Long-term outcomes of early exposure to repeated general anaesthesia in children with cystic fibrosis (CF-GAIN): a multicentre, open-label, randomised controlled phase 4 trial.

BACKGROUND: Long-term effects of early, recurrent human exposure to general anaesthesia remain unknown. The Australasian Cystic Fibrosis Bronchoalveolar Lavage (ACFBAL) trial provided an opportunity to examine this issue in children randomly assigned in infancy to either repeated bronchoalveolar-lavage (BAL)-directed therapy with general anaesthesia or standard care with no planned lavages up to 5 years of age when all children received BAL-directed therapy under general anaesthesia. METHODS: This multicentre, randomised, open-label phase 4 trial (CF-GAIN) used the original ACFBAL trial randomisation at 3·6 months (SD 1·6) to BAL-directed therapy or standard-care groups to assess the impact of general anaesthesia exposures over early childhood. Children who completed the ACFBAL trial, with a mean age of 5·1 (SD 0·18) years, received standardised neurobehavioural and health-related-quality-of-life assessment and brain MRI scans between Oct 8, 2013, and June 30, 2017, at a mean age of 12·8 (SD 1·7) years at three hospitals in Australia and one hospital in New Zealand. The primary outcome was a composite score of performance on a standardised, computer-based assessment of child attention, processing speed, and response inhibition skills (Conners Continuous Performance test, second edition). Secondary outcomes included intellectual function, other neurobehavioural measures, and brain imaging as an exploratory outcome. The trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN 12613000057785) and is completed. FINDINGS: At 2 years, the BAL-directed therapy group (n=52) and standard-care group (n=45) had a median of 2·0 (IQR 1·0-3·0) and 0·0 (0·0-0·0) exposures, respectively. At completion of the ACFBAL trial, the BAL-directed therapy group had a median of 6·0 (4·0-9·5) exposures and the standard-care group 2·0 (1·0-4·0) exposures. At CF-GAIN completion, the BAL-directed therapy group had a median of 10·0 (IQR 6·5-14·5) exposures and the standard-care group 4·0 (3·0-7·0) exposures. Cumulative general anaesthesia exposure time was not prospectively collected but, for those with complete cumulative exposure time data to the end of the ACFBAL trial, the median cumulative exposure time for the BAL-directed therapy group (n=29) was 180 (IQR 140-285) min and for the standard-care group (n=32) was 48 (30-122) min. The mean Conners Continuous Performance test, second edition composite score was 51 (SD 8·1) in BAL-directed therapy group and 53 (8·8) in the standard-care group; difference -1·7 (95% CI -5·2 to 1·7; p=0·32) with similar performance on other neurobehavioural measures, including measures of executive function, intellectual quotient scores, and brain imaging. INTERPRETATION: Our findings suggest that repeated general anaesthesia exposure in young children with cystic fibrosis is not related to functional impairment in attention, intellectual quotient, executive function, or brain structure compared with a group with fewer and shorter cumulative anaesthesia durations. FUNDING: National Health and Medical Research Council Australia, Queensland Government Health Service and Clinical Innovation Fellowship, and the Children's Hospital Foundation Queensland.

Quality of life is poorly correlated to lung disease severity in school-aged children with cystic fibrosis.

