Asthma is associated with airway hyperresponsiveness and enhanced T-cell number/activity on one hand and increased levels of exhaled nitric oxide (NO) with expression of inducible NO synthase (iNOS) on the other hand. These findings are in paradox, as NO also relaxes airway smooth muscle and has immunosuppressive properties. The exact role of the endothelial NOS (eNOS) isoform in asthma is still unknown. We hypothezised that a delicate regulation in the production of NO and its bioactive forms by eNOS might be the key to the pathogenesis of asthma.
The contribution of eNOS on the development of asthmatic features was examined. We used transgenic mice that overexpress eNOS and measured characteristic features of allergic asthma after sensitisation and challenge of these mice with the allergen ovalbumin.
eNOS overexpression resulted in both increased eNOS activity and NO production in the lungs. Isolated thoracic lymph nodes cells from eNOS overexpressing mice that have been sensitized and challenged with ovalbumin produced significantly less of the cytokines IFN-γ, IL-5 and IL-10. No difference in serum IgE levels could be found. Further, there was a 50% reduction in the number of lymphocytes and eosinophils in the lung lavage fluid of these animals. Finally, airway hyperresponsiveness to methacholine was abolished in eNOS overexpressing mice.
These findings demonstrate that eNOS overexpression attenuates both airway inflammation and airway hyperresponsiveness in a model of allergic asthma. We suggest that a delicate balance in the production of bioactive forms of NO derived from eNOS might be essential in the pathophysiology of asthma.
Exhaled nitric oxide (eNO) has been proposed as a noninvasive marker of airway inflammation in asthma. In asthmatic patients, exhaled NO levels have been shown to relate with other markers of eosinophilic recruitment, which are detected in blood, sputum, bronchoalveolar lavage fluid and bronchial biopsy samples. The purpose of this study was to assess the possible relationship between eNO and allergic inflammation or sensitization in childhood asthma and allergic rhinitis. Subjects consisted of 118 asthmatic children, 79 patients with allergic rhinitis, and 74 controls. Their age ranged from 6 to 15 yr old. eNO level, peripheral blood eosinophil count, eosinophil cationic protein (ECP), serum total IgE level and specific IgE levels were measured. Methacholine challenge test and allergic skin prick test for common allergens were performed in all subjects. Atopic group (n = 206, 44.48 ± 30.45 ppb) had higher eNO values than non-atopic group (n = 65, 20.54 ± 16.57 ppb, P < 0.001). eNO level was significantly higher in patients with asthma (42.84 ± 31.92 ppb) and in those with allergic rhinitis (43.59 ± 29.84 ppb) than in healthy controls (27.01 ± 21.34 ppb, P < 0.001) but there was no difference between asthma and allergic rhinitis group. eNO also had significant positive correlations with Dermatophagoides pteronyssinus IgE level (r = 0.348, P < 0.001), Dermatophagoides farinae IgE level (r = 0.376, P < 0.001), and the number of positive allergens in skin prick test (r = 0.329, P = 0.001). eNO had significant positive correlations with peripheral blood eosinophil count (r = 0.356, P < 0.001), serum total IgE level (r = 0.221, P < 0.001), and ECP (r = 0.436, P < 0.001). This study reveals that eNO level is associated with allergic inflammation and the degree of allergic sensitization.
Exhaled Nitric Oxide; Asthma; Allergic Rhinitis; Allergy; Sensitization
Inhaled asbestos fibres can cause inflammation and fibrosis in the lungs called asbestosis. However, there are no non‐invasive means to assess and follow the severity of the inflammation. Exhaled nitric oxide (NO) measured at multiple exhalation flow rates can be used to assess the alveolar NO concentration and bronchial NO flux, which reflect inflammation in the lung parenchyma and airways, respectively. The aim of the present study was to investigate whether exhaled NO or markers in exhaled breath condensate could be used to assess inflammation in asbestosis.
Exhaled NO and inflammatory markers (leukotriene B4 and 8‐isoprostane) in exhaled breath condensate were measured in 15 non‐smoking patients with asbestosis and in 15 healthy controls. Exhaled NO concentrations were measured at four constant exhalation flow rates (50, 100, 200 and 300 ml/s) and alveolar NO concentration and bronchial NO flux were calculated according to the linear model of pulmonary NO dynamics.
The mean (SE) alveolar NO concentration was significantly higher in patients with asbestosis than in controls (3.2 (0.4) vs 2.0 (0.2) ppb, p = 0.008). There was no difference in bronchial NO flux (0.9 (0.1) vs 0.9 (0.1) nl/s, p = 0.93) or NO concentration measured at ATS standard flow rate of 50 ml/s (20.0 (2.0) vs 19.7 (1.8) ppb, p = 0.89). Patients with asbestosis had increased levels of leukotriene B4 (39.5 (6.0) vs 15.4 (2.9) pg/ml, p = 0.002) and 8‐isoprostane (33.5 (9.6) vs 11.9 (2.8) pg/ml, p = 0.048) in exhaled breath condensate and raised serum levels of C‐reactive protein (2.3 (0.3) vs 1.1 (0.2) μg/ml, p = 0.003), interleukin‐6 (3.5 (0.5) vs 1.7 (0.4) pg/ml, p = 0.007) and myeloperoxidase (356 (48) vs 240 (20) ng/ml, p = 0.034) compared with healthy controls.
