Duration of amoxicillin-clavulanate for protracted bacterial bronchitis in children (DACS): a multi-centre, double blind, randomised controlled trial.

BACKGROUND: Protracted bacterial bronchitis (PBB) is a leading cause of chronic wet cough in children. The current standard treatment in European and American guidelines is 2 weeks of antibiotics, but the optimal duration of therapy is unknown. We describe the first randomised controlled trial to assess the duration of antibiotic treatment in children with chronic wet cough and suspected PBB. We hypothesise that 4 weeks of amoxicillin-clavulanate is superior to 2 weeks for improving clinical outcomes. METHODS: Our parallel, double-blind, placebo-controlled, randomised controlled trial was completed in four Australian hospitals. Children aged 2 months to 19 years with chronic (>4 weeks duration) wet cough, and suspected PBB were randomly assigned (1:1) using permuted block randomisation (stratified by age and site) to 4 weeks of amoxicillin-clavulanate (25-35 mg/kg twice daily oral suspension; 4-week group) or 2 weeks of amoxicillin-clavulanate followed by 2 weeks of placebo (2-week group). The children, caregivers, all the study coordinators, and investigators were masked to treatment assignment until data analysis was completed. The primary outcome was clinical cure (cough resolution) by day 28. Secondary outcomes were recurrence of PBB at 6 months, time to next exacerbation, change in Parent-proxy Cough-Specific Quality-of-Life (PC-QoL) score from baseline to day 28 and from day 28 to 7 months, adverse events, nasal swab bacteriology, and antimicrobial resistance. Analyses followed the intention-to-treat principle. This trial is complete and registered with Australian/New Zealand Registry, ACTRN12616001725459. FINDINGS: Between March 8, 2017, and Sept 30, 2019, 106 children were randomly assigned (52 in the 4-week group, median age 2·2 years [IQR 1·3-4·1]; 54 in the 2-week group, median age 1·7 years [1·2-3·8]) with 90 children completing the 4-week treatment. By day 28, the primary endpoint of clinical cure in the 4-week group (32 [62%] of 52 patients) was not significantly different to the 2-week group (38 [70%] of 54 patients; adjusted relative risk 0·87 [95% CI 0·60 to 1·28]; p=0·49). Time to next wet cough exacerbation was significantly longer in the 4-week group than the 2-week group (median 150 days [IQR 38-181] vs 36 days [15-181]; adjusted hazard ratio 0·47 [0·25 to 0·90]; p=0·02). The rate of recurrence of PBB at 6 months was 17 (53%) of 32 patients in the 4-week group vs 28 (74%) of 38 patients in the 2-week group, but the difference between the groups was not significant (adjusted odds ratio 0·39 [0·14 to 1·04]; p=0·07). PC-QoL significantly improved from baseline to day 28 in both groups, but there was no significant difference between them (mean difference in change -0·2 [95% CI -1·0 to 0·6]; p=0·64). From day 28 to 7 months, median PC-QoL remained stable in both groups with no difference in change between them. Data on respiratory pathogens and antimicrobial resistance (paired swabs available for 48 children) were similar between groups. Adverse events occurred in 13 (25%) children in the 2-week group and ten (19%) in the 4-week group (p=0·57). INTERPRETATION: A 4-week course of amoxicillin-clavulanate for treating children with chronic wet cough and suspected PBB confers little advantage compared with a 2-week course in achieving clinical cure by 28 days. However, as a 4-week duration led to a longer cough-free period, identifying children who would benefit from a longer antibiotic course is a priority. FUNDING: Queensland Children's Hospital Foundation.

Outcomes of protracted bacterial bronchitis in children: A 5-year prospective cohort study.

