Are exhaled nitric oxide measurements using the portable NIOX MINO repeatable?

Asthma is a chronic inflammatory disorder of the airways associated with airway hyperresponsiveness and recurrent episodes of reversible airflow limitation that are accompanied by wheeze, shortness of breath, chest tightness and cough [1]. It is the most common chronic condition of childhood [2] affecting approximately 20% of school-aged children in the United Kingdom [3]. Decisions regarding asthma management are currently based on symptoms and conventional lung function tests. Exhaled nitric oxide (FeNO) has recently emerged as a potentially useful tool in the assessment of patients with asthma [4]. Exhaled nitric oxide measurements correlate well with measures of airway inflammation, including sputum levels of eosinophils [5], airway eosinophilia in bronchial biopsies [6] and allergen exposure [7]. Measurements can be made within minutes, even in young school children. Furthermore, FeNO has been shown to rise prior to asthma exacerbations [8] and decrease following administration of inhaled corticosteroids [9] or leukotriene receptor antagonists [10]. Potential applications for FeNO may therefore be found in the diagnostic work up of patients with possible asthma, monitoring of treatment responses, adherence with treatment and prediction of exacerbations [4, 11]. Its role in directing the chronic management of asthma has though been questioned recently [12, 13]. Previously, FeNO measurement required static, chemiluminesence-based NO analysers, such as the NIOX Nitric Oxide Monitoring System (Aerocrine AB, Solna, Sweden). The use of these analysers in routine clinical practice is, however, limited by their size and expense. A portable hand-held NO-analyser, the NIOX MINO Asthma Inflammation Monitor (Aerocrine AB, Solna, Sweden), which uses electrochemical sensors to measure FeNO levels, is now available. This is ideally suited for use in primary care, where the majority of asthma patients are managed [14].

Studies comparing the performance of the NIOX MINO and the NIOX have shown that the level of agreement between the two devices is clinically acceptable [15‐18] and the NIOX MINO is now approved by the Federal Drugs Administration in the United States for assessing asthma-related airway inflammation [19]. The manufacturer recommends that one measurement is sufficient when using the NIOX MINO [20] rather than two as recommended in the latest ATS/ERS guidelines [4]. The manufacturer states an accuracy of ±5 ppb of measured value below 50 ppb and ±10% at or above 50 ppb [20]. There are a number of studies that support this recommendation of a single measurement [15, 16, 21, 22], however, to date only one small paediatric study has addressed this question [18]. In this study of fifty-five children aged 4-15 years, the first acceptable FeNO measurement obtained using the NIOX MINO was not significantly different from the mean of all measurements (24 versus 27 ppb, p > 0.5) but the median coefficient of variation for the NIOX MINO was 7.4% (range: 0-44.6) suggesting that one FeNO measurement is not sufficient when using the NIOX MINO. The aim of the current validation study was to assess the reproducibility of NIOX MINO measurements in children and teenagers across age, sex and lung function, in terms of both the absolute and categorical FeNO values.

This study aimed to validate the reproducibility of a new, portable NO-analyser (the NIOX MINO, Aerocrine AB, Solna, Sweden) in children and teenagers. The results from two complementary groups of children and teenagers indicate that the reproducibility of NIOX MINO measurements across the paediatric age range is poor when considering the absolute value FeNO but is acceptable when FeNO values are categorised as low, normal, intermediate or high. This suggests that if clinical decisions in future are based on specific cut-off values of FeNO, the mean of at least two FeNO measurements should be reported when using the NIOX MINO. However, for treatment algorithms based on FeNO categories, one NIOX MINO measurement would be sufficient, saving cost and time in clinic. This study is the largest of its kind to date and is the first to consider the effect of patient characteristics on reproducibility of NIOX MINO measurements.

Our findings contradict those of other studies, which have reported excellent reproducibility of the absolute value of FeNO measurements obtained using the NIOX MINO [15, 16, 21, 22]. These studies have, however, included both adults and children, so their results do not validate the use of the NIOX MINO in paediatric practice. Much of this intra-subject variability is seen at higher levels of FeNO and so it may be more patient related than monitor related [26] and unlikely to cause any indecision about clinical management. For the intervention asthma study participants, the reproducibility of the absolute value of FeNO was poorer in those with a low FEV₁ whilst in the birth cohort participants, greater variability was observed in participants with asthma. These are precisely the participants in whom FeNO measurement would be performed in clinical practice. Our results therefore support McGill's recommendation that the mean of at least two FeNO measurements should be used when reporting absolute values using the NIOX MINO with children and teenagers [18]. It has been suggested that greater variability between FeNO measurements is more likely in those who are not consistently able to record FeNO [18]. Given that the success rate with the NIOX MINO increases with age [15], it is therefore surprising that we observed closer agreement between paired NIOX MINO measurements in the youngest participants (Table 5). Potentially, taking the average of three or more measurements may have further increased the reliability of the FeNO value but this was outside the scope of this study. The other potential limitation of this study is that a gold standard measure of FeNO, such as the NIOX monitor (Aerocrine AB, Solna, Sweden) was not included; again this was outside the scope of this study which was focusing on the reproducibility of NIOX MINO readings within one assessment rather than their validity.

No previous studies have evaluated the reproducibility of categorical FeNO values obtained using the NIOX MINO. Our data suggests that the reproducibility of this approach is acceptable although 10% of subjects may be misclassified by one category. These categories are based on cut off values from a number of studies [25, 27] and there may be a certain amount of imprecision in the boundaries chosen. The small amount of misclassification bias is likely to be of minimal clinical importance unless FeNO levels are being used in isolation to diagnose asthma [28] or direct the clinical management of patients with asthma [4]. Different research groups are, however, using different cut off values, so it is important to assess whether reproducibility is comparable with other cut off values. Additionally, future research should seek to determine whether the accuracy of NIOX MINO measurements is affected by the number of attempts required to record FeNO, as this would have implications for the interpretation of FeNO measurements in clinical practice. This is particularly important for patients less than 12 years of age who often need more attempts and were relatively poorly represented in our study. Lastly, given the number of influences on FeNO levels, these measurement may proved to be most useful when standardised to the patient's baseline FeNO level while their asthma is well controlled as we have previously suggested [7]. Such a strategy would necessitate a further look at the consequences of relying on a single estimate of the level of FeNO in driving clinical management.

In summary, the NIOX MINO could improve the management of children with asthma by enabling physicians to monitor underlying airway inflammation more easily than has been possible to date. According to the manufacturer (Aerocrine AB, Solna, Sweden), one FeNO measurement is sufficient when using the NIOX MINO, instead of two as recommended by the ATS/ERS guidelines. This study has found that in two distinct groups of children and teenagers, one NIOX MINO measurement is acceptable when using FeNO to direct asthma management, based on FeNO categories, but when using the absolute value of FeNO, the mean of at least two NIOX MINO measurements should be used.