Patients with asbestosis have an increased alveolar NO concentration and high levels of leukotriene B4 and 8‐isoprostane in exhaled breath. Measurement of exhaled NO at multiple exhalation flow rates and analysis of inflammatory markers in exhaled breath condensate are promising non‐invasive means for assessing inflammation in patients with asbestosis.
Exhaled nitric oxide (eNO) detects airway inflammation. Hyperbaric oxygen therapy (HBOT)
is used for tissue hypoxia, but can cause lung damage. We measured eNO following
inhalation of oxygen at different tensions and pressures. Methods. Part 1, eNO was
measured before and after HBOT. Part 2, normal subjects breathed 40% oxygen. Results.
Baseline eNO levels in patients prior to HBOT exposure were significantly higher than in
normal subjects (P < .05). After HBOT, eNO significantly decreased in patients (15.4 ± 2.0 versus 4.4 ± 0.5 ppb, P < .001), but not in normal subjects, after either 100% O2 at increased pressure
or 40% oxygen, 1 ATA. In an in vitro study, nitrate/nitrite release decreased after 90 minutes
HBOT in airway epithelial (A549) cells. Conclusion. HBO exposure causes a fall in eNO.
Inducible nitric oxide synthase (iNOS) may cause elevated eNO in patients secondary to
inflammation, and inhibition of iNOS may be the mechanism of the reduction of eNO seen
Asthma is an inflammatory disease of the airways, for which many therapeutic options are available. Guidelines for the management of asthma suggest a stepwise approach to pharmacotherapy based on assessment of asthma severity and control. However, the assessment of asthma control presently relies on surrogate measures, such as the frequency of symptoms or the frequency of use of short-acting beta2-adrenergic agonists. There is no simple, noninvasive technique for the assessment of severity of actual airway inflammation in asthma. The collection and analysis of nitric oxide (NO) levels in exhaled breath has recently become feasible in humans. Based on increased exhaled NO (eNO) levels in patients with asthma, eNO analysis has been proposed as a novel, noninvasive approach to the assessment and monitoring of airway inflammation, and as a basis for adjustments in asthma therapy. In the present paper, the relationship of elevated eNO levels in asthma with inflammatory, physiological and clinical markers of asthma in adults was reviewed. Use of eNO is a promising tool for diagnosing asthma, for monitoring asthma control and for guiding optimal anti-inflammatory asthma therapy. However, because of many unresolved questions, eNO cannot be recommended at present for routine clinical management of adults with asthma.
Airways inflammation; Asthma; Exhaled nitric oxide
fibrosis is characterised by oxidative stress in the airways.
Isoprostanes are prostaglandin isomers formed by free radical catalysed
peroxidation of arachidonic acid. 8-Isoprostane is increased in
interstitial lung diseases, asthma, chronic obstructive pulmonary
disease, and adult respiratory distress syndrome. Exhaled nitric oxide
(NO) and carbon monoxide (CO) are biomarkers of inflammation and
oxidative stress in the airways, respectively.
of 8-isoprostane in the breath condensate of 10 normal subjects and
19 patients with stable cystic fibrosis were measured using an enzyme
immunoassay (EIA). Breath condensate is a non-invasive method of
collecting airway secretions. Exhaled nitric oxide (NO) and carbon
monoxide (CO) levels were measured by a chemiluminescence analyser.
of 8-isoprostane in the breath condensate of patients with stable
cystic fibrosis were increased about threefold compared with normal
subjects (42.7 (4.5) pg/ml vs 15.2 (1.7) pg/ml; p<0.005, 95% CI
14.6 to 40.9). 8-Isoprostane concentrations were negatively
correlated with forced expiratory volume in one second in patients with
cystic fibrosis (r = −0.61; p<0.005). Exhaled CO was also increased in patients with cystic fibrosis compared
with normal subjects (6.7 (1.2) ppm vs 2.9 (0.3) ppm; p<0.05, 95%
CI 0.2 to 7.4). 8-Isoprostane concentrations were significantly
correlated with CO levels (r = 0.66;
results of this study show that oxidative stress is increased in cystic
fibrosis and may be quantified by measuring 8-isoprostane concentrations in breath condensate.
