A systematic review of early life factors which adversely affect subsequent lung function.

It has been known for many years that multiple early life factors can adversely affect lung function and future respiratory health. This is the first systematic review to attempt to analyse all these factors simultaneously. We adhered to strict a priori criteria for inclusion and exclusion of studies. The initial search yielded 29,351 citations of which 208 articles were reviewed in full and 25 were included in the review. This included 6 birth cohorts and 19 longitudinal population studies. The 25 studies reported the effect of 74 childhood factors (on their own or in combinations with other factors) on subsequent lung function reported as percent predicted forced expiration in one second (FEV1). The childhood factors that were associated with a significant reduction in future FEV1 could be grouped as: early infection, bronchial hyper-reactivity (BHR) / airway lability, a diagnosis of asthma, wheeze, family history of atopy or asthma, respiratory symptoms and prematurity / low birth weight. A complete mathematical model will only be possible if the raw data from all previous studies is made available. This highlights the need for increased cooperation between researchers and the need for international consensus about the outcome measures for future longitudinal studies.

Two case reports of the successful eradication of new isolates of Burkholderia cepacia complex in children with cystic fibrosis.

BACKGROUND: Chronic infection with Burkholderia cepacia complex (BCC) has a detrimental effect on morbidity and mortality for patients with cystic fibrosis (CF). It is therefore logical to attempt to eradicate new isolates however there is a paucity of information to guide treatment. We report the successful eradication of new isolates of BCC in two children with CF. CASE PRESENTATION: Burkholderia cepacia was successfully eradicated in a 14 year old boy with CF and Burkholderia gladioli was successfully eradicated in a six year old girl with CF. In both children two weeks of intravenous (IV) tobramycin, ceftazidime and temocillin were used followed by three months of inhaled tobramycin. Bronchoalveolar lavage samples taken during flexible bronchoscopy were used prior to treatment to exclude spontaneous clearance as well as after treatment to confirm eradication. CONCLUSIONS: New isolates of BCC can be successfully eradicated in children with CF. More research is urgently required in this area to identify the best treatment regimen for BCC eradication.

Management of Asthma in School age Children On Therapy (MASCOT): a randomised, double-blind, placebo-controlled, parallel study of efficacy and safety.

BACKGROUND: Asthma affects one in eight children in the UK. National management guidelines have been available for many years but, unlike in adults, studies in children have been few, with their methodologies often based on inappropriate adult models. Sound medical evidence in support of the national guidelines for asthma management in children is lacking. The MASCOT study has been developed to address this need. OBJECTIVES: To determine whether adding salmeterol or montelukast to low-dose inhaled corticosteroids (ICSs) can reduce the number of exacerbations requiring treatment with oral corticosteroids in children with uncontrolled asthma. DESIGN: A randomised, double-blind, placebo-controlled trial with a 4-week run-in period on a fluticasone propionate inhaler (100 µg twice daily) with inhaler technique correction. Patients who met the post run-in period eligibility criteria were randomised in the ratio of 1 : 1 : 1 and were followed for 48 weeks. SETTING: Secondary care hospitals based in England and Scotland with recruitment from primary and secondary care. PARTICIPANTS: Children aged 6-14 years with asthma requiring frequent short-acting beta-2 agonist relief, with symptoms of asthma resulting in nocturnal wakening and/or asthma that has interfered with usual activities. INTERVENTIONS: Three groups were compared: (1) inhaled fluticasone propionate 100 µg twice daily plus placebo tablet once daily; (2) inhaled fluticasone propionate 100 µg and salmeterol 50 µg twice daily (combination inhaler) plus placebo tablet once daily; and (3) inhaled fluticasone propionate 100 µg twice daily plus montelukast 5-mg tablet once daily. MAIN OUTCOME MEASURES: The primary outcome was the number of exacerbations requiring treatment with oral corticosteroids over 48 weeks. Secondary outcome measures included quality of life as measured by the Paediatric Asthma Quality of Life Questionnaire with Standardised Activities [PAQLQ(S)] and the Paediatric Asthma Caregiver's Quality of Life Questionnaire (PACQLQ); time from randomisation to first exacerbation requiring treatment with a short course of oral corticosteroids; school attendance; hospital admissions; amount of rescue beta-2 agonist therapy prescribed; time from randomisation to treatment withdrawal (because of lack of efficacy or side effects); lung function at 48 weeks (as assessed by spirometry); cost-effectiveness; adverse events. RESULTS: The study was closed prematurely because of poor recruitment and the target sample size of 450 was not achieved. In total, 898 children were screened to enter the trial, 166 were registered for the 4-week run-in period and 63 were randomised (group 1: 19, group 2: 23, group 3: 21), with 38 contributing data for the primary outcome analysis. There were no significant differences between groups for any of the outcomes. Adverse events were similar between the groups except for nervous system disorders, which were more frequently reported on fluticasone plus montelukast. CONCLUSIONS: Based on the results of the MASCOT study it is not possible to conclude whether adding salmeterol or montelukast to ICSs can reduce the number of exacerbations requiring treatment with oral corticosteroids in children with uncontrolled asthma. TRIAL REGISTRATION: Current Controlled Trials ISRCTN03556343. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 17, No. 4. See the HTA programme website for further project information.

