Leukotriene receptor antagonists as maintenance and intermittent therapy for episodic viral wheeze in children.

BACKGROUND: Episodic viral wheeze (EVW) associated with viral respiratory tract infections is a common reason for pre-school children to utilise health care resources and for carers to take time away from employment. About a third of children experience a wheezing episode before the age of five years. EVW therefore represents a significant public health problem. Many pre-school children only wheeze in association with viral infections and in such cases EVW appears to be a separate entity from atopic asthma. Some trials have explored the effectiveness of leukotriene receptor antagonists (LTRAs) as regular (maintenance) or episodic (intermittent) treatment in this context. OBJECTIVES: To evaluate the evidence for the efficacy and safety of maintenance and intermittent LTRAs in the management of EVW in children aged one to six years. SEARCH METHODS: We searched the Cochrane Airways Group register of trials with pre-specified terms. We performed additional searches by consulting the authors of identified trials, online trial registries of manufacturers' web sites, and reference lists of identified primary papers and reviews. Search results are current to June 2015. SELECTION CRITERIA: We included randomised controlled trials with a parallel-group or cross-over (for intermittent LTRA only) design. Maintenance was considered as treatment for more than two months and intermittent as less than 14 days. EVW was defined as a history of at least one previous episode of wheezing in association with a viral respiratory tract infection in the absence of symptoms between episodes. As far as possible, relevant specific data were obtained from authors of studies that included children of a wider age group or phenotype.   DATA COLLECTION AND ANALYSIS: Two authors independently assessed studies for inclusion in the review and assessed risk of bias. The primary outcome was number of children with one or more viral-induced episodes requiring one or more treatments with rescue oral corticosteroids. We analysed combined continuous data outcomes with the mean difference and dichotomous data outcomes with an odds ratio (OR). MAIN RESULTS: We identified five studies eligible for inclusion in the review (one investigated maintenance treatment, three intermittent therapy and one had both maintenance and intermittent treatment arms) these included 3741 participants. Each study involved oral montelukast and was of good methodological quality, but differed in choice of outcome measures thus limiting our ability to aggregate data across studies. Only primary outcome and adverse event data are reported in this abstract.For maintenance treatment, specific data obtained from a single study, pertaining to children with only an EVW phenotype, showed no statistically significant group reduction in the number of episodes requiring rescue oral corticosteroids associated with daily montelukast versus placebo (OR 1.20, 95% CI 0.70 to 2.06, moderate quality evidence).For intermittent LTRA, pooled data showed no statistically significant reduction in the number of episodes requiring rescue oral steroids in children treated with LTRA versus placebo (OR 0.77, 95% CI 0.48 to 1.25, moderate quality evidence). Specific data for children with an EVW phenotype obtained from a single study of intermittent montelukast treatment showed a small, but statistically significant reduction in unscheduled medical attendances due to wheeze (RR 0.83, 95% CI 0.71 to 0.98).For maintenance compared to intermittent LTRA treatment no data relating to the primary outcome of the review were identified.There were no other significant group differences identified in other secondary efficacy outcomes for maintenance or intermittent LTRA treatment versus placebo, or maintenance versus intermittent LTRA treatment. We collected descriptive data on adverse events as reported by four of the five included studies, and rates were similar between treatment and placebo groups.Potential heterogeneity in the phenotype of participants within and across trials is a limitation of the evidence. AUTHORS' CONCLUSIONS: In pre-school children with EVW, there is no evidence of benefit associated with maintenance or intermittent LTRA treatment, compared to placebo, for reducing the number of children with one or more viral-induced episodes requiring rescue oral corticosteroids, and little evidence of significant clinical benefit for other secondary outcomes. Therefore until further data are available, LTRA should be used with caution in individual children. When used, we suggest a therapeutic trial is undertaken, during which efficacy should be carefully monitored. It is likely that children with an apparent EVW phenotype are not a homogeneous group and that subgroups may respond to LTRA treatment depending on the exact patho-physiological mechanisms involved.

The evidence for high flow nasal cannula devices in infants.

High flow nasal cannula (HFNC) devices deliver an adjustable mixture of heated and humidified oxygen and air at a variable flow rate. Over recent years HFNC devices have become a frequently used method of non-invasive respiratory support in infants and preterm neonates that is generally popular amongst clinicians and nursing staff due to ease of use and being well tolerated by patients. Despite this rapid adoption relatively little is known about the exact mechanisms of action of HFNC however and only recently have data from randomised controlled trials started to become available. We describe the features of a modern HFNC device and discuss current knowledge about the mechanisms of action and results of clinical studies in preterm neonates and infants with bronchiolitis. We also highlight future areas of research that are likely to increase our understanding, inform best clinical practice and strengthen the evidence base for the use of HFNC.