BACKGROUND AND OBJECTIVE: Long-term data on children with PBB has been identified as a research priority. We describe the 5-year outcomes for children with PBB to ascertain the presence of chronic respiratory disease (bronchiectasis, recurrent PBB and asthma) and identify the risk factors for these. METHODS: Prospective cohort study was undertaken at the Queensland Children's Hospital, Brisbane, Australia, of 166 children with PBB and 28 controls (undergoing bronchoscopy for symptoms other than chronic wet cough). Monitoring was by monthly contact via research staff. Clinical review, spirometry and CT chest were performed as clinically indicated. RESULTS: A total of 194 children were included in the analysis. Median duration of follow-up was 59 months (IQR: 50-71 months) post-index PBB episode, 67.5% had ongoing symptoms and 9.6% had bronchiectasis. Significant predictors of bronchiectasis were recurrent PBB in year 1 of follow-up (ORadj = 9.6, 95% CI: 1.8-50.1) and the presence of Haemophilus influenzae in the BAL (ORadj = 5.1, 95% CI: 1.4-19.1). Clinician-diagnosed asthma at final follow-up was present in 27.1% of children with PBB. A significant BDR (FEV1 improvement >12%) was obtained in 63.5% of the children who underwent reversibility testing. Positive allergen-specific IgE (ORadj = 14.8, 95% CI: 2.2-100.8) at baseline and bronchomalacia (ORadj = 5.9, 95% CI: 1.2-29.7) were significant predictors of asthma diagnosis. Spirometry parameters were in the normal range. CONCLUSION: As a significant proportion of children with PBB have ongoing symptoms at 5 years, and outcomes include bronchiectasis and asthma, they should be carefully followed up clinically. Defining biomarkers, endotypes and mechanistic studies elucidating the different outcomes are now required.

Effectiveness of a chronic cough management algorithm at the transitional stage from acute to chronic cough in children: a multicenter, nested, single-blind, randomised controlled trial.

BACKGROUND: Chronic (lasting at least 4 weeks) cough in children is an important cause of morbidity. An algorithmic approach to the management of coughs in children evaluated in observational studies and a randomised controlled trial (RCT) enrolled children referred with median cough duration of 16 weeks to specialist centres. We investigated whether applying an evidence-based cough management algorithm in non-specialist settings earlier, once cough persisted for more than 4 weeks, improved cough resolution compared with usual care. METHODS: We undertook a multicentre, single-blind RCT nested within a prospective cohort study of children (<15 years) in Australia presenting to three primary care or three hospital emergency departments with an acute respiratory illness with cough. Children were excluded if they had a known diagnosis of an underlying chronic medical condition (excluding asthma) or had an immunosuppressive illness or were taking immunomodulating drugs for more than 2 weeks in the preceding 30 days, or had severe symptoms requiring inpatient hospitalisation. Children were followed up for 8 weeks; those with a persistent cough at day 28 were randomly assigned to the cough management algorithm or to usual care. Randomisation was stratified by reason for presentation, study site, and cough duration (4 weeks to <6 weeks vs ≥6 weeks) using computer-generated permuted blocks (block size of four) with a 1:1 allocation. The primary outcome was the proportion of children with cough resolution at day 56 (defined as resolved if the child did not cough for at least 3 days and nights since day 28 or a more than 75% reduction in their average day and night cough score). Absolute risk differences (RDabsolute) were calculated by modified intention-to-treat analysis (ITT). This trial is registered with the Australia New Zealand Clinical Trials Registry, ACTRN12615000132549. FINDINGS: Between July 7, 2015, and Oct 31, 2018, 1018 children were screened, 509 were enrolled in the cohort study, and of 115 children in the ITT analysis, 57 were randomly assigned to the intervention group and 58 to the control group. Children had a median age of 1·6 years (IQR 1·0-4·5); 45 (39%) of 115 were Indigenous, and 59 (51%) were boys. By day 56, 33 (58%) of 57 children in the intervention group achieved cough resolution compared with 23 (40%) 58 in the control group; cough resolution was unknown in 12 (21%) of 57 children receiving the intervention and in 13 (22%) of 58 receiving the control. The RDabsolute assuming children with an unknown cough outcome were still coughing at day 56 was 18·3% (95% CI 0·3-36·2); the number needed-to-treat for benefit was five (95% CI 3-364); the adjusted odds ratio was 1·5 (95% CI 1·3-1·6), favouring the intervention group. INTERPRETATION: This study suggests an evidence-based cough management algorithm improves cough resolution in community-based children in the early phases of chronic cough. However, larger studies to confirm these findings in primary care are required. FUNDING: National Health and Medical Research Council.

Health-resource use and quality of life in children with bronchiectasis: a multi-center pilot cohort study.