Variation in hydrogen cyanide production between different strains of Pseudomonas aeruginosa.

There is increasing interest in using the cyanogenic properties of Pseudomonas aeruginosa to develop a nonmicrobiological method for its detection. Prior to this, the variation in cyanide production between different P. aeruginosa strains needs to be investigated. Hydrogen cyanide (HCN) released into the gas phase by 96 genotyped P. aeruginosa samples was measured using selected ion flow tube-mass spectrometry after 24, 48, 72 and 96 h of incubation. The HCN produced by a range of non-P. aeruginosa cultures and incubated blank plates was also measured. All P. aeruginosa strains produced more HCN than the control samples, which generated extremely low levels. Analysis across all time-points demonstrated that nonmucoid samples produced more HCN than the mucoid samples (p=0.003), but this relationship varied according to strain. There were clear differences in the headspace HCN concentration for different strains. Multivariate analysis of headspace HCN for the commonest strains (Liverpool, Midlands_1 and Stoke-on-Trent, UK) revealed a significant effect of strain (p<0.001) and a borderline interaction of strain and phenotype (p=0.051). This evidence confirms that all P. aeruginosa strains produce HCN but to varying degrees and generates interest in the possible future clinical applications of the cyanogenic properties of P. aeruginosa.

Bronchoalveolar lavage in children with cystic fibrosis: how many lobes should be sampled?

BACKGROUND: The European Respiratory Society guidance on bronchoalveolar lavage (BAL) in children was published in 2000. It recommended taking one BAL specimen from the most affected lobe or from the right middle lobe in diffuse disease. In 2007, the European Respiratory Society modified the recommendations for children with cystic fibrosis (CF), suggesting two BAL specimens (right middle lobe and the lingula or the most affected lobe). OBJECTIVE: To determine if BAL samples from one or two lobes give the full picture of lower airway infection in children with CF. DESIGN, SETTING AND PATIENTS: A retrospective review of all paediatric patients with CF who underwent flexible bronchoscopy between May 2007 and May 2009 was undertaken. MAIN OUTCOME MEASURES: As BAL specimens from all six lobes were collected, the BAL results were reviewed to identify if positive cultures would have been missed if only one lobe (right middle or most affected) or two lobes (right middle plus the lingula or most affected) had been sampled. RESULTS: The results of 39 bronchoscopic procedures in 31 children were reviewed. The BAL samples were taken from 6 lobes in all 39 procedures. Had only one lobe been used, 26 positive cultures (14 organisms) would have been missed in 11 patients. Had two lobes been used, 12 positive cultures (8 organisms) would have been missed in 7 patients. CONCLUSION: A single-lobe BAL is insufficient in assessing patients with CF for lower airway infection. Even when BAL specimens are taken from two lobes, a number of infections may be missed.

