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

Asthma severity and control can be measured both subjectively and objectively. Traditionally asthma treatments have been individualised using symptoms and spirometry/peak flow. Increasingly treatment tailored in accordance with inflammatory markers (sputum eosinophil counts or fractional exhaled nitric oxide (FeNO) data) is advocated as an alternative strategy. The objective of this review was to evaluate the efficacy of tailoring asthma interventions based on inflammatory markers (sputum analysis and FeNO) in comparison with clinical symptoms (with or without spirometry/peak flow) for asthma-related outcomes in children and adults. Cochrane Airways Group Specialised Register of Trials, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and reference lists of articles were searched. The last searches were in February 2009. All randomised controlled comparisons of adjustment of asthma treatment based on sputum analysis or FeNO compared with traditional methods (primarily clinical symptoms and spirometry/peak flow) were selected. Results of searches were reviewed against predetermined criteria for inclusion. Relevant studies were selected, assessed and data extracted independently by at least two people. The trial authors were contacted for further information. Data were analysed as 'intervention received' and sensitivity analyses performed. Six (2 adults and 4 children/adolescent) studies utilising FeNO and three adult studies utilising sputum eosinophils were included. These studies had a degree of clinical heterogeneity including definition of asthma exacerbations, duration of study and variations in cut-off levels for percentage of sputum eosinophils and FeNO to alter management in each study. Adults who had treatment adjusted according to sputum eosinophils had a reduced number of exacerbations compared with the control group (52 vs. 77 patients with ≥1 exacerbation in the study period; p=0.0006). There was no significant difference in exacerbations between groups for FeNO compared with controls. The daily dose of inhaled corticosteroids at the end of the study was decreased in adults whose treatment was based on FeNO in comparison with the control group (mean difference -450.03 µg, 95% CI -676.73 to -223.34; p<0.0001). However, children who had treatment adjusted according to FeNO had an increase in their mean daily dose of inhaled corticosteroids (mean difference 140.18 µg, 95% CI 28.94 to 251.42; p=0.014). It was concluded that tailoring of asthma treatment based on sputum eosinophils is effective in decreasing asthma exacerbations. However, tailoring of asthma treatment based on FeNO levels has not been shown to be effective in improving asthma outcomes in children and adults. At present, there is insufficient justification to advocate the routine use of either sputum analysis (due to technical expertise required) or FeNO in everyday clinical practice.

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

BACKGROUND: The 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. OBJECTIVES: To 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 STRATEGY: 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 search was completed in December 2006. SELECTION CRITERIA: All 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 ANALYSIS: Results 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 but none were received. Data was analysed as "intervention received" and sensitivity analyses performed. MAIN RESULTS: Four (2 adult and 2 paediatric) studies were included; these studies differed in a variety of ways including definition of asthma exacerbations, FeNO cut off levels and duration of study. Of 356 participants randomised, 324 completed the trials. In the meta-analysis, there was no 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; WMD -282.46 (95% CI -422.08 to -142.84). There was no difference in ICS dose between the groups in the overall daily dose in the adult studies or in the paediatric studies. AUTHORS' CONCLUSIONS: Tailoring the dose of inhaled corticosteroids based on exhaled nitric oxide in comparison to clinical symptoms was carried out in different ways in the four studies that were found, and the results show only modest differences. The role of utilising exhaled nitric oxide to tailor the dose of inhaled corticosteroids is currently uncertain.

Tailored interventions based on sputum eosinophils versus clinical symptoms for asthma in children and adults.

BACKGROUND: Asthma severity and control can be measured both subjectively and objectively. Sputum analysis for evaluation of percentage of sputum eosinophilia directly measures airway inflammation, and is one method of objectively monitoring asthma. Interventions for asthma therapies have been traditionally based on symptoms and spirometry. OBJECTIVES: To evaluate the efficacy of tailoring asthma interventions based on sputum analysis in comparison to clinical symptoms (with or without spirometry/peak flow) for asthma related outcomes in children and adults. SEARCH STRATEGY: 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 search was on 31 October 2006. SELECTION CRITERIA: All randomised controlled comparisons of adjustment of asthma therapy based on sputum eosinophils compared to traditional methods (primarily clinical symptoms and spirometry/peak flow). DATA COLLECTION AND ANALYSIS: Results of searches were reviewed against pre-determined criteria for inclusion. Three sets of reviewers selected relevant studies. Two review authors independently assessed trial quality extracted data. Authors were contacted for further information but none were received. Data was analysed as "treatment received" and sensitivity analyses performed. MAIN RESULTS: Three adult studies were included; these studies were clinically and methodologically heterogenous (use of medications, cut off for percentage of sputum eosinophils and definition of asthma exacerbation). There were no eligible paediatric studies. Of 246 participants randomised, 221 completed the trials. In the meta-analysis, a significant reduction in number of participants who had one or more asthma exacerbations occurred when treatment was based on sputum eosinophils in comparison to clinical symptoms; pooled odds ratio (OR) was 0.49 (95% CI 0.28 to 0.87); number needed to treat to benefit (NNTB) was 6 (95% CI 4 to 32). There were also differences between groups in the rate of exacerbation (any exacerbation per year) and severity of exacerbations defined by requirement for use of oral corticosteroids but the reduction in hospitalisations was not statistically significant. Data for clinical symptoms, quality of life and spirometry were not significantly different between groups. The mean dose of inhaled corticosteroids per day was similar in both groups and no adverse events were reported. However sputum induction was not always possible. AUTHORS' CONCLUSIONS: Tailored asthma interventions based on sputum eosinophils is beneficial in reducing the frequency of asthma exacerbations in adults with asthma. This review supports the use of sputum eosinophils to tailor asthma therapy for adults with frequent exacerbations and severe asthma. Further studies need to be undertaken to strengthen these results and no conclusion can be drawn for children with asthma.

