smirnov d = 0.77, P > 0.2). No difference was found between boys (mean value, 8.4 ppb; 95% C.I., 7.3-9.4 ppb) and girls (mean value, 8.9 ppb; 95% C.I., 7.9-9.9 ppb). No significant correlation was found between age, height, or spirometric data and exhaled NO levels (r < 0.2). The mean value of nasal NO concentrations was 216 ppb (95% C.I., 204-228 ppb). There was no correlation between exhaled and nasal NO values (r = 0.16, P = ns). In conclusion, this study establishes a reference range for exhaled NO values measured by a tidal breathing method in children between age 6-15 years. The observed levels are independent of age, gender, and lung function, and can be used to monitor airway inflammation in asthmatic children.     

Exhaled nitric oxide among pulpmill workers reporting gassing incidents involving ozone and chlorine dioxide.

The aim of the study was to investigate whether measurement of nitric oxide in exhaled air could be used for assessing the effects of irritants on the respiratory system, in this case recurrent ozone gassing in an occupational setting. The study population comprised bleachery workers (n=56) from a Swedish pulpmill carrying out ozone-based pulp bleaching since 1992 and controls (n=39). Both groups were investigated by measuring NO in exhaled air, methacholine challenge test and answers to a questionnaire concerning history of respiratory symptoms and accidental exposure to ozone peaks. There was no significant difference in NO output between exposed subjects and controls (median 67.2 versus 55.0 nL x min(-1), p=0.64). However, among bleachery workers reporting ozone gassings, the median NO output was 90.0 nL x min(-1) compared to 58.8 nL x min(-1) among those not reporting such incidents (p=0.019). There was no relation between exhaled NO and the prevalence of respiratory symptoms or bronchial hyperresponsiveness. In a multiple regression model, only reported ozone gassings were associated (p=0.016) with NO output. The results indicate an association between previous response to ozone gassing and nitric oxide output. The increased nitric oxide output among the bleachery workers reporting peak ozone exposure may indicate that chronic airway inflammation is present. Further studies are needed to evaluate the extent to which nitric oxide can be used for biological monitoring of respiratory health effects, and to relate it to other markers of airway inflammation.     

Gas and dust exposure in underground construction is associated with signs of airway inflammation.

Exposure to gases and dust may induce airway inflammation. It was hypothesized that heavy construction workers who had been exposed to dust and gases in underground construction work for 1 yr, would have early signs of upper and lower airway inflammation, as compared to outdoor workers. A study group comprising 29 nonsmoking underground concrete workers (mean +/- SD age 44+/-12 yrs), and a reference group of 26 outdoor concrete workers (39+/-12 yrs) were examined by acoustic rhinometry, nasal and exhaled nitric oxide spirometry and a questionnaire on respiratory symptoms. Exposure measurements were carried out. The underground workers had higher exposure to total and respirable dust, alpha-quartz and nitrogen dioxide than the references (p<0.001). The occurrence of respiratory symptoms was higher in the underground workers than in the references (p<0.05). Exhaled nitric oxide (NO) (geometric mean+/-SEM) was higher in the underground workers than in the references (8.4+/-1.09 versus 5.6+/-1.07 parts per billion (ppb), p = 0.001), whereas spirometric values were comparable. The underground workers had smaller nasal cross-sectional area and volume than the references, and more pronounced increases after decongestion (p<0.001). To conclude the exposure in underground construction may cause nasal mucosal swelling and increased levels of exhaled nitric oxide, indicating signs of upper and lower airway inflammation.     

