Helen Buntain

Bone mineral density in Australian children, adolescents and adults with cystic fibrosis: a controlled cross sectional study

Background: Low bone mineral density (BMD) is recognised in individuals with cystic fibrosis (CF) although the pathogenesis remains unclear. The aims of this study were to compare BMD over a broad continuum of Australian individuals with CF with healthy controls and to examine the relationship between BMD and clinical parameters including physical activity, nutrition, and vitamin D levels. Methods: BMD of the lumbar spine (LS), total body (TB), femoral neck (FN), cortical wrist (R33%), and distal wrist (RUD) was examined in 153 individuals with CF aged 5.3–55.8 years (84 males) and in 149 local controls aged 5.6–48.3 years (66 males) using dual energy x ray absorptiometry. Anthropometric variables, body cell mass, markers of disease severity, corticosteroid usage, measures of physical activity, dietary calcium and caloric intake and serum vitamin D were assessed and related to BMD. Results: Compared with controls, mean BMD was not significantly different in children aged 5–10 years with CF. Adolescents (females 11–18 years, males 11–20 years) had reduced TB and R33% BMD when adjusted for age, sex, and height (difference in BMD (g/cm2) adjusted means between control and CF: TB = 0.04 (95% CI 0.01 to 0.07); R33% = 0.03 (95% CI 0.01 to 0.06)). BMD was reduced at all sites except R33% in adults (difference in BMD (g/cm2) adjusted means between control and CF: TB = 0.05 (95% CI 0.02 to 0.09); LS = 0.08 (95% CI 0.03 to 0.14); FN = 0.09 (95% CI 0.03 to 0.15); RUD = 0.03 (95% CI 0.01 to 0.05)). In children/adolescents BMD was weakly associated with nutritional status and disease severity. Conclusions: BMD was normal in a well nourished group of prepubertal children with CF. A BMD deficit appears to evolve during adolescence and becomes more marked in adults. Individuals with CF should optimise nutrition, partake in physical activity, and maximise lung health in order to optimise BMD. Further longitudinal studies are required to understand the evolution of reduced BMD in young people and adults with CF.

Controlled longitudinal study of bone mass accrual in children and adolescents with cystic fibrosis

Background: A study was undertaken to observe the gains in bone mass in children and adolescents with cystic fibrosis (CF) over 24 months and to examine the relationship between areal bone mineral density (aBMD) and associated clinical parameters including physical activity, nutrition, and 25-hydroxyvitamin D (25OHD). Methods: Areal BMD of the total body (TB), lumbar spine (LS), and total femoral neck (FNt) were repeatedly measured in 85 subjects aged 5–18 years with CF and 100 age and sex matched controls over 2 years. At each visit anthropometric variables, nutritional parameters, pubertal status, disease severity, physical activity, dietary calcium, caloric intake, and serum 25OHD were assessed and related to aBMD. Results: After adjusting for age, sex, and height Z-score, gains in LS aBMD in children (5–10 years) and TB and FNt aBMD in adolescents (11–18 years) with CF were significantly less than in controls. Lean tissue mass was significantly associated with TB and LS aBMD gains in children and adolescents and explained a significant proportion of the aBMD deficit observed. Lung function parameters were significantly associated with aBMD gains in adolescents with CF. Conclusions: Inadequate bone mass accrual during childhood and adolescence contributes to the low bone mass observed in adults with CF. Accounting for the height discrepancy which is frequently observed in those with CF, in addition to age and sex, is important when assessing low bone mass in children and adolescents with CF. To optimise an individual’s potential to acquire maximal bone mass, it is necessary to maximise nutritional status and limit the progression of chronic suppurative lung disease.

Pubertal development and its influences on bone mineral density in Australian children and adolescents with cystic fibrosis

Background:  Pubertal delay is thought to contribute to suboptimal peak bone mass acquisition in young people with cystic fibrosis (CF), leading to an increased fracture incidence. This study aims to compare pubertal development in young people with CF with that of a local healthy population and assess the influence it has on areal bone mineral density (aBMD).