BACKGROUND: Bronchiectasis in children is an important, but under-researched, chronic pulmonary disorder that has negative impacts on health-related quality of life. Despite this, it does not receive the same attention as other chronic pulmonary conditions in children such as cystic fibrosis. We measured health resource use and health-related quality of life over a 12-month period in children with bronchiectasis. METHODS: We undertook a prospective cohort study of 85 children aged < 18-years with high-resolution chest computed-tomography confirmed bronchiectasis undergoing management in three pediatric respiratory medical clinics in Darwin and Brisbane, Australia and Auckland, New Zealand. Children with cystic fibrosis or receiving cancer treatment were excluded. Data collected included the frequency of healthcare attendances (general practice, specialists, hospital and/or emergency departments, and other), medication use, work and school/childcare absences for parents/carers and children respectively, and both parent/carer and child reported quality of life and cough severity. RESULTS: Overall, 951 child-months of observation were completed for 85 children (median age 8.7-years, interquartile range 5.4-11.3). The mean (standard deviation) number of exacerbations was 3.3 (2.2) per child-year. Thirty of 264 (11.4%) exacerbation episodes required hospitalization. Healthcare attendance and antibiotic use rates were high (30 and 50 per 100 child-months of observation respectively). A carer took leave from work for 53/236 (22.5%) routine clinic visits. Absences from school/childcare due to bronchiectasis were 24.9 children per 100 child-months. Quality of life scores for both the parent/carer and child were highly-correlated with one another, remained stable over time and were negatively associated with cough severity. CONCLUSIONS: Health resource use in this cohort of children is high, reflecting their severe disease burden. Studies are now needed to quantify the direct and societal costs of disease and to evaluate interventions that may reduce disease burden, particularly hospitalizations.

Efficacy of oral amoxicillin-clavulanate or azithromycin for non-severe respiratory exacerbations in children with bronchiectasis (BEST-1): a multicentre, three-arm, double-blind, randomised placebo-controlled trial.

BACKGROUND: Bronchiectasis guidelines recommend antibiotics for the treatment of acute respiratory exacerbations, but randomised placebo-controlled trials in children are lacking. We hypothesised that oral amoxicillin-clavulanate and azithromycin would each be superior to placebo in achieving symptom resolution of non-severe exacerbations in children by day 14 of treatment. METHODS: In this multicentre, three-arm, parallel, double-dummy, double-blind, randomised placebo-controlled trial at four paediatric centres in Australia and New Zealand, we enrolled children aged 1-18 years with CT-confirmed bronchiectasis unrelated to cystic fibrosis, who were under the care of a respiratory physician and who had had at least two respiratory exacerbations in the 18 months before study entry. Participants were allocated (1:1:1) at exacerbation onset to receive oral suspensions of amoxicillin-clavulanate (45 mg/kg per day) plus placebo azithromycin, azithromycin (5 mg/kg per day) plus placebo amoxicillin-clavulanate, or both placebos for 14 days. An independent statistician prepared a computer-generated, permuted-block (size 2-8) randomisation sequence, stratified by centre, age, and cause. Participants, caregivers, study coordinators, and investigators were masked to treatment assignment until data analysis was completed. The primary outcome was the proportion of children with exacerbation resolution by day 14 in the intention-to-treat population. Treatment groups were compared using generalised linear models. Statistical significance was set at p<0·0245 to account for multiple comparisons. This trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12612000011886) and is completed. FINDINGS: Between April 17, 2012, and March 1, 2017, 604 children were screened and 252 were enrolled. Between July 31, 2012, and June 26, 2017, 197 children were allocated at the start of an exacerbation (63 to the amoxicillin-clavulanate group, 67 to the azithromycin group, and 67 to the placebo group). Respiratory viruses were identified in 82 (53%) of 154 children with available nasal swabs on day 1 of treatment. Primary outcome data were available for 196 (99%) children (one child with missing data [placebo group] was recorded as non-resolved according to criteria defined a priori). By day 14, exacerbations had resolved in 41 (65%) children in the amoxicillin-clavulanate group, 41 (61%) in the azithromycin group, and 29 (43%) in the placebo group. Compared with placebo, relative risk for resolution by day 14 was 1·50 (95% CI 1·08-2·09, p=0·015; number-needed-to-treat [NNT] 5 [95% CI 3-20]) in the amoxicillin-clavulanate group and 1·41 (1·01-1·97, p=0·042; NNT 6 [3-79]) in the azithromycin group. Adverse events were recorded in 19 (30%) children in the amoxicillin-clavulanate group, 20 (30%) in the azithromycin group, and 14 (21%) in the placebo group, but no events were severe or life-threatening. INTERPRETATION: Amoxicillin-clavulanate treatment is beneficial in terms of resolution of non-severe exacerbations of bronchiectasis in children, and should remain the first-line oral antibiotic in this setting. FUNDING: National Health and Medical Research Council (Australia), Cure Kids (New Zealand).