Exhaled and nasal nitric oxide as a marker of pneumonia in ventilated patients

Because inflammation stimulates the expression of inducible nitric oxide (NO) synthase (iNOS) with an associated increased local NO production, we hypothesized that patients with pneumonia would have increased excretion of NO into their airways. To test this hypothesis, NO was measured in the exhaled air and from the nasal cavities of 49 consecutively intubated and mechanically ventilated patients in our ICU. After excluding NO gas contamination in the inspiratory circuit, nasal NO and end-expiratory and mean exhaled tracheal NO levels and plasma nitrate concentrations were measured using a fast response chemiluminescence analyzer. Twenty-one patients (43%) presented with infectious pneumonia. End- expiratory exhaled NO concentrations were significantly higher in patients with pneumonia as compared with patients without pneumonia (5.9 +/- 1 ppb versus 3.2 +/- 0.5 ppb, p < 0.01). Similarly, mean nasal NO was higher in patients with pneumonia (1039 +/- 138 ppb versus 367 +/- 58 ppb, p = 0.003). Plasma nitrate levels did not differ between patient groups. Threshold values of tracheal or nasal NO were defined and subsequently validated in 60 other patients. Positive and negative values of a maximal tracheal level > 5 ppb for pneumonia were 74% and 89%, respectively. Thus tracheal and nasal NO levels may be of help in distinguishing patients with acute pneumonia from other causes. Furthermore, because these differences in airway NO levels were not paralleled in blood nitrite concentrations, we conclude that pneumonia per se is not associated with systemic NO production.     

Nitric oxide synthase inhibitors attenuate ozone-induced airway inflammation in guinea pigs. Possible role of interleukin-8

Nitric oxide (NO) is increased in exhaled air of asthmatics. We hypothesized that endogenous NO contributes to airway inflammation and hyperresponsiveness, and that interleukin-8 (IL-8) might be involved in this mechanism. In human transformed bronchial epithelial cells in vitro, NO donors increased IL-8 production dose-dependently. In addition, tumor necrosis factor-alpha (TNF-alpha) plus IL-1beta plus interferon-gamma (IFN-gamma) increased IL-8 in culture supernatant of epithelial cells; the combination of NO synthase (NOS) inhibitors, aminoguanidine (AG) plus N(G)-nitro-L-arginine methyl ester (L-NAME) attenuated the cytokine-induced IL-8 production in epithelial cells. In guinea pigs in vivo, ozone exposure induced airway hyperresponsiveness to acetylcholine and increased neutrophils in bronchoalveolar lavage fluid (BALF), and these changes persisted for at least 5 h. Pretreatment with NOS inhibitors had no effect on airway hyperresponsiveness or neutrophil accumulation immediately after ozone, but significantly inhibited the changes 5 h after ozone. NOS inhibitors also attenuated the increases of nitrite/nitrate levels in BALF and the IL-8 mRNA expression in epithelial cells and in neutrophils in guinea pig airways 5 h after ozone. These results suggest that endogenous NO may play an important role in the persistent airway inflammation and hyperresponsiveness after ozone exposure, presumably partly through the upregulation of IL-8.     

Off-line sampling of exhaled air for nitric oxide measurement in children: methodological aspects.

Measurement of nitric oxide in exhaled air is a noninvasive method to assess airway inflammation in asthma. This study was undertaken to establish the reference range of exhaled NO in healthy school-aged children and to determine the influence of ambient NO, noseclip and breath-holding on exhaled NO, using an off-line balloon sampling method. All children attending a primary school (age range 8-13 yrs) underwent NO measurements on two occasions with high and low ambient NO. Each time, the children performed four expiratory manoeuvres into NO-impermeable balloons, with and without 10 s of breath-holding and with and without wearing a noseclip. Exhalation flow and pressure were not controlled. NO was measured within 4 h after collection, by means of chemiluminescence. All children completed a questionnaire on respiratory and allergic disorders, and performed flow/volume spirometry. With low ambient NO, the mean exhaled NO value of 72 healthy children with negative questionnaires and normal lung function was 5.1 +/- 0.2 parts per billion (ppb) versus a mean of 6.8 +/- 0.3 ppb in the remaining 49 children with positive questionnaires for asthma and allergy, and/or recent symptoms of cold (p=0.001). Exhaled and ambient NO were significantly related, especially with ambient NO > 10 ppb (r = 0.86, p=0.0001 versus r=0.34, p=0.004 for ambient values <10 ppb). The use of a noseclip, with low ambient NO and without breath-holding, caused a small decrease in exhaled NO values (p=0.001). The effect of breath-holding on exhaled NO depended on ambient NO. With ambient NO > 10 ppb, exhaled NO decreased, whereas with ambient NO < 10 ppb, exhaled NO increased after 10 s breath-hold. It is concluded that off-line sampling in balloons is a simple and, hence, attractive method for exhaled nitric oxide measurements in children which differentiates between groups with and without self-reported asthma, allergy and colds, when ambient nitric oxide is < 10 parts per billion. Wearing a noseclip and breath-holding affected measured values and should, therefore be standardized or, preferably, avoided.     

