Flexible fibreoptic bronchoscopy is beneficial in children on extracorporeal membrane oxygenation support.

BACKGROUND: Flexible fibreoptic bronchoscopy (FFB) has the potential to enhance diagnostic capabilities and improve pulmonary function in children on extracorporeal membrane oxygenation (ECMO). OBJECTIVES: The objective of this study was to evaluate the benefits (clinical, radiological, and microbiological) of FFB and assess associated complications in children on ECMO. METHODS: We conducted a single-centre retrospective observational cohort study in a tertiary paediatric intensive care unit. All FFB episodes performed during the study period on children aged 0-18 years on ECMO were included. RESULTS: Out of the 155 children who received ECMO, 36 (23%) underwent a total of 92 episodes of FFB. FFB provided anatomical and pathological information in 53% (19/36) of cases and proved beneficial in clearing the airways in 62% (54/87) of the episodes. Overall, patients exhibited transient increases in ECMO and mechanical ventilation support 1 h post FFB in 14% (13/92) and 9.7% (9/92) episodes, respectively. At 6 h, the mean fraction of inspired oxygen on the mechanical ventilator was lower (0.46 [±0.21] vs 0.53 [±0.21] p < 0.01), with no change in mean airway pressure. Similarly, compared to pre-FFB, the fraction of inspired oxygen on the mechanical ventilator on ECMO was lower at 6 h and 24 h (0.65 [±0.25] vs 0.71 [±0.23] p < 0.01 and 0.006, respectively), with no significant change in the sweep gas flow and ECMO flow. The radiological imaging indicated improved or stable findings in 91% (83/91) of FFB episodes. FFB contributed to the identification of new and previously unknown microbiological information in 75% (27/36) of the patients. The incidence of major complications was 7.6%. Minor self-resolving bleeding occurred in 25% (23/92) episodes, and major bleeding occurred in two episodes, with a total of 10 episodes needing blood product transfusion. CONCLUSIONS: FFB is a valuable adjunct in managing children with severe respiratory failure on ECMO, offering clinical benefits with a low rate of major complications. Further studies should aim to develop a consensus approach encompassing criteria and clinical management around FFB in patients on ECMO.

Radiographic Outcomes in Pediatric Bronchiectasis and Factors Associated with Reversibility.

Rationale: Conventionally considered irreversible, bronchiectasis has been demonstrated to be reversible in children in small studies. However, the factors associated with radiographic reversibility of bronchiectasis have yet to be defined. Objectives: In a large cohort of children with bronchiectasis, we aimed to determine: 1) if and to what extent bronchiectasis is reversible and 2) factors associated with radiographic chest high-resolution computed tomography (cHRCT) resolution. Methods: We identified children with bronchiectasis who had a repeat multidetector cHRCT scan between 2010 and 2021. We excluded those with cystic fibrosis, surgical pulmonary resection, traction bronchiectasis only, or lobar opacification. Measurements and Main Results: cHRCT scans were scored using the modified Reiff score (MRS) with a pediatric correction. Resolution was defined as an absence of abnormal bronchoarterial ratio (>0.8) on the second cHRCT scan. We included 142 children (median age, 5 years; IQR, 2.6-7.4). Inter- and intrarater agreement in MRSs was excellent (weighted κ = 0.83-0.86 and 0.95, respectively). There was radiographic resolution in 57 of 142 patients (40.1%), improvement in 56 of 142 (39.4%), and no change or worsening in 29 of 142 (20.4%). Pseudomonas aeruginosa (PsA) was absolutely associated with a lack of resolution. On multivariable regression, in those without PsA cultured, younger age at the time of diagnosis (risk ratio [RR], 0.94; 95% confidence interval [CI], 0.88-0.99), lower MRS (RR, 0.89; 95% CI, 0.82-0.97), and lower annual rate of exacerbations requiring intravenous antibiotic therapy (RR, 0.60; 95% CI, 0.37-0.98) increased the likelihood of radiographic resolution. Conclusions: This first large cohort confirms that bronchiectasis in children is often reversible with appropriate management. Younger children and those with lesser radiographic severity at diagnosis were most likely to exhibit radiographic reversibility, whereas those with PsA infection were least likely.