Safety of formoterol in children and adolescents: experience from asthma clinical trials.

BACKGROUND: The safety of long-acting ß(2) agonist (LABA) therapy in asthma remains controversial but no large scale analyses have been published of LABA safety in children. METHODS: The frequency of asthma-related deaths and hospitalisations following formoterol use in children (4-11 years) and adolescents (12-17 years), compared with non-LABA treatment, was assessed in all AstraZeneca-sponsored, randomised, controlled, parallel-group trials (≥3 months) where formoterol was used as maintenance and/or as reliever therapy. RESULTS: 11,849 children and adolescents under the age of 18 years from 41 trials were identified, 82% of whom used an inhaled corticosteroid (ICS) as concomitant medication. The number of asthma-related deaths (one 13-year-old boy among 7796 formoterol-treated patients, and none among 4053 non-LABA-treated patients) was too low to allow any between-group comparison. The frequency of patients with asthma-related hospitalisations was not different in formoterol-treated versus non-LABA-treated patients, either in children (1.16% (38/3263) vs 1.11% (24/2165)) or in adolescents (0.51% (23/4533) vs 0.85% (16/1888)). Asthma-related hospitalisations based on daily dose of formoterol were: (A) 4.5 or 9 µg: 1.9% (18/980); (B) 18 µg: 0.5% (14/2870); (C) 36 µg: 0% (0/67); and (D) variable dosing: 0.75% (29/3879). There was no difference between formoterol-treated and non-LABA-treated patients as regards ethnicity. CONCLUSIONS: Formoterol use in children and adolescents (4-17 years) with asthma in this large study where the majority are prescribed concomitant ICS is not associated with any increased risk of asthma-related hospitalisations. The results are not influenced by dose or ethnicity.

Childhood evaluation of salmeterol tolerance--a double-blind randomized controlled trial.

Long acting beta(2)-agonists (LABA) are widely used in children with asthma. Data from adults suggest that there is tachyphylaxis particularly to the bronchoprotective effects of LABA. There are no data in children. To determine whether LABA are subject to tachyphylaxis in school-aged children. Children were eligible for participation if they remained symptomatic on 400 microg of beclometasone dipropionate equivalent/day. Participants undertook a 4-wk run in period with open-label fluticasone 100 microg BD via Diskus. Children were then randomized to receive fluticasone 100 microg BD or salmeterol/fluticasone 50/100 microg BD via Diskus in a double-blind manner. Children underwent spirometry, cold air challenge and salbutamol reversibility testing at baseline, 4 and 8 wk. 37/42 children completed the study. There were significant improvements in basal FEV1 (% predicted) in the salmeterol/fluticasone group (n = 21) (+6.4% (95% CI: 2.4-10.5) p = 0.0033) but not in the fluticasone group (n = 16) [+1.2 (95% CI: -3.4 to 5.8) p = 0.5900]. There was a non-significant reduction in fall in FEV1 provoked by cold air in both groups. There was a significant lessening in the acute salbutamol response after 8 wk in the salmeterol/fluticasone group [-11.4% (95% CI: -17.6 to -5.2) p = 0.0010] but not in the fluticasone group [-1.6% (95% CI: -9.8 to 6.6) p = 0.6827]. Salmeterol/fluticasone therapy significantly improves basal FEV(1) in asthmatic children however, there is negligible additional bronchoprotection by week 4 of treatment and there is significant attenuation of salbutamol responsiveness when compared with fluticasone alone. Some of this reduction in salbutamol response may relate to the concurrent improvements in baseline lung function.

Medicines used in respiratory diseases only seen in children.

