Abstract
The aim of this review was to evaluate the clinical effectiveness of fractional exhaled nitric oxide (FeNO) measured in a clinical setting for the management of asthma in adults.
13 electronic databases were searched and studies were selected against predefined inclusion criteria. Quality assessment was conducted using QUADAS-2. Class effect meta-analyses were performed.
Six studies were included. Despite high levels of heterogeneity in multiple study characteristics, exploratory class effect meta-analyses were conducted. Four studies reported a wider definition of exacerbation rates (major or severe exacerbation) with a pooled rate ratio of 0.80 (95% CI 0.63–1.02). Two studies reported rates of severe exacerbations (requiring oral corticosteroid use) with a pooled rate ratio of 0.89 (95% CI 0.43–1.72). Inhaled corticosteroid use was reported by four studies, with a pooled standardised mean difference of −0.24 (95% CI −0.56–0.07). No statistically significant differences for health-related quality of life or asthma control were found.
FeNO guided management showed no statistically significant benefit in terms of severe exacerbations or inhaled corticosteroid use, but showed a statistically significant reduction in exacerbations of any severity. However, further research is warranted to clearly define which management protocols (including cut-off points) offer best efficacy and which patient groups would benefit the most.
Abstract
FeNO testing for adult asthma management may confer clinical benefit, but research is needed to establish its role http://ow.ly/WGWkx
Introduction
Asthma is a chronic disorder of the airways, caused primarily by inflammatory processes and bronchoconstriction. Poorly controlled asthma can have a significant impact on the quality of life of the affected individual and their family. An estimated 5.4 million people in the UK are currently receiving treatment for asthma [1, 2]. Despite the high prevalence rates, deaths resulting from asthma are uncommon.
The pharmacological management of asthma in adults aims to control symptoms (including nocturnal symptoms and exercise induced asthma), prevent exacerbations and achieve the best possible lung function, with minimal side-effects of treatment. Inhaled corticosteroids (ICSs) are the main treatment for asthma, and although at low dosage the side-effects are few, high dosage or long-term use of ICS is associated with an increased risk of systemic side-effects [3]. The current British guidelines on the management of asthma recommend a stepwise approach, with escalation of medication until control is reached or stepping down when control is good [4]. However, in certain cases there is suspected over- and under-treatment.
Fractional exhaled nitric oxide (FeNO) is a noninvasive biomarker of airway inflammation in asthma. High FeNO in the breath of patients with symptoms of asthma are correlated with eosinophilic airway inflammation (a distinct corticosteroid responsive phenotype of asthma) [5–7]. The presence of eosinophils may be used to direct treatment as patients without eosinophilic inflammation are thought to be less responsive to ICS treatment [8]. Therefore, in order to reach a balance between treatment and control, the addition of FeNO monitoring might allow optimisation of treatment in the different disease phenotypes. Existing reviews of FeNO monitors suggest some benefits associated with FeNO [9–11]; however, none were statistically conclusive. In addition, these reviews focused on number of people with an exacerbation, inappropriately included the cohort of pregnant women in the meta-analysis (pregnancy can substantially affect the course of asthma) [12] and are out-of-date. To address these limitations we have updated an existing review [9], with the addition of three new studies [13–16], to determine the potential role of FeNO monitors in the management and monitoring of asthma in adults. This systematic review was undertaken to inform a UK National Institute for Health and Care Excellence appraisal which included an assessment of the use of the electrochemical FeNO monitors NIOX MINO (Aerocrine AB, Solna, Sweden), NIOX VERO (Aerocrine AB) and NObreath (Bedfont Scientific Ltd, Maidstone, UK) in the diagnosis and management of asthma [17, 18].
Methods
A systematic review was undertaken in accordance with the general principles recommended in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement [19].
Data sources and searches
13 electronic databases and research registers were searched (including MEDLINE and the Cochrane Library) between March and April 2013, with update searches conducted in September 2013 and November 2014. Terms for NIOX VERO, a new FeNO device, were added to the strategy in August 2013. The search strategy used free-text terms and subject headings for the tests (e.g. NIOX MINO, NObreath and FeNO) combined with keywords for the condition (i.e. asthma or lower respiratory tract symptoms). No language restrictions were applied. As part of updating an earlier systematic review [9], searches were limited by date from 2009 (the last search date from the earlier review). Searches were supplemented by hand-searching reference lists of relevant studies and contact with experts in the field. Further details of the search strategy are provided in the online supplementary appendix 1.
