Peter Van Asperen

Normal Development of the Lung and Premature Birth

The following review focuses on the normal development of the lung from conception to birth. The defined periods of lung development-Embryonic, Pseudoglandular, Canalicular, Saccular and Alveolar-will be explored in detail in relation to gestational age. Cellular differentiation, formation of the conducting airways and respiratory zone and development of the alveoli will be reviewed. Pulmonary vascular development will also be examined within these periods to relate the formation of the blood-air barrier to the lungs for their essential function of gas exchange after birth. The development of the surfactant and cortisol systems will also be discussed as these need to be mature before the lungs are able to take on their role of respiration following birth. It is clear that premature birth interrupts normal lung development so the effect of preterm birth on lung development will be examined and the respiratory consequences of very preterm birth will be briefly explored.

A Multicenter Study on Chronic Cough in Children Burden and Etiologies Based on a Standardized Management Pathway

BACKGROUND While the burden of chronic cough in children has been documented, etiologic factors across multiple settings and age have not been described. In children with chronic cough, we aimed (1) to evaluate the burden and etiologies using a standard management pathway in various settings, and (2) to determine the influence of age and setting on disease burden and etiologies and etiology on disease burden. We hypothesized that the etiology, but not the burden, of chronic cough in children is dependent on the clinical setting and age. METHODS From five major hospitals and three rural-remote clinics, 346 children (mean age 4.5 years) newly referred with chronic cough (> 4 weeks) were prospectively managed in accordance with an evidence-based cough algorithm. We used a priori definitions, timeframes, and validated outcome measures (parent-proxy cough-specific quality of life [PC-QOL], a generic QOL [pediatric quality of life (PedsQL)], and cough diary). RESULTS The burden of chronic cough (PC-QOL, cough duration) significantly differed between settings (P = .014, 0.021, respectively), but was not influenced by age or etiology. PC-QOL and PedsQL did not correlate with age. The frequency of etiologies was significantly different in dissimilar settings (P = .0001); 17.6% of children had a serious underlying diagnosis (bronchiectasis, aspiration, cystic fibrosis). Except for protracted bacterial bronchitis, the frequency of other common diagnoses (asthma, bronchiectasis, resolved without specific-diagnosis) was similar across age categories. CONCLUSIONS The high burden of cough is independent of children’s age and etiology but dependent on clinical setting. Irrespective of setting and age, children with chronic cough should be carefully evaluated and child-specific evidence-based algorithms used.

Safety of the Newer Inhaled Corticosteroids in Childhood Asthma

Inhaled corticosteroids (ICS) remain a vital part of the management of persistent asthma, but concerns have been raised about their potential adverse effects in children. This review examines the safety data on three new ICS — fluticasone propionate, mometasone, and extrafine beclomethasone in hydrofluoroalkane (HFA-134a) propellant (QVAR®1 formulation) in relation to the older corticosteroids.Topical adverse effects such as thrush and dysphonia are rare, but dental erosion is a possibility with powder forms of ICS because of their low pH. Thus, it is important to stress mouth rinsing after administration and maintaining good dental hygiene to minimize this risk.Biochemical adrenal suppression can be readily demonstrated, particularly with high doses of all ICS. The clinical relevance of this was uncertain in the past, but there have now been >50 reported cases of acute adrenal crises in children receiving ICS, most of whom were on fluticasone propionate. In order to minimize the risk of symptomatic adrenal suppression, it is important to back-titrate the ICS dose and alert families of children receiving high-dose ICS of this potential adverse effect. A pediatric endocrine opinion should be sought if adrenal suppression is suspected. The older ICS cause temporary slowing of growth velocity, but the limited data available do not show any significant compromise of final adult height. The effect on growth of fluticasone propionate may not be as great as with the older ICS, but the studies have been short term and only used low doses of fluticasone propionate. There have been case reports of growth suppression in children receiving high doses of fluticasone propionate. The limited studies performed on the effect of ICS on bone mineral density in children did not show any adverse effects, but there may be an increased risk of fractures.Hydrofluoroalkane beclomethasone (QVAR) is essentially the same drug as chlorofluorocarbon beclomethasone, but with double the lung deposition owing to the smaller particle size. Thus, it could be expected that any adverse effects seen with chlorofluorocarbon beclomethasone would be the same with hydrofluoroalkane beclomethasone. However, some of the published data, particularly in adults, suggest that hydrofluoroalkane beclomethasone may be less systemically active than chlorofluorocarbon beclomethasone, even at equipotent doses. As yet, there are no long-term data on mometasone, but initial studies in adults suggest there may be less suppression of the hypothalamic-pituitary-adrenal axis, although further studies are required, particularly in children.ICS will remain a cornerstone in the management of persistent pediatric asthma, provided that the diagnosis of asthma is secure. It is very important to use ICS appropriately and to ensure the lowest possible doses are used to achieve symptom control, thus minimizing the risk of serious adverse effects.

