Alveolar Nitric Oxide Concentration Research Articles

Exhaled nitric oxide and carbon monoxide in lung transplanted patients

BackgroundExhaled nitric oxide (eNO) and carbon monoxide (eCO) are markers of pulmonary inflammation associated with acute graft rejection and lung infections in lung transplant (LTX) recipients. Regarding eNO and eCO levels in LTX patients affected by bronchiolitis obliterans syndrome (BOS), published data are discordant. ObjectivesWe aim to evaluate eNO at multiple flows, alveolar concentration of nitric oxide (CalvNO), maximum conducting airway wall flux (J'awNO) and eCO levels in LTX patients to assess the potential role of these parameters in BOS evaluation. MethodsFractional exhaled nitric oxide (FeNO), CalvNO and J'awNO were analysed in 30 healthy subjects and 27 stable LTX patients (12 BOS patients). Pulmonary function tests were performed after eNO and eCO assessment. Receiver operating characteristic (ROC) curves were conducted to evaluate diagnostic accuracy for BOS of eNO parameters. ResultsLTX patients reported higher values of FeNO at flow rates of 50 (p < 0.01), 150 (p < 0.05), 350 ml/s (p < 0.001), and CalvNO (p < 0.0001) than healthy controls. BOS patients showed higher FeNO at flow rates of 150 (p < 0.05) and 350 ml/s (p < 0.01) and CalvNO (p < 0.001) than non-BOS patients. CalvNO reported a remarkable diagnostic accuracy for BOS (AUC: 0.82). There were no significant differences of eCO levels between LTX patients and healthy controls. ConclusionLTX patients affected by BOS showed higher levels of FeNO 150 and 350, and CalvNO than non-BOS LTX patients, probably due to chronic airway inflammation and fibrotic remodelling. CalvNO may be a potential biomarker of BOS in LTX patients.

Increased alveolar nitric oxide concentration is related to nocturnal oxygen desaturation in obstructive sleep apnoea

PurposeTo assess distal/alveolar inflammation in patients with suggestive symptoms of obstructive sleep apnoea (OSA) using exhaled nitric oxide (NO) measured by two-compartment model (2-CM) after correction for axial NO back-diffusion (trumpet model). MethodsNinety five patients suspected for OSA prospectively underwent pulmonary function test, overnight polysomnography (PSG), and exhaled NO measurement. Patients with apnoea–hypopnoea index (AHI) < 5/hour were included in non-OSA group. Exhaled NO was repeatedly measured after PSG in 21 OSA patients and 8 non-OSA subjects. ResultsAlveolar NO concentration (CANO) was significantly higher in OSA patients (n = 71; 4.07 ± 1.7ppb) as compared with non-OSA subjects (n = 24; 2.24 ± 1.06ppb; p < 0.0001) whilst maximal bronchial NO flux (J′awNO) and fractional exhaled NO (FENO) did not differ between the two groups. CANO was strongly associated to AHI (r = 0.701; p < 0.0001) and to recording time with SaO2 < 90% (ST-90%; r = 0.659; p < 0.0001) in OSA patients but not in non-OSA persons. The area under ROC curve for screening patients with OSA and significant nocturnal oxygen desaturation (ST-90% > 1%) was 0.865 ± 0.036 (95% IC, 0.793–0.937; p < 0.0001). CANO at 4.5 ppb could detect these patients with specificity of 94% and sensitivity of 46%. Increase of CANO measured after PSG was significantly related to oxygen desaturation index (ST-90%) in OSA patients. ConclusionsIncreased alveolar NO concentration was related to the severity of nocturnal oxygen desaturation in patients with OSA, linking the distal airway inflammation to intermittent hypoxia. (250 words)

Alveolar nitric oxide and its role in pediatric asthma control assessment.