Decreased concentration of exhaled nitric oxide (NO) in patients with cystic fibrosis

Nitric oxide (NO) is produced by various cell types in the human respiratory tract. Endogenously produced nitric oxide is detectable in the exhaled air of healthy individuals. Exhaled NO has been shown to be increased in airway inflammation, most probably due to cytokine-mediated activation of NO synthases. To assess whether NO can serve as a marker of inflammation in cystic fibrosis (CF) lung disease, we measured exhaled NO in CF patients with a chemiluminescence analyser. Single breath measurements were performed in 27 stable CF patients (age range, 6–40 years) and 30 non-smoking controls (age range, 6–37 years). Exhaled NO concentrations were 9.1 ± 3.6 ppb in the controls and 5.9 ± 2.6 ppb (P < 0.001) in CF patients. To account for room air NO concentrations on the measurement of exhaled NO, we also calculated the difference between exhaled NO and ambient NO concentrations. Difference values were also significantly lower in CF compared with controls (P < 0.0001). In CF patients there was a positive correlation between exhaled NO and forced vital capacity (r = 0.43, P = 0.033), suggesting that exhaled NO is lower in patients with severe lung disease than in those with mild disease. We conclude that measurements of exhaled NO in CF does not reflect activity of CF airway inflammation. The decreased concentrations of exhaled NO may be due to inhibitory effects of inflammatory cytokines on NO synthases in the airways and alveolar epithelial cells or to increased retention in airway secretions. Pediatr. Pulmonol. 1997; 24:173–177. © 1997 Wiley-Liss, Inc.     

Exhaled nitric oxide--is it really a good marker of airway inflammation in bronchial asthma?

BACKGROUND: The concentration of exhaled nitric oxide ([NO]) has been reported to reflect the inflammatory process of airways in patients with bronchial asthma, particularly when they are steroid naive. However, it is not fully understood whether it equally reflects the degree of airway inflammation in patients receiving inhaled corticosteroids, but whose symptoms are not necessarily well controlled. OBJECTIVE: To examine whether the exhaled [NO] really reflects airway inflammation in patients with bronchial asthma, regardless of treatment with inhaled steroids. METHODS: Exhaled [NO] was measured in patients with bronchial asthma (43 steroid treated and 32 steroid naive), chronic obstructive pulmonary disease (COPD) (n = 36), bronchiectasis (n = 10) and in control subjects (n = 26). We examined in each asthmatic group whether the exhaled [NO] correlated with parameters reflecting airway inflammation. RESULTS: Exhaled [NO] was significantly correlated with symptom score, clinical severity, circulating eosinophil count, and the percentage of eosinophils in induced sputum in the steroid-naive asthmatics, but not in the steroid-treated asthmatics, although airway inflammation in this group was not well controlled, as evidenced by clinical symptoms and the higher percentage of eosinophils in induced sputum. Exhaled [NO] from the patients with COPD (6.2 +/- 0. 7 ppb) or bronchiectasis (5.4 +/- 1.3 ppb) was not significantly increased compared with the controls (6.0 +/- 1.0 ppb), and was significantly lower than in the asthmatic patients as a whole (19.0 +/- 2.0 ppb). CONCLUSIONS: Although exhaled [NO] is a useful marker of airway inflammation for differential diagnosis and evaluation of severity in steroid-naive patients with bronchial asthma, it may not be as useful in steroid-treated patients.     