Ceramide is increased in the lower airway epithelium of people with advanced cystic fibrosis lung disease.

RATIONALE: Ceramide accumulates in the airway epithelium of mice deficient in cystic fibrosis transmembrane conductance regulator, resulting in susceptibility to Pseudomonas aeruginosa infection and inflammation. OBJECTIVES: To investigate quantitatively ceramide levels in the lower airway of people with cystic fibrosis compared with pulmonary hypertension, emphysema, and lung donors. METHODS: Immunohistochemistry was performed on the lower airway epithelium of explanted lungs (eight cystic fibrosis, emphysema, and pulmonary hypertension, respectively) and eight donor lungs using ceramide, neutrophil elastase, and myeloperoxidase antibodies. High-performance liquid chromatography-mass spectrometry was performed on tissue from five lungs with cystic fibrosis and five with pulmonary hypertension. MEASUREMENTS AND MAIN RESULTS: Staining for ceramide was significantly increased in the lower airway epithelium of people with cystic fibrosis (median, 14.11%) compared with pulmonary hypertension (3.03%; P = 0.0009); unused lung donors (3.44%; P = 0.0009); and emphysema (5.06%; P = 0.01). Ceramide staining was increased in emphysematous lungs compared with pulmonary hypertension (P = 0.0135) and unused donors (P = 0.0009). The number of neutrophil elastase- and myeloperoxidase-positive cells in the airway was positively correlated with the percentage of epithelium staining for ceramide (P = 0.001). Ceramide staining was significantly increased in lungs colonized with Pseudomonas aeruginosa (10.1%) compared with those not colonized (3.14%; P = 0.0106). Significantly raised levels of ceramides C16:0, C18:0, and C20:0 were detected by mass spectrometry in lungs with cystic fibrosis compared with pulmonary hypertension. Differences in C22:0 were not significant. CONCLUSIONS: Immunoreactive ceramide is increased in the lower airway epithelium of people with advanced cystic fibrosis. Detected by mass-spectrometry ceramide species C16:0, C18:0, and C20:0 but not C22:0 are increased.

Primary bronchial epithelial cell culture from explanted cystic fibrosis lungs.

Lung disease is responsible for more than 95% of morbidity and mortality in cystic fibrosis. The exact pathogenesis of cystic fibrosis lung disease remains poorly understood. Experimental models are therefore vital for use in research. Animal models and immortalized cell lines both have inherent limitations. Explanted lungs removed from people with cystic fibrosis at the time of transplantation represent a potentially valuable but technically and logistically challenging source of primary cystic fibrosis bronchial epithelial cells. In this study, pieces of segmental bronchus from explanted lungs were treated with patient-specific antimicrobials prior to isolation of bronchial epithelial cells. Cultured cells were characterized by their morphology under light microscopy, cytokeratin and hematoxylin-eosin staining, and electrophysiological profile. Primary bronchial epithelial cells were successfully cultured from 15 of 22 patients attempted. The cells exhibited typical epithelial morphology, staining for cytokeratin, lack of responsiveness to forskolin treatment, and remained viable after storage in liquid nitrogen. Seven unsuccessful cultures failed due to early infection with bacteria known to colonize the airways pretransplant. The results show that primary bronchial epithelial cell culture is possible from explanted cystic fibrosis lungs. This provides an important cellular model to elucidate the pathogenic mechanisms in cystic fibrosis lung disease and to investigate potential therapeutic targets.

Adenotonsillectomy for obstructive sleep apnoea in children.

BACKGROUND: Current treatment of sleep apnoea in children consists of largely surgical based treatments. Adenotonsillectomy is the most commonly used intervention to treat sleep apnoea in children. OBJECTIVES: To determine the efficacy of adenotonsillectomy in the treatment of obstructive sleep apnoea in children. SEARCH STRATEGY: The Cochrane Airways Group Specialised Register was searched with pre-specified terms. Searches were current as of August 2008. SELECTION CRITERIA: Randomised trials recruiting children with a diagnosis of obstructive sleep apnoea. DATA COLLECTION AND ANALYSIS: Two reviewers examined the search results and collected data from the studies in terms of their characteristics before deciding which ones would be included in the review. MAIN RESULTS: One study met the review entry criteria. This study addressed the relative merits of two surgical techniques in treating OSA in children (temperature controlled radiofrequency tonsillectomy and adenoidectomy, and complete tonsillectomy and adenoidectomy). No significant difference was apparent for either symptoms or respiratory disturbance index. More children in the TCFR&A group were able to return to normal diet at 7 days compared with complete T&A. No significant complications were observed in the study. AUTHORS' CONCLUSIONS: One small study failed to find a difference between two surgical techniques, although return to normal diet was more frequent in the group treated by temperature controlled radiofrequency tonsillectomy and adenoidectomy. At present there is still debate as to the criteria required to diagnose significant obstructive sleep apnoea in children. Also the natural history of the condition has not been fully delineated. There is an absence of randomised controlled trials investigating the efficacy of treatment of confirmed obstructive sleep apnoea with adenotonsillectomy in children. Research is required before recommendations for the treatment of obstructive sleep apnoea in children can be formulated. The quality of research in this area could be improved with the use of sleep studies at baseline to determine the extent of severity of sleep apnoea in children who are recruited to studies in this area. Long-term follow up is also required in order to explore the effect of adenotonsillectomy on paediatric sleep apnoea.