BackgroundNitric oxide can be measured at multiple flow rates to determine proximal (maximum airway nitric oxide flux; JawNO) and distal inflammation (alveolar nitric oxide concentration; CANO). The main aim was to study the association among symptoms, lung function, proximal (maximum airway nitric oxide flux) and distal (alveolar nitric oxide concentration) airway inflammation in asthmatic children treated and not treated with inhaled glucocorticoids.MethodsA cross-sectional study with prospective data collection was carried out in a consecutive sample of girls and boys aged between 6 and 16 years with a medical diagnosis of asthma. Maximum airway nitric oxide flux and alveolar nitric oxide concentration were calculated according to the two-compartment model. In asthmatic patients, the asthma control questionnaire (CAN) was completed and forced spirometry was performed. In controls, differences between the sexes in alveolar nitric oxide concentration and maximum airway nitric oxide flux and their correlation with height were studied. The correlation among the fraction of exhaled NO at 50 ml/s (FENO50), CANO, JawNO, forced expiratory volume in 1 second (FEV1) and the CAN questionnaire was measured and the degree of agreement regarding asthma control assessment was studied using Cohen’s kappa.ResultsWe studied 162 children; 49 healthy (group 1), 23 asthmatic participants without treatment (group 2) and 80 asthmatic patients treated with inhaled corticosteroids (group 3). CANO (ppb) was 2.2 (0.1-4.5), 3 (0.2-9.2) and 2.45 (0.1-24), respectively. JawNO (pl/s) was 516 (98.3-1470), 2356.67 (120–6110) and 1426 (156–11805), respectively. There was a strong association (r = 0.97) between FENO50 and JawNO and the degree of agreement was very good in group 2 and was good in group 3. There was no agreement or only slight agreement between the measures used to monitor asthma control (FEV1, CAN questionnaire, CANO and JawNO).ConclusionsThe results for CANO and JawNO in controls were similar to those found in other reports. There was no agreement or only slight agreement among the three measure instruments analyzed to assess asthma control. In our sample, no additional information was provided by CANO and JawNO.

Exhaled NO predicts cyclophosphamide response in scleroderma-related lung disease

Cyclophosphamide (CYC) is not always effective in patients with scleroderma-related interstitial lung disease (SSc-ILD), hence the need for biomarkers able to predict beneficial responses to CYC therapy. We therefore assessed whether baseline alveolar concentration of nitric oxide (CANO) could predict the favourable response to CYC therapy in patients with SSc-ILD.Nineteen non-smoker patients with SSc-ILD, were enrolled and treated with 6 courses of CYC (0.75g/m2/monthly) for lung function decline the year before inclusion, and followed-up for 2years period. We assessed the proportion of favourable response to CYC, defined as improvement of forced vital capacity (FVC) or total pulmonary capacity (TLC) more than 10% between the inclusion and each following visit, according to the validated cut-off of CANO at 8.5ppb identifying progressive SSc-ILD subset.At inclusion, 7 patients out of 19 had CANO >8.5ppb. Clinical parameters were comparable between patients with high (>8.5ppb) and low level of CANO (≤8.5ppb). After CYC therapy, and during the follow-up, 9 out of 19 patients had favourable response to CYC therapy, 10 did not meet responder’s criteria, from whom 4 patients died from respiratory failure. Six out of 7 patients with CANO >8.5ppb at inclusion had favourable response to CYC therapy, while only 3 out of 12 patients with CANO ≤8.5ppb responded favourably to CYC therapy (p=0.001).High level of CANO >8.5ppb reflecting alveolar inflammation identify SSc patients with a greater chance to benefit from CYC treatment with a significant lung function improvement.

The effect of omalizumab on small airway inflammation as measured by exhaled nitric oxide in moderate-to-severe asthmatic patients

Measurement of fractional nitric oxide concentration in exhaled breath (FENO) is a simple, noninvasive method to evaluate eosinophilic airway inflammation. Nitric oxide (NO) arising from peripheral small airways/alveoli (alveolar NO concentration [CalvNO]) can be estimated using multiple flow rates and a two-compartment model of the airways and alveoli. Omalizumab, a monoclonal anti-IgE antibody, is approved for the treatment of allergic asthma and also has been shown to decrease FENO levels. This study investigates the effects of omalizumab, when added to an inhaled corticosteroid (ICS) ± long-acting beta-adrenergic agonist (LABA) treatment, on peripheral small airway/alveolar inflammation reflected by FENO measurements at higher flow rates. We hypothesized that compared with placebo, omalizumab would decrease CalvNO levels in asthmatic patients on ICS ± LABA. Forty-two patients with moderate-to-severe asthma were randomly assigned 2:1 to either omalizumab (n = 29) or placebo treatment (n = 13) for 16 weeks. Selection criteria included moderate-to-severe asthmatic patients on an ICS ± LABA, positive skin test to one or more perennial allergen, screening FENO of >13 ppb, and a baseline IgE of 30-700 IU/mL. FENO measured at multiple flow rates was used to calculate CalvNO over the course of 16 weeks. FENO levels decrease with increasing flow rates (p < 0.05 repeated measures ANOVA) but no differences between the placebo and treatment groups in overall CalvNO levels or in the changes of CalvNO with time were found. Omalizumab did not lower the CalvNO, which could have been caused by the initial low CalvNO in this asthmatic population. The model used may not be completely sufficient and/or sensitive enough to detect small changes in CalvNO.