BACKGROUND: There is no data exclusively on the relationship between health-related quality-of-life (HRQOL) and lung disease severity in early school-aged children with cystic fibrosis (CF). Using data from the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) we assessed the relationships between HRQOL, lung function and structure. METHODS: 125 children aged 6.5-10 years enrolled in the AREST CF program were included from CF clinics at Royal Children's Hospital (RCH), Melbourne (n = 66) and Perth Children's Hospital (PCH), Perth (n = 59), Australia. Demographics, HRQOL measured by Cystic Fibrosis Questionnaire-Revised (CFQ-R), spirometry, multiple-breath washout (MBW) and chest CT were collected across two years. Correlation between CFQ-R scores and lung structure/function parameters and agreement between parent-proxy and child-reported HRQOL were evaluated. RESULTS: No correlation was observed between most CFQ-R domain scores and FEV1 z-scores, excepting weak-positive correlation with parent CFQ-R Physical (rho = 0.21, CI 0.02-0.37), and Weight (rho = 0.21, CI 0.03-0.38) domain and child Body domain (rho = 0.26, CI 0.00-0.48). No correlation between most CFQ-R domain scores and LCI values was noted excepting weak-negative correlation with parent Respiratory (rho = -0.23, CI -0.41--0.05), Emotional (rho = -0.24, CI -0.43--0.04), and Physical (-0.21, CI -0.39--0.02) domains. Furthermore, structural lung disease on CT data demonstrated little to no association with CFQ-R parent and child domain scores. Additionally, no agreement between child self-report and parent-proxy CFQ-R scores was observed across the majority of domains and visits. CONCLUSION: HRQOL correlated poorly with lung function and structure in early school-aged children with CF, hence clinical trials should consider these outcomes independently when determining study end-points.

The clinical features that contribute to poor bone health in young Australians living with cystic fibrosis: A recommendation for BMD screening.

BACKGROUND: For Australians living with cystic fibrosis (CF), increased longevity means greater consideration needs to be given to long-term endocrine sequelae such as CF-related bone disease. Deficits in bone mass accrual are most likely to occur during childhood and adolescence. Current guidelines in Australia suggest repeat dual-energy X-ray absorptiometry (DXA) scans every 2 years. This study aims to stratify clinical factors that determine future bone health in the Australian CF population and use this to guide a more streamlined approach to bone health screening. METHODS: This study was a retrospective audit of all patients diagnosed with CF who were treated at the Royal Children's Hospital Melbourne, Australia from 2000 to 2016 (n = 453). Two hundred and two patients had a DXA scan in the study period (191 with height-adjusted data) and 111 patients had more than one scan (108 with height-adjusted data). An investigation into the associations between bone mineral density (BMD) Z score and potential risk factors was conducted using DXA and historical data. RESULTS: The main predictor of future BMD was the previous BMD Z score (p < .001). Other factors found to be determinants of BMD included nutritional status, lung function (FEV1 ), age, history of previous fracture, oral corticosteroid use, and the number of hospital admissions. However, after adjusting for previous BMD, evidence of an association remained only with nutritional status, FEV1 , and number of hospital admissions. CONCLUSION: Second yearly scans may be unnecessary in children with an adequate DXA score on the initial scan who remain clinically stable. However, clinical deterioration in those whose BMD was previously normal, may require closer monitoring of bone health. We propose a guideline for the frequency of DXA monitoring in relation to clinical risk factors.

Characteristics and outcomes of children receiving intensive care therapy within 12 hours following a medical emergency team event.

Objectives: To describe characteristics and outcomes of children requiring intensive care therapy (ICT) within 12 hours following a medical emergency team (MET) event. Design: Retrospective cohort study. Setting: Quaternary paediatric hospital. Patients: Children experiencing a MET event. Measurements and main results: Between July 2017 and March 2019, 890 MET events occurred in 566 patients over 631 admissions. Admission to intensive care followed 183/890 (21%) MET events. 76/183 (42%) patients required ICT, defined as positive pressure ventilation or vasoactive support in intensive care, within 12 hours. Older children had a lower risk of requiring ICT than infants aged < 1 year (age 1-5 years [risk difference, -6.4%; 95% CI, -11% to -1.6%; P = 0.01] v age > 5 years [risk difference, -8.0%; 95% CI, -12% to -3.8%; P < 0.001]), while experiencing a critical event increased this risk (risk difference, 16%; 95% CI, 3.3-29%; P = 0.01). The duration of respiratory support and intensive care length of stay was approximately double in patients requiring ICT (ratio of geometric means, 2.0 [95% CI, 1.4-3.0] v 2.1 [95% CI, 1.5-2.8]; P < 0.001) and the intensive care mortality increased (risk difference, 9.6%; 95% CI, 2.4-17%; P = 0.01). Heart rate, oxygen saturation and respiratory rate were the most commonly measured vital signs in the 6 hours before the MET event. Conclusions: Approximately one-fifth of MET events resulted in intensive care admission and nearly half of these required ICT within 12 hours. This group had greater duration of respiratory support, intensive care and hospital length of stay, and higher mortality. Age < 1 year and a critical event increased the risk of ICT.