Endotoxin, a component of the cell walls of gram-negative bacteria, is a contaminant in organic dusts (house dust) and aerosols. In humans, small amounts of endotoxin may cause a local inflammatory response. Exhaled nitric oxide (eNO) levels, an inflammation indicator, are associated with the pH values of exhaled breath condensate (EBC). This study evaluated seasonal changes on indoor endotoxin concentrations in homes and the relationships between endotoxin exposure and eNO/EBC pH levels for healthy children and children with allergy-related respiratory diseases. In total, 34 children with allergy-related respiratory diseases and 24 healthy children were enrolled. Indoor air quality measurements and dust sample analysis for endotoxin were conducted once each season inside 58 surveyed homes. The eNO, EBC pH levels, and pulmonary function of the children were also determined. The highest endotoxin concentrations were on kitchen floors of homes of children with allergy-related respiratory diseases and healthy children, and on bedroom floors of homes of asthmatic children and healthy children. Seasonal changes existed in endotoxin concentrations in dust samples from homes of children with allergic rhinitis, with or without asthma, and in EBC pH values among healthy children and those with allergy-related respiratory diseases. Strong relationships existed between endotoxin exposure and EBC pH values in children with allergic rhinitis.
Little information is available on the effect of allergen-specific immunotherapy on airway responsiveness and markers in exhaled air. The aims of this study were to assess the safety of immunotherapy with purified natural Alt a1 and its effect on airway responsiveness to direct and indirect bronchoconstrictor agents and markers in exhaled air.
This was a randomized double-blind trial. Subjects with allergic rhinitis with or without mild/moderate asthma sensitized to A alternata and who also had a positive skin prick test to Alt a1 were randomized to treatment with placebo (n = 18) or purified natural Alt a1 (n = 22) subcutaneously for 12 months. Bronchial responsiveness to adenosine 5'-monophosphate (AMP) and methacholine, exhaled nitric oxide (ENO), exhaled breath condensate (EBC) pH, and serum Alt a1-specific IgG4 antibodies were measured at baseline and after 6 and 12 months of treatment. Local and systemic adverse events were also registered.
The mean (95% CI) allergen-specific IgG4 value for the active treatment group increased from 0.07 μg/mL (0.03-0.11) at baseline to 1.21 μg/mL (0.69-1.73, P < 0.001) at 6 months and to 1.62 μg/mL (1.02-2.22, P < 0.001) at 12 months of treatment. In the placebo group, IgG4 value increased nonsignificantly from 0.09 μg/mL (0.06-0.12) at baseline to 0.13 μg/mL (0.07-0.18) at 6 months and to 0.11 μg/mL (0.07-0.15) at 12 months of treatment. Changes in the active treatment group were significantly higher than in the placebo group both at 6 months (P < 0.001) and at 12 months of treatment (P < 0.0001). However, changes in AMP and methacholine responsiveness, ENO and EBC pH levels were not significantly different between treatment groups. The overall incidence of adverse events was comparable between the treatment groups.
Although allergen-specific immunotherapy with purified natural Alt a1 is well tolerated and induces an allergen-specific IgG4 response, treatment is not associated with changes in AMP or methacholine responsiveness or with significant improvements in markers of inflammation in exhaled air. These findings suggest dissociation between the immunotherapy-induced increase in IgG4 levels and its effect on airway responsiveness and inflammation.
Background: Dose dependent anti-inflammatory effects of inhaled corticosteroids in asthma are difficult to demonstrate in clinical practice. The anti-inflammatory effect of low dose inhaled budesonide on non-invasive exhaled markers of inflammation and oxidative stress were assessed in patients with mild asthma.
Methods: 28 patients entered a double blind, placebo controlled, parallel group study and were randomly given either 100 or 400 µg budesonide or placebo once daily, inhaled from a dry powder inhaler (Turbohaler), for 3 weeks followed by 1 week without treatment. Exhaled nitric oxide (NO), exhaled carbon monoxide (CO), nitrite/nitrate, S-nitrosothiols, and 8-isoprostanes in exhaled breath condensate were measured four times during weeks 1 and 4, and once a week during weeks 2 and 3.
Results: A dose-dependent speed of onset and cessation of action of budesonide was seen on exhaled NO and asthma symptoms. Treatment with 400 µg/day reduced exhaled NO faster (–2.06 (0.37) ppb/day) than 100 µg/day (–0.51 (0.35) ppb/day; p<0.01). The mean difference between the effect of 100 and 400 µg budesonide was –1.55 ppb/day (95% CI –2.50 to –0.60). Pretreatment NO levels were positively related to the subsequent speed of reduction during the first 3–5 days of treatment. Faster recovery of exhaled NO was seen after stopping treatment with budesonide 400 µg/day (1.89 (1.43) ppb/day) than 100 µg/day (0.49 (0.34) ppb/day, p<0.01). The mean difference between the effect of 100 and 400 µg budesonide was 1.40 ppb/day (95% CI –0.49 to 2.31). Symptom improvement was dose-dependent, although symptoms returned faster in patients treated with 400 µg/day. A significant reduction in exhaled nitrite/nitrate and S-nitrosothiols after budesonide treatment was not dose-dependent. There were no significant changes in exhaled CO or 8-isoprostanes in breath condensate.