Relationship between alveolar nitric oxide concentration in exhaled air and small airway function in COPD

Nitrative stress is thought to be involved in the inflammatory process in COPD airways, and the alveolar nitric oxide concentration (CAlv) has been reported to be increased. However, the CAlv levels are also regulated by gas diffusion at alveolar sites. The aim of the study was to assess the relationship between the CAlv and pulmonary function in COPD patients, while taking into account the lung diffusion capacity. Twenty stable COPD patients (GOLD stage1/2/3/4 = 6/8/6/0) and 16 healthy subjects took part in this cross-sectional study. Fractional exhaled nitric oxide (FENO), CAlv, and pulmonary functions were measured. Pulmonary function, including single nitrogen washout curve (dN2) and diffusion capacity for carbon monoxide (DLCO), was also evaluated in patients with COPD. The mean FENO levels (20.7 ppb versus 16.3 ppb, p < 0.05) and the mean CAlv levels (6.4 ppb versus 4.2 ppb, p < 0.01) in COPD patients were significantly increased compared to those in HS. The CAlv level in COPD was significantly correlated with dN2, %DLCO/alveolar volume (VA). Using the standard entry method of multivariate analysis to adjust for dN2 and %DLCO/VA, dN2 (β = 0.54, p = 0.005) and %DLCO/VA (β = −0.44, p = 0.018) still showed significant correlations with the CAlv levels. These results suggest that the CAlv could be a useful marker for the small airway dysfunction in COPD. Airway inflammation, including excess nitric oxide generation in the peripheral airways, might be related to the pathophysiology of COPD.

Increase of club cell (Clara) protein (CC16) in plasma and urine after exercise challenge in asthmatics and healthy controls, and correlations to exhaled breath temperature and exhaled nitric oxide

Exercise is known to affect the airway epithelium through dehydration, followed by a release of mediators, such as club cell (Clara) protein (CC16). The aim of this study was to follow the CC16 levels at repeated time points in plasma and urine after exercise in asthmatic subjects and controls, and to relate the findings to exhaled breath temperature (EBT) and exhaled nitric oxide (NO). Twenty-two asthmatics and 18 healthy subjects performed an exercise challenge test on a treadmill. Lung function, CC16 in plasma and urine, EBT and fractional exhaled NO were investigated before and repeatedly for 60min after the exercise. The increase in CC16 concentration in plasma was seen already one minute after exercise (p<0.001) and increased further after 20 (p=0.009) until 60min (p=0.001). An increase in urinary levels of CC16 peaked after 30min (p<0.001), and declined after 60min but were still higher than baseline (p=0.002). There were no differences in plasma or urine CC16 levels between asthmatics and controls, but males had higher plasma levels compared to females (p<0.001) at all time points. EBT peaked at 15min (p<0.001) and thereafter declined, and FENO50 (p<0.0001), alveolar NO concentration (p=0.049) and bronchial flux of NO (p=0.0055) decreased after exercise. In conclusion, this study shows that CC16 in plasma increased during 60min after exercise, not synchronized with CC16 levels in urine. CC16 levels in plasma correlated to EBT and exhaled NO, reflecting an overall epithelial involvement. There was no difference between asthmatics and healthy controls, showing a physiological rather than pathophysiological response.

Very low birth weight and respiratory outcome: association between airway inflammation and hyperresponsiveness

BackgroundThe respiratory outcomes after preterm birth have changed, and it is unclear whether increased airway hyperresponsiveness (AHR) later in childhood is associated with airway inflammation. ObjectiveTo investigate the association between AHR and fractional exhaled nitric oxide (FeNO), including the alveolar concentration of nitric oxide, in school-age children with very low birth weight (VLBW). MethodsTwenty-nine children with VLBW, 33 children with a history of early wheeze, and 60 healthy controls underwent a FeNO measurement and bronchial challenge test with histamine. Atopy was assessed with skin prick tests. ResultsChildren with VLBW had well-preserved baseline lung function but significantly increased AHR, expressed as the dose response slope (P < .001). Geometric mean FeNO levels were similar between VLBW children and healthy controls, and a history of bronchopulmonary dysplasia had no effect. In the VLBW and early wheeze groups, AHR was associated with FeNO (r = 0.47, P = .01, and r = 0.43, P = .013, respectively), but in a stratified analysis, this association was significant only in atopic individuals. By using the multiple flow FeNO technique, the bronchial nitric oxide flux rather than alveolar nitric oxide concentrations were associated with AHR in both children with early wheeze and VLBW. ConclusionWe conclude that in VLBW children AHR is related to FeNO but only in atopic individuals. Similar to children with early wheeze, this association is dependent on bronchial flux rather than alveolar nitric oxide concentration. It is likely that AHR is modified by atopic inflammation rather than by inflammatory process due to prematurity.