Does routine spirometry impact on clinical decisions and patient-related outcome measures of children seen in respiratory clinics: an open-label randomised controlled trial.

INTRODUCTION: There is limited evidence on the efficacy of using spirometry routinely in paediatric practice for improving outcomes. OBJECTIVE: To determine whether the routine use of spirometry alters clinical decisions and patient-related outcome measures for children managed by respiratory paediatricians. METHODS: We undertook a parallel open-label randomised controlled trial involving children (aged 4-18 years) able to perform spirometry in a specialist children's hospital in Australia. Children were randomised to either routine use of spirometry (intervention) or clinical review without use of spirometry (control) for one clinic visit. The primary outcomes were the (a) proportion of children with 'any change in clinical decisions' and (b) 'change score' in clinical decisions. Secondary outcomes were change in patient-related outcome measures assessed by State-Trait Anxiety Inventory (STAI) and Parent-Proxy QoL questionnaire for paediatric chronic cough (PC-QoL). RESULTS: Of 136 eligible children, 106 were randomised. Compared with controls, the intervention group had significantly higher proportion of children with 'any change in clinical decisions' (n=54/54 (100%) vs n=34/52 (65.4%), p<0.001) and higher clinical decision 'change score' (median=2 (IQR 1-4) vs 1 (0-2), p<0.001). Also, improvement was significantly greater in the intervention group for overall STAI score (median=-5 (IQR -10 to -2) vs -2.5 (-8.5, 0), p=0.021) and PC-QoL social domain (median=3 (IQR 0 to 5) vs 0 (-1, 1), p=0.017). CONCLUSION: The routine use of spirometry in children evaluated for respiratory issues at clinical outpatient review is beneficial for optimising clinical management and improving parent psychosocial well-being. REGISTRATION: Australia and New Zealand Clinical Trials Registry ACTRN12619001686190.

The 'knee' pattern in spirometry flow-volume curves in children: Does it relate to tracheomalacia?

BACKGROUND: There is little data on patterns of spirometry curves in children with tracheomalacia but convex inflection on flow-volume curves (identified as the 'knee') is thought to represent tracheomalacia. OBJECTIVES: To determine (a) the prevalence of tracheomalacia in children with the 'knee' pattern on spirometry, and (b) whether spirometry parameters and visual characteristics of the 'knee' can identify presence/absence or severity of tracheomalacia. PATIENTS/METHODS: We reviewed the spirometry undertaken at Queensland Children's Hospital between 2016 and 2019 and retrieved spirometry with the 'knee' pattern in the flow-volume curves. Flexible bronchoscopy videos of these children were reviewed for tracheomalacia diagnosis and severity in a blinded manner. We also evaluated several 'knee' characteristics (onset of inflection, angle of inflection, a scoop before plateau, plateau progression), spirometry parameters and tracheomalacia severity. RESULTS: Of the 78 children with the 'knee', 51 (65.4%) had tracheomalacia. Spirometry values were significantly lower in those with tracheomalacia, compared to those without (predicted FEV1 = 86.1% vs 99.9%, FVC = 95.1% vs 104%, FEF25-75% = 68.6% vs 89.6%, all p < 0.02). A scoop before plateau was significantly associated with tracheomalacia (66.7% vs 40.7%, p = 0.03). There was no significant difference in spirometry parameters or the 'knee' characteristics between children with mild versus moderate-to-severe tracheomalacia. CONCLUSION: Most but not all children with the 'knee' pattern have flexible bronchoscopy-defined tracheomalacia. Those with tracheomalacia had lower spirometry values and the presence of a scoop before plateau was the most characteristic feature. A prospective longitudinal study is required to determine the diagnostic value of spirometry flow-volume curve characteristics in children.

Pulmonary function of children with tracheomalacia and associated clinical factors.