Health-related quality-of-life in children with cystic fibrosis aged 5-years and associations with health outcomes.

BACKGROUND: The impact of early cystic fibrosis (CF) on health-related quality-of-life (HRQOL) in preschool children is poorly characterised, and data on relationships between HRQOL and health outcomes in young children with CF are limited. We aimed to characterise and compare parent-proxy and child-reported HRQOL and evaluate relationships with clinical outcomes at age 5-years. METHODS: Subjects were participating in the multi-centre Australasian Cystic Fibrosis Bronchoalveolar Lavage (ACFBAL) trial investigating BAL-directed versus standard CF therapy. Children aged 5-years and their parents rated HRQOL using the Pediatric Quality of Life Inventory (PedsQL™) and Cystic Fibrosis Questionnaire-Revised (CFQ-R) questionnaires. RESULTS: PedsQL and CFQ-R questionnaires were completed by 141 primary caregivers and 135 and 130 children, respectively. There were no differences in HRQOL between children randomised to BAL-directed versus standard CF therapy. Children with CF rated worse HRQOL than healthy children and there was poor parent-child concordance across HRQOL domains. Nutritional status, CF-CT scan score, forced expiratory volume in 1-second (FEV1), and pulmonary exacerbations correlated with HRQOL at age 5-years. FEV1 z-scores positively correlated with parent-proxy HRQOL in CFQ-R Respiratory (p = 0.018), Physical (<0.001), Emotional (p = 0.007) subscales and PedsQL Total-score (p = 0.021), Physical (p = 0.019) domains. Pulmonary exacerbation rates were inversely associated with parent-proxy CFQ-R Respiratory (p = 0.004), Physical (p = 0.022), PedsQL Total (p = 0.009) and Physical (p = 0.009) scores. CONCLUSION: Parent-reported HRQOL is a meaningful clinical endpoint to evaluate interventions in young children. Parent and child HRQOL reports provide different, complementary information. A preschool version of the CFQ-R is needed to assess relationships between HRQOL and clinical outcomes in young children.

Early markers of cystic fibrosis structural lung disease: follow-up of the ACFBAL cohort.

Little is known about early predictors of later cystic fibrosis (CF) structural lung disease. This study examined early predictors of progressive structural lung abnormalities in children who completed the Australasian CF Bronchoalveolar Lavage (ACFBAL) clinical trial at age 5-years and participated in an observational follow-up study (CF-FAB).Eight Australian and New Zealand CF centres participated in CF-FAB and provided follow-up chest computed-tomography (CT) scans for children who had completed the ACFBAL study with baseline scans at age 5-years. CT scans were annotated using PRAGMA-CF scoring. Ordinal regression analysis and linear regression were used to investigate associations between PRAGMA-CF (Perth-Rotterdam Annotated Grid Morphometric Analysis for CF) outcomes at follow-up and variables measured during the ACFBAL study.99 out of 157 ACFBAL children (mean±sd age 13±1.5 years) participated in the CF-FAB study. The probability of bronchiectasis at follow-up increased with airway disease severity on the baseline CT scan. In multiple regression (retaining factors at p<0.05) the extent of bronchiectasis at follow-up was associated with baseline atelectasis (OR 7.2, 95% CI 2.4-22; p≤ 0.001), bronchoalveolar lavage (BAL) log2 interleukin (IL)-8 (OR 1.2, 95% CI 1.05-1.5; p=0.010) and body mass index z-score (OR 0.49, 95% CI 0.24-1.00; p=0.05) at age 5 years. Percentage trapped air at follow-up was associated with BAL log2 IL-8 (coefficient 1.3, 95% CI 0.57-2.1; p<0.001) at age 5 years.The extent of airway disease, atelectasis, airway inflammation and poor nutritional status in early childhood are risk factors for progressive structural lung disease in adolescence.