Conclusion: Measurement of exhaled NO levels can indicate a dose-dependent onset and cessation of anti-inflammatory action of inhaled corticosteroids in patients with mild asthma.
oxide (NO) is detectable in the exhaled breath, is involved in airway
defence and inflammation, and probably modulates bronchial smooth
muscle tone. Given the sensitivity of nitrogen oxides to local redox
conditions, we postulated that exposure to oxidant or antioxidant
compounds could alter concentrations of NO in the exhaled breath (eNO).
We assessed the effect of nitrogen dioxide (NO2) and
ascorbic acid exposure on eNO in healthy human subjects.
subjects were randomised to undergo a 20 minute single blind exposure
to NO2 (1.5 parts per million) or medical air in a
crossover fashion. Exhaled NO and pulmonary function were measured
before and for 3 hours after exposure. In a separate double blind
crossover study 20 healthy subjects received ascorbic acid 500 mg
twice daily or placebo for 2 weeks with a 6 week interim washout. Serum
ascorbic acid levels and eNO were measured before and after each
induced a decrease of 0.62 (95% CI 0.32 to 0.92) ppb in the mean
post-exposure eNO (p<0.01) with no change in forced expiratory volume
in 1 second (FEV1). Oral supplementation with ascorbic acid
increased the mean serum ascorbic acid concentration by 7.4(95% CI
5.1 to 9.7) µg/ml (63%) but did not alter eNO.
exposure causes a decrease in eNO, an effect which may be mediated
through changes in epithelial lining fluid redox state or through a
direct effect on epithelial cells. In contrast, ascorbic acid does not
appear to play a significant role in the metabolism of NO in the
epithelial lining fluid.
Exhaled nitric oxide (ENO) is elevated in bronchial asthma patients, and inhaled corticosteroid therapy lowers the elevated ENO levels in such patients. ENO appears to be an inflammatory marker, but its role in the pathophysiology of cough remains unclear. This study aimed to elucidate the relationship between NO and increased cough reflex sensitivity induced by allergic airway reactions.
Cough reflex sensitivity to inhaled capsaicin was observed under NO depletion caused by NO synthase (NOS) inhibitors in non-sensitized and ovalbumin (OVA)-sensitized guinea pigs. The bronchoalveolar lavage fluid (BALF) was analyzed in an NO depletion setting using the inducible NOS (iNOS) inhibitor ONO1714 in OVA-sensitized guinea pigs.
NO depletion by the non-selective NOS inhibitor L-NAME suppressed cough reflex sensitivity in non-sensitized guinea pigs and OVA-induced increase in cough reflex sensitivity in sensitized guinea pigs; however, iNOS inhibition caused by ONO1714 partially suppressed the OVA-induced increase in cough reflex sensitivity, but not the normal cough response in non-sensitized guinea pigs. ONO1714 did not change BAL cell components in OVA-sensitized guinea pigs.
The results suggest that NO may be involved not only in the normal cough reflex circuit, but also in the OVA-induced increase in cough reflex sensitivity, possibly via a different mechanism of action. Further studies are needed to clarify the precise mechanism.
Exhaled nitric oxide is a non-invasive marker of airway inflammation and a portable analyser, the NIOX MINO (Aerocrine AB, Solna, Sweden), is now available. This study aimed to assess the reproducibility of the NIOX MINO measurements across age, sex and lung function for both absolute and categorical exhaled nitric oxide values in two distinct groups of children and teenagers.
Paired exhaled nitric oxide readings were obtained from 494 teenagers, aged 16-18 years, enrolled in an unselected birth cohort and 65 young people, aged 6-17 years, with asthma enrolled in an interventional asthma management study.
The birth cohort participants showed a high degree of variability between first and second exhaled nitric oxide readings (mean intra-participant difference 1.37 ppb, 95% limits of agreement -7.61 to 10.34 ppb), although there was very close agreement when values were categorised as low, normal, intermediate or high (kappa = 0.907, p < 0.001). Similar findings were seen in subgroup analyses by sex, lung function and asthma status. Similar findings were seen in the interventional study participants.
The reproducibility of exhaled nitric oxide is poor for absolute values but acceptable when values are categorised as low, normal, intermediate or high in children and teenagers. One measurement is therefore sufficient when using categorical exhaled nitric oxide values to direct asthma management but a mean of at least two measurements is required for absolute values.
Background: Exhaled nitric oxide (eNO), which has been proposed as a measure of airway inflammation, is increased in atopic subjects. This raises the question of whether eNO provides any additional information about airway inflammation in asthmatic subjects, other than as a marker for atopy. A study was undertaken to determine whether eNO levels in a population of atopic children are associated with sensitisation or natural exposure to specific allergens, and to examine the relationship between eNO, airway responsiveness, and current respiratory symptoms.
Methods: Exhaled NO and airway responsiveness to histamine were measured in winter and in summer in 235 children aged 8–14 years who had been classified as atopic by skin prick testing. Current respiratory symptoms, defined as wheeze or cough during the month preceding the test, were measured by a parent completed questionnaire. Airway hyperresponsiveness (AHR) was defined as a dose response ratio (DRR) of >8.1 (% fall in forced expiratory volume in 1 second (FEV1)/µmol + 3).