Interventions for educating children who are at risk of asthma-related emergency department attendance.

BACKGROUND: Asthma is the most common chronic childhood illness and is a leading cause for paediatric admission to hospital. Asthma management for children results in substantial costs. There is evidence to suggest that hospital admissions could be reduced with effective education for parents and children about asthma and its management. OBJECTIVES: To conduct a systematic review of the literature and update the previous review as to whether asthma education leads to improved health outcomes in children who have attended the emergency room for asthma. SEARCH STRATEGY: We searched the Cochrane Airways Group Trials Register, including the MEDLINE, EMBASE and CINAHL databases, and reference lists of trials and review articles (last search May 2008). SELECTION CRITERIA: We included randomised controlled trials of asthma education for children who had attended the emergency department for asthma, with or without hospitalisation, within the previous 12 months. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information. We pooled dichotomous data with a fixed-effect risk ratio. We used a random-effects risk ratio for sensitivity analysis of heterogenous data. MAIN RESULTS: A total of 38 studies involving 7843 children were included. Following educational intervention delivered to children, their parents or both, there was a significantly reduced risk of subsequent emergency department visits (RR 0.73, 95% CI 0.65 to 0.81, N = 3008) and hospital admissions (RR 0.79, 95% CI 0.69 to 0.92, N = 4019) compared with control. There were also fewer unscheduled doctor visits (RR 0.68, 95% CI 0.57 to 0.81, N = 1009). Very few data were available for other outcomes (FEV1, PEF, rescue medication use, quality of life or symptoms) and there was no statistically significant difference between education and control. AUTHORS' CONCLUSIONS: Asthma education aimed at children and their carers who present to the emergency department for acute exacerbations can result in lower risk of future emergency department presentation and hospital admission. There remains uncertainty as to the long-term effect of education on other markers of asthma morbidity such as quality of life, symptoms and lung function. It remains unclear as to what type, duration and intensity of educational packages are the most effective in reducing acute care utilisation.

The oral corticosteroid-sparing effect of omalizumab in children with severe asthma.

OBJECTIVE: To report the oral corticosteroid-sparing effect of omalizumab in children with severe asthma. DESIGN: 16-week therapeutic trial. SETTING: Tertiary paediatric asthma clinic. PATIENTS: 34 children with severe asthma maintained on oral prednisolone (median age 12 years; 15 children <12 years and 19 children ≥12 years). INTERVENTIONS: Fortnightly or monthly subcutaneous injections of omalizumab; the dose was calculated as per manufacturer's instructions based on body weight and serum immunoglobulin E concentration. MAIN OUTCOME MEASURES: Reduction in prednisolone dose; mini-Asthma Quality of Life Questionnaire (AQLQ); Childhood Asthma Control Test (ACT); forced expiratory volume in 1 s (FEV(1)). RESULTS: Median daily prednisolone dose reduced from 20 mg to 5 mg (n=34, p<0.0001), including seven children who stopped prednisolone completely. Mini-AQLQ score increased from 3.5 to 5.9 (n=24, p<0.0001). Childhood ACT score increased from 12 to 20 (n=23, p=0.0001). FEV(1) increased from 2.10 to 2.25 litres (n=31, non-significant). The reduction in prednisolone dose and improvements in mini-AQLQ and childhood ACT were significant in children both under and over 12 years of age, with no differences in outcome detected between these two groups. CONCLUSIONS: A 16-week therapeutic trial of omalizumab allowed a significant reduction in daily prednisolone dose and was associated with improvements in asthma control and quality of life in 34 children with severe asthma. Similar benefits were seen in children both above and below 12 years of age. These uncontrolled data are very encouraging. There is an urgent requirement for a multicentre randomised placebo-controlled trial of omalizumab in children with severe asthma, with reduction in oral corticosteroid dose as the primary outcome measure.