Glycoprotein A as a biomarker of pulmonary infection and inflammation in children with cystic fibrosis.

BACKGROUND: Serum Glycoprotein A (GlycA) levels are increased in a variety of inflammatory disease states. However, GlycA has not been previously evaluated in children with cystic fibrosis (CF). We assessed the relationship between GlycA and pulmonary infection, inflammation, bronchial wall thickening (BWT) and bronchiectasis in young children with CF. METHODS: From 95 patients, we obtained 311 paired serum and bronchoalveolar lavage (BAL) samples at multiple timepoints, with concurrent chest computed tomography on 168 occasions. Quantitative GlycA was determined using high-throughput nuclear magnetic resonance metabolomic testing. Participants were considered to be infected if ≥1 significant proinflammatory organism was isolated from their BAL. The presence of free neutrophil elastase (NE) above the limit of detection was considered evidence of inflammation. The relationships between GlycA levels and infection state, inflammation, and bronchiectasis were examined using a generalized estimating equation approach. RESULTS: There was a positive relationship between GlycA (mean 1.01 mmol/L, range 0.68-1.92 mmol/L) and being infected with one or more proinflammatory organisms, even after adjusting for age and gender (odds ratio [OR], 1.2 per 0.1 mmol/L, 95% confidence interval [CI], 1.02, 1.4, P = .03). There was also a positive relationship between GlycA and NE (unadjusted OR, 1.2 95% CI, 1.01, 1.4, P = .04), not significant after adjustment. GlycA concentration was associated with BWT but not bronchiectasis. CONCLUSIONS: Although GlycA levels were higher on average in those who had an infection or neutrophilic inflammation, there was also considerable variability, limiting the clinical utility of this biomarker alone in determining early disease status in CF.

Regional differences in infection and structural lung disease in infants and young children with cystic fibrosis.

BACKGROUND: Both infection and inflammation are critical to the progression of cystic fibrosis (CF) lung disease. Potential anatomical differences in lower airway infection, inflammation and bronchiectasis in young children with CF raise questions regarding the pathogenesis of early structural lung disease. METHODS: A longitudinal multi-centre birth cohort study of infants newly diagnosed with CF was conducted. Paired bronchoalveolar lavage (BAL) samples were obtained from the right middle lobe (RML) and lingula bronchi. Chest computed tomography (CT) was performed biennially and analysed using the modified CF-CT scoring system. RESULTS: One hundred and twenty-four children (0.11 - 7.0 years) contributed 527 BAL samples and underwent 388 CT chest scans. Pro-inflammatory microbes were detected in 279 BAL samples (53%), either in both lingula and RML samples (69%), in the lingula alone (24%), or in the RML alone in only 7% of samples. Overall, the prevalence of structural lung disease was greater in the setting of pro-inflammatory microbes. Although infection was less commonly isolated in the right lung, bronchiectasis was more commonly detected in the right lung compared with the left. No anatomical differences in the presence of air trapping were detected. CONCLUSION: Overall, the detection of pro-inflammatory microbes in the lower airways was associated with increased risk of both air trapping and bronchiectasis. However, the apparent discordance between commonest sites of isolation of pro-inflammatory microbes and the anatomical site of early bronchiectasis warrants further exploration.

The role of geographical location and climate on recurrent Pseudomonas infection in young children with Cystic Fibrosis.