Results: Sensitisation to house dust mite was associated with raised eNO levels in winter while sensitisation to Cladosporium was associated with raised eNO levels in both winter and summer. Grass pollen sensitisation was not associated with raised eNO levels in either season. Exhaled NO correlated significantly with DRR histamine (r=0.43, p<0.001) independently of whether the children had current symptoms or not. In children with current wheeze, those with AHR had eNO levels 1.53 (95% CI 1.41 to 1.66) times higher than those without AHR (p=0.006). Neither DRR (p=1.0) nor eNO levels (p=0.92) differed significantly between children with or without persistent dry cough in the absence of wheeze.
Conclusions: In atopic children, raised eNO levels are associated with sensitisation to perennial allergens, but not to seasonal allergens such as grass pollen. In this population, an increase in eNO is associated with AHR and current wheezing, suggesting that eNO is more than just a marker for atopy.
Methods: The levels of exhaled nitric oxide (eNO), carbon monoxide (eCO) and nasal NO (nNO) from bronchiectatic patients with PCD (n=14) were compared with those from patients with non-PCD bronchiectasis without (n=31) and with cystic fibrosis (CF) (n=20) and from normal subjects (n=37) to assess the clinical usefulness of these measurements in discriminating between PCD and other causes of bronchiectasis.
Results: Exhaled NO levels were lower in patients with PCD than in patients with non-PCD non-CF bronchiectasis or healthy subjects (median (range) 2.1 (1.3–3.5) ppb v 8.7 (4.5–26.0) ppb, p<0.001; 6.7 (2.6–11.9) ppb, p<0.001, respectively) but not lower than bronchiectatic patients with CF (3.0 (1.5–7.5) ppb, p>0.05). Nasal levels of nNO were significantly lower in PCD patients than in any other subjects (PCD: 54.5 (5.0–269) ppb, non-PCD bronchiectasis without CF: 680 (310–1000) ppb, non-PCD bronchiectasis with CF: 343 (30–997) ppb, control: 663 (322–1343) ppb). In contrast, eCO levels were higher in all patient groups than in control subjects (PCD: 4.5 (3.0–24.0) ppm, p<0.01, other bronchiectasis without CF: 5.0 (3.0–15.0) ppm, p<0.001; CF: 5.3 (2.0–23.0) ppm, p<0.001 v 3.0 (0.5–5.0) ppm). Low values in both eNO and nNO readings (<2.4 ppb and <187 ppb, respectively) identified PCD patients from other bronchiectatic patients with a specificity of 98% and a positive predictive value of 92%.
Conclusion: The simultaneous measurement of eNO and nNO is a useful screening tool for PCD.
Exhaled nitric oxide (eNO) has been suggested as a marker of airway inflammatory diseases. The level of eNO is influenced by many various factor including age, sex, menstrual cycle, exercise, food, drugs, etc. The aim of our study was to investigate a potential influence of circadian variation on eNO level in healthy subjects.
Measurements were performed in 44 women and 10 men, non-smokers, without respiratory tract infection in last 2 weeks. The eNO was detected at 4-hour intervals from 6 a.m. to 10 p.m. using an NIOX analyzer. We followed the ATS/ERS guidelines for eNO measurement and analysis.
Peak of eNO levels were observed at 10 a.m. (11.1 ± 7.2 ppb), the lowest value was detected at 10 p.m. (10.0 ± 5.8 ppb). The difference was statistically significant (paired t-test, P < 0.001).
The daily variations in eNO, with the peak in the morning hours, could be of importance in clinical practice regarding the choice of optimal time for monitoring eNO in patients with respiratory disease.
exhaled nitric oxide; circadian variation
BACKGROUND—The aim of
this study was to validate exhaled nitric oxide (eNO) values obtained
with an alternative off line, single breath, low flow balloon sampling
method against on line sampling according to ERS and ATS guidelines in
children who could perform both methods.
and twenty seven white children of median age 14.1 years, all pupils of
a secondary school, participated in the study. They performed the two
different sampling techniques at three different flows of 50, 100, 150 ml/s. Additional measurements were done in random subgroups to
determine the influence of the dead space air on eNO values obtained
off line by excluding the first 220 ml of exhaled air. All children
completed a questionnaire on respiratory and allergic disorders and
underwent spirometric tests.
RESULTS—The off line
eNO values were significantly higher than the on line values at all
flows. At 50 ml/s the geometric mean (SE) off line eNO was 18.7 (1.1) ppb and the on line eNO was 15.1 (1.1) ppb (p<0.0001).
