Exhaled nitric oxide levels to guide treatment for adults with asthma

Background
Asthma guidelines aimto guide health practitioners to optimise treatment for patients so as tominimise symptoms, improve ormaintain
good lung function, and prevent acute exacerbations or flare-ups. The principle of asthma guidelines is based on a step-up or stepdown
regimen of asthma medications to maximise good health outcomes using minimum medications. Asthma maintenance therapies
reduce airway inflammation that is usually eosinophilic. Tailoring asthma medications in accordance with airway eosinophilic levels
may improve asthma outcomes such as indices of control or reduce exacerbations or both. Fractional exhaled nitric oxide (FeNO)
is a marker of eosinophilic inflammation, and as it is easy to measure, has an advantage over other measurements of eosinophilic
inflammation (for example sputum eosinophils).
Objectives
To evaluate the efficacy of tailoring asthma interventions based on exhaled nitric oxide (FeNO), in comparison to not using FeNO, that
is management based on clinical symptoms (with or without spirometry/peak flow) or asthma guidelines or both, for asthma-related
outcomes in adults.
Search methods
We searched the Cochrane Airways Group Specialised Register of Trials, the Cochrane Central Register of Controlled Trials (CENTRAL),
MEDLINE, EMBASE, and reference lists of articles. The last searches were undertaken in June 2016.
Selection criteria
All randomised controlled trials (RCTs) comparing adjustment of asthma medications based on exhaled nitric oxide levels compared
to not using FeNO, that is management based on clinical symptoms (with or without spirometry/peak flow) or asthma guidelines or
both.
Data collection and analysis
We reviewed results of searches against predetermined criteria for inclusion.We independently selected relevant studies in duplicate.Two
review authors independently assessed trial quality and extracted data. We contacted study authors for further information, receiving
responses from four. 
Main results
We included seven adult studies; these studies differed in a variety of ways including definition of asthma exacerbations, FeNO cutoff
levels used (15 to 35 ppb), the way in which FeNO was used to adjust therapy, and duration of study (4 to 12 months). Of 1700
randomised participants, 1546 completed the trials. The mean ages of the participants ranged from 28 to 54 years old. The inclusion
criteria for the participants in each study varied, but all had a diagnosis of asthma and required asthma medications. In the metaanalysis,
there was a significant difference in the primary outcome of asthma exacerbations between the groups, favouring the FeNO
group. The number of people having one or more asthma exacerbations was significantly lower in the FeNO group compared to the
control group (odds ratio (OR) 0.60, 95% confidence interval (CI) 0.43 to 0.84). The number needed to treat to benefit (NNTB)
over 52 weeks was 12 (95% CI 8 to 32). Those in the FeNO group were also significantly more likely to have a lower exacerbation rate
than the controls (rate ratio 0.59, 95% CI 0.45 to 0.77). However, we did not find a difference between the groups for exacerbations
requiring hospitalisation (OR 0.14, 95% CI 0.01 to 2.67) or rescue oral corticosteroids (OR 0.86, 95% CI 0.50 to 1.48). There was
also no significant difference between groups for any of the secondary outcomes (FEV1, FeNO levels, symptoms scores, or inhaled
corticosteroid doses at final visit).
We considered three included studies that had inadequate blinding to have a high risk of bias. However, when these studies were
excluded from the meta-analysis, the difference between the groups for the primary outcomes (exacerbations) remained statistically
significant. The GRADE quality of the evidence ranged from moderate (for the outcome ’exacerbations’) to very low (for the outcome
’inhaled corticosteroid dose at final visit’) based on the lack of blinding and statistical heterogeneity. Six of the seven studies were
industry supported, but the company had no role in the study design or data analyses.
Authors’ conclusions
With new studies included since the last version of this review, which included adults and children, this updated meta-analysis in
adults with asthma showed that tailoring asthma medications based on FeNO levels (compared with primarily on clinical symptoms)
decreased the frequency of asthma exacerbations but did not impact on day-to-day clinical symptoms, end-of-study FeNO levels, or
inhaled corticosteroid dose. Thus, the universal use of FeNO to help guide therapy in adults with asthma cannot be advocated. As
the main benefit shown in the studies in this review was a reduction in asthma exacerbations, the intervention may be most useful in
adults who have frequent exacerbations. Further RCTs encompassing different asthma severity, ethnic groups in less affluent settings,
and taking into account different FeNO cutoffs are required.Full Tex