OBJECTIVES: Spirometry is easily accessible yet there is limited data in children with tracheomalacia. Availability of such data may inform clinical practice. We aimed to describe spirometry indices of children with tracheomalacia, including Empey index and flow-volume curve pattern, and determine whether these indices relate with bronchoscopic features. METHODS: From the database of children with tracheomalacia diagnosed during 2016-2019, we reviewed their flexible bronchoscopy and spirometry data in a blinded manner. We specially evaluated several spirometry indices and tracheomalacia features (cross-sectional lumen reduction, malacic length, and presence of bronchomalacia) and determined their association using multivariable regression. RESULTS: Of 53 children with tracheomalacia, the mean (SD) peak expiratory flow (PEF) was below the normal range [68.9 percent of predicted value (23.08)]. However, all other spirometry parameters were within normal range [Z-score forced expired volume in 1 s (FEV1 ) = -1.18 (1.39), forced vital capacity (FVC) = -0.61 (1.46), forced expiratory flow between 25% and 75% of vital capacity​​​​​​ (FEF25%-75% ) = -1.43 (1.10), FEV1 /FVC = -1.04 (1.08)], Empey Index = 8.21 (1.59). The most common flow-volume curve pattern was the "knee" pattern (n = 39, 73.6%). Multivariable linear regression identified the presence of bronchomalacia was significantly associated with lower flows: FEV1 [coefficient (95% CI) -0.78 (-1.54, -0.02)], FEF25%-75% [-0.61 (-1.22, 0)], and PEF [-12.69 (-21.13, -4.25)], all p ≤ 0.05. Other bronchoscopic-defined tracheomalacia features examined (cross-sectional lumen reduction, malacic length) were not significantly associated with spirometry indices. CONCLUSION: The "knee" pattern in spirometry flow-volume curve is common in children with tracheomalacia but other indices, including Empey index, cannot be used to characterize tracheomalacia. Spirometry indices were not significantly associated with bronchoscopic tracheomalacia features but children with tracheobronchomalacia have significantly lower flow than those with tracheomalacia alone.

Bronchiectasis - Exercise as Therapy (BREATH): rationale and study protocol for a multi-center randomized controlled trial.

BACKGROUND: Globally, bronchiectasis (BE) unrelated to cystic fibrosis (CF) is recognized as a major cause of respiratory morbidity, mortality, and healthcare utilization. Children with BE regularly experience exacerbations of their condition resulting in frequent hospitalizations and decreased health-related quality of life (HR-QoL). Guidelines for the treatment and management of BE call for regular exercise as a means of improving aerobic fitness and HR-QoL. Moreover, research in adults with BE has shown that exercise can reduce the frequency of exacerbations, a potent predictor of future lung function decline and respiratory morbidity. Yet, to date, the health benefits resulting from therapeutic exercise have not been investigated in children with BE. The BREATH, Bronchiectasis - Exercise as Therapy, trial will test the efficacy of a novel 8-week, play-based therapeutic exercise program to reduce the frequency of acute exacerbations over 12 months in children with BE (aged ≥ 4 and < 13 years). Secondary aims are to determine the cost-effectiveness of the intervention and assess the program's impact on aerobic fitness, fundamental movement skill (FMS) proficiency, habitual physical activity, HR-QoL, and lung function. METHODS: This multi-center, observer-blinded, parallel-group (1:1 allocation), randomized controlled trial (RCT) will be conducted at three sites. One hundred and seventy-four children ≥ 4 and < 13 years of age with BE will be randomized to a developmentally appropriate, play-based therapeutic exercise program (eight, 60-min weekly sessions, supplemented by a home-based program) or usual care. After completing the baseline assessments, the number of exacerbations and secondary outcomes will be assessed immediately post-intervention, after 6 months of follow-up, and after 12 months of follow-up. Monthly, parental contact and medical review will document acute respiratory exacerbations and parameters for cost-effectiveness outcomes. DISCUSSION: The BREATH trial is the first fully powered RCT to test the effects of a therapeutic exercise on exacerbation frequency, fitness, movement competence, and HR-QoL in children with bronchiectasis. By implementing a developmentally appropriate, play-based exercise program tailored to the individual needs of children with bronchiectasis, the results have the potential for a major paradigm shift in the way in which therapeutic exercise is prescribed and implemented in children with chronic respiratory conditions. The exercise program can be readily translated. It does not require expensive equipment and can be delivered in a variety of settings, including the participant's home. The program has strong potential for translation to other pediatric patient groups with similar needs for exercise therapy, including those with obesity, childhood cancers, and neurological conditions such as cerebral palsy. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Register (ANZCTR) ACTRN12619001008112.