However, when dead space air was discarded, off line and on line values
were similar: at 50 ml/s off line eNO was 17.7 (1.0) ppb and on line
eNO 16.0 (1.2) ppb. There was a good agreement between off line eNO
values without dead space air and on line eNO: for 50 ml/s the mean
on/off line ratio was 0.95 (95% agreement limits 0.63 to 1.27). The
off line eNO level at 50 ml/s in 80 children with negative
questionnaires for asthma, rhinitis, and eczema was 13.6 (1.0) ppb
compared with 33.3 (1.1) ppb in the remaining children with positive
questionnaires on asthma and allergy and/or recent symptoms of cold
children, off line assessment of eNO using constant low flow sampling
and excluding dead space air is feasible and produces similar results
as on line assessment with the same exhalation flow rate. Both sampling
methods are sufficiently sensitive to differentiate between groups of
otherwise healthy school children with and without self-reported
asthma, allergy, and/or colds. We propose that, for off line sampling,
similar low flow rates should be used as are recommended for on line measurements.
The non-invasive assessment of airway inflammation is potentially advantageous in asthma management. Exhaled carbon monoxide (eCO) measurement is cheap and has been proposed to reflect airway inflammation and oxidative stress but current data are conflicting. The purpose of this meta-analysis is to determine whether eCO is elevated in asthmatics, is regulated by steroid treatment and reflects disease severity and control.
A systematic search for English language articles published between 1997 and 2009 was performed using Medline, Embase and Cochrane databases. Observational studies comparing eCO in non-smoking asthmatics and healthy subjects or asthmatics before and after steroid treatment were included. Data were independently extracted by two investigators and analyzed to generate weighted mean differences using either a fixed or random effects meta-analysis depending upon the degree of heterogeneity.
18 studies were included in the meta-analysis. The eCO level was significantly higher in asthmatics as compared to healthy subjects and in intermittent asthma as compared to persistent asthma. However, eCO could not distinguish between steroid-treated asthmatics and steroid-free patients nor separate controlled and partly-controlled asthma from uncontrolled asthma in cross-sectional studies. In contrast, eCO was significantly reduced following a course of corticosteroid treatment.
eCO is elevated in asthmatics but levels only partially reflect disease severity and control. eCO might be a potentially useful non-invasive biomarker of airway inflammation and oxidative stress in nonsmoking asthmatics.
hyperresponsiveness and airway inflammation are distinctive features of
asthma. Evaluation of nitric oxide (NO) levels in expired air have been
proposed as a reliable method for assessing the airway inflammatory
events in asthmatic subjects. A study was undertaken to evaluate
whether airway hyperresponsiveness is related to levels of exhaled NO.
steroid-naive atopic children with mild intermittent asthma of mean
(SD) age 11.8 (2.3) years and 28 age matched healthy controls were
studied to investigate whether baseline lung function or airway
hyperresponsiveness is related to levels of exhaled NO. Airway
responsiveness was assessed as the dose of methacholine causing a 20%
decrease in forced expiratory volume in one second (FEV1)
from control (PD20 methacholine) and exhaled NO levels were
measured by chemiluminescence analysis of exhaled air.
asthmatic children had significantly higher NO levels than controls
(mean difference 25.87 ppb (95% CI 18.91 to 32.83); p<0.0001) but
there were no significant differences in lung function parameters
(forced vital capacity (FVC), FEV1 (%pred), and forced
expiratory flows at 25-75% of vital capacity (FEF25-75%)). In the asthmatic group exhaled NO levels were not significantly correlated with baseline lung function values or
results suggest that levels of exhaled NO are not accurate predictors
of the degree of airway responsiveness to inhaled methacholine in
children with mild intermittent asthma.
BACKGROUND: The concentration of nitric oxide (NO) is increased in the exhaled air of patients with inflammation of the airways, suggesting that this may be a useful measurement to monitor inflammation in diseases such as asthma. However, there have been concerns that exhaled NO may be contaminated by the high concentrations of NO derived from the upper airways, and that this may account for differences in reported values of exhaled NO using different techniques. A study was performed, with argon as a tracer, to determine the extent of nasal contamination of exhaled NO using different expiratory manoeuvres. METHODS: Exhaled and nasal NO were measured by a chemiluminescence analyser. Argon (4.8%) was delivered continuously to the nose. Gas was sampled from the posterior oropharynx and argon and carbon dioxide were measured by mass spectrometry at the same time as NO. RESULTS: During a single expiration against a low resistance and during breath holding there was no evidence for nasal contamination, whereas during exhalation without resistance argon concentration in the oropharynx was increased from 0.91% (95% CI 0.84% to 0.98%) in ambient air to 1.28% (0.9% to 2.24%, p < 0.0001) during a single breath or 2.37% (2.29% to 2.51%, p < 0.0001) during tidal breathing. CONCLUSIONS: Collection of exhaled NO in a reservoir during tidal breathing is likely to be contaminated by NO derived from the nose and this may underestimate any increases in NO derived from the lower respiratory tract in inflammatory diseases. However, with slow expiration against a resistance and created back pressure to close the soft palate, there is no contamination of exhaled air which then reflects concentrations of NO in the lower airways.