Mechanisms of Decrease in Fractional Exhaled Nitric Oxide During Acute Bronchoconstriction

Fractional exhaled nitric oxide measured at expiratory flow of 50 mL/s (Feno50), a biomarker of airway inflammation, is affected by changes in airway caliber. Whether a lower Feno50 level during bronchoconstriction is only an artifact due to the strong flow dependence of this parameter is controversial. We aimed to evaluate the dynamics of airway and alveolar nitric oxide (NO) during acute bronchoconstriction induced by methacholine. Exhaled NO was measured at expiratory flows of 10, 50, 100, 150, and 250 mL/s before and after metacholine in 26 responders to methacholine and 37 nonresponders. Flow-independent parameters (airway wall NO flux, airway NO diffusing capacity, airway wall NO concentration, alveolar NO concentration) were calculated using a two-compartment model, and correction for NO axial back diffusion was applied. Bronchoconstriction in responders was associated with a decrease in Feno50 (-28%, P &lt; .0001), in airway wall NO flux (-34%, P &lt; .0001), and in airway NO diffusing capacity (-15%, P &lt; .05). In contrast, alveolar NO concentration was not affected by bronchoconstriction. Postmethacholine changes in Feno50 were more strictly related to the ventilation distribution, assessed by single-breath carbon monoxide uptake, than to larger airways caliber, assessed by FEV1. When bronchoconstriction was reversed by salbutamol, airway wall NO flux and airway NO diffusing capacity returned to values comparable to those measured premethacholine. The changes in airway caliber induced by noninflammatory stimuli alter NO transport in the lung. The changes in NO dynamics are limited to conductive airways and are characterized by a reduction of NO flow to luminal space.

Respiratory mechanics and peripheral airway inflammation and dysfunction in asthma

Clinical application of the forced oscillation technique (FOT) has progressed with the spread of commercially available FOT devices. The correlation between respiratory impedance and spirometry has been reported; however, the association with airway inflammation and pulmonary function, in the lung periphery in particular, is unclear. To assess whether respiratory impedance is associated with peripheral airway inflammation and dysfunction in asthma. Subjects included 78 patients with overall controlled asthma. We measured whole-breath or within-breath respiratory system resistance (Rrs) and reactance (Xrs) using a commercially available multi-frequency FOT device (MostGraph-01), and assessed the correlation with the fraction of exhaled nitric oxide (FeNO), alveolar nitric oxide concentration (CANO), maximal NO flux in the conductive airways (J'awNO), and the N2 phase III slope of single breath N2 washout (delta N2 ). The differences between inspiratory and expiratory phases of Xrs at 5 Hz (X5), resonant frequency (Fres), and a low-frequency reactance area (ALX) were significantly correlated with CANO; however, there was no correlation between respiratory impedance and FeNO or J'awNO. The delta N2 values were significantly correlated with whole-breath, inspiratory, and expiratory Rrs and Xrs, except for R20. We conclude that respiratory impedance reflects peripheral airway inflammation and ventilation inhomogeneity.

Alveolar nitric oxide concentration reflects peripheral airway obstruction in stable asthma

