Comparison of two exhaled nitric oxide analyzers: the NIOX MINO hand-held electrochemical analyzer and the NOA280i stationary chemiluminescence analyzer

Background and objective: Measurement of the fraction of nitric oxide (FeNO) in exhaled air is useful in the management of asthma. A new hand‐held nitric oxide (NO) analyzer, the NIOX MINO, is simple and easy to use in clinical practice. In this study, FeNO values measured using the NIOX MINO were compared with those obtained using a stationary chemiluminescence analyzer, the Sievers NOA280i. Methods: FeNO was measured in 100 adults, using both the NIOX MINO and the NOA280i. Nine (9.0%) of these subjects had asthma. The first acceptable measurement with the NIOX MINO and the mean of two acceptable measurements with the NOA280i were compared. Results: There was a significant correlation between FeNO concentrations measured with the two devices (r = 0.876, P < 0.001). A Bland–Altman plot showed a high degree of agreement between the two devices: the mean inter‐device difference was 3.3 parts per billion (ppb), and the 95% limits of agreement were ?7.0 and 13.6 ppb. In addition, the mean relative difference was 14.5%, with the 95% limits of agreement being ?33.7 and 62.7%. The mean value (± standard error of the mean) for FeNO as measured with the NIOX MINO (18.8 ± 0.9 ppb) was significantly lower than that measured with the NOA280i (22.1 ± 1.2 ppb, P < 0.001). Conclusions: There was a significant correlation, but only moderate agreement, between FeNO values measured with the NIOX MINO and those measured with the NOA280i, with the NIOX MINO values being significantly lower than the NOA280i values. Significant differences in FeNO values obtained with these two NO analyzers should be considered when interpreting the results of FeNO measurements.     

Comparison of exhaled nitric oxide analysers

Currently no published data are available concerning the comparability of different types of NO analysers, making inter-laboratory comparisons difficult. In two sets of experiments we compared 4 and 5 NO analysers, respectively, from 3 different manufacturers using different calibration regimes: calibration with (1) a separate recommended calibration gas for each analyser, (2) a single low concentration for all (394 ppb), and (3) a single high concentration (12.8 ppm). We measured three subjects with known low (L), moderate (M) and high (H) bronchial exhaled nitric oxide concentrations as well as standard gases (SG). In the first set of experiments, calibration regime 1 resulted in the largest differences between analysers (coefficient of variation (CV) for L, M, H, SG: 0.42, 0.22, 0.20, 0.14). The lowest CV between analysers was observed after calibration 2 (0.34, 0.19, 0.12, 0.02). Very similar results were obtained in the second set of comparisons. Thus, differences between analysers existed, but were mainly due to differences in recommended calibration gases/procedures. Only a small part was explainable by deviations from target flow. These differences need to be taken into account when comparing data between laboratories or replacing the calibration gas of an analyser, as well as for the establishment and interpretation of normal values.     

Off-line exhaled nitric oxide measurements in children

The concentration of exhaled nitric oxide (eNO) is a useful marker of asthmatic bronchial inflammation. eNO can now be measured away from the laboratory (off-line), even in children. Short exhalation maneuvers (8 sec) and small samples (1 L) of exhaled gas are probably sufficient in children, but more information is needed about the effect of different measurement conditions. As a preliminary step before conducting epidemiological studies in schoolchildren, we investigated the effects of expiratory flow, dead space, and expiratory time on eNO concentrations collected in 1-L mylar collection bags. We studied 101 cooperative subjects (62 males) aged 5-18 years (30 healthy volunteers, 51 asthmatics, and 20 children with various other respiratory diseases) in our pulmonary function laboratory. On-line and off-line eNO were compared in a single session, and analyzed with a Sievers NOA 280 nitric oxide analyzer. For both methods of collecting expired gas, subjects did a single exhalation without breath-holding against an expiratory pressure 10 cm H(2)O. We investigated the effects of expiratory flow, dead space, and exhalation time on eNO; we also compared on-line and off-line eNO measurements, and the repeatability of both techniques at a given flow rate. Expiratory flows of 58 mL/sec provided more reproducible data than lower flows (coefficient of repeatability 1.1 ppb for 58 mL/sec vs. 2.8 for 27 mL/sec vs. 5.7 for 18 mL/sec). eNO concentrations were about 25% higher in off-line than in on-line recordings if the initial 250 mL of exhaled gas were not eliminated, and 37% higher if exhalation lasted longer (16 sec vs. 8 sec). Eliminating 250 mL of dead space and shortening the filling time to 8 sec yielded off-line eNO values close to those on-line (geometric mean off-line eNO 14.4 ppb, 95% confidence interval: 12.2-17.0) vs. on-line eNO 13.8 ppb (95% confidence interval: 11.6-16.5). On-line and off-line results were highly correlated (r = 0.996, P = 0.000) and had similar coefficients of variation (on-line eNO 2.6%, off-line 2.8%). Neither agreement nor repeatability of eNO measurements were affected by disease status or baseline FEV(1) (% predicted values). Once standardized, the off-line eNO technique using 1-L gas collection bags will provide results similar to those recorded on-line.     