Breath analysis is a powerful non-invasive technique for the diagnosis and monitoring of respiratory diseases, including asthma and chronic obstructive pulmonary disease (COPD). Exhaled nitric oxide (NO) and carbon monoxide (CO) are markers of airway inflammation and can indicate the extent of respiratory diseases. We have developed a compact fast response quantum cascade laser system for analysis of multiple gases by tunable infrared absorption spectroscopy (TILDAS). The ARI breath analysis instrument has been deployed in a study of exhaled breath from patients with asthma or COPD. A total of 173 subjects participated, including both adult and pediatric patients. Patients in asthma or COPD exacerbations were evaluated twice—during the exacerbation and at a follow-up visit—to compare variations in breath biomarkers during these events. The change in exhaled NO levels between exacerbation and ‘well’ visits is consistent with spirometry data collected. Respiratory models are important for understanding the exchange dynamics of nitric oxide and other species in the lungs and airways. At each patient visit, tests were conducted at four expiratory flow rates. We have applied a trumpet model with axial diffusion to the multi-flow exhaled nitric oxide data, obtaining NO alveolar concentrations and airway fluxes. We found higher airway fluxes for those with more severe asthma and during exacerbation events. The alveolar concentrations from the model were higher in adults with asthma and COPD, but this trend was less clear among the pediatric subjects.
Background. Allergic diseases impair health-related quality of life (HR-QoL). However, the relationship between airway inflammation and HR-QoL in patients with asthma and rhinitis has not been fully investigated. We explored whether the inflammation of upper and lower airways is associated with HR-QoL. Methods. Twenty-two mild allergic asthmatics with concomitant rhinitis (10 males, 38 ± 17 years) were recruited. The Rhinasthma was used to identify HR-QoL, and the Asthma Control Test (ACT) was used to assess asthma control. Subjects underwent lung function and exhaled nitric oxide (eNO) test, collection of exhaled breath condensate (EBC), and nasal wash. Results. The Rhinasthma Global Summary score (GS) was 25 ± 11. No relationships were found between GS and markers of nasal allergic inflammation (% eosinophils: r = 0.34, P = 0.24; ECP: r = 0.06, P = 0.87) or bronchial inflammation (pH of the EBC: r = 0.12, P = 0.44; bronchial NO: r = 0.27, P = 0.22; alveolar NO: r = 0.38, P = 0.10). The mean ACT score was 18. When subjects were divided into controlled (ACT ≥ 20) and uncontrolled (ACT < 20), the alveolar NO significantly correlated with GS in uncontrolled asthmatics (r = 0.60, P = 0.04). Conclusions. Upper and lower airways inflammation appears unrelated to HR-QoL associated with respiratory symptoms. These preliminary findings suggest that, in uncontrolled asthma, peripheral airway inflammation could be responsible for impaired HR-QoL.
High levels of exhaled carbon monoxide (eCO) are a marker of airway or lung inflammation. We investigated whether hypo- or hyperventilation can affect measured values.
Ten healthy volunteers were trained to achieve sustained end-tidal CO2 (etCO2) concentrations of 30 (hyperventilation), 40 (normoventilation), and 50 mmHg (hypoventilation). As soon as target etCO2 values were achieved for 120 sec, exhaled breath was analyzed for eCO with a photoacoustic spectrometer. At etCO2 values of 30 and 40 mmHg exhaled breath was sampled both after a deep inspiration and after a normal one. All measurements were performed in two different environmental conditions: A) ambient CO concentration = 0.8 ppm and B) ambient CO concentration = 1.7 ppm.
During normoventilation, eCO mean (standard deviation) was 11.5 (0.8) ppm; it decreased to 10.3 (0.8) ppm during hyperventilation (p < 0.01) and increased to 11.9 (0.8) ppm during hypoventilation (p < 0.01). eCO changes were less pronounced than the correspondent etCO2 changes (hyperventilation: 10% Vs 25% decrease; hypoventilation 3% Vs 25% increase). Taking a deep inspiration before breath sampling was associated with lower eCO values (p < 0.01), while environmental CO levels did not affect eCO measurement.
eCO measurements should not be performed during marked acute hyperventilation, like that induced in this study, but the influence of less pronounced hyperventilation or of hypoventilation is probably negligible in clinical practice
Background: The fractional concentration of nitric oxide (NO) in exhaled breath (FeNO) is increased in asthma. There is a general assumption that NO synthase (NOS) 2 in epithelium is the main source of NO in exhaled breath. However, there is no direct evidence to support the assumption and data from animal models suggest that non-inducible NOS systems have important roles in determining airway reactivity, regulating inflammation, and might contribute significantly to NO measured in exhaled breath.
Methods: Bronchial epithelial cells were obtained from healthy, atopic, and asthmatic children by non-bronchoscopic brushing. Exhaled NO (FeNO) was measured directly using a fast response chemiluminescence NO analyser. RNA was extracted from the epithelial cells and real time polymerase chain reaction was used to determine the expression of NOS isoenzymes. NOS2 was examined in macrophages and epithelial cells by immunohistochemistry.