Permeability, inflammation and oxidant status in airspace epithelium exposed to ozone

The aim of the study was to investigate possible mechanisms of epithelial injury in normal subjects exposed to environmentally relevant concentrations of ozone. Fifteen healthy non-smoking subjects (M:F 12:3) were studied. Five of the 15 subjects were exposed to filtered air, six were exposed to ozone 100 parts per billion (ppb) and seven were exposed to ozone 400 ppb with 99mtechnetium labelled diethylene-triamine-penta-acetate (99mTc-DTPA) or bronchoalveolar lavage (BAL) performed 1 or 6 h after exposure as indicated above. All the above studies were performed on different occasions at least 5 days apart. The subjects were exposed on each occasion for 1h during intermittent exercise at a ventilation of 40l min-1. 99mTc-DTPA lung clearance did not change after either level of ozone exposure, but neutrophils increased in BAL 6 h after exposure to 400 ppb. Superoxide anion release from mixed BAL leucocytes decreased 1 h after 100 ppb and 6 h after 400 ppb. Products of lipid peroxidation in epithelial lining fluid decreased both 1 and 6 h after 400 ppb. There was no change in anti-oxidant capacity or glutathione concentrations. Ozone exposure did not increase epithelial permeability, but was associated with neutrophil influx into the airspaces, without evidence of increased oxidative stress.     

Clinical aspects of exhaled nitric oxide.

There has been intense research into the role nitric oxide (NO) plays in physiological and pathological mechanisms and its clinical significance in respiratory medicine. Elevated levels of exhaled levels of exhaled NO in asthma and other inflammatory lung diseases lead to many studies examining NO as potential markers of airway inflammation, enabling repeated noninvasive and standardized monitoring of airway inflammation. In airway inflammation, NO is not merely a marker but may have anti-inflammatory and pro-inflammatory effects. Significant correlation has been found between exhaled NO and skin test scores in steroid naive asthmatic patients, allowing to discriminate patients with and without airway responsiveness. Exhaled NO is significantly elevated in acute asthma, or steroid-resistant severe asthma, or when the maintenance dose of inhaled steroids is reduced, and quickly reduced down to the levels in patients with stable asthma after steroid treatment. Exhaled NO has been successfully used to monitor anti-inflammatory treatment with inhaled corticosteroids in asthma. Exhaled NO is extremely sensitive and rapid marker of the dose-dependent effect of steroid treatment, or asthma deterioration, which is increased to any changes in lung function, provocative concentration causing a 20% fall in forced expiratory volume, sputum eosinophilia or asthma symptoms. Exhaled NO is not increased in stable chronic obstructive pulmonary disease (COPD), but patients with unstable COPD, or bronchiectasis have high NO levels. Exhaled and nasal NO are diagnostically low in cystic fibrosis and primary pulmonary dyskinesia. Analysis of exhaled air, including nitric oxide, is feasible and could provide a noninvasive method for use in monitoring and management of lung diseases.     

Early rise in exhaled nitric oxide and mast cell activation in repeated low-dose allergen challenge.

Repeated low-dose allergen inhalation challenge mimics natural allergen exposure, providing a model for early mechanisms in the triggering of asthma. The current authors performed a controlled study to evaluate the time course of changes in exhaled nitric oxide fraction (F(e,NO)) and urinary biomarkers of airway inflammation. Eight subjects with mild allergic asthma completed two 7-day repeated low-dose challenge periods, with diluent and allergen, respectively. Subjects were symptom free at inclusion and were investigated when not exposed to specific allergen. Pulmonary function and symptoms were followed, and F(e,NO) and urinary mediators were correlated to changes in airway responsiveness to histamine and adenosine. Despite no change in pulmonary function (forced expiratory volume in one second mean+/-sem fall 0.3+/-0.7 versus 0.6+/-1.0%, for diluent and allergen, respectively) and no asthma symptoms, repeated allergen exposure, in contrast to diluent, caused significant increases in histamine responsiveness (2.3 doubling doses), an early and gradual increase in F(e,NO) (up to a doubling from baseline) and a small increase in the mast cell marker 9alpha11beta-prostaglandin F(2) after adenosine challenge. In conclusion, serial measurements of exhaled nitric oxide fraction have the potential to provide a very sensitive strategy for early detection of emerging airway inflammation and subsequent changes in airway hyperresponsiveness to histamine.     

