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.

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.

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.

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.

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.

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

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.

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.

Preschool healthcare utilisation related to home oxygen status.

OBJECTIVE: To determine, in prematurely born children who had bronchopulmonary dysplasia (BPD), if respiratory morbidity, healthcare utilisation, and cost of care during the preschool years were influenced by use of supplementary oxygen at home after discharge from the neonatal intensive care unit. DESIGN: Observational study. SETTING: Four tertiary neonatal intensive care units. PATIENTS: 190 children, median gestational age 27 weeks (range 22-31), 70 of whom received supplementary oxygen when discharged home. INTERVENTIONS: Review of hospital and general practitioner records together with a parent completed respiratory questionnaire. MAIN OUTCOME MEASURES: Healthcare utilisation, cost of care, cough, wheeze, and use of an inhaler. RESULTS: Seventy children had supplementary oxygen at home (home oxygen group), but only one had a continuous requirement for home oxygen beyond 2 years of age. There were no significant differences in the gestational age or birth weight of the home oxygen group compared with the rest of the cohort. However, between 2 and 4 years of age inclusive, the home oxygen group had more outpatient attendances (p = 0.0021) and specialist attendances (p = 0.0023), and, for respiratory problems, required more prescriptions (p<0.0001). Their total cost of care was higher (p<0.0001). In addition, more of the home oxygen group wheezed more than once a week (p = 0.0486) and were more likely to use an inhaler (p<0.0001). CONCLUSIONS: Children with BPD who have supplementary oxygen at home after discharge have increased respiratory morbidity and healthcare utilisation in the preschool years.

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.

Regional variation of airway hyperresponsiveness in children with asthma.

Families with asthmatic children were recruited to take part in a multi-centre collaborative study into the genetics of asthma. Detailed phenotypic information was collected on all family members including: lung function, anthropomorphic measurements, response to methacholine challenge, skin prick testing, serum IgE measurements and a detailed nurse-administered questionnaire. Families were eligible for entry into the study if they had two children with a doctor-diagnosis of asthma. Bennett/Twin nebulisers were supplied to each centre from a single source and these were calibrated to determine gravimetric nebuliser output prior to use. Asthmatic probands from each centre had similar degrees of asthma severity and atopy. There was no significant difference in the sex ratios or ages of the probands or numbers of parents with a history of smoking in the families recruited at each centre. However, there was a significant difference in the number of children with airway hyperresponsiveness, with 90% of the North Staffordshire group but only 60% of the Sheffield group having a PC20 of <8 mg/ml for methacholine. This difference highlights the difficulty of using families from different centres in genetic and epidemiological studies.

Vascular access in cystic fibrosis--does size matter?

UNLABELLED: Vascular access is an important part of patient management in cystic fibrosis. In most instances, vascular access is straightforward. However, a single bad experience with venepuncture has a lasting impact. Clinical experience suggested that for some individuals a smaller, shorter intravenous catheter (Leaderflex 22G, 0.7 mm 8.0 cm, Vygon) might be a suitable alternative to standard vascular access via a standard long-line (2 Fr or 3 Fr Nutriline, Vygon). METHODS: Between September 2002 and May 2004 we offered a free, fully informed choice between a standard 30 cm long line or a shorter (8 cm) Leaderflex line and audited this change in practice. RESULTS: A total of 56 lines were inserted over the study period. Data were available for 54 of these (22 Leaderflex and 32 standard long lines). Mean and median line survival was omparable. Leaderflex lines survived for a mean of 12.2 days and median of 14 days. Standard long lines survived for a mean of 12.6 days and median of 14 days. DISCUSSION: Leaderflex lines offer a well-tolerated alternative to standard long lines for the administration of a 14-day course of intravenous antibiotics. Their reduced size and cost offer advantages to patients and doctors.

Use of pulse oximetry in the hospital management of acute asthma in childhood.

