Tailoring asthma treatment on eosinophilic markers (exhaled nitric oxide or sputum eosinophils): a systematic review and meta-analysis.

BACKGROUND: Asthma guidelines guide health practitioners to adjust treatments to the minimum level required for asthma control. As many people with asthma have an eosinophilic endotype, tailoring asthma medications based on airway eosinophilic levels (sputum eosinophils or exhaled nitric oxide, FeNO) may improve asthma outcomes. OBJECTIVE: To synthesise the evidence from our updated Cochrane systematic reviews, for tailoring asthma medication based on eosinophilic inflammatory markers (sputum analysis and FeNO) for improving asthma-related outcomes in children and adults. DATA SOURCES: Cochrane reviews with standardised searches up to February 2017. STUDY SELECTION: The Cochrane reviews included randomised controlled comparisons of tailoring asthma medications based on sputum analysis or FeNO compared with controls (primarily clinical symptoms and/or spirometry/peak flow). RESULTS: The 16 included studies of FeNO-based management (seven in adults) and 6 of sputum-based management (five in adults) were clinically heterogeneous. On follow-up, participants randomised to the sputum eosinophils strategy (compared with controls) were significantly less likely to have exacerbations (62 vs 82/100 participants with ≥1 exacerbation; OR 0.36, 95% CI 0.21 to 0.62). For the FeNO strategy, the respective numbers were adults OR 0.60 (95% CI 0.43 to 0.84) and children 0.58 (95% CI 0.45 to 0.75). However, there were no significant group differences for either strategy on daily inhaled corticosteroids dose (at end of study), asthma control or lung function. CONCLUSION: Adjusting treatment based on airway eosinophilic markers reduced the likelihood of asthma exacerbations but had no significant impact on asthma control or lung function

Exhaled nitric oxide levels to guide treatment for children with asthma (Protocol)

This is the protocol for a review and there is no abstract. The objectives are as follows: To evaluate the efficacy of tailoring asthma medications based on exhaled nitric oxide (FeNO) for asthma related outcomes in children. We will compare this with not using FeNO i.e. management based on clinical symptoms (with or without spirometry/peak flow) and/or asthma guidelines

Management based on exhaled nitric oxidelevels adjusted for atopy reduces asthma exacerbations in children : A dual centre randomised controlled trial

While several randomised control trials (RCTs) have evaluated the use of fractional exhaled nitric oxide (FeNO) to improve asthma outcomes, none used FeNO cut-offs adjusted for atopy, a determinant of FeNO levels. In a dual centre RCT, we assessed whether a treatment strategy based on FeNO levels, adjusted for atopy, reduces asthma exacerbations compared with the symptoms-based management (controls). Children with asthma from hospital clinics of two hospitals were randomly allocated to receive an a-priori determined treatment hierarchy based on symptoms or FeNO levels. There was a 2-week run-in period and they were then reviewed ten times over 12-months. The primary outcome was the number of children with exacerbations over 12-months. Sixty-three children were randomised (FeNO=31, controls=32); 55 (86%) completed the study. Although we did achieve our planned sample size, significantly fewer children in the FeNO group (6 of 27) had an asthma exacerbation compared to controls (15 of 28), p=0.021; number to treat for benefit=4 (95%CI 3-24). There was no difference between groups for any secondary outcomes (quality of life, symptoms, FEV1). The final daily inhaled corticosteroids (ICS) dose was significantly (p=0.037) higher in the FeNO group (median 400µg, IQR 250-600) compared to the controls (200, IQR100-400). Taking atopy into account when using FeNO to tailor asthma medications is likely beneficial in reducing the number of children with severe exacerbations at the expense of increased ICS use. However, the strategy is unlikely beneficial for improving asthma control. A larger study is required to confirm or refute our findings

Codeine versus placebo for chronic cough in children (Review)