A comparative study of the RuiBreath and NIOX VERO analyzers for detecting fractional exhaled nitric oxide

BackgroundFractional exhaled nitric oxide (FeNO) measurement is a reliable, noninvasive marker of airway inflammation. Portable FeNO analyzers facilitate the assessment of airway inflammation in primary care. Differences between analyzers from different manufacturers are not comparable. Here, we aimed to compare the FeNO values obtained by a new portable device (RuiBreath, Guangzhou Ruipu Medical Technology Co., Ltd, Guangzhou, China) to those obtained by the widely used NIOX VERO portable analyzer (Aerocrine AB, Solna, Sweden) in patients with asthma.MethodsThis prospective validation study enrolled patients (≥14 years old) with asthma over a 2-month period (July and August 2019) at the Beijing Chao-Yang Hospital. At least one valid FeNO measurement was obtained using each analyzer for all the participants.ResultsThere were 197 participants in this study. The FeNONIOX and FeNORuiBreath values significantly differed (P=0.016). After log-transformation, a difference was found only when the FeNONIOX was <25 ppb (P<0.001). The FeNONIOX and FeNORuiBreath values had a significant correlation (r=0.938, P<0.001), which was confirmed by the Altman-Bland plot. Using a receiver-operating characteristic curve analysis, when using 49 ppb as the cut-off point for the two devices in identifying patients with symptomatic asthma symptoms, the sensitivity and specificity were 0.42 and 0.88, respectively, by NIOX, and 0.40 and 0.89, respectively, by RuiBreath.ConclusionsThis is the first report of FeNO values obtained by the new portable RuiBreath FeNO analyzer. The FeNORuiBreath values are reliable and directly comparable with the FeNONIOX values.     

Diagnosing asthma: comparisons between exhaled nitric oxide measurements and conventional tests

International guidelines recommend a range of clinical tests to confirm the diagnosis of asthma. These focus largely on identifying variable airflow obstruction and responses to bronchodilator or corticosteroid. More recently, exhaled nitric oxide (FE(NO)) measurements and induced sputum analysis to assess airway inflammation have been highlighted. However, to date, no systematic comparisons to confirm the diagnostic utility of each of these methods have been performed. To do so, we investigated 47 consecutive patients with symptoms suggestive of asthma, using a comprehensive fixed-sequence series of diagnostic tests. Sensitivities and specificities were obtained for peak flow measurements, spirometry, and changes in these parameters after a trial of steroid. Comparisons were made against FE(NO) and sputum cell counts. Sensitivities for each of the conventional tests (0-47%) were lower than for FE(NO) (88%) and sputum eosinophils (86%). Overall, the diagnostic accuracy when using FE(NO) and sputum eosinophils was significantly greater. Results for conventional tests were not improved, using a trial of steroid. We conclude that FE(NO) measurements and induced sputum analysis are superior to conventional approaches, with exhaled nitric oxide being most advantageous because the test is quick and easy to perform.     

Advances in the clinical applications of exhaled nitric oxide measurements

This article focuses on recent data which highlight the clinical settings in which exhaled nitric oxide (F(E)NO) is potentially helpful, or not, as a clinical tool. It is becoming clearer that, selectively applied, F(E)NO measurements can provide reliable clinical guidance, particularly when values are low. Such values are associated with high negative predictive values (>90%). Increased F(E)NO levels are associated with much more modest positive predictive values (75%-85%) and these are less reliable. These general principles apply when diagnosing steroid responsiveness in relation to asthma, chronic cough, and COPD. Although randomised trials do not support routine use of exhaled NO measurements in uncomplicated bronchial asthma, there is evidence that in patients with difficult asthma, or asthma associated with pregnancy, F(E)NO enhances overall management, and the decision to commence or increase inhaled steroid therapy (yes/no) may be made more accurately. Exhaled NO is potentially relevant in the assessment of occupational asthma (serial measurements) and also in diagnosing bronchiolitis obliterans in lung transplant patients.     