Detailed literature searches were carried out in seven respiratory disease areas. Therapeutic evidence for efficacy of medicinal products was assessed using the Grades of Recommendation, Assessment and Evaluation (GRADE) methodology, as well as an assessment of safety and side-effects. Systemic corticosteroids may reduce the development of bronchopulmonary dysplasia but have serious side-effects. Antioxidants need further study to demonstrate whether they have long-term benefits. Treatments for acute bronchiolitis have shown little benefit but new antiviral and monoclonal antibodies need further assessment. Well-constructed studies are needed to confirm the value of inhaled corticosteroids and/or montelukast in the management of viral-induced wheeze. Corticosteroids are the treatment of choice in croup. Minimal or no information is available for the treatment of congenital lung abnormalities, bronchiolitis obliterans and interstitial lung disease.

School age outcome of hospitalisation with respiratory syncytial virus infection of prematurely born infants.

BACKGROUND: Hospitalisation due to respiratory syncytial virus (RSV) infection in the first 2 years after birth has been associated with increased healthcare utilisation and associated costs up to 5 years of age in children born prematurely at less than 32 weeks of gestation who developed bronchopulmonary dysplasia (BPD). A study was undertaken to determine whether hospitalisation due to RSV infection in the first 2 years was associated with increased morbidity and lung function abnormalities in such children at school age, and if any effects were influenced by age. METHODS: Healthcare utilisation and cost of care in years 5-7 were reviewed in 147 children and changes in healthcare utilisation between 0 and 8 years were assessed also using results from two previous studies. At age 8-10 years, 77 children had their lung function assessed and bronchial hyper-responsiveness determined. RESULTS: Children hospitalised with RSV infection (n = 25) in the first 2 years had a greater cost of care related to outpatient attendance than those with a non-respiratory or no admission (n = 72) when aged 5-7 years (p = 0.008). At 8-10 years of age, children hospitalised with RSV infection (n = 14) had lower forced expiratory volume in 0.75 s (FEV(0.75)) (p = 0.015), FEV(0.75)/forced vital capacity (p = 0.027) and flows at 50% (p = 0.034) and 75% (p = 0.006) of vital capacity than children hospitalised for non-RSV causes (n = 63). Healthcare utilisation decreased with increasing age regardless of RSV hospitalisation status. CONCLUSIONS: In prematurely born children who had BPD, hospitalisation due to RSV infection in the first 2 years is associated with reduced airway calibre at school age.

Hydrogen cyanide as a biomarker for Pseudomonas aeruginosa in the breath of children with cystic fibrosis.

HYPOTHESIS: Hydrogen cyanide (HCN) is emitted by Pseudomonas aeruginosa (PA) in vitro. We hypothesized that exhaled HCN could be measured using Selected Ion Flow Tube Mass Spectrometry (SIFT-MS) and that concentrations would be higher in children with cystic fibrosis (CF) and PA infection than in children with asthma. METHODS: Children aged 7-17 years with CF (n = 16) or asthma (n = 21) attending outpatient clinics provided breath samples between July and December 2007. HCN was measured using the SIFT-MS Profile 3 instrument. FeNO was measured with a Sievers NOA 280i analyzer. Baseline inter-group differences between HCN and FeNO concentrations were compared using the Mann-Whitney U test. Children were invited to re-attend fortnightly. Breath samples, spirometry, growth and clinical status were measured at each visit. RESULTS: There were significant baseline differences in exhaled HCN and FeNO concentrations between the two groups. Children with CF had higher median HCN concentrations than those with asthma: 13.5 parts per billion (ppb) (IQR 8.1-16.5) versus 2.0 ppb (IQR 0.0-4.8) (P < 0.001). Children with CF had lower median FeNO levels compared to children with asthma: 13.4 ppb (IQR 8.9-17.6) versus 57.9 ppb (IQR 34.0-85.7) (P < 0.001). Intra-subject variability was high and significant changes in HCN concentrations were not observed related to changes in lung function or clinical status. CONCLUSION: This study provides proof of principle that HCN is detectable in the breath of children with CF and is elevated compared to children with asthma. Further studies are required to capture data from acutely unwell children and more accurately delineate responses to treatment.