OBJECTIVES: To determine the association between residence and climate with risk of Pseudomonas aeruginosa (Pa) and other respiratory outcomes. METHODS: We performed regular bronchoalveolar lavage and upper airway cultures in young children with CF to identify Pa infection. Children were classified for residence as regional or metropolitan. Bronchiectasis was detected on periodic chest computed tomography scans. Multilocus sequence typing determined Pa genotype. Lung function was assessed using Multiple Breath Washout. RESULTS: Of infants diagnosed with CF between 2006 and 2017, 129 were included in the study. Seven patients moved between metropolitan and regional Victoria and were excluded from analysis. Of the remaining 122 subjects, seventy-four (61%) children resided in metropolitan areas and over half (54%) were male. There were 83 Pa episodes in the 122 children who lived consistently in a geographical location. The incidence rate was 0.15 episodes per person-years. We found weak evidence of a 15% increase in the rate of Pa episodes with increasing average annual maximum temperature (95%CI (0.98, 1.36); p = .086), while the rate of Pa acquision decreased with average annual 3 pm humidity (IRR = 0.96; 95%CI(0.92, 1.0008); p = .054). The rate of Pa episodes was 2.1 times higher in regional participants (95%CI (1.4, 3.1); p = .001) and risk of second episode was more than five times greater (HR 5.7; 95%CI 1.9, 17); p = .002). No difference between regions in lung clearance index and presence of bronchiectasis was detected. CONCLUSION: Regional residence is associated with risk of acquiring recurrent infection with Pseudomonas aeruginosa in young children with CF.

Treatment of fecal impaction in children using combined polyethylene glycol and sodium picosulphate.

BACKGROUND AND AIM: Polyethylene glycol (PEG) is the gold standard for fecal disimpaction in constipation. A regimen of PEG combined with the stimulant laxative sodium picosulphate (SPS) produced fecal disimpaction in chronically constipated children in the community, but it is unknown if it is effective for more severe constipation. To determine the stool output and effect of a combined PEG and SPS regimen on fecaloma in children with severe constipation and impaction. METHODS: Children with symptoms for a duration of ≥2 years, a palpable fecaloma, and enlarged rectum on X-ray (rectal: pelvic ratio > 0.6) were recruited from a tertiary hospital. Daily diaries recorded laxative dose, stool frequency, volume, and consistency (Bristol stool scale, BSS). Abdominal X-rays were taken on day 1 and day 8, and stool loading was assessed using the Leech score. Laxative doses were based on the child's age. The dose of PEG with electrolytes taken was 2-8 sachets (14.7 g/sachet) on days 1-2, reducing to 2-6 sachets on day 3. The SPS dose was 15-20 drops on days 2-3. RESULTS: Eighty-nine children (4-18 years) produced a large volume of soft stool (median/inter-quartile-range: 2.2/1.6-3.1 L) over 7 days. Stool volume on X-rays decreased significantly in the colon (P < 0.001). Fecalomas resolved in 40 of 89 children, while 49 needed a second high dose. Rectal:pelvic ratios did not change. CONCLUSIONS: A combined high dose of PEG and SPS on days 1 and 2 was effective in removing the fecaloma in half of the children. Administering high doses for a longer period should be tested to provide outpatient disimpaction for severe fecalomas. Rectums remained flaccid after emptying.

Frequency of revision orchidopexy in Australia 1995-2014.

BACKGROUND/AIM: International criteria currently suggest orchidopexy at 6-12months for congenital undescended testis (UDT). Some children require repeat orchidopexy for recurrent UDT. This study aimed to assess practice in Australia over a 20-year period. METHODS: We examined 20years of Australian orchidopexy data (1995-2014) from the Department of Human Services to explore the national revision orchidopexy rates over time. RESULTS: The total number of orchidopexy revisions was 890 over 20years compared with 25,984 primary operations. More than 50% of all primary and revision orchidopexies in 0-14year-old boys were performed in major population centers of NSW and Victoria (which hold 52% male population of same age), with a small number of revisions on 15-24year-old males. The incidence of revision orchidopexy significantly decreased over the 20-year period in boys ages 0-14years old, from 276 operations between 1995 and 1999 decreasing to 165 operations between 2010 and 2014 (-53%), compared to a population increase of +15% (p<0.05). CONCLUSION: These data demonstrate a decrease in revision orchidopexy since 1995, which may be related to change in referral practice with more children undergoing orchidopexy (primary and revision) by pediatric surgeons over the 20-year period. LEVEL OF EVIDENCE: Level IV. TYPE OF STUDY: Therapeutic Case Series with no Comparison Group.