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

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.

Multiple inflammasomes may regulate the interleukin-1-driven inflammation in protracted bacterial bronchitis.

Protracted bacterial bronchitis (PBB) in young children is characterised by prolonged wet cough, prominent airway interleukin (IL)-1ß expression and infection, often with nontypeable Haemophilus influenzae (NTHi). The mechanisms responsible for IL-1-driven inflammation in PBB are poorly understood. We hypothesised that the inflammation in PBB involves the NLRP3 and/or AIM2 inflammasome/IL-1ß axis. Lung macrophages obtained from bronchoalveolar lavage (BAL), peripheral blood mononuclear cells (PBMCs), blood monocytes and monocyte-derived macrophages from patients with PBB and age-matched healthy controls were cultured in control medium or exposed to live NTHi. In healthy adult PBMCs, CD14+ monocytes contributed to 95% of total IL-1ß-producing cells upon NTHi stimulation. Stimulation of PBB PBMCs with NTHi significantly increased IL-1ß expression (p<0.001), but decreased NLRC4 expression (p<0.01). NTHi induced IL-1ß secretion in PBMCs from both healthy controls and patients with recurrent PBB. This was inhibited by Z-YVAD-FMK (a caspase-1 selective inhibitor) and by MCC950 (a NLRP3 selective inhibitor). In PBB BAL macrophages inflammasome complexes were visualised as fluorescence specks of NLRP3 or AIM2 colocalised with cleaved caspase-1 and cleaved IL-1ß. NTHi stimulation induced formation of specks of cleaved IL-1ß, NLRP3 and AIM2 in PBMCs, blood monocytes and monocyte-derived macrophages. We conclude that both the NLRP3 and AIM2 inflammasomes probably drive the IL-1ß-dominated inflammation in PBB.

Airway cells from protracted bacterial bronchitis and bronchiectasis share similar gene expression profiles.

AIM: Protracted bacterial bronchitis (PBB) is a common cause of prolonged cough in young children, and may be a precursor of bronchiectasis. Bacteria are often present in the lower airways in both PBB and bronchiectasis and may cause persistent infections. However, there is a paucity of information available on the pathogenesis of PBB and the factors associated with persistent bacterial infection and progression to bronchiectasis. This study hypothesised that lung immune cells in recurrent PBB and bronchiectasis differentially express genes related to immune cell dysfunction compared to lung immune cells from control subjects. METHOD: Cells isolated from bronchoalveolar lavage (adult-control and PBB BAL cells) were stimulated with nontypeable Haemophilus influenzae (NTHi), and expression of genes involved in various inflammatory pathways was assessed. RESULT: NTHi induced production of large amounts of IL-1ß, IL-6, and IL-8 in adult-control BAL cells, however BAL cells from PBB airways appeared refractory to NTHi stimulation. BAL cells from PBB and bronchiectasis showed differential expression of several genes relative to control cells, including CCL20, MARCO, CCL24, IL-10, PPAR-γ, CD200R, TREM2, RelB. Expression of genes involved in resolution of inflammation and anti-inflammation response, such as CD200R and IL-10, was associated with the number of pathogenic bacteria found in the airways. CONCLUSION: In summary, we have shown that the expression of genes related to macrophage function and resolution of inflammation are similar in PBB and bronchiectasis. Lung immune cell dysfunction in PBB and bronchiectasis may contribute to poor bacterial clearance and prolonged resolution of inflammation.

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

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)-1ß signature, the contribution of the IL-1ß 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-1ß 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-1ß, 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-1ß regulates the cellular immune response against two common respiratory pathogens. While blocking the IL-1ß pathway has the potential to reduce inflammation, this may come at the cost of protective immunity against NTHi and rhinovirus.

Effectiveness of a cough management algorithm at the transitional phase from acute to chronic cough in Australian children aged <15†years: protocol for a randomised controlled trial.