Concentrations of some metabolites in the breath of healthy children aged 7-18 years measured using selected ion flow tube mass spectrometry (SIFT-MS).

Using selected ion flow tube mass spectrometry (SIFT-MS), measurements have been made of the levels of several metabolites in the exhaled breath of 200 healthy school children. Thus, concentration distributions of each metabolite have been obtained for the first time in the paediatric age range. The median values (in parentheses) of the concentrations in parts per billion, ppb, were ammonia (628), acetone (297), methanol (193), ethanol (187), isoprene (37), propanol (16), acetaldehyde (23) and pentanol (15). Hydrogen cyanide was not present in the breath above the detection limit of 2 ppb in the majority of subjects. The water vapour level (humidity) of the breath samples was routinely measured as a check on the sample integrity. Such data are essential if SIFT-MS breath analyses are to be used as a clinical tool to aid diagnosis and/or as a monitor of disease in children. The levels of metabolites usually followed a log-normal distribution and the levels of some compounds were similar to those obtained previously in adults. Lower values were found in the levels of acetone, ammonia, methanol and isoprene. There were no major variations in relation to gender. Some metabolites showed significant variation in relation to age and body mass index. To our knowledge, these are the first measurements of exhaled mouth breath pentanol levels. The median ammonia levels in mouth-exhaled breath of these children decreased with age, whereas in older adults, ammonia has been shown to increase with age. Breath acetone levels were significantly increased for those who had not eaten for more than 6 h prior to providing the breath sample, although dietary control was not a mandatory aspect of the protocol.

Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach.

There is poor agreement on definitions of different phenotypes of preschool wheezing disorders. The present Task Force proposes to use the terms episodic (viral) wheeze to describe children who wheeze intermittently and are well between episodes, and multiple-trigger wheeze for children who wheeze both during and outside discrete episodes. Investigations are only needed when in doubt about the diagnosis. Based on the limited evidence available, inhaled short-acting beta(2)-agonists by metered-dose inhaler/spacer combination are recommended for symptomatic relief. Educating parents regarding causative factors and treatment is useful. Exposure to tobacco smoke should be avoided; allergen avoidance may be considered when sensitisation has been established. Maintenance treatment with inhaled corticosteroids is recommended for multiple-trigger wheeze; benefits are often small. Montelukast is recommended for the treatment of episodic (viral) wheeze and can be started when symptoms of a viral cold develop. Given the large overlap in phenotypes, and the fact that patients can move from one phenotype to another, inhaled corticosteroids and montelukast may be considered on a trial basis in almost any preschool child with recurrent wheeze, but should be discontinued if there is no clear clinical benefit. Large well-designed randomised controlled trials with clear descriptions of patients are needed to improve the present recommendations on the treatment of these common syndromes.

Children admitted with acute wheeze/asthma during November 1998-2005: a national UK audit.

OBJECTIVE: To report 8 years' data from a UK-wide audit of acute wheeze/asthma management in children carried out annually since 1998. DESIGN: Paediatricians were invited to complete a simple form based on British Thoracic Society (BTS) asthma guidelines for any child over 1 year of age admitted with acute wheeze/asthma each November from 1998 to 2005. Information was collected about patient demographics, initial hospital severity assessment, in-hospital treatment, asthma education and emergency planning, discharge treatment and follow-up. RESULTS: Data on 9429 admissions were available, with between 53 and 67 centres participating each year. The majority of children were under 5 years of age (median age 3 years). Nearly all were treated with bronchodilators, and around 90% received systemic steroids. Vital signs (pulse and respiratory rate) and oxygen saturation on admission remained stable over the audit period. However, the proportion of admitted children given bronchodilators exclusively by spacer increased from 7% to 44% between 1998 and 2005. The proportion discharged with written asthma plans increased from 24% to 41%. Wide variations were noted between centres in the proportions of children receiving chest x rays and written asthma plans. Children admitted under the care of a respiratory specialist were more likely to have documentation that they had been given written asthma information and a written asthma plan and had had their inhaler device technique checked than if under the care of a general paediatrician. CONCLUSIONS: In many areas, hospital treatment closely followed published guidance. However, some important deficiencies were noted and variations remain. As well as monitoring guideline implementation, national audit can highlight opportunities for research and improving care locally and nationally.