Comparing emergency department presentations among children with cerebral palsy with general childhood presentations: a data linkage study.

AIM: The aims of this study were to estimate the proportion of emergency department presentations attributable to children with cerebral palsy (CP), investigate the frequency of emergency department presentations in a CP cohort, and compare emergency department presentations among children with CP with those of other children. METHOD: This was a retrospective cohort study. The Victorian Cerebral Palsy Register was linked to the Victorian Emergency Minimum Dataset. Data on emergency department presentations for the CP cohort occurring between 2007 and 2014 and population control data were obtained. RESULTS: The CP cohort (n=1748) had 7015 emergency department presentations during the 7-year period, accounting for 0.4% of the 1.69 million age-specific presentations during that time. The number of annual presentations per 1000 children rose with increasing CP severity. Compared with presentations among the general population, higher proportions of presentations among the CP cohort were preceded by ambulance arrivals (27% vs 8%), triaged as urgent (66% vs 32%), and required hospital admission (38% vs 12%). INTERPRETATION: The marked differences in presentations between the CP cohort and the general population in the proportions that were urgent and required ambulance arrivals and hospital admissions was an important finding. Strategies to ensure appropriate use of services, including encouragement to seek earlier assistance from primary care providers, may prevent problems escalating to the need for urgent care. WHAT THIS PAPER ADDS: Children with cerebral palsy (CP) account for 0.4% of childhood emergency department presentations. More emergency department presentations among children with CP require ambulance arrival. More CP emergency department presentations are urgent and require hospital admission. Traditional emergency department triage scales seem less accurate for this group.

Hospital admissions in children with cerebral palsy: a data linkage study.

AIM: The overall aim was to investigate the feasibility and utility of linking a cerebral palsy (CP) register to an administrative data set for health services research purposes. We sought to compare CP hospital admissions to general childhood population admissions, and identify factors associated with type and frequency of admissions in a CP cohort. METHOD: The CP register for Victoria, Australia was linked to the state's hospital admissions database. Data pertaining to the admissions of a CP cohort (n=1748) that took place between 2007 and 2014 were extracted. Population data were also obtained. RESULTS: Overall, 80% of the CP cohort (n=1401) had at least admission between 2007 and 2014, accounting for 11 012 admissions or 1.5% of all admissions in their age group. Compared to general population admissions, CP admissions were more costly and more likely to be elective (66% vs 57%; p<0.001), medical (71% vs 57%; p<0.001), and to take place in metropolitan hospitals (92% vs 78%; p<0.001). Increased CP severity and complexity were associated with having more admissions and a higher proportion of admissions attributable to respiratory illness. INTERPRETATION: By linking with administrative data sets, CP registers may be useful for health services research and inform health service delivery.

High-level mobility skills in children and adolescents with traumatic brain injury.

AIM: To evaluate the reliability, validity and responsiveness of the High-level Mobility Assessment Tool (HiMAT) in children and adolescents with traumatic brain injury (TBI) and to compare the mobility skills of children with TBI to those of healthy peers. METHOD: The mobility skills of 52 children with moderate and severe TBI (36 males; mean age = 12 years, range = 6-17) were assessed using the HiMAT and the Pediatric Evaluation of Disability Inventory (PEDI). Inter-rater reliability, re-test reliability and responsiveness of the HiMAT were evaluated in sub-groups by comparing results scored at several time-points. The HiMAT scores of children with TBI were compared with those of a healthy comparative cohort. RESULTS: The HiMAT demonstrated excellent inter-rater reliability (ICC = 0.93), re-test reliability (ICC = 0.98) and responsiveness to change (p = 0.002). The PEDI demonstrated a ceiling effect in mobility assessment of ambulant children with TBI. The HiMAT scores of children with TBI were lower than those of their healthy peers (p < 0.001). INTERPRETATION: The HiMAT is a reliable, valid and sensitive measure of high-level mobility skills following childhood TBI. The high-level mobility skills of children with TBI are less proficient than their peers.