INTRODUCTION: Acute respiratory infections (ARIs) are leading causes of hospitalisation in Australian children and, if recurrent, are associated with increased risk of chronic pulmonary disorders later in life. Chronic (>4 weeks) cough in children following ARI is associated with decreased quality-of-life scores and increased health and societal economic costs. We will determine whether a validated evidence-based cough algorithm, initiated when chronic cough is first diagnosed after presentation with ARI, improves clinical outcomes in children compared with usual care. METHODS AND ANALYSIS: A multicentre, parallel group, open-label, randomised controlled trial, nested within a prospective cohort study in Southeast Queensland, Australia, is underway. 750 children aged <15 years will be enrolled and followed weekly for 8 weeks after presenting with an ARI with cough. 214 children from this cohort with persistent cough at day 28 will be randomised to either early initiation of a cough management algorithm or usual care (107 per group). Randomisation is stratified by reason for presentation, site and total cough duration at day 28 (<6 and ≥6 weeks). Demographic details, risk factors, clinical histories, examination findings, cost-of-illness data, an anterior nasal swab and parent and child exhaled carbon monoxide levels (when age appropriate) are collected at enrolment. Weekly contacts will collect cough status and cost-of-illness data. Additional nasal swabs are collected at days 28 and 56. The primary outcome is time-to-cough resolution. Secondary outcomes include direct and indirect costs of illness and the predictors of chronic cough postpresentation. ETHICS AND DISSEMINATION: The Children's Health Queensland (HREC/15/QRCH/15) and the Queensland University of Technology University (1500000132) Research Ethics Committees have approved the study. The study will inform best-practice management of cough in children. TRIAL REGISTRATION NUMBER: ACTRN12615000132549.

Nutritional status of children with clinical conditions.

BACKGROUND & AIMS: Nutritional status is an important consideration in many pediatric clinical conditions. This paper aimed to examine and compare the nutritional status, represented by body cell mass (BCM), of children with cancer, Crohn's disease (CD), cystic fibrosis (CF) and anorexia nervosa (AN). METHODS: Anthropometry was measured and BCM was calculated from whole body potassium-40 counting in 259 children being treated for clinical conditions (n = 66 cancer; n = 59 AN; n = 75 CF; n = 59 CD) and 108 healthy children. BCM was adjusted for height (BCMI) and expressed as a Z-score relative to laboratory reference data. RESULTS: The CD (-0.80 ± 1.61; p = 0.0001) and AN (-1.13 ± 0.99; p = 0.0001) groups had significantly lower BMI Z-score than the healthy control (0.13 ± 0.75), cancer (0.50 ± 1.40) and CF groups (-0.09 ± 0.95). The cancer (-1.16 ± 1.60; p = 0.0001), CD (-1.13 ± 1.36; p = 0.0001) and AN (-0.97 ± 1.18; p = 0.0001) groups had significantly reduced BCM compared to the healthy control (0.07 ± 0.93) and CF group (0.31 ± 1.08). According to BCMI Z-score, 42.4% of patients with cancer, 41.7% of the patients with CD, 27.1% of patients with AN, and 4.0% of patients with CF were considered malnourished. CONCLUSIONS: This study demonstrates that children undergoing treatment for clinical conditions may have alterations in BCM, independent of BMI. Children with cancer, CD and AN all had a high prevalence of malnutrition. Assessment of body composition, not just body size, is vital to understand nutritional status in children with clinical conditions.

A comparison of virtual bronchoscopy versus flexible bronchoscopy in the diagnosis of tracheobronchomalacia in children.