A Cough Algorithm for Chronic Cough in Children: A Multicenter, Randomized Controlled Study

OBJECTIVES The goals of this study were to: (1) determine if management according to a standardized clinical management pathway/algorithm (compared with usual treatment) improves clinical outcomes by 6 weeks; and (2) assess the reliability and validity of a standardized clinical management pathway for chronic cough in children. METHODS: A total of 272 children (mean ± SD age: 4.5 ± 3.7 years) were enrolled in a pragmatic, multicenter, randomized controlled trial in 5 Australian centers. Children were randomly allocated to 1 of 2 arms: (1) early review and use of cough algorithm (“early-arm”); or (2) usual care until review and use of cough algorithm (“delayed-arm”). The primary outcomes were proportion of children whose cough resolved and cough-specific quality of life scores at week 6. Secondary measures included cough duration postrandomization and the algorithm’s reliability, validity, and feasibility. RESULTS: Cough resolution (at week 6) was significantly more likely in the early-arm group compared with the delayed-arm group (absolute risk reduction: 24.7% [95% confidence interval: 13–35]). The difference between cough-specific quality of life scores at week 6 compared with baseline was significantly better in the early-arm group (mean difference between groups: 0.6 [95% confidence interval: 0.29–1.0]). Duration of cough postrandomization was significantly shorter in the early-arm group than in the delayed-arm group (P = .001). The cough algorithm was reliable (κ = 1 in key steps). Feasibility was demonstrated by the algorithm’s validity (93%–100%) and efficacy (99.6%). Eighty-five percent of children had etiologies easily diagnosed in primary care. CONCLUSIONS: Management of children with chronic cough, in accordance with a standardized algorithm, improves clinical outcomes irrespective of when it is implemented. Further testing of this standardized clinical algorithm in different settings is recommended.

Using Index of Ventilation to Assess Response to Treatment for Acute Pulmonary Exacerbation in Children With Cystic Fibrosis

The use of alternative more sensitive measures has become a focus of research in CF. The utility of indexes of ventilation, Lung Clearance Index (LCI) and peak aerobic capacity (peak VO2), were studied as assessment tools in gauging response to intravenous (IV) therapy in acute pulmonary exacerbation, in comparison to the more commonly used index of forced expiratory volume in 1 sec (FEV1). The utility of a previously published clinical score was further explored.

Randomized, double-blind, placebo-controlled trial of intravenous salbutamol and nebulized ipratropium bromide in early management of severe acute asthma in children presenting to an emergency department

Background In acute severe asthma, treatment must be initiated early to reverse the pathophysiology that may render airways less responsive to bronchodilation. The addition of nebulized ipratropium bromide to initial emergency department therapy improves pulmonary function, but it is unclear whether this approach results in earlier hospital discharge. The early use of bolus intravenous salbutamol has also been shown to improve outcome, including earlier discharge. We therefore assessed the relative benefits of intravenous salbutamol and nebulized ipratropium bromide in the early management of acute severe asthma in children by a double-blind, randomized, controlled trial. Methods This study was undertaken at a tertiary children’s hospital, The Children’s Hospital at Westmead, The Royal Alexandra Hospital for Children, Westmead, Sydney, Australia. Only children with severe acute asthma as determined by the National Asthma Campaign guidelines criteria and pulmonary index were included. All children received initial nebulized salbutamol therapy (2.5–5 mg salbutamol in 4 mL of normal saline depending on age) at initial emergency department presentation. If asthma remained severe 20 mins later, an intravenous cannula was inserted and intravenous methylprednisolone (1 mg/kg) was administered to all children receiving nebulized salbutamol every 20 mins. Children were then randomized to one of three groups: intravenous salbutamol (15 &mgr;g/kg as a single bolus over 10 mins), ipratropium bromide (250 &mgr;g), or intravenous salbutamol plus ipratropium bromide. All observers were blinded to treatment groups. Children were randomly assigned to receive a single-dose intravenous bolus of either saline or salbutamol and either nebulized saline or ipratropium bromide determined by a number generated randomly in the hospital pharmacy. The primary outcomes were recovery time and discharge time of each group. Respiratory and hemodynamic monitoring were continuous during the first 2 hrs of the study and then children were monitored clinically for 24 hrs. Results A total of 55 children with acute severe asthma were entered into the study over an 18-month period. The three groups were similar demographically, with a mean age of 5.9 yrs, and mean duration of attack of 19.6 hrs. No side effects or treatment intolerance were reported. Children in the groups that received intravenous salbutamol had a significant reduction in recovery time to achieving second hourly inhaled salbutamol (p = .008) compared with those administered inhaled bronchodilator alone. The addition of ipratropium bromide to intravenous salbutamol provided no significant further benefit in terms of nebulizer therapy (intravenous salbutamol compared with intravenous salbutamol plus ipratropium bromide). Children administered intravenous salbutamol ceased supplemental oxygen therapy earlier than those administered ipratropium alone at 12 hrs postrandomization (p = .0003). Children administered intravenous salbutamol could be discharged from the hospital 28 hrs earlier than those administered ipratropium bromide (p = .013). Conclusion Children administered intravenous salbutamol for severe acute asthma showed a more rapid recovery time, which resulted in earlier discharge from the hospital than those administered inhaled ipratropium bromide. There was no additional benefit obtained by combining ipratropium bromide and intravenous salbutamol administration.