Pseudomonas aeruginosa genotypes acquired by children with cystic fibrosis by age 5-years.

BACKGROUND: We describe Pseudomonas aeruginosa acquisitions in children with cystic fibrosis (CF) aged ≤5-years, eradication treatment efficacy, and genotypic relationships between upper and lower airway isolates and strains from non-CF sources. METHODS: Of 168 CF children aged ≤5-years in a bronchoalveolar lavage (BAL)-directed therapy trial, 155 had detailed microbiological results. Overall, 201/271 (74%) P. aeruginosa isolates from BAL and oropharyngeal cultures were available for genotyping, including those collected before and after eradication therapy. RESULTS: Eighty-two (53%) subjects acquired P. aeruginosa, of which most were unique strains. Initial eradication success rate was 90%, but 36 (44%) reacquired P. aeruginosa, with genotypic substitutions more common in BAL (12/14) than oropharyngeal (3/11) cultures. Moreover, oropharyngeal cultures did not predict BAL genotypes reliably. CONCLUSIONS: CF children acquire environmental P. aeruginosa strains frequently. However, discordance between BAL and oropharyngeal strains raises questions over upper airway reservoirs and how to best determine eradication in non-expectorating children.

Costs of bronchoalveolar lavage-directed therapy in the first 5 years of life for children with cystic fibrosis.

OBJECTIVES: To determine whether bronchoalveolar lavage (BAL)-directed therapy for infants and young children with cystic fibrosis (CF), rather than standard therapy, was justified on the grounds of a decrease in average costs and whether the use of BAL reduced treatment costs associated with hospital admissions. STUDY DESIGN: Costs were assessed in a randomized controlled trial conducted in Australia and New Zealand on infants diagnosed with CF after newborn screening and assigned to receive either BAL-directed or standard therapy until they reached 5 years of age. A health care funder perspective was adopted. Resource use measurement was based on standardized data collection forms administered for patients across all sites. Unit costs were obtained primarily from government schedules. RESULTS: Mean costs per child during the study period were Australian dollars (AUD)92 860 in BAL-directed therapy group and AUD90 958 in standard therapy group (mean difference AUD1902, 95% CI AUD-27 782 to 31 586, P = .90). Mean hospital costs per child during the study period were AUD57 302 in the BAL-directed therapy group and AUD66 590 in the standard therapy group (mean difference AUD-9288; 95% CI AUD-35 252 to 16 676, P = .48). CONCLUSIONS: BAL-directed therapy did not result in either lower mean hospital admission costs or mean costs overall compared with managing patients with CF by a standard protocol based upon clinical features and oropharyngeal culture results alone. Following on our previous findings that BAL-directed treatment offers no clinical advantage over standard therapy at age 5 years, flexible bronchoscopy with BAL cannot be recommended for the routine management of preschool children with CF on the basis of overall cost savings.

Safety of inhaled (Tobi®) and intravenous tobramycin in young children with cystic fibrosis.