Study selection
All titles were examined for inclusion by one reviewer and any citations that did not meet the inclusion criteria (e.g. non-human or unrelated to asthma) were excluded. All abstracts and full-text articles were then examined independently by two reviewers. Any disagreements in the selection process were resolved through discussion. Details of the selection criteria are provided in table 1. This review focuses on studies relating to adults only. Details of FeNO for the management of asthma in children have been published elsewhere [21].
Study selection criteria
Data abstraction
Data relating to study design, patient characteristics and outcomes were extracted by one reviewer into a standardised data extraction form and independently checked for accuracy by a second reviewer. Any discrepancies were resolved through discussion. Where necessary, study authors were contacted for missing information or additional data.
Assessment of methodological quality
The methodological quality of each included study was assessed according to the Cochrane Collaboration's tool for assessing the risk of bias in randomised controlled trials (RCTs) [22]. The studies were assessed by one reviewer and independently checked by another.
Data synthesis and analysis
Data were tabulated and discussed in a narrative review. Meta-analyses were planned, where appropriate, to estimate a summary measure of effect on relevant outcomes using the methods documented in the Cochrane Handbook [22, 23]. For rate outcomes, rates per person year were the preferred outcome metric, as this accounts for multiple events in a single patient. The generic inverse variance method was used to meta-analyse rate ratios using Review Manager software (Version 5.3. The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). For continuous outcomes, a standardised mean difference analysis was conducted where outcomes were not reported in a standardised way. In all cases, fixed effects were used first, and random effects applied if the I2 statistic indicated that heterogeneity was moderate or high. This was judged to be the case at >40%. Studies in pregnant women were analysed separately as FeNO may be affected by pregnancy [12].
Results
Trial flow
Of the 5354 citations identified, three RCTs [13, 14, 16] met the inclusion criteria and were added to the three existing trials [24–26] identified in the previous systematic reviews [9, 11]. The majority of the excluded articles did not use FeNO to guide step-up/step-down therapy or the study design was not an RCT. A summary of the process of identifying and selecting the relevant literature can be found in online supplementary appendix 2.
Characteristics of included studies
Table 2 presents the study characteristics of the six included studies [13, 14, 16, 24–26]. All the included studies compared FeNO-guided asthma management to non-FeNO-guided management and all patients were recruited in primary care, except for Calhoun et al. [13], where the recruitment setting was unclear. The device used to measure FeNO was not clearly reported in three studies. Most studies were of a small to moderate size, with the number of patients ranging from 94 [24] to 611 [16]. All studies recruited adults of either sex [13, 14, 16, 24, 25], apart from Powell et al. [26], which recruited only pregnant women. The comparability of study populations in terms of severity at baseline is difficult to determine as different scales for severity and different metrics for medication use were reported. Inclusion and exclusion criteria suggest that at least four studies [13, 14, 24, 26] recruited populations with mild to moderate asthma; while the other two studies [16, 25] included a broader spectrum of severity. However, overall the patient population is predominantly milder asthmatics (mean forced expiratory volume in 1 s (FEV1) range 81–96% predicted). In addition, no studies followed the same timeline, visit frequency, management protocols, number and points of FeNO cut-offs, and treatment doses varied across the included studies (table 3).
Study and population characteristics
Description of management strategies
Risk of bias within studies
Table 4 summarises the methodological quality of the included studies. Generally, two studies [25, 26] performed well receiving a positive assessment of at least six of the seven quality items. The most frequently identified potential sources of a high risk of bias concerned “other biases” related to the receipt of commercial funding (67%) [13, 14, 16, 24]. A high number of publications poorly reported the following aspects: random sequence generation (33%) [13, 24], allocation concealment (33%) [13, 24] and blinding of outcome assessment (50%) [13, 24, 25]. It should be noted that poor performance in quality assessment for the study by Syk et al. [14] was due to its open label study design, which was necessary to influence patients' adherence to treatment and to capture these clinically valuable effects.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study
Outcomes and synthesis of results
Despite wide variation in all aspects of study design across the five studies [13, 14, 16, 24, 25] (excluding the study on pregnant women) [26]; exploratory meta-analyses were conducted where possible for all relevant outcomes (table 5).
Exacerbations and inhaled corticosteroid (ICS) use in adult patients with or without fractional exhaled nitric oxide (FeNO)-guided management
Healthcare utilisation
Unscheduled healthcare utilisation, defined as emergency department/accident and emergency visits, out-of-hours general practitioner's surgery visits or hospitalisation, was only reported in Honkoop et al. [16]. Although the result showed improvement in healthcare utilisation with FeNO management (table 5), this was not statistically significant for all comparisons (p>0.05). In the remaining four studies [13, 14, 24, 25], unscheduled healthcare utilisation was included as either treatment failure or severe exacerbations (see later), since exacerbations of asthma can lead to both unscheduled healthcare utilisation and the need for a course of oral corticosteroids (OCSs).
