Exhaled nitric oxide levels to guide treatment for children with asthma

Background
Asthma guidelines aim to guide health practitioners to optimise treatment for patients to minimise symptoms, improve or maintain
good lung function, and prevent acute exacerbations. The principle of asthma guidelines is based on a step-up or step-down regimen
of asthma medications to maximise health using minimum doses. Fractional exhaled nitric oxide (FeNO) is a marker of eosinophilic
inflammation and tailoring asthma medications in accordance to airway eosinophilic levels may improve asthma outcomes such as
indices of control or reduce exacerbations, or both.
Objectives
To evaluate the efficacy of tailoring asthma interventions based on fractional 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 children.
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 in June 2016.
Selection criteria
All randomised controlled trials (RCTs) comparing adjustment of asthma medications based on FeNO levels compared to those not
using FeNO, that is, management based on clinical symptoms or asthma guidelines (or both) involving children.
Data collection and analysis
We reviewed results of searches against predetermined criteria for inclusion. Two review authors independently selected relevant studies,
assessed trial quality and extracted data. We contacted study authors for further information with responses provided from three.
Main results
The review included nine studies; these studies differed in a variety of ways including definition of asthma exacerbations, FeNO cutoff
levels used (12 parts per billion (ppb) to 30 ppb), the way in which FeNO was used to adjust therapy and duration of study (6 to
12 months). Of 1426 children randomised, 1329 completed the studies. The inclusion criteria for the participants in each study varied
but all had a diagnosis of asthma. There was a significant difference in the number of children having one or more asthma exacerbations
over the study period, they were significantly lower in the FeNO group in comparison to the control group (odds ratio (OR) 0.58,
95% confidence interval (CI) 0.45 to 0.75; 1279 participants; 8 studies). The number needed to treat for an additional beneficial
outcome (NNTB) over 52 weeks was 9 (95% CI 6 to 15). There was no difference between the groups when comparing exacerbation
rates (mean difference (MD) -0.37, 95% CI -0.8 to 0.06; 736 participants; 4 studies; I2 = 67%). The number of children in the FeNO
group requiring oral corticosteroid courses was lower in comparison to the children in the control group (OR 0.63, 95% CI 0.48
to 0.83; 1169 participants; 7 studies; I2 = 0%). There was no statistically significant difference between the groups for exacerbations
requiring hospitalisation (OR 0.75, 95% CI 0.41 to 1.36; 1110 participants; 6 studies; I2 = 0%). There were no significant differences
between the groups for any of the secondary outcomes (forced expiratory volume in one second (FEV1), FeNO levels, symptom scores
or inhaled corticosteroid doses at final visit). The included studies recorded no adverse events.
Three studies had inadequate blinding and were thus considered to have a high risk of bias. However, when these studies were removed
in subgroup analysis, the difference between the groups for the primary outcome (exacerbations) remained statistically significant. The
GRADE quality of the evidence ranged from moderate (for the outcome ’Number of participants who had one or more exacerbations
over the study period’) to very low (for the outcome ’Exacerbation rates’), based on lack of blinding, statistical heterogeneity and
imprecision.
Authors’ conclusions
In this updated review with five new included studies, tailoring asthmamedications based on FeNOlevels (in comparison with primarily
guideline management) significantly decreased the number of children who had one or more exacerbations over the study period but
did not impact on the day-to-day clinical symptoms or inhaled corticosteroid doses. Therefore, the use of FeNO to guide asthma
therapy in children may be beneficial in a subset of children, it cannot be universally recommended for all children with asthma.
Further RCTs need to be conducted and these should encompass different asthma severities, different settings including primary care
and less affluent settings, and consider different FeNO cut-offs.Full Tex