Diagnosis and management of asthma in adolescents

Objectives:  In this review we explore some of the issues surrounding the diagnosis and misdiagnosis of asthma in adolescents and suggest a management approach which might facilitate the provision of optimal treatment in order to minimise morbidity from asthma in this vulnerable and often difficult‐to‐manage age group.

Medication Use in Children with Asthma: Not a Child Size Problem

Objective. The global burden of pediatric asthma is high. Governments and health-care systems are affected by the increasing costs of childhood asthma—in terms of direct health-care costs and indirect costs due to loss of parental productivity, missed school days, and hospitalizations. Despite the availability of effective treatment, the current use of medications in children with asthma is suboptimal. The purpose of this review is to scope the empirical literature to identify the problems associated with the use of pediatric asthma medications. The findings will help to design interventions aiming to improve the use of asthma medications among children. Methods. A literature search using electronic search engines (i.e., Medline, International Pharmaceutical Abstracts (IPA), PubMed, PsycINFO, and Cumulative Index to Nursing and Allied Health Literature (CINAHL)) and the search terms “asthma,” “children,” and “medicines” (and derivatives of these keywords) was conducted. Results. The search terms were expanded to include emergent themes arising out of search findings. Content themes relating to parents, children themselves, health-care professionals, organizational systems, and specific medications and devices were found. Within these themes, key issues included a lack of parental knowledge about asthma and asthma medications, lack of information provided to parents, parental beliefs and fears, parental behavioral problems, the high costs of medications and devices, the child’s self-image, the need for more child responsibility, physician nonadherence to prescribing guidelines, “off-label” prescribing, poor understanding of teachers, lack of access to educational resources, and specific medications. Conclusion. These key issues should be taken into account when modifying the development of educational tools. These tools should focus on targeting the children themselves, the parent/carers, the health-care professionals, and various organizational systems.

Longitudinal analysis of resting energy expenditure in patients with cystic fibrosis.

OBJECTIVE To assess whether elevated resting energy expenditure (REE) in female patients with cystic fibrosis (CF) persists longitudinally during late childhood and puberty. STUDY DESIGN REE and body composition were measured 3 times in 2 years in 86 children with CF. Pubertal status, bacterial colonization, liver disease, pancreatic and pulmonary function, and genotype were determined, and linear mixed model analyses were used to determine predictors and changes in REE longitudinally. RESULTS REE did not change with time allowing for fat free mass, pancreatic insufficiency (PI), or severe mutations. Pulmonary function and liver disease were not significant predictors of REE. Percentage predicted REE compared with control data was higher (P = .002) in female patients with CF (109.5%) and lower in male patients with CF (104%) and persisted with time. In post-menarchal female patients with CF, REE adjusted for fat free mass was 366 kJ/d lower than in pre-menarchal female patients, but still 112% predicted. CONCLUSIONS This longitudinal study demonstrates that REE is elevated in patients with CF with PI and severe mutations. The elevation of percentage predicted REE was greater in female patients than male patients and persisted for 2 years, and during pubertal maturation, independent of pulmonary and liver disease. These results highlight the need for a high-energy diet throughout childhood and adolescence, particularly in female patients with PI.

Lentivirus vector-mediated gene transfer to the developing bronchiolar airway epithelium in the fetal lamb.

Development of effective and durable gene therapy for treatment of the respiratory manifestations of cystic fibrosis remains a formidable challenge. Obstacles include difficulty in achieving efficient gene transfer to mature airway epithelium and the need to stably transduce self‐renewing epithelial progenitor cells in order to avoid loss of transgene expression through epithelial turnover. Targeting the developing airway epithelium during fetal life offers the prospect of circumventing these challenges.