Increased fraction of exhaled nitric oxide (FeNO) has been shown to reflect airway inflammation in asthma. Central airway NO flux (J'awNO; nL/s) and peripheral airway/alveolar NO concentration (CANO; ppb) can be calculated separately. CANO has been reported to reflect small airway inflammation. The aim of the present study is to correlate CANO levels with clinical and physiological parameters in patients with stable asthma. Seventy-three well-controlled asthmatics (mean age 61) were enrolled. Measurement of FeNO (at 50, 100, 150 and 200 mL/s) and pulmonary function test were performed. J'awNO(TMAD) and CANO(TMAD) were calculated and corrected by the trumpet shape of the airway tree and axial back-diffusion (TMAD). CANO(TMAD) was significantly correlated with forced expiratory flow between 25-75% of the forced vital capacity (FVC) (FEF(25 -75)), FEF(25 -75) percentage of the predicted value (%pred), forced expiratory flow at 50% of the FVC (FEF(50)) and FEF(50) %pred (R = -0.39 P = 0.002, R = -0.29 P = 0.02, R = -0.39 P = 0.001, R = -0.29 P = 0.02, respectively). CANO(TMAD) was positively correlated with age (R = -0.45 P = 0.0002) and weakly correlated with duration of asthma (R = -0.27 P = 0.03). Forced expiratory volume in 1 s/FVC was negatively correlated with CANO(TMAD), J'awNO(TMAD) and FeNO 50 mL/s. Among these, correlation between forced expiratory volume in 1 s/FVC and FeNO 50 mL/s was the strongest (R = -0.34 P = 0.004). CANO(TMAD) may be a more specific marker of peripheral airway obstruction than FeNO and J'awNO(TMAD) in stable asthma.

Clinical and anti-inflammatory effects of ultra-short preseasonal vaccine to Parietaria in asthma

The ultra-short course preseasonal allergy vaccine, containing the adjuvant monophosphoryl lipid A (MPL), is effective in treating allergic symptoms; however, the efficacy in controlling asthmatics symptoms has not been fully demonstrated. We aimed at evaluating whether the ultra-short preseasonal course of immunotherapy contributes to asthma control. Four subcutaneous injections of the active product (Pollinex Quattro) were administered, before the pollen season, to 20 Parietaria-sensitive mild, untreated asthmatics (M/F: 12/8; age: 38 ± 14 years). After the screening visit (visit 1), asthma control was assessed by the Asthma Control Test (ACT) immediately before the first (visit 2) and immediately after the last (visit 5) injections, as well as during the pollen season (visit 6). Bronchial and alveolar exhaled nitric oxide (NO) concentrations were also measured. Nine Parietaria-sensitive mild asthmatics (M/F: 3/6; age: 40 ± 12 years) served as untreated controls. The ACT remained constant during allergen exposure in specific immunotherapy (SIT)-treated asthmatics (visit 2: 22 ± 3.2; visit 5: 23 ± 2.8; visit 6: 22 ± 3.6; analysis of variance [ANOVA], p = 0.47), whereas it dropped during pollen exposure in controls (visit 2: 20 ± 2.5; visit 5: 21 ± 2.8; visit 6: 16 ± 5.7; ANOVA, p = 0.01). The forced expiratory NO (FENO) values significantly increased during pollen exposure in both groups; however, the alveolar NO concentrations remained stable in SIT-treated asthmatics (p = 0.11), whereas they doubled in controls (p = 0.01). The current findings show that the preseasonal vaccine adjuvated with MPL contributes to the maintenance of control of asthma during the pollen season.

Small-airways dysfunction associates with respiratory symptoms and clinical features of asthma: A systematic review

Traditionally, asthma has been considered a disease that predominantly involves the large airways. Today, this concept is being challenged, and increasing evidence has become available showing that abnormalities in the small airways also contribute to the clinical expression of asthma. The small airways can be affected by inflammation, remodeling, and changes in the surrounding tissue, all contributing to small-airways dysfunction. In this article we have performed a systematic review of the literature on the association between small-airways dysfunction and clinical signs and symptoms of asthma. This review shows that small-airways dysfunction associates with worse control of asthma, higher numbers of exacerbations, the presence of nocturnal asthma, more severe bronchial hyperresponsiveness, exercise-induced asthma, and the late-phase allergic response. Importantly, small-airways dysfunction can already be present in patients with mild asthma. Our review provides suggestive evidence that a better response of the small airways to inhaled steroids or montelukast associates with better asthma control. For this reason, an early recognition of small-airways dysfunction is important because it enables the physician to start timely treatment to target the small airways. It is important to develop simpler and more reliable tools (eg, questionnaires or bronchial provocation tests with small-particle stimuli) to assess the presence and extent of small-airways dysfunction in daily clinical practice.