Is Alveolar Macrophage Phagocytic Dysfunction in Children With Protracted Bacterial Bronchitis a Forerunner to Bronchiectasis

BACKGROUND Children with recurrent protracted bacterial bronchitis (PBB) and bronchiectasis share common features, and PBB is likely a forerunner to bronchiectasis. Both diseases are associated with neutrophilic inflammation and frequent isolation of potentially pathogenic microorganisms, including nontypeable Haemophilus influenzae (NTHi), from the lower airway. Defective alveolar macrophage phagocytosis of apoptotic bronchial epithelial cells (efferocytosis), as found in other chronic lung diseases, may also contribute to tissue damage and neutrophil persistence. Thus, in children with bronchiectasis or PBB and in control subjects, we quantified the phagocytosis of airway apoptotic cells and NTHi by alveolar macrophages and related the phagocytic capacity to clinical and airway inflammation. METHODS Children with bronchiectasis (n = 55) or PBB (n = 13) and control subjects (n = 13) were recruited. Alveolar macrophage phagocytosis, efferocytosis, and expression of phagocytic scavenger receptors were assessed by flow cytometry. Bronchoalveolar lavage fluid interleukin (IL) 1β was measured by enzyme-linked immunosorbent assay. RESULTS For children with PBB or bronchiectasis, macrophage phagocytic capacity was significantly lower than for control subjects (P = .003 and P < .001 for efferocytosis and P = .041 and P = .004 for phagocytosis of NTHi; PBB and bronchiectasis, respectively); median phagocytosis of NTHi for the groups was as follows: bronchiectasis, 13.7% (interquartile range [IQR], 11%-16%); PBB, 16% (IQR, 11%-16%); control subjects, 19.0% (IQR, 13%-21%); and median efferocytosis for the groups was as follows: bronchiectasis, 14.1% (IQR, 10%-16%); PBB, 16.2% (IQR, 14%-17%); control subjects, 18.1% (IQR, 16%-21%). Mannose receptor expression was significantly reduced in the bronchiectasis group (P = .019), and IL-1β increased in both bronchiectasis and PBB groups vs control subjects. CONCLUSIONS A reduced alveolar macrophage phagocytic host response to apoptotic cells or NTHi may contribute to neutrophilic inflammation and NTHi colonization in both PBB and bronchiectasis. Whether this mechanism also contributes to the progression of PBB to bronchiectasis remains unknown.

Bronchiectasis exacerbation study on azithromycin and amoxycillin-clavulanate for respiratory exacerbations in children (BEST-2): study protocol for a randomized controlled trial

BackgroundBronchiectasis unrelated to cystic fibrosis (CF) is being increasingly recognized in children and adults globally, both in resource-poor and in affluent countries. However, high-quality evidence to inform management is scarce. Oral amoxycillin-clavulanate is often the first antibiotic chosen for non-severe respiratory exacerbations, because of the antibiotic-susceptibility patterns detected in the respiratory pathogens commonly associated with bronchiectasis. Azithromycin has a prolonged half-life, and with its unique anti-bacterial, immunomodulatory, and anti-inflammatory properties, presents an attractive alternative. Our proposed study will test the hypothesis that oral azithromycin is non-inferior (within a 20% margin) to amoxycillin-clavulanate at achieving resolution of non-severe respiratory exacerbations by day 21 of treatment in children with non-CF bronchiectasis.MethodsThis will be a multicenter, randomized, double-blind, double-dummy, placebo-controlled, parallel group trial involving six Australian and New Zealand centers. In total, 170 eligible children will be stratified by site and bronchiectasis etiology, and randomized (allocation concealed) to receive: 1) azithromycin (5 mg/kg daily) with placebo amoxycillin-clavulanate or 2) amoxycillin-clavulanate (22.5 mg/kg twice daily) with placebo azithromycin for 21 days as treatment for non-severe respiratory exacerbations. Clinical data and a parent-proxy cough-specific quality of life (PC-QOL) score will be obtained at baseline, at the start and resolution of exacerbations, and on day 21. In most children, blood and deep-nasal swabs will also be collected at the same time points. The primary outcome is the proportion of children whose exacerbations have resolved at day 21. The main secondary outcome is the PC-QOL score. Other outcomes are: time to next exacerbation; requirement for hospitalization; duration of exacerbation, and spirometry data. Descriptive viral and bacteriological data from nasal samples and blood inflammatory markers will be reported where available.DiscussionCurrently, there are no published randomized controlled trials (RCT) to underpin effective, evidence-based management of acute respiratory exacerbations in children with non-CF bronchiectasis. To help address this information gap, we are conducting two RCTs. The first (b ronchiectasis e xacerbation st udy; BEST-1) evaluates the efficacy of azithromycin and amoxycillin-clavulanate compared with placebo, and the second RCT (BEST-2), described here, is designed to determine if azithromycin is non-inferior to amoxycillin-clavulanate in achieving symptom resolution by day 21 of treatment in children with acute respiratory exacerbations.Trial registrationAustralia and New Zealand Clinical Trials Register (ANZCTR) number http://ACTRN12612000010897. http://www.anzctr.org.au/trial_view.aspx?id=347879