INTRODUCTION: 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. METHODS: Children aged <18-years scheduled for FB and MDCT were recruited. FB and MDCT were undertaken within 30-min to 7-days of each other. Tracheobronchomalacia (mild, moderate, severe, very severe) diagnosed on FB were independently scored by two pediatric pulmonologists; VB was independently scored by two pairs (each pair = pediatric pulmonologist and radiologist), in a blinded manner. RESULTS: In 53 children (median age = 2.5 years, range 0.8-14.3) evaluated for airway abnormalities, tracheomalacia was detected in 37 (70%) children at FB. Of these, VB detected tracheomalacia in 20 children, with a sensitivity of 54.1% (95%CI 37.1-70.2), specificity = 87.5% (95%CI 60.4-97.8), and positive predictive value = 90.9% (95%CI 69.4-98.4). The agreement between pediatric pulmonologists for diagnosing tracheomalacia by FB was excellent, weighted κ = 0.8 (95%CI 0.64-0.97); but only fair between the pairs of pediatric pulmonologists/radiologists for VB, weighted κ = 0.47 (95%CI 0.23-0.71). There were 42 cases of bronchomalacia detected on FB. VB had a sensitivity = 45.2% (95%CI 30.2-61.2), specificity = 95.5% (95%CI 94.2-96.5), and positive predictive value = 23.2 (95%CI 14.9-34.0) compared to FB in detecting bronchomalacia. CONCLUSION: VB cannot replace FB as the gold standard for detecting tracheobronchomalacia in children. However, VB could be considered as an alternative diagnostic modality in children with symptoms suggestive of tracheobronchomalacia where FB is unavailable. Pediatr Pulmonol. 2017;52:480-486. © 2016 Wiley Periodicals, Inc.

Protracted Bacterial Bronchitis in Children: Natural History and Risk Factors for Bronchiectasis.

BACKGROUND: Protracted bacterial bronchitis (PBB) and bronchiectasis are distinct diagnostic entities that share common clinical and laboratory features. It is postulated, but remains unproved, that PBB precedes a diagnosis of bronchiectasis in a subgroup of children. In a cohort of children with PBB, our objectives were to (1) determine the medium-term risk of bronchiectasis and (2) identify risk factors for bronchiectasis and recurrent episodes of PBB. METHODS: One hundred sixty-one children with PBB and 25 control subjects were prospectively recruited to this cohort study. A subset of 106 children was followed for 2 years. Flexible bronchoscopy, BAL, and basic immune function tests were performed. Chest CT was undertaken if clinical features were suggestive of bronchiectasis. RESULTS: Of 161 children with PBB (66% boys), 13 were diagnosed with bronchiectasis over the study period (8.1%). Almost one-half with PBB (43.5%) had recurrent episodes (> 3/y). Major risk factors for bronchiectasis included lower airway infection with Haemophilus influenzae (recovered in BAL fluid) (P = .013) and recurrent episodes of PBB (P = .003). H influenzae infection conferred a more than seven times higher risk of bronchiectasis (hazard ratio, 7.55; 95% CI, 1.66-34.28; P = .009) compared with no H influenzae infection. The majority of isolates (82%) were nontypeable H influenzae. No risk factors for recurrent PBB were identified. CONCLUSIONS: PBB is associated with a future diagnosis of bronchiectasis in a subgroup of children. Lower airway infection with H influenzae and recurrent PBB are significant predictors. Clinicians should be cognizant of the relationship between PBB and bronchiectasis, and appropriate follow-up measures should be taken in those with risk factors.

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) 1ß 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-1ß 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.

BACKGROUND: Bronchiectasis 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. METHODS: This 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. DISCUSSION: Currently, 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 (bronchiectasis exacerbation study; 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 REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR) number http://ACTRN12612000010897. http://www.anzctr.org.au/trial_view.aspx?id=347879.

Antibiotics for bronchiectasis exacerbations in children: rationale and study protocol for a randomised placebo-controlled trial.