Effects of 24-week add-on treatment with ciclesonide and montelukast on small airways inflammation in asthma

BackgroundEosinophilic inflammation of the small airways is a key process in asthma that often smolders in treated patients. The long-term effects of add-on therapy on the persistent inflammation in the small airways remain unknown. ObjectiveTo examine the effects of add-on therapy with either ciclesonide, an inhaled corticosteroid with extrafine particles, or montelukast on small airway inflammation. MethodsSixty patients with stable asthma receiving inhaled corticosteroid treatment were enrolled in a randomized, open-label, parallel comparison study of 24-week add-on treatment with ciclesonide or montelukast. Patients were randomly assigned to 3 groups: ciclesonide (n = 19), montelukast (n = 22), or no add-on as controls (n = 19). At baseline and at weeks 4, 12, and 24, extended nitric oxide analysis; pulmonary function tests, including impulse oscillometry; blood eosinophil counts; and asthma control tests (ACTs) were performed. ResultsA total of 18 patients in the ciclesonide group, 19 in the montelukast group, and 15 in the control group completed the study and were analyzed. With repeated-measures analysis of variance, ciclesonide produced a significant decrease in alveolar nitric oxide and a significant improvement in ACT scores over time. Montelukast produced significant decreases in alveolar nitric oxide concentrations and blood eosinophil counts over time and slightly improved ACT scores, whereas no such changes were observed in the control group. Alveolar nitric oxide concentrations with ciclesonide and reactance area at low frequencies with montelukast produced greater improvements over time compared with control. ConclusionCiclesonide add-on therapy and montelukast add-on therapy may act differently, but both separately can improve small airway abnormalities and provide better asthma control. Trial Registrationumin.ac.jp/ctr Identifier: UMIN000001083

High alveolar concentration of nitric oxide is associated with alveolitis in scleroderma

Alveolar concentration of nitric oxide (CANO) is a non invasive prognostic marker of systemic sclerosis (SSc) lung disease. There is, however, as yet no direct evidence showing concomitant increase of CANO and the presence of inflammatory cells in alveoli. We have therefore measured CANO and performed broncho-alveolar lavage (BAL) in SSc patients. Exhaled NO was measured, by the means of two different models, the two-compartment model (2CM) and the trumpet model with axial diffusion (TMAD), in 22 SSc patients and compared with 15 healthy controls. BAL was performed in all SSc patients. Alveolitis was defined as lymphocytes >14%, polymorphonuclears >4%, or eosinophils >3% on cell count in BAL fluid. Comparisons of CANO levels were made between SSc patients with, and without, alveolitis. Levels of CANO were significantly higher in SSc patients as compared with controls (p<0.001). Median CANO was significantly higher in SSc patients with alveolitis as compared with SSc patients without alveolitis (8.4ppb; 1st and 3rd interquartile range: 6.0–10.5 vs 3.3ppb; 2.2–3.5; p=0.004 for 2CM and 5.4ppb; 3.2–9.2 vs 3.2ppb; 1.4–3.3, p=0.02 for TMAD), while bronchial airway output of NO (J′awNO, p=0.19), and fractional exhaled NO (FENO, p=0.12) were comparable. CANO was consistently high in SSc patients with alveolitis irrespective of the methods chosen (TMAD or 2CM). Our findings showed that increased CANO was associated with alveolitis in patients with SSc. We submit that CANO could be used as a reliable non-invasive surrogate biomarker of alveolitis in scleroderma lung disease.

Bronchial and alveolar nitric oxide in exercise‐induced bronchoconstriction in asthmatic children

Epidemiological studies have shown an association between the severity of exercise-induced bronchoconstriction (EIB) and fractional exhaled nitric oxide at the flow of 50 mL/s (FeNO(50)). However, no study has assessed the correlation between alveolar production (C(alv)) and bronchial flux (J(NO)) of nitric oxide (NO) and EIB in asthmatic children. To identify the relationship between severity of EIB and bronchial or alveolar nitric oxide. Our group included 36 allergic children with intermittent asthma. The EIB was determined by a standard exercise challenge and the severity was expressed as the maximum change in percentage from the baseline value of lung function (ΔFEV(1)%, ΔFEF(25-75)%) after exercising. A chemiluminescence analyser at multiple flows was used to calculate FeNO(50), J(NO) and C(alv,) which reflect large airways, J(NO) and alveolar concentration of NO respectively. Sixteen (44.4%) children presented a ∆FEV(1) ≥ 10%, eight (22.2%) had ∆FEV(1) ≥ 15% and nine (25%) children had a ∆FEF(25-75) ≥ 26%. A significant correlation was observed between severity of EIB and FeNO(50) , J(NO) and C(alv.) EIB was significantly more severe in children sensitive to indoor allergens compared with outdoor allergens only (P = 0.014); those children showed also higher levels of C(alv) (P = 0.003) and of J(NO) (P = 0.044). Our results suggest that inflammation is present in the central and peripheral airways and that it is associated with the severity of EIB. Clinicaltrials.gov NCT00952835.