Effect of atmospheric nitric oxide (NO) on measurements of exhaled NO in asthmatic children

The measurement of exhaled nitric oxide concentrations [NO] may provide a simple, noninvasive means for measuring airway inflammation. However, several measurement conditions may influence exhaled NO levels, and ambient NO may be one of these. We measured exhaled NO levels in 47 stable asthmatic children age 5 to 17 years and in 47 healthy children, gender and age matched. Exhaled [NO] in expired air was measured by a tidal breathing method with a chemiluminescence analyzer, sampling at the expiratory side of the mouthpiece. NO steady-state levels were recorded. In order to keep the soft palate closed and avoid nasal contamination, the breathing circuit had a restrictor providing an expiratory pressure of 3–4 cm H₂O at the mouthpiece. To evaluate the effect of [NO] in ambient air, measurements were randomly performed by breathing ambient air or NO-free air from a closed circuit. Breathing NO-free air, exhaled [NO] in asthmatics (mean ± SEM) was 23.7 ± 1.4 ppb, significantly higher (P < 0.001) than in healthy controls (8.7 ± 0.4 ppb). Exhaled NO concentrations measured during ambient air breathing were higher (49 ± 4.6 ppb, P < 0.001) than when breathing NO-free air (23.7 ± 1.4 ppb) and were significantly correlated (r = 0.89, P < 0.001) with atmospheric concentrations of NO (range 3–430 ppb). These findings show that (1) exhaled [NO] values of asthmatic children are significantly higher than in healthy controls, and (2) atmospheric NO levels critically influence the measurement of exhaled [NO]. Therefore, using a tidal breathing method the inhalation of NO-free air during the test is recommended. Pediatr Pulmonol. 1998; 26:30–34. © 1998 Wiley-Liss, Inc.     

Orally exhaled nitric oxide levels are related to the degree of blood eosinophilia in atopic children with mild-intermittent asthma.

Increased levels of nitric oxide have been found in expired air of patients with asthma, and these are thought to be related to the airway inflammatory events that characterize this disorder. Since, in adults, bronchial inflammatory changes are present even in mild disease, the present study was designed to evaluate whether a significant proportion of children with mild-intermittent asthma could have increased exhaled air NO concentrations. Twenty-two atopic children (aged 11.1+/-0.8 yrs) with mild-intermittent asthma, treated only with inhaled beta2-adrenoreceptor agonists on demand and 22 age-matched controls were studied. NO concentrations in orally exhaled air, measured by chemiluminescence, were significantly higher in asthmatics, as compared to controls (19.4+/-3.3 parts per billion (ppb) and 4.0+/-0.5 ppb, respectively; p<0.01). Interestingly, 14 out of 22 asthmatic children had NO levels >8.8 ppb (i.e. >2 standard deviations of the mean in controls). In asthmatic patients, but not in control subjects, statistically significant correlations were found between exhaled NO levels and absolute number or percentage of blood eosinophils (r=0.63 and 0.56, respectively; p<0.01, each comparison). In contrast, exhaled NO levels were not correlated with forced expiratory volume in one second (FEV1) or forced expiratory flows at 25-75% of vital capacity (FEF25-75%) or forced vital capacity (FVC), either in control subjects, or in asthmatic patients (p>0.1, each correlation). These results suggest that a significant proportion of children with mild-intermittent asthma may have airway inflammation, as shown by the presence of elevated levels of nitric oxide in the exhaled air. The clinical relevance of this observation remains to be established.     

Nasal nitric oxide improved by continuous positive airway pressure therapy for upper airway inflammation in obstructive sleep apnea

Purpose

In this report, we examined the association between obstructive sleep apnea (OSA) and upper and lower airway inflammation based on nitric oxide (NO) measurements.