Validation of a hand-held exhaled nitric oxide analyzer for use in children

Measurements of exhaled nitric oxide (FE(NO)) may be useful in the diagnosis and management of asthma in children. A new hand-held device (MINO, Aerocrine) for measuring FE(NO) has been marketed but has not been validated in a pediatric population. The objective is to validate the MINO against the NIOX analyzer. This was a randomized cross-over study where FE(NO) was measured in a single assessment using the MINO and NIOX. Children were recruited from a respiratory clinic and had six attempts to provide a FE(NO) measurement with each analyzer. Fifty-five children were enrolled, 33 boys, median age 9 years. A mean FE(NO) value was obtained in 39 children with MINO and 44 with NIOX. Paired mean FE(NO) values were obtained in 34 children and the values were higher for the NIOX (mean difference 3.9 ppb limits of agreement -1.1, 8.9). The differences between analyzers became greater at higher FE(NO) values. The first FE(NO) value using the MINO was 24 ppb and the mean of all FE(NO) values using the MINO was 27 ppb (difference not significant). Exhaled NO values were comparable between the two analyzers although there was greater consistency at lower values. The findings of the study do not contradict the manufacturer's recommendation that only one FE(NO) value is required with the MINO, however, we suggest that the mean of at least two values should be reported in children.     

Relationship between exhaled air temperature and exhaled nitric oxide in childhood asthma.

Airway inflammation is a characteristic of asthma. Exhaled nitric oxide (eNO) has been demonstrated to be related to actual levels of airway inflammation in asthmatic patients. The purpose of this study was to investigate whether the temperature of exhaled air is related to eNO levels. Temperature of exhaled air and eNO were measured in 52 asthmatic children with a cross-sectional design. A significant relationship was demonstrated between eNO and temperature of peak and plateau exhaled air temperature. The relationship between both the peak and the plateau values and eNO was more evident when it was corrected for environmental temperature. These results suggest a relationship between exhaled nitric oxide and the temperature of exhaled air in asthmatic patients not treated with systemic steroids.     

Characterization of exhaled nitric oxide: introducing a new reproducible method for nasal nitric oxide measurements.

Nitric oxide (NO) is present in the human nasal airways and has been suggested to originate primarily from the paranasal sinuses. The aim of this study was to establish a new and reproducible method for measurement of nasal NO. Through repeated single-breath measurements the intra- and inter-individual variations of NO levels in nasally (into a tightly fitting mask covering the nose) and orally exhaled air were determined in healthy humans. Variations due to the methods used were investigated. The contribution of oral NO to the nasal exhalations by introducing a mouthwash procedure was also studied. This study shows distinct individual values of NO in nasally and orally exhaled air of healthy humans. Some diurnal variability was also found with a rise in NO in nasally and orally exhaled air over the day, but no, or little, day-to-day variability when comparing the results from separate mornings. There was no correlation between NO levels in nasally and orally exhaled air, whereas there was a strong correlation between NO levels in air exhaled through the left and right nostril. The levels of NO in air exhaled at 0.17 L x s(-1) through either nostril separately were higher than in air exhaled at the same flow rate through both nostrils simultaneously. After the introduction of a mouthwash procedure the level of NO in orally, but not nasally exhaled air was reduced. To conclude the method using nasal exhalation into a nose mask is highly reproducible. It is also suggested that subtracting the level of NO in orally exhaled air, after mouthwash, from that in nasally exhaled air, would adequately reflect nasal NO levels.     

儿童口鼻呼出气一氧化氮的临床应用

呼出气一氧化氮目前被认为是气道嗜酸性炎症的重要生物标志物之一,因其操作简便性、无创性、安全性等优势,现广泛用于哮喘、变应性鼻炎、鼻窦炎等上下气道疾病的诊疗。本文就呼出气一氧化氮的基础生物学特性、测定方法、代表意义,及其与临床常见呼吸道过敏性疾病或少见罕见的基因相关疾病的关系和临床实际应用展开阐述。     

A comparison of exhaled nitric oxide measurements performed using three different analysers

INTRODUCTION: Exhaled nitric oxide (NO) is an established technique for monitoring airway inflammation. We have compared exhaled NO measurements from 3 different analysers; Ecomedics (E), Niox (N) and Logan (L). METHODS: Thirty subjects (10 non-smoking healthy subjects, 10 non-smoking patients with asthma and 10 ex-smoking COPD patients) performed 3 repeated measurements of exhaled NO at a flow rate of 50 ml/s on each of the 3 analysers. Within analyser variability was determined by calculating the repeatability coefficient for each analyser. Differences between analysers were assessed by (1) the differences between group means and (2) the Bland Altman method to estimate the variability expected for an individual using the 3 analysers. RESULTS: The repeatability coefficients (expressed as ratios) were 1.12, 1.19 and 1.19 for N, E and L, respectively. There were significant differences (P<0.05) between analysers; the Logan analyser gave the highest group mean values and Ecomedics gave the lowest group mean values. Differences between analysers were observed in all subject groups (healthy, asthma, COPD). Similar results were obtained in the 3 groups when analysed separately. Bland Altman analysis gave the following ratios [data are mean ratio (95% limits of agreement)]; N:E 1.59 (1.02-2.50), L:N 1.23 (0.72-2.13), L:E 1.96 (1.09-3.57). CONCLUSION: Our findings indicate that exhaled NO measurements in healthy subjects and patients with airways disease differ according to the type of analyser used.     