Severe exacerbations
This outcome was defined differently across studies (table 5). Syk et al. [14] and Honkoop et al. [16] defined it as “worsening requiring a course of OCS”; Shaw et al. [25] defined it as “exacerbations resulting in the use of OCS or antibiotics”; and Calhoun et al. [13] reported it as “exacerbations”, which included exacerbations leading to OCS use, increased ICS use or additional medication for asthma. A meta-analysis of four studies (the study of Smith et al. [24] was not included as follow-up data were not calculable as rates per person year) showed that severe exacerbations (while statistically not significant) were less likely in the FeNO-guided-management group compared with the control group (figure 1a), with rate ratio of 0.80 (95% CI 0.63–1.02; p=0.08).
Random effects meta-analysis. a) Effects of fractional exhaled nitric oxide (FeNO)-guided asthma management on major/severe exacerbation rates. b) Number of severe exacerbations resulting in the use of oral corticosteroids. c) Effects of FeNO-guided asthma management on the composite outcome of all exacerbation and treatment failure rates. d) Effects of FeNO-guided asthma management on mean inhaled corticosteroids use (standardised (Std) mean difference analysis).
Severe exacerbations resulting in the use of OCS
Analysis of studies reporting the number of severe exacerbations resulting in the use of OCS (figure 1b) was limited to only two studies [14, 16], which showed opposite directions of effect. This may be due to variations in the step-up/step-down protocols employed in the studies, or due to the populations being slightly different.
Moderate and minor exacerbations
Two studies [14, 24] reported data on less severe exacerbations; however, this data was not amenable to meta-analysis due to unreported data (table 5). Both studies observed lower rates of minor/moderate asthma exacerbations in the intervention group compared with the control group. In Smith et al. [24], the rate was 0.36 versus 0.75 (p=0.24) and in Syk et al. [14], 0.1 versus 0.325 events per person year respectively (p-value not reported).
Composite of all exacerbations and failure rates
Three studies reported composite outcomes that were considered to be broadly similar and represent what may be termed “treatment failure” (table 5). In Smith et al. [24] and Syk et al. [14] this was “any major or minor exacerbation”, while in Calhoun et al. [13] it was exacerbation or any loss of control by a variety of measures. A meta-analysis of these studies (fig. 1c) showed a statistically significant effect in favour of using FeNO-guided management in adults, with a rate ratio of 0.53 (95% CI 0.46–0.61; p<0.00001). However, due to high degree of heterogeneity in composite outcomes, the effect is therefore liable to high risk of bias.
ICS use
Four studies reported some data on ICS use [13, 14, 24, 25]; however, outcomes were not reported in a standardised manner (table 5). As shown in figure 1d, a meta-analysis using the standardised mean difference analysis showed a beneficial overall effect of −0.24 (95% CI −0.56–0.07) in favour of FeNO-guided management; however, the findings were not statistically significant (p=0.13).
Relationship between ICS use, step-up/step-down protocol and exacerbations
A post hoc analysis was undertaken to examine the relationship between ICS use, exacerbations and which step-up/step-down approach was used. A summary of the data is presented in table 6. Two studies that used FeNO levels in conjunction with symptoms showed a statistically significant decrease in ICS use in the FeNO-guided management groups and a nonsignificant decrease in any type of exacerbation [24, 25], thus indicating improved management overall. By contrast, the studies which managed asthma based on FeNO levels alone were less clear. Syk et al. [14] reported no change in ICS use and a nonsignificant decrease in moderate exacerbation and a nonsignificant increase in severe exacerbation, but a significant decrease in any exacerbation. Calhoun et al. [13] reported no difference in ICS use and exacerbations.
Relationship between inhaled corticosteroid (ICS) use, step-up/step-down protocol and exacerbations
Other outcomes
Health-related quality of life was infrequently reported. Three studies [13, 14, 16] used versions of the Asthma Quality of Life Questionnaire to measure quality of life. Two studies showed no effect in the global score (pooled standardised mean difference: 0.00 (95%CI −0.20–0.20); p=0.96) [13, 16]. However, one study investigated domains and found a statistically significant difference in the symptoms score (p=0.041) with a between group difference in change from baseline of 0.10 in favour of FeNO management [14]. Asthma control was reported in all studies, but showed no statistically significant difference. Further details on other outcomes are summarised in online supplementary appendix 3.