Results: NOS1 mRNA was not detectable. NOS3 mRNA was detected in 36 of 43 samples at lower levels than NOS2 mRNA which was detectable in all samples. The median FeNO was 15.5 ppb (95% CI 10 to 18.1). There was a significant correlation between FeNO and NOS2 expression (R = 0.672, p<0.001). All epithelial cells exhibited NOS2 staining, whereas staining in the macrophages was variable and not related to phenotype.
Conclusions: Only NOS2 expression was associated with FeNO in respiratory epithelial cells obtained from children (R = 0.672; p<0.001). This suggests that FeNO variability is largely determined by epithelial NOS2 expression with little contribution from other isoforms.
oxidative stress, and recurrent pulmonary infections are major
aggravating factors in cystic fibrosis. Nitric oxide (NO), a marker of
inflammation, is not increased, however, probably because it is
metabolised to peroxynitrite. Exhaled carbon monoxide (CO), a product
of heme degradation by heme oxygenase 1 (HO-1) which is induced by
inflammatory cytokines and oxidants, was therefore tested as a
non-invasive marker of airway inflammation and oxidative stress.
CO and NO concentrations were measured in 29 patients (15 men)
with cystic fibrosis of mean (SD) age 25 (1) years, forced expiratory
volume in one second (FEV1) 43 (6)%, 14 of whom were
receiving steroid treatment.
concentration of exhaled CO was higher in patients with cystic fibrosis
(6.7 (0.6) ppm) than in 15 healthy subjects (eight men) aged 31 (3)
years (2.4 (0.4) ppm, mean difference 4.3 (95% CI 2.3 to 6.1),
p<0.001). Patients not receiving steroid treatment had higher CO
levels (8.4 (1.0) ppm) than treated patients (5.1(0.5) ppm, mean
difference 3.3 (95% CI -5.7 to -0.9), p<0.01). Normal subjects had
higher NO levels (6.8 (0.4) ppb) than patients with cystic fibrosis
(3.2 (0.2) ppb, mean difference 3.8 (95% CI 2.6 to 4.9), p<0.05) and
were not influenced by steroid treatment (3.8 (0.4) ppb and 2.7 (0.3) ppb for treated and untreated patients, respectively, mean
difference 0.8 (95% CI -0.6 to 2.3), p>0.05). Patients homozygous
for the ΔF508 CFTR mutation had higher CO and NO concentrations than
heterozygous patients (CO: 7.7 (1.8) ppm and 4.0 (0.6) ppm,
respectively, mean difference 3.7 (95% CI -7.1 to -0.3), p<0.05;
NO: 4.1 (0.5) ppb and 1.9 (0.7) ppb, respectively, mean difference
2.2 (95% CI -3.7 to -0.6), p<0.05).
exhaled CO concentrations in patients with cystic fibrosis may reflect
induction of HO-1. Measurement of exhaled CO concentrations may be
clinically useful in the management and monitoring of oxidation and
inflammatory mediated lung injury.
The exhaled nitric oxide (eNO) signal is a marker of inflammation, and can be partitioned into proximal [J'awNO (nl/s), maximum airway flux] and distal contributions [CANO (ppb), distal airway/alveolar NO concentration]. We hypothesized that J'awNO and CANO are selectively elevated in asthmatics, permitting identification of four inflammatory categories with distinct clinical features.
In 200 consecutive children with asthma, and 21 non-asthmatic, non-atopic controls, we measured baseline spirometry, bronchodilator response, asthma control and morbidity, atopic status, use of inhaled corticosteroids, and eNO at multiple flows (50, 100, and 200 ml/s) in a cross-sectional study design. A trumpet-shaped axial diffusion model of NO exchange was used to characterize J'awNO and CANO.
J'awNO was not correlated with CANO, and thus asthmatic subjects were grouped into four eNO categories based on upper limit thresholds of non-asthmatics for J'awNO (≥ 1.5 nl/s) and CANO (≥ 2.3 ppb): Type I (normal J'awNO and CANO), Type II (elevated J'awNO and normal CANO), Type III (elevated J'awNO and CANO) and Type IV (normal J'awNO and elevated CANO). The rate of inhaled corticosteroid use (lowest in Type III) and atopy (highest in Type II) varied significantly amongst the categories influencing J'awNO, but was not related to CANO, asthma control or morbidity. All categories demonstrated normal to near-normal baseline spirometry; however, only eNO categories with increased CANO (III and IV) had significantly worse asthma control and morbidity when compared to categories I and II.
J'awNO and CANO reveal inflammatory categories in children with asthma that have distinct clinical features including sensitivity to inhaled corticosteroids and atopy. Only categories with increase CANO were related to poor asthma control and morbidity independent of baseline spirometry, bronchodilator response, atopic status, or use of inhaled corticosteroids.