BACKGROUND: Despite bronchiectasis being increasingly recognised as an important cause of chronic respiratory morbidity in both indigenous and non-indigenous settings globally, high quality evidence to inform management is scarce. It is assumed that antibiotics are efficacious for all bronchiectasis exacerbations, but not all practitioners agree. Inadequately treated exacerbations may risk lung function deterioration. Our study tests the hypothesis that both oral azithromycin and amoxicillin-clavulanic acid are superior to placebo at improving resolution rates of respiratory exacerbations by day 14 in children with bronchiectasis unrelated to cystic fibrosis. METHODS: We are conducting a bronchiectasis exacerbation study (BEST), which is a multicentre, randomised, double-blind, double-dummy, placebo-controlled, parallel group trial, in five centres (Brisbane, Perth, Darwin, Melbourne, Auckland). In the component of BEST presented here, 189 children fulfilling inclusion criteria are randomised (allocation-concealed) to receive amoxicillin-clavulanic acid (22.5 mg/kg twice daily) with placebo-azithromycin; azithromycin (5 mg/kg daily) with placebo-amoxicillin-clavulanic acid; or placebo-azithromycin with placebo-amoxicillin-clavulanic acid for 14 days. Clinical data and a paediatric cough-specific quality of life score are obtained at baseline, at the start and resolution of exacerbations, and at day 14. In most children, blood and deep nasal swabs are also collected at the same time points. The primary outcome is the proportion of children whose exacerbations have resolved at day 14. The main secondary outcome is the paediatric cough-specific quality of life score. Other outcomes are time to next exacerbation; requirement for hospitalisation; duration of exacerbation; and spirometry data. Descriptive viral and bacteriological data from nasal samples and blood markers will also be reported. DISCUSSION: Effective, evidence-based management of exacerbations in people with bronchiectasis is clinically important. Yet, there are few randomised controlled trials (RCTs) in the neglected area of non-cystic fibrosis bronchiectasis. Indeed, no published RCTs addressing the treatment of bronchiectasis exacerbations in children exist. Our multicentre, double-blind RCT is designed to determine if azithromycin and amoxicillin-clavulanic acid, compared with placebo, improve symptom resolution on day 14 in children with acute respiratory exacerbations. Our planned assessment of the predictors of antibiotic response, the role of antibiotic-resistant respiratory pathogens, and whether early treatment with antibiotics affects duration and time to the next exacerbation, are also all novel. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR) number ACTRN12612000011886.

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 patient's life to counteract the changes that occur with age.

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). METHODS: Tanner stage, age of menarche, bone age (BA), sex hormone levels and aBMD were examined in 85 individuals with CF (aged 5.3-18.1 years, 39 females) and 100 local controls (5.6-17.9 years, 54 females). RESULTS: Tanner stage and age of menarche were not significantly different between controls and CF. Tanner stage-adjusted mean values for follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone (T) were lower in males with CF (FSH: P = 0.004, LH: P = 0.01 and T: P = 0.002). Bone age was delayed in adolescents with CF compared to controls (chronological age-BA: controls = 0.13 years (SE = 0.16), CF = 0.95 years (SE = 0.22), P = 0.003). Areal bone mineral density (adjusted for age, sex, height and lean tissue mass) was not significantly different between CF and controls. Moderate negative correlations were found between delayed BA and weight (r = -0.41, P < 0.001) and height (r = -0.41, P < 0.001). CONCLUSIONS: There was no evidence of clinical pubertal delay or low aBMD (adjusted for short stature and lean tissue mass) in young people with CF when compared with a local population, despite lower nutritional markers, height and weight and delayed skeletal maturation.

Vitamin A levels in patients with CF are influenced by the inflammatory response.

BACKGROUND: Serum vitamin A, normally depressed in inflammatory conditions, is frequently low in people with CF. Vitamin A is important in respiratory epithelial regeneration and repair. We hypothesised that serum vitamin A would be associated with inflammation and disease severity. METHODS: Serum vitamin A (as retinol), C-reactive protein (CRP), vitamin E, 25-hydroxy vitamin D (25OHD), 1,25-dihydroxy vitamin D (1,25(OH)(2)D), weight, and lumbar spine bone mineral density (LSBMD) were measured in 138 subjects with CF (5-56 years) and 138 control subjects (5-48 years). FEV(1), presence of CF liver disease (CFLD) and hospital admissions were recorded in those with CF. RESULTS: Serum vitamin A level was lower in CF subjects than in controls (mean, 95% CI: 1.29, 1.0-1.37 vs. 1.80, 1.7-1.87 micromol/l, p < 0.0001), and inversely correlated with CRP (r(s) = -0.37, p < 0.0001). CF subjects with low vitamin A (45%) level had poorer FEV(1), weight z-score, LSBMD z-score, and higher CRP compared with those with normal levels. In the CF group CRP, vitamin E, 1,25(OH)(2)D, presence of CFLD, admissions, and age were associated with vitamin A level. CONCLUSIONS: Serum vitamin A is negatively associated with CRP in subjects with CF, consistent with normal population studies. It is important to distinguish between low serum vitamin A associated with the inflammatory response and that due to poor nutritional stores. The role of vitamin A in CF warrants further study, in the contexts both of chronic recurrent inflammatory disease and acute pulmonary exacerbation.