Efficacy of FeNO in pregnant women
One study reported the efficacy of FeNO-guided management of asthma in pregnant women [26]. The composite outcome of all exacerbations was statistically significantly reduced in the intervention arm, with an incidence rate ratio of 0.496 per pregnancy (95% CI 0.325–0.755; p=0.001). This difference was mostly driven by the rate of OCS use and the rate of doctors’ visits during pregnancy (table 7). Mean OCS use in the FeNO and control arm was 0.08 (95% CI 0.03–0.133) and 0.19 (95% CI 0.08–0.31), respectively (p=0.042). Similarly, the rate of doctors’ visits was 0.26 (95% CI 0.16–0.36) in the FeNO arm and 0.56 (95% CI 0.40–0.72) in the control arm with a p-value of 0.002 in favour of FeNO management. Other components of the exacerbation outcome (hospitalisations and emergency room/labour ward visits) did not differ between groups. The change in mean value from baseline to final visit for ICS use decreased by 210 µg·day−1 in the intervention arm and increased by 50 µg·day−1 in the control arm. The difference was statistically significant in favour of FeNO management (p=0.043). However, overall more patients received ICS (68% versus 42%) in the FeNO group than in the control group by the end of the study. Other outcomes are summarised in table 7.
Pregnant women: all outcomes
Discussion
In this systematic review, six RCTs were identified that assessed the use of FeNO for the management of asthma in adults [13, 14, 16, 24–26]. In general, using exploratory meta-analysis, a fall in exacerbation rates per person year were observed, but none were statistically significant apart from the composite of all exacerbations and failure rates. However, the findings should be interpreted with caution due to the high degree of heterogeneity in the outcome definition. The effects on ICS use were heterogeneous, although the direction of the effect was towards a decrease in ICS use. The effect on healthcare utilisation was not statistically significant; however, as this outcome was only reported in one low quality study [16], to base any conclusion on this could be misleading. The use of FeNO to guide asthma management in pregnant women in the second trimester appears to be as effective, if not more so, than in other adults [26], and appears to reduce exacerbations and ICS use, but by the end of the study more patients in FeNO group had received ICS. The differences in outcome between studies may have occurred due to some step-up/step-down protocols being better at decreasing ICS use than others, or may be due to the characteristics of the study populations. Other potential factors as to why the FeNO monitoring studies have been predominately negative could be due to the difference in severity of asthma at baseline, different treatment strategies used (i.e. some studies controlled only ICS while some also controlled other medications), differences in the number and points of FeNO cut-off used, and also the comparator groups did not all use the same algorithm.
There are at least two previous systematic reviews on the effectiveness of FeNO monitoring to guide management [9, 11]. Petsky et al. [9] compared adjustments of asthma therapy based on FeNO with conventional methods (typically clinical symptoms and spirometry). The review suggested some benefits associated with FeNO for several outcomes, in particular the number of subjects with >1 exacerbation, exacerbation rates, FEV1 % predicted at final visit and geometric change in FeNO from baseline; however, none of these results were statistically conclusive. FeNO appeared to have some beneficial effect on symptom score (mean difference: −0.14, 95% CI −0.42–0.14) and lowered ICS dose (mean difference: −450.03 μg, 95% CI −676.73– −223.34 μg). Furthermore, there was substantial clinical heterogeneity among the study cohorts, with no two studies using exactly the same step-up/step-down protocols. There is some agreement between the review by Petsky et al. [9] and our own review, especially relating to the lack of statistically significant effects in most outcomes. The strength of our review lies in the inclusion of subsequently published studies (Calhoun et al. [13], Syk et al. [14] and Honkoop et al. [16]), the focus on exacerbation rates rather than number of people with an exacerbation, and the prior separation of pregnant women into a different subgroup. The second review by Donohue and Jain [11] updated the meta-analyses of the number of patients with >1 exacerbation and exacerbation rates from the aforementioned Cochrane review [9], and included a study in pregnant women [26]. Inclusion of this study resulted in improvements on all measures of exacerbations (mean difference: −0.27, 95% CI −0.42– −0.12), and the relative rate of asthma exacerbations (relative rate: 0.57, 95% CI 0.41–0.80). However, since it is known that pregnancy can substantially affect the course of asthma [12], it was arguably inappropriate to include the cohort of pregnant women in a meta-analysis of adults with asthma.
