Central and peripheral airway/alveolar sites of exhaled nitric oxide in acute asthma

Abstract

Introduction Central airway nitric oxide flux (J' awNO ) and peripheral airway/alveolar nitric oxide concentration (C ANO ) during asthma exacerbation has not been investigated after correction for axial NO back-diffusion. Methods After measuring exhaled NO (fraction of exhaled nitric oxide (F E NO); ppb) at 50, 100, 150 and 200 ml/s, J' awNO (nl/s) and C ANO (ppb) were calculated using the two-compartment model and corrected for axial NO back-diffusion. Fifteen (8 males), non-smoking, patients with moderate-to-severe treated (inhaled corticosteroid (ICS) and inhaled long-acting b 2 -agonist (LABA)) asthma, age 57613 years (mean6SD), were studied at baseline, during exacerbation prior to oral corticosteroid, and during recovery after an 8 day tapering prednisone course. Based on earlier asthma studies without correction, it was hypothesised that with correction for NO axial back-diffusion, the incidence of abnormal J' awNO and C ANO at baseline and after exacerbation would be $30% in 15 patients with asthma with 80% power.Results At baseline when clinically stable, after 180 mg of albuterol, forced expiratory volume in 1 s (FEV 1 ; litres) was 78626% predicted (p¼0.009) with increased F E NO at 50 ml/s (p¼0.01) and J' awNO (p¼0.02), but C ANO was normal compared with the controls. During exacerbation FEV 1 (litres) was 57620% predicted (p¼0.02), with increased F E NO at 50 ml/s (p¼0.01) and J' awNO (p¼0.004), but C ANO was normal. Recovery results were similar to baseline. Two of 15 patients with asthma always had normal exhaled NO gas exchange. Conclusions The central airways were the major site of abnormal NO flux in 13 of 15 patients with moderateesevere asthma when stable and during exacerbation and could be easily detected with abnormal F E NO at 50 ml/s. C ANO was normal. Clinical trial number NCT00576069.Measurement of the fraction of exhaled nitric oxide (F E NO; ppb) is a relatively simple, reproducible and non-invasive test for monitoring airway inflammation.1 Increased F E NO in asthma is accepted as a surrogate for predominantly eosinophilic-mediated inflammation in central airways and increased response to inhaled corticosteroid (ICS).1e5 The currently accepted method of measuring F E NO at a single constant expiratory flow rate, usually 50 ml/s, is incapable of separating out whether the source of increased NO production is the large central airways or the peripheral small airway/ alveolar site, or both. clinically stable asthma. However, two groups independently 12 22 have also demonstrated, both experimentally and theoretically, axial back-diffusion of NO from proximal to peripheral airway/ alveoli, against the direction of exhalation. Furthermore, this may contaminate peripheral airway/alveolar levels, leading to an underestimation of central airway NO flux and an overestimation of peripheral airway/alveolar NO levels. Axial NO back-diffusion has not been previously accounted for in those with asthma with abnormal expiratory airflow limitation.The current prospective outpatient study eva...

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

“…One study found no increased alveolar NO levels during an exacerbation. 38 Two studies demonstrated no association between alveolar NO values and ACQ scores. 28,29 The studies of Oosterhoff et al 42 ACT, Asthma Control Test; BDI, Baseline Dyspnea Index; CC, closing capacity; CT, computed tomography; CV, closing volume; dN2, slope of phase III of SBNT; FOT, forced oscillation technique; FRC, functional residual capacity; FVC, forced vital capacity; IC, inspiratory capacity; R5, resistance of the respiratory system at 5 Hz; R20, resistance of the respiratory system at 20 Hz; R5-R20, difference of R5 and R20; Rp, peripheral lung resistance; SF6, sulfur hexafluoride; VC, vital capacity; X5, reactance of the respiratory system at 5 Hz.…”

In moderate-to-severe asthma patients monitoring exhaled nitric oxide during exacerbation is not a good predictor of spirometric response to oral corticosteroid

“…22 In 13 of the 15 evaluated adults with asthma, there was increased NO flux in predominantly central airway sites in patients with clinically stable, moderate-to-severe asthma at baseline with abnormal spirometry despite moderatedose ICS and long-acting b 2 -agonist (LABA). 23 NO production in central airway sites was further increased in the same 13 of the 15 patients during exacerbation prior to the initiation of oral corticosteroid with robust clinical and spirometric response following an 8-day tapering course. The absence of increased C ANO was in contrast to our previous observations of increased C ANO in patients with clinically stable asthma 13,14 even after correction for axial NO back-diffusion.…”

“…None of the above asthma studies [8][9][10][11][13][14][15][16][17][18][19][20][21] corrected for NO axial back-diffusion. 12, 22 Gelb et al 23 recently reported outpatient studies in acute asthma using the 2-compartment NO model 11 back-diffusion of NO. 22 In 13 of the 15 evaluated adults with asthma, there was increased NO flux in predominantly central airway sites in patients with clinically stable, moderate-to-severe asthma at baseline with abnormal spirometry despite moderatedose ICS and long-acting b 2 -agonist (LABA).…”

Bronchial and alveolar components of exhaled nitric oxide and their relationship

“…Figure 1b shows data from 15 interventional studies in asthma patients [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] including five studies (solid symbols and lines) where two treatment arms were compared, either within the same group of asthma patients or between two comparable patient groups [6][7][8][9][10][11]. It can be seen that the majority of studies follows the ''normal'' CA,NO decrease with respect to J9aw,NO decrease, in which case the treatment effectively lowers bronchial nitric oxide production but does not really affect alveolar nitric oxide when taking into account the back-diffusion effect.…”