The use of air displacement plethysmography in children and adolescents with cystic fibrosis

Objectives: The purpose of this paper was to evaluate the use of air displacement plethysmography (ADP) in children and adolescents with cystic fibrosis (CF). Specifically, the primary aim of this study was to compare estimates of fat-free mass (FFM) measured from ADP and dual energy X-ray absorptiometry (DEXA) in children and adolescents with CF. The secondary aim was to compare the effect of using predicted thoracic gas volume (V TG) and measured V TG for the calculation of FFM by ADP in this population.Methods: Cross-sectional FFM measurements were taken using ADP and DEXA in 52 children and adolescents with CF, ranging in age from 6.3 to 16.6 y.Results: Bland–Altman analysis showed that ADP values of FFM were on average 0.59 kg higher than DEXA values (95% limits of agreement = 3.61 to −2.43 kg); however this difference was not significant. There was no significant correlation (r=−0.26, P=0.07) between the mean FFM and difference in FFM between ADP and DEXA. Using either predicted or measured V TG did not significantly affect FFM estimates in individuals with CF who had normal lung function (bias=−0.39±0.86 kg; r=−0.02, P=0.93).Conclusions: ADP is an appropriate technique for use in children and adolescents with CF.

The nutritional status of children with cystic fibrosis

The importance of nutritional intervention for children with cystic fibrosis (CF) is well recognised. It would be expected that the increase in knowledge over the past decade would be reflected in improvements in nutritional status for the CF paediatric population. The aim of the present paper was to evaluate the nutritional status of children with CF, cross-sectionally and longitudinally. Body cell mass adjusted for gender and size (BCM/Htp) was measured in sixty-four children with CF to represent nutritional status and expressed as a Z-score. The cross-sectional results showed a mean BCM/Htp Z-score of 0.54 (sd 1.21), with males having a slightly higher Z-score than females but with a larger variation. At the initial measurement, only one female and one male were considered sub-optimally nourished. The longitudinal analysis after 2 years showed that the mean population had a significantly decreased BCM/Htp Z-score; however, when each gender was analysed separately, this decrease was significant only in the males. At the final measurement, only two females and three males were considered sub-optimally nourished. It is evident from our results that children with CF are well nourished, with only a small percentage considered malnourished. It appears that nutritional status decreases with age, with this decline being more evident in males. These results signify that although children with CF are better nourished with current treatment support, intervention needs to continue throughout a CF patients life to counteract the changes that occur with age.

A Comparison of Virtual Bronchoscopy Versus Flexible Bronchoscopy in the Diagnosis of Tracheobronchomalacia in Children

Flexible bronchoscopy (FB) is the current gold standard for diagnosing tracheobronchomalacia. However, it is not always feasible and virtual bronchoscopy (VB), acquired from chest multi‐detector CT (MDCT) scan is an alternative diagnostic tool. We determined the sensitivity, specificity, and positive and negative predictive values of VB compared to FB in diagnosing tracheobronchomalacia.