One of the putative benefits of using FeNO for the management of asthma is the identification of patients for whom increased ICS use will not improve control. These patients are likely to present with symptoms, which would indicate an increase in pharmaceutical management under standard clinical guidelines, and under most of the FeNO protocols that have been studied to date, whereas they may be better treated with other asthma control medications. A key limitation is therefore the paucity of studies that allowed step-down of ICS to be performed on the basis of low FeNO values alone. Only two studies [13, 14] and the study in pregnant women [26] included such a strategy, and only Powell et al. [26] made provision for adjusting other treatments which may offer superior control in these patients in response to their reported symptomatology. We did not plan or perform a sensitivity analysis of this data, but did present a rudimentary analysis of the relationship between ICS use, management protocols and exacerbations (table 6). It is interesting to note that the two studies that managed patients on the basis of FeNO only (Syk et al. [14] and Calhoun et al. [13]) did not report any change in ICS use, which is perhaps contrary to expectations, or in severe exacerbations. However, Syk et al. [14] did report a fall in exacerbations overall. In comparison, the two studies that managed patients on the basis of FeNO and symptoms (Smith et al. [24] and Shaw et al. [25]) reported a statistically significant decrease in ICS use and a nonsignificant decrease in exacerbations. This perhaps indicates a shift in treatment patterns, with better targeting of treatment with the addition of FeNO to the patients who will benefit most. In addition, although there was no significant difference in compliance with treatment between the FeNO management and control group, there is a potential that FeNO may help improve compliance with ICS use.
There are a number of limitations to our review which warrant caution in its interpretation to clinical practice. The evidence from the included studies are of low quality and there is significant heterogeneity in all aspects of study design across the studies, including patient characteristics, outcome definitions, FeNO cut-off points and in management protocols, hence an exploratory meta-analysis was used to overcome these differences. In addition, the management plan used in some studies did not reflect real life practice, for example in the study by Smith et al. [24], long-acting β2-agonist (LABA) was not used and patients underwent a step-down therapy approach in the pre-study phase. It is noteworthy that LABA in combination with ICS are key steps in asthma management. The equivalence of devices is assumed and this may not hold true in practice. As such, FeNO cut-off values as reported in the primary research may not be applicable to measurements using other devices. Smoking affects FeNO levels and majority of the patients in this review were nonsmokers, hence it is not clear if the results can be generalised to the smoking population. Also, the average age of patients in this review was around 40 years old. However, the majority of asthma deaths occur in older people with severe disease. All the included studies recruited patients that were stable during the run-in period and excluded the more severe/difficult patients with recent hospital admissions. So, by definition, some of the real life “difficult” patients, who require more help, were excluded. Finally, the criteria used for the diagnosis of asthma across the included studies varied with limited data and as recent studies have reported the potential of overdiagnosis of asthma, this may have implications for the results. It is important to note that these limitations are principally sourced in the evidence base, rather than the methods used to interrogate and evaluate it. One should also bear in mind that the addition of FeNO to the current management strategy will require change in organisation and to the philosophy of care in self-management.
Conclusion
FeNO guided management showed no statistically significant benefit in terms of severe exacerbations or ICS use, but showed a statistically significant reduction in exacerbations of any severity. Due to heterogeneity in the studies it was not possible to draw any firm conclusions as to which management protocol or cut-off points offer the best efficacy. Further research is required to investigate the best way to use FeNO in the management of asthma, which management protocol and cut-offs to use; to establish which patient groups are likely to benefit from FeNO monitoring, e.g. individuals with atopy, frequent exacerbations or those with poor adherence; and how treatment effect will progress over time. Larger, well designed RCT studies, taking into account issues such as severity as defined by previous exacerbations, blinding and approximating to routine care are warranted to clearly define the role of FeNO in clinical practice.
Acknowledgements
We would like to thank John W. Stevens (School of Health and Related Research, University of Sheffield, Sheffield, UK) for providing statistical support.
Footnotes
This article has supplementary material available from erj.ersjournals.com
Support statement: This project was funded by the National Institute for Health Research Health Technology Assessment (NIHR HTA) Programme (project number: 12/60/01) as part of a review on “Measurement of exhaled nitric oxide concentration in asthma; NIOX MINO, NIOX VERO and Nobreath”, and published as part of a full report in Health Technology Assessment (PROSPERO registration number: CRD42013004149 (www.crd.york.ac.uk/prospero/)). The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NHS, the NIHR, MRC, CCF, NETSCC, the NIHR HTA programme or the UK Department of Health. Funding information for this article has been deposited with FundRef.
Conflict of interest: Disclosures can be found alongside the online version of this article at erj.ersjournals.com
- Received November 12, 2015.
- Accepted December 6, 2015.
- Copyright ©ERS 2016
ERJ Open articles are open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0.
References
