Background
We examined whether exhaled nitric oxide (a marker in the breath which can show a type of lung inflammation) is useful in adjusting asthma medications in adults in comparison to the usual ways that asthma medications are adjusted. Exhaled nitric oxide levels are easily obtained by getting the person to breathe into a commercially available analyser.
Study characteristics
We included all randomised controlled trials that compared adjustment of asthma medications by usual clinical care (control group) versus using exhaled nitric oxide. The participants included in the trials had asthma diagnosed as per relevant asthma guidelines.
The evidence is current to June 2016, when the searches were last completed.
We found seven studies in the searches. Of 1700 randomised participants, 1546 completed the trials. The studies varied in a few aspects including duration, cutoff levels used for altering medications based on fractional exhaled nitric oxide (FeNO), and the way each study defined exacerbations. The included studies ranged from 4 months to 12 months in duration. The FeNO cutoff values the studies used also varied. The levels used for decreasing medications ranged from 10 ppb to 25 ppb. Likewise, the levels used for increasing medications ranged from 15 ppb to 35 ppb in the included studies. The majority of the studies were industry supported.
The mean ages of the participants ranged from 28 to 54 years old.
Key results
In this review involving 1700 adults with asthma, we found that guiding the dose of asthma medications based on exhaled nitric oxide (compared to a control group) was beneficial in reducing the number of exacerbations (flare-ups) during the study period. However, we did not find a difference between groups for other asthma outcomes that impact on day-to-day clinical symptoms, hospitalisations, or inhaled steroid dose. Thus, using exhaled nitric oxide levels to adjust asthma therapy may reduce the risk of adults having an asthma flare-up but did not impact on day-to-day symptoms.
Quality of the evidence
The quality of evidence ranged from moderate when comparing the two groups for the exacerbation outcomes, to very low when comparing the groups for inhaled corticosteroid dose at final visit.
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.
Asthma guidelines aim to guide health practitioners to optimise treatment for patients so as to minimise symptoms, improve or maintain good lung function, and prevent acute exacerbations or flare-ups. The principle of asthma guidelines is based on a step-up or step-down 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).
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.
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.
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.
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.
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 meta-analysis, 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.