Amoxicillin–clavulanate versus azithromycin for respiratory exacerbations in children with bronchiectasis (BEST-2): a multicentre, double-blind, non-inferiority, randomised controlled trial

Summary Background Although amoxicillin–clavulanate is the recommended first-line empirical oral antibiotic treatment for non-severe exacerbations in children with bronchiectasis, azithromycin is also often prescribed for its convenient once-daily dosing. No randomised controlled trials involving acute exacerbations in children with bronchiectasis have been published to our knowledge. We hypothesised that azithromycin is non-inferior to amoxicillin-clavulanate for resolving exacerbations in children with bronchiectasis. Methods We did this parallel-group, double-dummy, double-blind, non-inferiority randomised controlled trial in three Australian and one New Zealand hospital between April, 2012, and August, 2016. We enrolled children aged 1–19 years with radiographically proven bronchiectasis unrelated to cystic fibrosis. At the start of an exacerbation, children were randomly assigned to oral suspensions of either amoxicillin–clavulanate (22·5 mg/kg, twice daily) and placebo or azithromycin (5 mg/kg per day) and placebo for 21 days. We used permuted block randomisation (stratified by age, site, and cause) with concealed allocation. The primary outcome was resolution of exacerbation (defined as a return to baseline) by 21 days in the per-protocol population, with a non-inferiority margin of −20%. We assessed several secondary outcomes including duration of exacerbation, time to next exacerbation, laboratory, respiratory, and quality-of-life measurements, and microbiology. This trial was registered with the Australian/New Zealand Registry (ACTRN12612000010897). Findings We screened 604 children and enrolled 236. 179 children had an exacerbation and were assigned to treatment: 97 to amoxicillin–clavulanate, 82 to azithromycin). By day 21, 61 (84%) of 73 exacerbations had resolved in the azithromycin group versus 73 (84%) of 87 in the amoxicillin–clavulanate group. The risk difference showed non-inferiority (−0·3%, 95% CI −11·8 to 11·1). Exacerbations were significantly shorter in the amoxicillin–clavulanate group than in the azithromycin group (median 10 days [IQR 6–15] vs 14 days [8–16]; p=0·014). Adverse events were attributed to the trial medication in 17 (21%) of 82 children in the azithromycin group versus 23 (24%) of 97 in the amoxicillin–clavulanate group (relative risk 0·9, 95% CI 0·5 to 1·5). Interpretation By 21 days of treatment, azithromycin is non-inferior to amoxicillin–clavulanate for resolving exacerbations in children with non-severe bronchiectasis. In some patients, such as those with penicillin hypersensitivity or those likely to have poor adherence, azithromycin provides another option for treating exacerbations, but must be balanced with risk of treatment failure (within a 20% margin), longer exacerbation duration, and the risk of inducing macrolide resistance. Funding Australian National Health and Medical Research Council.

Cytokine responses to two common respiratory pathogens in children are dependent on interleukin-1β

Protracted bacterial bronchitis (PBB) in young children is a common cause of prolonged wet cough and may be a precursor to bronchiectasis in some children. Although PBB and bronchiectasis are both characterised by neutrophilic airway inflammation and a prominent interleukin (IL)-1β signature, the contribution of the IL-1β pathway to host defence is not clear. This study aimed to compare systemic immune responses against common pathogens in children with PBB, bronchiectasis and control children and to determine the importance of the IL-1β pathway. Non-typeable Haemophilus influenzae (NTHi) stimulation of peripheral blood mononuclear cells (PBMCs) from control subjects (n=20), those with recurrent PBB (n=20) and bronchiectasis (n=20) induced high concentrations of IL-1β, IL-6, interferon (IFN)-γ and IL-10. Blocking with an IL-1 receptor antagonist (IL-1Ra) modified the cellular response to pathogens, inhibiting cytokine synthesis by NTHi-stimulated PBMCs and rhinovirus-stimulated PBMCs (in a separate PBB cohort). Inhibition of IFN-γ production by IL-1Ra was observed across multiple cell types, including CD3+ T cells and CD56+ NK cells. Our findings highlight the extent to which IL-1β regulates the cellular immune response against two common respiratory pathogens. While blocking the IL-1β pathway has the potential to reduce inflammation, this may come at the cost of protective immunity against NTHi and rhinovirus. IL-1β blockade limits infection response http://ow.ly/nCtE30eTbyg