A bronchoscopic scoring system for airway secretions--airway cellularity and microbiological validation.

There is currently no validated scoring system for quantification of airway secretions in children. A user friendly, valid scoring system of airway secretions during flexible bronchoscopy (FB) would be useful for comparative purposes in clinical medicine and research. The objective of this study was to validate our bronchoscopic secretion (BS) scoring system by examining the relationship between the amount of secretions seen at bronchoscopy with airway cellularity and microbiology. In 106 children undergoing FB, the relationship of BS grades with bronchocalveolar lavage (BAL) cellularity and infective state (bacterial and viral infections) were examined using receptor operator curves (ROC). BAL was obtained according to European Respiratory Society guidelines; first lavage for microbiology and second lavage for cellularity. Area under the ROC was significant for total cell count (TCC) and neutrophil % but not for lymphocyte %. BS grade significantly related to infection positive state (chi(trend) (2) = 5.85, P = 0.016). The area under the ROC for infection positive state versus BS grade was 0.645, 95% CI 0.527-0.763. The BS scoring system is a valid method for quantifying airway secretions in children undergoing bronchoscopy. The system related well to airway cellularity and neutrophilia, as well as to an airway infective state. However, the system is only complementary to cell counts and cultures and cannot replace these laboratory quantification techniques.

Methylxanthines for prolonged non-specific cough in children.

BACKGROUND: Non-specific cough is defined as non-productive cough in the absence of identifiable respiratory disease or known aetiology. It is commonly seen in paediatric practice. These children are treated with a variety of therapies including a variety of asthma medications. Methylxanthines, the main medication used for paediatric asthma for many decades in Western countries, is still widely used in non-Western countries. Also, methylxanthines have other pharmacological properties and their bronchodilator effect is only modest. OBJECTIVES: To evaluate the efficacy of methylxanthines in treating children with non-specific cough. SEARCH STRATEGY: The Cochrane Register of Controlled Trials (CENTRAL), the Cochrane Airways Group Specialised Register Collaboration and Cochrane Airways Group, MEDLINE and EMBASE databases were searched by the Cochrane Airways Group. The latest searches were performed in Jan 2005. SELECTION CRITERIA: All randomised controlled trials comparing methylxanthines with a placebo medication in treating children with non-specific cough. DATA COLLECTION AND ANALYSIS: Results of searches were reviewed against pre-determined criteria for inclusion. No eligible trials were identified and thus no data were available for analysis. Four small non-randomised controlled trials were reported. MAIN RESULTS: No randomised controlled trials that examined the efficacy of methylxanthines in the management of prolonged non-specific cough in children were found. In the non randomised trials above, a significant effect was seen within 2-14 days of therapy. AUTHORS' CONCLUSIONS: There is currently an absence of reliable evidence to support the routine use of methylxanthines for symptomatic control of non-specific cough in children. If methylxanthines were to be trialled in children with prolonged non-specific cough, cohort data (thus limited) suggest a clinical response (subjective cough severity) would be seen within 2-5 days (and certainly within 14 days) of therapy. However methylxanthine use has to be balanced against the well known risk of toxicity and its low therapeutic range in children. Further research examining the efficacy of this intervention is needed.

An objective study of acid reflux and cough in children using an ambulatory pHmetry-cough logger.

OBJECTIVE: There are no objective ambulatory studies on the temporal relationship between reflux and cough in children. Commercial pHmetry loggers have slow capture rates (0.25 Hz) that limit objective quantification of reflux and cough. The authors aimed to evaluate if there is a temporal association between cough and acid pH in ambulatory children with chronic cough. DESIGN, SETTING AND PATIENTS: The authors studied children (aged <14 years) with chronic cough, suspected of acid reflux and considered for pHmetry using a specifically built ambulatory pHmetry-cough logger that enabled the simultaneous ambulatory recording of cough and pH with a fast (10 Hz) capture rate. MAIN OUTCOME MEASURES: Coughs within (before and after) 10, 30, 60 and 120 s of a reflux episode (pH<4 for >0.5 s). RESULTS: Analysis of 5628 coughs in 20 children. Most coughs (83.9%) were independent of a reflux event. Cough-reflux (median 19, IQR 3-45) and reflux-cough (24.5, 13-51) sequences were equally likely to occur within 120 s. Within the 10 and 30 s time frame, reflux-cough (10 s=median 2.5, IQR 0-7.25; 30 s=6.5, 1.25-22.25) sequences were significantly less frequent than reflux-no cough (10 s=27, IQR 15-65; 30 s=24.5, 14.5-55.5) sequences, (p=0.0001 and p=0.001, respectively). No differences were found for 60 and 120 s time frame. Cough-reflux sequence (median 1.0, IQR 0-8) within 10 s was significantly less (p=0.0001) than no cough-reflux sequences (median 29.5, 15-67), within 30 s (p=0.006) and 60 s (p=0.048) but not within 120 s (p=0.47). CONCLUSIONS: In children with chronic cough and suspected of having gastro-oesophageal reflux disease, the temporal relationship between acid reflux and cough is unlikely causal.