Bronchial and alveolar components of exhaled nitric oxide and their relationship

To the Editors: Considerable confusion exists about the clinical use of exhaled nitric oxide measurement in general, and its bronchial and alveolar contributions in particular, for instance in response to treatment. An additional effect needs to be factored in when considering the degree of alveolar nitric oxide abnormality and its response to therapeutic interventions that may or may not be targeted to the lung periphery. Indeed, the alveolar nitric oxide value computed from exhaled nitric oxide measurement at multiple flows with the so-called slope-intercept method [1, 2] can overestimate the true nitric oxide produced by inflammation in the alveolar air spaces. Such overestimation arises when the bronchial nitric oxide back-diffuses into the alveolar air space and thus contaminates the alveolar nitric oxide measurement with nitric oxide that originates from the more proximal airways. Two correction formulas have been published independently [3, 4] proposing to estimate true alveolar nitric oxide by subtracting from the measured alveolar nitric oxide a bronchial nitric oxide-dependent portion corresponding to back-diffusion. However, it has also been shown that airway constriction of peripheral conductive airways may at least partly impair back-diffusion [5]. Thus, in the case of peripheral lung disease, the application of correction formulas that assume unimpaired back-diffusion can erroneously lead to overcorrection and, ultimately, to negative alveolar nitric oxide values. The problem with the real lung is that it is difficult to judge whether and to what extent back-diffusion is impaired, although independent measures of small airway constriction could be envisioned in an attempt to determine this. In the meantime, we advocate here a more pragmatic approach. One way to inspect uncorrected alveolar nitric oxide concentration ( C A,NO) for true abnormality is by first plotting it …

Alveolar concentration and bronchial flux of nitric oxide: Two linear modeling methods evaluated in children and adolescents with allergic rhinitis and atopic asthma

Alveolar concentration (C(A)NO) and bronchial flux (J(aw)NO) of nitric oxide (NO) characterize the contributions of peripheral and proximal airways to exhaled NO. Both parameters can be estimated using a two-compartment model if the fraction of NO in orally exhaled air (FE(NO)) is measured at multiple constant expiratory flow rates (V). The aim of this study was to evaluate how departures from linearity influence the estimates of C(A)NO and J(aw)NO obtained with the help of linear regression analysis of the relationships between FE(NO) and 1/V (method P), and between the NO output (V(NO) = FE(NO) × V) and V (method T). Furthermore, differences between patients with atopic asthma (AA) and allergic rhinitis (AR) and between methods P and T were assessed. Measurements of FE(NO) were performed with a chemiluminiscence analyzer at five levels of V ranging from 50 to 250 ml/sec in school children and adolescents with mild to moderate-severe AA treated by inhaled corticosteroids (N = 42) and AR (N = 20). Violation of the linearity condition at V ≤ 100 ml/sec caused shifts between methods with regard to the partition of exhaled NO into alveolar (C(A)NO: P > T) and bronchial (J(aw)NO: T > P) components. Both methods gave similar results in the linear range of 150-250 ml/sec: The mean ratios P/T and limits of agreement calculated in AA and AR patients were 1.03 (0.49-1.56) and 1.07 (0.55-1.59) for C(A)NO and 1.03 (0.73-1.33) and 0.99 (0.90-1.10) for J(aw)NO, respectively. No significant differences between AA and AR were found in C(A)NO and J(aw)NO calculated in the linear range by the T method {medians (inter-quartile ranges): 1.7 ppb (0.9-3.9) vs. 2.3 ppb (0.8-3.7), P = 0.91; 1,800 pl/sec (950-3,560) vs. 1,180 pl/sec (639-1,950), P = 0.061}. However, the flow-dependency of the estimates was markedly higher in AA than in AR patients: C(A) NO was decreased 2.8-fold vs. 1.5-fold and J(aw) NO was increased 1.5-fold vs. 1.2-fold in the linear range as compared to the range of 50-250 ml/sec. In both groups, the median standard errors (SE) of the J(aw) NO estimates were similar for the metods P and T and small (<15%) regardless of the range for expiratory flows. The precision of C(A) NO estimates was less in all ranges. For both methods, the SE of the estimates obtained in the range of 150-250 ml/sec exceeded 50% in asthmatics and 30% in AR patients, respectively. The results show that FE(NO) has to be measured at several expiratory flows ≥100 ml/sec for the accurate estimation of C(A) NO and J(aw) NO using linear methods P and T in children and adolescents with AA and AR. A stepwise procedure for detecting nonlinearity and evaluating the quality of FE(NO) measurements is suggested.