BACKGROUND: Use of inhaled tobramycin therapy for treatment of Pseudomonas aeruginosa infections in young children with cystic fibrosis (CF) is increasing. Safety data for pre-school children are sparse. METHODS: The aim of this study was to assess the safety of tobramycin solution for inhalation (TOBI®-TSI) administered twice daily for 2 months/course concurrently to intravenous (IV) tobramycin during P. aeruginosa eradication therapy in children (0-5 years). Audiological assessment and estimation of glomerular filtration rate (GFR) was measured prior to any exposure and end of the study. RESULTS: Data were available from 142 patients who were either never exposed to aminoglycosides (n=39), exposed to IV aminoglycosides only (n=36) or exposed to IV+TSI (n=67). Median exposure to TSI was 113 days [59, 119]. Comparison of effects on audiometry results and GFR, showed no detectable difference between the groups. CONCLUSIONS: Use of TSI and IV tobramycin in pre-school children with CF was not associated with detectable renal toxicity or ototoxicity.

Outcomes of childhood asthma to the age of 50 years.

BACKGROUND: In 1964, The Melbourne Asthma Study was established to describe the spectrum and natural history of childhood asthma. OBJECTIVE: To describe the clinical and lung function outcome of childhood asthma to the age of 50 years. METHOD: Subjects were invited to complete an interviewer-administered questionnaire, skin prick testing, and measurement of lung function from the age of 7 years to the age of 50 years at 7-year intervals. RESULTS: Of 458 survivors (from the original 484 subjects at recruitment), 346 subjects (76%) participated, of whom, 197 completed lung function measurement. Asthma remission at the age of 50 years was 64% in those with wheezy bronchitis, 47% for those with persistent asthma, and 15% for those with severe asthma in childhood. Multivariable analysis identified severe asthma in childhood (odds ratio [OR] 11.9 [95% CI, 3.4-41.8]), female sex (OR 2.0 [95% CI, 1.1-3.6]), and childhood hay fever (OR 2.0 [95% CI, 1.0-4.0]) as risk factors for "current asthma" at age 50 years. There was no evidence of a difference in the rate of decline in FEV1 (mL/y, 95% CI) between the severe asthma group (15 mL/y [95% CI, 9-22 mL/y]) and all the other recruitment groups: control (16 mL/y [95% CI, 12-20 mL/y]), mild wheezy bronchitis (14 mL/y [95% CI, 8-19 mL/y]), wheezy bronchitis (16 mL/y [95% CI, 11-20 mL/y]), and persistent asthma (19 mL/y [95% CI, 13-24 mL/y]). CONCLUSION: The clinical and lung function outcome in adult life is strongly determined by asthma severity in childhood. The reduced lung function seen in adults is established in childhood and does not appear to decline more rapidly in adult years despite continuing symptoms.

Prospective evaluation of respiratory exacerbations in children with cystic fibrosis from newborn screening to 5 years of age.

BACKGROUND: Newborn screening allows novel treatments for cystic fibrosis (CF) to be trialled in early childhood before irreversible lung injury occurs. As respiratory exacerbations are a potential trial outcome variable, we determined their rate, duration and clinical features in preschool children with CF; and whether they were associated with growth, lung structure and function at age 5 years. METHODS: Respiratory exacerbations were recorded prospectively in Australasian CF Bronchoalveolar Lavage trial subjects from enrolment after newborn screening to age 5 years, when all participants underwent clinical assessment, chest CT scans and spirometry. RESULTS: 168 children (88 boys) experienced 2080 exacerbations, at an average rate of 3.66 exacerbations per person-year; 80.1% were community managed and 19.9% required hospital admission. There was an average increase in exacerbation rate of 9% (95% CI 4% to 14%; p<0.001) per year of age. Exacerbation rate differed by site (p<0.001) and was 26% lower (95% CI 12% to 38%) in children receiving 12 months of prophylactic antibiotics. The rate of exacerbations in the first 2 years was associated with reduced forced expiratory volume in 1 s z scores. Ever having a hospital-managed exacerbation was associated with bronchiectasis (OR 2.67, 95% CI 1.13 to 6.31) in chest CT scans, and lower weight z scores at 5 years of age (coefficient -0.39, 95% CI -0.74 to -0.05). CONCLUSIONS: Respiratory exacerbations in young children are markers for progressive CF lung disease and are potential trial outcome measures for novel treatments in this age group.