Oxyhemoglobin saturation values were recorded before and 10 minutes after 5 mg of nebulized salbutamol in 75 children (age, 1.5-14.6 years) admitted to hospital with acute asthma. Other assessments included heart rate, respiratory rate, peak expiratory flow rate, pulsus paradoxus, and an asthma severity score. All assessments were performed by the same observer (GC) and subsequent hospital care was transferred to the on-call pediatricians, who were not told the initial saturation values. Six children required intravenous therapy after hospital admission when their symptoms were not improved after nebulized salbutamol. Cutoff points for each continuous variable were selected so that they identified at least 5 of these 6 children (i.e., with a sensitivity of at least 83 percent). The resulting specificities and positive predictive values were calculated for each variable before and after nebulized therapy. A postnebulizer saturation of less than 91% had a sensitivity of 100% [95% confidence interval (CI), (54-100] with a specificity of 98% (95% CI, 92-100) and a positive predictive value of 86%. This was the best predictor of the need for intravenous (IV) therapy. Correlation coefficients were calculated for the 75 admissions and 2 others who required immediate IV treatment to determine how closely saturation values were related to the other recorded clinical variables. Saturation values were significantly, though weakly, correlated with asthma severity scores and prenebulizer heart rate, but they were not associated with any of the other variables. These results highlight the difficulties encountered when assessing acute asthma in a hospital population with a large number of preschool children.(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy of nebulized fluticasone propionate compared with oral prednisolone in children with an acute exacerbation of asthma.

The aim of the present study was to investigate the efficacy and safety of nebulized fluticasone propionate (FP Nebules) compared with oral soluble prednisolone in children with an acute exacerbation of asthma. The study used an international, multi-centre, randomized, double-blind, parallel group design. Three hundred and twenty-one patients, aged 4-16 years old, who presented with an acute exacerbation of asthma, were randomly allocated to either nebulized FP (1 mg b.d.) or oral prednisolone (2 mg kg(-1) day(-1) for 4 days then 1 mg kg(-1) day(-1) for 3 days) for 7 days. Patients in the FP group showed a significantly greater increase in diary card morning peak expiratory flow (PEF) over 7 days compared with patients in the prednisolone group (difference = 9.51 min(-1), CI = 2.1, 16.8, P = 0.034). Similar increases for both treatments were shown for evening PEF. Clinic PEF improved with both treatments, but was significantly greater in patients taking FP after 7 days (difference = 11.41 min(-1), CI = 2.8, 20.0, P = 0.029). Both treatments reduced symptom scores to a similar extent. The two treatments were well tolerated, and there was no difference in the incidence of adverse events. The present study demonstrated that nebulized FP is at least as effective as oral prednisolone in the treatment of children presenting with an acute exacerbation of asthma.

Pilgrim's progress: the effect of salmeterol in older children with chronic severe asthma.

Twenty-four children aged 12-17 years entered a randomized, double-blind placebo-controlled study investigating the use of salmeterol in chronic severe asthma. In addition to their usual medication, the children were given either placebo or 100 micrograms salmeterol b.d. by dry powder inhalation. Treatment was continued throughout one term at a residential school for asthma. Symptom scores, peak expiratory flow rates, spirometry and quality-of-life scores were compared between the two treatment groups. One child withdrew during the run-in period. Twelve pupils received placebo and 11 pupils received salmeterol. There were consistent improvements in favour of salmeterol, reaching statistical significance for morning and evening peak flow rates and spirometry when measured on four occasions during the study period. There were no medication-related adverse events recorded and no pulse rate changes. Salmeterol (100 micrograms b.d.) is well tolerated and efficacious in older children with chronic severe asthma.

Prednisolone in acute childhood asthma: clinical responses to three dosages.