Lungenfunktionsdiagnostik der kleinen Atemwege

In the recent years growing interest has focused on the involvement of the distal airways (internal diameter < 2 mm) in obstructive lung diseases and other pulmonary conditions. Inflammation in the small airways seems to play a major role in severe and uncontrolled asthma as a major determinant of airflow obstruction. Thus, small airways represent an important target for inhalation therapy. Currently there is no accepted single lung function parameter to detect small airway dysfunction. Various invasive and non-invasive techniques have been described. In future, non-invasive lung function testing will gain more importance. Using spirometry or body plethysmography, lung function parameters such as the ratio of forced vital capacity to slow vital capacity (FVC/SVC) and the residual volume (RV) can provide information about air trapping in small airway disease. Recent data show that techniques such as impulse oscillometry, nitrogen washout testing and analysis of exhaled nitric oxide are promising tools to assess involvement of the small airways. Impulse oscillometry is a sensitive method to calculate peripheral airway resistance, nitrogen washout allows one to detect air trapping and inhomogeneous ventilation in the distal lung, and the alveolar nitric oxide concentration represents a marker of peripheral inflammation. Further studies are needed to validate these functional tests or their combination for diagnosis and assessment of treatment response in pulmonary diseases involving small airways.

Relation of bronchial and alveolar nitric oxide to exercise‐induced bronchoconstriction in atopic children and adolescents

Exercise challenge test is widely used in diagnostics and follow-up of childhood asthma, but the method is complex, time consuming, and expensive. In this study, we aimed to find out whether flow-independent nitric oxide (NO) parameters (bronchial NO flux [J'aw(NO)] and alveolar NO concentration [CA(NO)]) predict exercise-induced bronchoconstriction (EIB) in atopic children and adolescents with asthma-like symptoms. Also, the respective NO parameters corrected for axial backward diffusion (J'aw(NO) [TMAD] and CA(NO) [TMAD]) were calculated and included in the analysis. Thirty patients (6-19 yr old) with confirmed atopy (positive skin prick tests or allergen-specific IgE) and asthma-like respiratory symptoms were included in the study. Before the current investigations, none of the patients had been diagnosed to have asthma and none were on inhaled corticosteroids. Exhaled NO was measured at multiple exhalation flow rates, and exercise challenge test was carried out. Bronchial NO flux and alveolar NO concentration were calculated according to the linear method with and without correction for axial backward diffusion. Sixty-six healthy school children served as controls. The patients were divided into two groups according to EIB. Patients with EIB (EIB+ group, n = 18) had enhanced bronchial NO output as compared to patients without EIB (EIB- group, n = 12); but the EIB- group did not differ from healthy controls. EIB+ group had also higher alveolar NO concentration than EIB- group and healthy controls, but EIB- group did not differ from healthy controls. When bronchial NO flux and alveolar NO concentration were corrected for axial diffusion, J'aw(NO) (TMAD) had equal difference as J'aw(NO) between the groups as expected. However, only EIB+ had higher CA(NO) (TMAD) than healthy controls, and the patient groups did not differ from each other. In patients, bronchial NO output correlated with the magnitude of exercise-induced change in PEF (r(s) = -0.388, p = 0.034), FEV(1) (r(s) = -0.395, p = 0.031), and FEF(50%) (r(s) = -0.431, p = 0.020), i.e., the higher the bronchial NO output, the larger the decrease in PEF/FEV(1) /FEF(50%) . Alveolar NO concentrations correlated with the change in FEV(1) (r(s) = -0.439, p = 0.015), FEF(50%) (r(s) = -0.454, p = 0.013), FEF(75%) (r(s) = -0.447, p = 0.017), and FVC (r(s) = -0.375, p = 0.045). For J'aw(NO) (TMAD), the correlations and p-values were equal to those of J'aw(NO) , but, interestingly, CA(NO) (TMAD) had no significant correlations with any of the exercise-induced changes in lung function. The results showed that in atopic children and adolescents, increased bronchial NO output as well as J'aw(NO) (TMAD) were associated with EIB, while alveolar NO concentration (but not CA(NO) [TMAD]) correlated with the degree of obstruction in smaller airways induced by exercise challenge.