Factor analysis in the Genetics of Asthma International Network family study identifies five major quantitative asthma phenotypes.

BACKGROUND: Asthma is a clinically heterogeneous disease caused by a complex interaction between genetic susceptibility and diverse environmental factors. In common with other complex diseases the lack of a standardized scheme to evaluate the phenotypic variability poses challenges in identifying the contribution of genes and environments to disease expression. OBJECTIVE: To determine the minimum number of sets of features required to characterize subjects with asthma which will be useful in identifying important genetic and environmental contributors. Methods Probands aged 7-35 years with physician diagnosed asthma and symptomatic siblings were identified in 1022 nuclear families from 11 centres in six countries forming the Genetics of Asthma International Network. Factor analysis was used to identify distinct phenotypes from questionnaire, clinical, and laboratory data, including baseline pulmonary function, allergen skin prick test (SPT). RESULTS: Five distinct factors were identified:(1) baseline pulmonary function measures [forced expiratory volume in 1 s (FEV(1)) and forced vital capacity (FVC)], (2) specific allergen sensitization by SPT, (3) self-reported allergies, (4) symptoms characteristic of rhinitis and (5) symptoms characteristic of asthma. Replication in symptomatic siblings was consistent with shared genetic and/or environmental effects, and was robust across age groups, gender, and centres. Cronbach's alpha ranged from 0.719 to 0.983 suggesting acceptable internal scale consistencies. Derived scales were correlated with serum IgE, methacholine PC(20), age and asthma severity (interrupted sleep). IgE correlated with all three atopy-related factors, the strongest with the SPT factor whereas severity only correlated with baseline lung function, and with symptoms characteristic of rhinitis and of asthma. CONCLUSION: In children and adolescents with established asthma, five distinct sets of correlated patient characteristics appear to represent important aspects of the disease. Factor scores as quantitative traits may be better phenotypes in epidemiological and genetic analyses than those categories derived from the presence or absence of combinations of +ve SPTs and/or elevated IgE.

Polymorphisms in the endothelin-1 (EDN1) are associated with asthma in two populations.

Endothelin-1 (EDN1) has been reported to be implicated in the pathophysiology of asthma. Literature results on the genetic association of EDN1 in asthma are inconsistent. Eleven single nucleotide polymorphisms in EDN1 were genotyped in 342 and 100 families from UK and Norway, respectively. Asthma, bronchial hyperreactivity (BHR) and atopic asthma phenotypes were analyzed for the family-based association. Five single nucleotide polymorphisms (SNPs) were associated with asthma (0.0017

"Blowing in the wind": a review of teenage smoking.

One quarter of all adults in the UK are regular smokers, the vast majority having started smoking in their teens. Teenage smoking, especially in females, continues to increase both as regards the numbers of cigarettes smoked and the numbers of teenagers who regularly smoke. The main factors influencing teenagers to smoke are peer pressure, family members who smoke and experimentation. Nicotine dependence can develop very quickly and in the UK little attention has been directed towards helping teenagers break the habit. In global terms the figures are frightening. Of the 1.25 billion smokers, 800 million live in developing countries. In the UK, government legislation, restrictions on advertising and educational programmes may improve the situation in the near future but there is still little recognition that smoking is responsible for 4 million deaths each year worldwide and insufficient attention has been paid to children and young families to try to prevent children and teenagers from smoking in the first place.