Ninety-eight children aged 1-15 years entered a randomized double-blind study investigating an appropriate dose of oral prednisolone in children admitted to hospital with an acute exacerbation of asthma. None of the children had recently been treated with oral prednisolone. Following admission, the children were randomized to receive prednisolone 0.5 mg kg-1, 1.0 mg kg-1 or 2.0 mg kg-1 in a single daily dose in addition to nebulized bronchodilators. Clinical asthma scores, oxygen saturations, pulse rate, duration of admission and number of nebulizers given were compared in the three treatment groups. Thirty-five children received 0.5 mg kg-1, 33 received 1.0 mg kg-1 and 30 received 2.0 mg kg-1. There were no significant differences in the pattern of recovery between the three treatment groups. There were no advantages in using higher doses of prednisolone. We recommend 0.5 mg kg-1 day-1 of prednisolone as an appropriate dose for treating an acute exacerbation of asthma.

Pseudomonas aeruginosa in cystic fibrosis: cross-infection and the need for segregation.

Evidence-based reasons for segregation of patients colonized with Pseudomonas aerugionsa in the outpatient setting are unclear. To clarify local decisions, Pseudomonas genotyping of the local environment, patients and patient contacts was undertaken in 1993. The hospital environment was re-swabbed in 1997. Pseudomonas genotyping of old and new patients attending the North Staffordshire cystic fibrosis clinic has subsequently been undertaken and more recently been repeated on an annual basis to assess whether the same Pseudomonas genotypes can be found in both the environment and in patients, and whether the same Pseudomonas genotype can be transferred from one patient to another. No Pseudomonas genotype found in the local environment in 1993 or in 1997 has been found in any of our patients. Nine children attending the same special school for many years and sharing the same physiotherapy facilities showed no evidence of cross-infectivity. Except for siblings living in the same household our cross-infectivity rate is very low and where cross-infection has potentially occurred the level of contact between these patients has been minimal. This study does not support the suggestion that patients with cystic fibrosis attending the North Staffordshire clinic and colonized with Pseudomonas aeruginosa should be segregated from non-colonized patients.

HPA-axis effects of nebulised fluticasone propionate compared with oral prednisolone in childhood asthma.

The aim of this study was to compare the effect of 7 days nebulised fluticasone propionate (FP) with oral prednisolone on 24-h urinary-free cortisol excretion, systemic exposure and safety. This was a randomised, double-blind, double-dummy, two-way crossover study. Thirty-one children (19 male, 12 female, mean age 8 years) with stable asthma were randomly assigned to 7 days treatment with either FP Nebules (2 x 0.5 mg/2 ml bd) or prednisolone tablets once daily (2 mg/kg/day for 4 days [maximum 40 mg] followed by 1 mg/kg/day or half the original dose for 3 days [maximum 20 mg]). After a 2-4 week washout period, patients received the second treatment for 7 days, followed by a 2-week follow-up visit. The primary outcome measure was 24-h urinary-free cortisol concentrations corrected for creatinine. Nebulised FP (1 mg bd) had significantly less effect on 24-h urinary-free cortisol excretion than oral prednisolone (8.9 ng/ml for FP and 5.0 ng/ml for prednisolone, P = 0.001). Systemic exposure to FP was also low. In conclusion, FP Nebules had significantly less effect on hypothalamic-pituitary-adrenal axis function than oral prednisolone in asthmatic children when used at doses recommended for the treatment of an acute exacerbation of asthma.

Role of plasma phosphate measurements in detecting rickets of prematurity and in monitoring treatment.

Twice weekly plasma and urine measurements were made in 24 very low birth weight infants. Intravenous feeding was given whilst infants required respiratory support. Subsequently they received breast milk or formula milk with a vitamin D supplement of 400 U/day. Fourteen babies required intravenous feeding for more than 10 days. Six developed radiological rickets or severe osteoporosis, and these infants had plasma phosphate levels < 1.2 mmol/L on breast milk or < 1.8 mmol/L on formula milk. Babies without radiological rickets had plasma phosphate levels > 1.2 mmol/L on breast milk and > 1.8 mmol/L in all but one on formula milk. Successful treatment of rickets was associated with a rise in plasma phosphate to the above levels. Untimed urine calcium and phosphate concentrations expressed as creatinine ratios were not helpful in detecting babies with rickets, but may be useful in monitoring therapy.