Methods

Study subjects included 51 consecutive participants. Sleep-disordered breathing was evaluated by a type 3 portable monitor and quantified by respiratory disturbance index (RDI). Airway inflammation was noninvasively analyzed by the measurement of nasally and orally exhaled NO; nasal value was presented as nasally exhaled NO minus orally exhaled NO. In 15 patients prescribed nasal continuous positive airway pressure (nCPAP) therapy, exhaled NO was re-evaluated in 10.7 ± 6.3 months after nCPAP therapy.

Results

Nasal NO was significantly higher in patients with severe OSA (RDI ≥ 30/h) than those with non-OSA (RDI < 10/h) (76.9 ± 26.0 ppb vs. 47.9 ± 22.0 ppb, respectively, p = 0.016) and correlated with RDI (rho = 0.36, p = 0.0099), whereas orally exhaled NO did not differ between non-OSA and OSA patients and was not correlated with RDI. In 15 patients, nasal NO after nCPAP therapy was significantly decreased than that before nCPAP therapy (81.9 ± 31.2 ppb vs. 53.7 ± 27.2 ppb, respectively, p = 0.0046); in 11 patients having good compliance to nCPAP therapy (nCPAP use >4 h per night on more than 70% of nights), this association was more remarkable.

Conclusions

In OSA, upper but not lower airway inflammation can be increased by repetitive collapse of the upper airway. Future studies are required to determine the role of nasal NO in OSA.

     

Exhaled and nasal NO levels in allergic rhinitis: relation to sensitization, pollen season and bronchial hyperresponsiveness.

Exhaled nitric oxide is a potential marker of lower airway inflammation. Allergic rhinitis is associated with asthma and bronchial hyperresponsiveness. To determine whether or not nasal and exhaled NO concentrations are increased in allergic rhinitis and to assess the relation between hyperresponsiveness and exhaled NO, 46 rhinitic and 12 control subjects, all nonasthmatic nonsmokers without upper respiratory tract infection, were randomly selected from a large-scale epidemiological survey in Central Norway. All were investigated with flow-volume spirometry, methacholine provocation test, allergy testing and measurement of nasal and exhaled NO concentration in the nonpollen season. Eighteen rhinitic subjects completed an identical follow-up investigation during the following pollen season. Exhaled NO was significantly elevated in allergic rhinitis in the nonpollen season, especially in perennially sensitized subjects, as compared with controls (p=0.01), and increased further in the pollen season (p=0.04), mainly due to a two-fold increase in those with seasonal sensitization. Nasal NO was not significantly different from controls in the nonpollen season and did not increase significantly in the pollen season. Exhaled NO was increased in hyperresponsive subjects, and decreased significantly after methacholine-induced bronchoconstriction, suggesting that NO production occurs in the peripheral airways. In allergic rhinitis, an increase in exhaled nitric oxide on allergen exposure, particularly in hyperresponsive subjects, may be suggestive of airway inflammation and an increased risk for developing asthma.     

Alveolar, but not bronchial nitric oxide production is elevated in cystic fibrosis

Exhaled nitric oxide (NO) remains a promising non-invasive marker for measuring inflammation in lung diseases. In cystic fibrosis (CF), exhaled NO measured at a single expiratory flow has been found to be normal or low. However, this measure cannot localize the anatomical site of NO production. The aims of this study were to apply a multiple-flow NO analysis to compare alveolar NO concentration and bronchial NO flux in CF children with healthy controls. Twenty-two children with CF and 17 healthy controls had exhaled NO measured at four different expiratory flows to calculate bronchial NO flux and alveolar NO concentration. Median (range) alveolar NO concentration was 2.2 (0.6-5.6) ppb for children with CF and 1.5 (0.4-2.6) ppb for healthy controls. Median (range) bronchial NO flux was 445 (64-1,256) pL/sec for children with CF and 509 (197-1,913) pL/sec for healthy controls. Children with CF had a significantly higher alveolar NO concentration, but no significant difference in bronchial NO flux compared to healthy children. In conclusion, children with CF have increased alveolar NO production, but not bronchial NO flux compared to healthy controls. The distal airway is a major site of inflammation in CF, and measuring alveolar NO may be a marker of distal inflammation in this disease.