Background: Cough in children is a commonly experienced symptom that is associated with increased health service utilisation and burden to parents. The presence of chronic (equal to or more than four weeks) cough in children may indicate a serious underlying condition such as inhaled foreign body or bronchiectasis. Codeine (and derivative)-based medications are sometimes used to treat cough due to their antitussive properties. However, there are inherent risks associated with the use of these medications such as respiratory drive suppression, anaesthetic-induced anaphylaxis, and addiction. Metabolic response and dosage variability place children at increased risk of experiencing such side effects. A systematic review evaluating the quality of the available literature would be useful to inform management practices. Objectives: To evaluate the safety and efficacy of codeine (and derivatives) in the treatment of chronic cough in children. Search methods: We searched the Cochrane Airways Group Register of Trials, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1946 to 8 June 2016), EMBASE (1974 to 8 June 2016), the online trials registries of the World Health Organization and ClinicalTrials.gov, and the bibliographic references of publications. We imposed no language restrictions. Selection criteria: We considered studies eligible for analysis when: the participant population included children aged less than 18 years with chronic cough (duration equal to or more than four weeks at the time of intervention); and the study design evaluated codeine or codeine-based derivatives against placebo through a randomised controlled trial. Data collection and analysis: Two review authors independently screened the search results to determine eligibility against a standardised criteria, and we had a pre-planned method for analysis. Main results: We identified a total of 556 records, of which 486 records were excluded on the basis of title and abstract. We retrieved the remaining 70 references in full to determine eligibility. No studies fulfilled the inclusion criteria of this review, and thus we found no evidence to support or oppose the use of codeine or derivatives as antitussive agents for chronic cough in children. While chronic cough is not the same as acute cough, systematic reviews on the use of codeine efficacy for acute cough in children conclude an overall lack of evidence to support or oppose the use of over-the-counter cough and cold medications containing codeine (or derivatives) for treatment of acute cough in children. The lack of sufficient evidence to support the use of these medications has been consistently reaffirmed by medical experts in international chronic cough guidelines and by governing medical and pharmaceutical authorities in the USA, Europe, Canada, New Zealand, and Australia. Due to the lack of sufficient evidence to support efficacy, and the known risks associated with use - in particular the increased risks for children - these medications are now not recommended for children less than 12 years of age and children between 12 to 18 years with respiratory conditions. Authors' conclusions: This review has highlighted the absence of any randomised controlled trials evaluating codeine-based medications in the treatment of childhood chronic cough. Given the potential adverse events of respiratory suppression and opioid toxicity, national therapeutic regulatory authorities recommend the contraindication of access to codeine in children less than 12 years of age. We suggest that clinical practice adhere to clinical practice guidelines and thus refrain from using codeine or its derivatives to treat cough in children. Aetiological-based management practices continue to be advocated for children with chronic cough

Exhaled nitric oxide levels to guide treatment for adults with asthma.

BACKGROUND: 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). 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 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. 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

Tailored interventions based on exhaled nitric oxide versus clinical symptoms for asthma in children and adults

BackgroundThe measurement of severity and control of asthma in both children and adults can be based on subjective or objective measures. It has been advocated that fractional exhaled nitric oxide (FeNO) can be used to monitor airway inflammation as it correlates with some markers of asthma. Interventions for asthma therapies have been traditionally based on symptoms and/or spirometry.ObjectivesTo evaluate the efficacy of tailoring asthma interventions based on exhaled nitric oxide in comparison to clinical symptoms (with or without spirometry/peak flow) for asthma related outcomes in children and adults.Search strategyWe 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 search was completed in February 2009.Selection criteriaAll randomised controlled comparisons of adjustment of asthma therapy based on exhaled nitric oxide compared to traditional methods (primarily clinical symptoms and spirometry/peak flow).Data collection and analysisResults of searches were reviewed against pre-determined criteria for inclusion. Relevant studies were independently selected in duplicate. Two authors independently assessed trial quality and extracted data. Authors were contacted for further information with response from one.Main resultsTwo studies have been added for this update, which now includes six (2 adults and 4 children/adolescent) studies; these studies differed in a variety of ways including definition of asthma exacerbations, FeNO cut off levels, the way in which FeNO was used to adjust therapy and duration of study. Of 1053 participants randomised, 1010 completed the trials. In the meta-analysis, there was no significant difference between groups for the primary outcome of asthma exacerbations or for other outcomes (clinical symptoms, FeNO level and spirometry). In post-hoc analysis, a significant reduction in mean final daily dose inhaled corticosteroid per adult was found in the group where treatment was based on FeNO in comparison to clinical symptoms, (mean difference -450 mcg; 95% CI -677 to 223 mcg budesonide equivalent/day). However, the total amount of inhaled corticosteroid used in one of the adult studies was 11% greater in the FeNO arm. In contrast, in the paediatric studies, there was a significant increase in inhaled corticosteroid dose in the FeNO strategy arm (mean difference of 140 mcg; 95% CI 29 to 251, mcg budesonide equivalent/day).Authors' conclusionsTailoring the dose of inhaled corticosteroids based on exhaled nitric oxide in comparison to clinical symptoms was carried out in different ways in the six studies and found only modest benefit at best and potentially higher doses of inhaled corticosteroids in children. The role of utilising exhaled nitric oxide to tailor the dose of inhaled corticosteroids cannot be routinely recommended for clinical practice at this stage and remains uncertain

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 cut-off 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; I(2) = 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; I(2) = 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; I(2) = 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 asthma medications based on FeNO levels (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