Predicted versus absolute values in the application of exhaled nitric oxide measurements

Background

Constitutional factors such as age, sex and height, and acquired factors such as atopy and smoking, influence exhaled nitric oxide (F_ENO) levels. The utility of predicted values based on reference equations which account for these factors has not been evaluated.

Aim

To compare the performance characteristics of absolute versus % predicted values for F_ENO as predictors of diagnosed asthma and steroid response.

Methods

We compared the sensitivities, specificities and likelihood ratios using F_ENO (% predicted) with absolute values for F_ENO (ppb) in 52 steroid-naive subjects with non-specific respiratory symptoms. The reference equations of Olin et al. (Chest, 2007) and Dressel et al. (Resp. Med., 2008) were used to derive predicted values. Receiver operating curve analyses were performed and the areas under the curve (AUC) were calculated for two outcomes: diagnosed asthma (yes/no), and steroid response after fluticasone for 4 weeks (defined as ≥12% increase in FEV₁; increase in mean morning PEF ≥15%; reduction in symptoms ≥1 point; increase in PC₂₀AMP of ≥2 doubling doses).

Results

The AUCs for diagnosed asthma were: F_ENO (absolute) 0.770; F_ENO (% pred.): 0.758 (Olin) and 0.775 (Dressel) (NS). The AUCs for F_ENO (abs.) and F_ENO (% pred.) with respect to the four indices of steroid response were likewise not significantly different.

Conclusion

Correcting F_ENO for combinations of age, sex, height, smoking and atopy using reference equations did not enhance the performance characteristics of F_ENO as a predictor of either the diagnosis of asthma or steroid responsiveness in patients with chronic airways-related symptoms.     

Reproducibility of exhaled nitric oxide measurements in healthy and asthmatic adults and children.

Airway inflammation in asthma is not measured routinely in clinical practice. Fractional exhaled nitric oxide (FE(NO)), a marker of airway inflammation, is increasingly used as an outcome measure in asthma intervention studies and yet the reproducibility of FE(NO) measurements is unknown. The reproducibility, day-to-day, diurnal variation and perception of standardised FE(NO) measurements were examined in 59 subjects (40 children aged 7-13 yrs and 19 adults aged 18-60 yrs), both healthy (n=30) and with mild (n = 29) asthma. FE(NO) was measured on five consecutive days (four measurements on the same day) for adults and twice on the same day for children. The coefficient of reproducibility expressed as the mean pooled standard deviation (n = 59, 675 estimations) was 2.11 parts per billion (ppb) and intraclass correlation coefficient was 0.99 in both children and adults. FE(NO) was significantly higher in asthma subjects (32.3 ppb) than in healthy subjects (16.3 ppb). There was no diurnal or day-to-day variation, or a learning effect, as the result of FE(NO) measurements were identical at results of the beginning and at the end of the study. It was concluded that fractional exhaled nitric oxide measurements are simple, reproducible, free from diurnal and day-to-day variation, and acceptable by both healthy and asthmatic adults and children, as a part of their routine visit to a physician.     

呼出气一氧化氮的研究进展

呼吸道炎症性疾病传统检查方法,如支气管镜检、肺泡灌洗技术、诱导痰检查等,都是侵入性的诊断方法[1]。而肺功能测试、可逆性试验、峰值流量监测等,目的是为了鉴别呼吸道阻塞和呼吸道生理性异常[2]。单凭上述方法来诊断、监控呼吸道疾病是不足以有效进行抗炎治疗的,而近年来出现的eNO检测,具有无创、易于配合检查、便于动态随访的特点,向患者提供了包括但不仅限于嗜酸性气道炎症的直接检测,帮助诊断、预测和调整吸入用糖皮质激素(ICS)或生物制剂,并评价治疗依从性[3-5]。从1997年欧洲呼吸学会(ERS)首次制订“eNO测定推荐意见”,2011年美国胸科学会(ATS)颁布“呼出气一氧化氮临床应用指南”,到2017年ERS再次更新了“肺部疾病呼气标志物技术标准”。期间相关指南多次更新,该技术在临床上得到了广泛应用,本文将对eNO的研究进展综述如下。