Abstract
Nitric oxide from the gas exchange area, but not from the airways, is increased in subjects with chronic obstructive pulmonary disease with low oxygen saturation after physical testing http://bit.ly/2ItUJy6
To the Editor:
Exhaled nitric oxide (FENO) is an inflammatory marker used in asthma management but its clinical role in chronic obstructive pulmonary disease (COPD) is less defined. FENO represents the NO production in the airways. Various mathematical models have been used to gain information regarding peripheral NO from the lung [1]. NO from the gas exchange area is referred to as alveolar NO (CANO). CANO has been shown to be increased in symptomatic asthmatic subjects [2]; whereas in COPD, there is an alveolar destruction with emphysema and higher values of CANO have been reported [3–5]. However, in subjects with severe emphysema, there was no increase in CANO and, therefore, the clinical value of CANO is not clear [6]. CANO has been found to correlate negatively to the distance travelled in 6-min walking tests [5]. It is of interest that in athletes, hypoxaemia develops due to prolonged exercise [7] and in marathon runners who are regularly exposed to hypoxaemia during strenuous training, CANO values have been reported to be increased [8]. COPD patients frequently report dyspnoea with exertion, and our hypothesis was that repeated hypoxaemia could lead to an increase in CANO. We therefore investigated CANO in a Swedish study [9].
The study design and the methods used were previously described by Högman et al. [9]. In short, patients in a stable condition who had been previously diagnosed by a physician as having COPD were recruited. The COPD diagnosis was confirmed at the study visit by a post-bronchodilator spirometry (SpiroPerfect spirometer; Welch Allyn, Skaneateles Falls, NY, USA). FENO at exhalation flows of 20, 100 and 300 mL·s−1 were measured in duplicate for the nonlinear modelling of NO exchange [1], which was in addition to 50 mL·s−1 (FENO50). The Eco Medics CLD 88 (Eco Medics, Duernten, Switzerland) NO analyser was used with the Högman-Meriläinen algorithm software. Resting oxygen saturation measured by pulse oximetry (SpO2) and FENO50 measurements were performed before any other tests. The physical tests, performed in random order, were the 30-m walking distance at maximal speed (30WT) and the 30-s chair-stand test (CST) [10, 11]. SpO2 was measured with the WristOx2 Model 3150 (Nonin Medical BV, Amsterdam, the Netherlands). SpO2 analyses were made using the resting value before and the mean value after the two physical tests. Grouping variables were used for SpO2 with the 25th percentile of 91%, CST with the 25th percentile of 10 repetitions and 30WT with the 75th percentile of ≥20 s walking time. Nonparametric tests, i.e. Mann–Whitney U-test and Spearman's ρ (SPSS version 24 for Windows; SPSS Inc., Chicago, IL, USA), were used for all statistical calculations. A p-value <0.05 was considered significant. Data are presented as median (interquartile range) with the exception of age and lung function (which are presented as mean±sd).
In total, 170 COPD subjects (61% female), aged 68±8 years, had FENO50 levels of 13 (8–19) ppb and CANO levels of 1.4 (0.7–2.3) ppb. Lung function measurements were: forced expiratory volume in 1 s (FEV1) 54±16% predicted and forced vital capacity (FVC) 67±16% predicted. In smokers (n=48), FENO50 was significantly lower 8 (5–14) ppb than in ex-smokers 15 (11–22) ppb (p<0.001) but for CANO, no difference was found (1.3 (0.7–2.1) and 1.4 (0.7–2.4) ppb, respectively; p=0.46). This was also the case for SpO2 (p=0.46). Therefore, subjects were not stratified by smoking status in the remaining analyses. The 30WT was 18 (16–21) s and the CST had 12 (10–14) repetitions. SpO2 was significantly lower after physical testing compared to the resting value (93% (91–94%) and 95% (93–96%), respectively; p<0.001). Significant correlations were found between CANO and SpO2 (ρ= −0.29, p<0.001), the difference in SpO2 pre- and post-physical testing (ρ=0.25, p=0.001), age (ρ=0.19, p=0.012), 30WT (ρ=0.17, p=0.03) and CTS (ρ= −0.16, p=0.044) but not to blood eosinophil levels. FENO50 was correlated to lung function, FEV1 % predicted (ρ=0.16, p=0.044), FVC % predicted (ρ=0.16, p=0.034) and blood eosinophil levels (ρ=0.24, p=0.002).
When stratifying subjects into SpO2 ≤91% (n=47) or >91% (n=123), there was a difference in CANO (p<0.001) but not in FENO50 (p=0.83) (figure 1). Subjects with SpO2 ≤91% had fewer repetitions in the CST (10 (9–12) and 13 (11–15), respectively; p=0.001) and longer times for the 30WT (19 (18–23) and 17 (16–20) s, respectively; p<0.001).
This study has found that CANO, but not FENO, is increased in subjects with low SpO2 after physical testing. Subjects with a low SpO2 performed worse in the physical tests. Unlike FENO, CANO is not affected by smoking. Subjects who had SpO2 ≤91% had a higher CANO; this could suggest that in COPD subjects, there is a potential for the lung to adapt to dyspnoea. We did not perform arterial oxygen saturation analysis but it has been shown that SpO2 accurately reflects arterial oxygen saturation with exercise. Further research is needed to explore the reason for the increase in CANO in COPD subjects. Longitudinal studies of CANO in COPD subjects are needed to understand whether CANO has the potential to be a prognostic biomarker of pulmonary performance.
Footnotes
Conflict of interest: M. Högman has nothing to disclose.
Conflict of interest: A. Thornadtsson has nothing to disclose.
Conflict of interest: K. Bröms has nothing to disclose.
Conflict of interest: C. Janson has nothing to disclose.
Conflict of interest: K. Lisspers has nothing to disclose.
Conflict of interest: B. Ställberg has nothing to disclose.
Conflict of interest: H. Hedenström has nothing to disclose.
Conflict of interest: A. Malinovschi has nothing to disclose.
- Received February 26, 2019.
- Accepted April 13, 2019.
- Copyright ©ERS 2019