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.

Development and validation of a bronchoscopically defined bronchitis scoring tool in children.

INTRODUCTION/AIM: A validated tool for scoring bronchitis during flexible bronchoscopy (FB) is potentially useful for clinical practice and research. We aimed to develop a bronchoscopically defined bronchitis scoring system in children (BScore) based on our pilot study. METHODS: Children undergoing FB were prospectively enrolled. Their FB was digitally recorded and assessed (two clinicians blinded to each other and clinical history) for six features: secretion amount (six-point scale), secretion color (BronkoTest, 0-8), mucosal oedema (0-3), ridging (0-3), erythema (0-3), and pallor (0-3) based on pre-determined criteria. We correlated (Spearman's rho) each feature with bronchoalveolar lavage (BAL) neutrophil percentage (neutrophil%). BScore was then derived using models with combinations of the six features that best related to airway BAL neutrophil%. The various models of BScore were plotted against BAL neutrophil% using receiver operating characteristic (ROC) curves. RESULTS: We analyzed 142 out of 150 children enrolled. Eight children were excluded for unavailability of BAL cytology or FB recordings. Chronic/recurrent cough was the commonest indication for FB (75%). The median age was 3 years (IQR, 1.5-5.3 years). Secretion amount (r = 0.42) and color (r = 0.46), mucosal oedema (r = 0.42), and erythema (r = 0.30) significantly correlated with BAL neutrophil%, P < .0001. The highest area under ROC (aROC) was obtained by the addition of the scores of all features excluding pallor (aROC = 0.84; 95% CI, 0.76-0.90) with airway neutrophilia (defined as BAL neutrophil% of >10%). CONCLUSION: This prospective study has developed the first validated bronchitis scoring tool in children based on bronchoscopic visual inspection of airways. Further validation in other cohorts is however required.

Pediatric Patients of Outreach Specialist Queensland Clinics Have Lung Function Improvement Comparable to That of Tertiary Pediatric Patients.

BACKGROUND: Inequitable access to quality health care contributes to the known poorer outcomes of people living in regional/remote areas (compared with urban-based), especially for First Nations people. Integration of specialist outreach services within primary care is one strategy that can reduce the inequity when modeled to the needs and available resources of target communities. RESEARCH QUESTION: To evaluate whether respiratory outreach clinics in regional and remote Queensland are as effective as tertiary respiratory services at improving the lung function of children. STUDY DESIGN AND METHODS: From existing databases, we obtained spirometry data of children (aged 3-18 years) seen at Indigenous-focused outreach clinics in regional and remote Queensland and Brisbane-based pediatric tertiary hospitals over the same contemporary period (October 2010 to July 2019). We compared the change in spirometry z scores (Δz) at follow-up for both groups of children. RESULTS: Lung function significantly improved in both groups: Tertiary hospital (n = 2,249; ΔzFEV1 = 0.22, 95% CI, 0.17 to 0.27; ΔzFVC = 0.23, 95% CI, 0.18 to 0.28); outreach (n = 252; ΔzFEV1 = 0.35, 95% CI, 0.22 to 0.48; ΔzFVC = 0.36, 95% CI, 0.23 to 0.50). No significant intergroup differences were found in ΔzFEV1 (0.13; 95%CI, -0.02 to 0.28; P = .10) or ΔzFVC (0.14; 95% CI, -0.02 to 0.29; P = .08) improvement from baseline. In both groups, the proportion of children with zFEV1 > 0 at follow-up (hospital = 31.7%; outreach = 46.8%) significantly increased (hospital P = .001; outreach P = .009) from baseline (hospital = 27.2%; outreach = 35.3%). Numbers of children with zFEV1 > 0 significantly increased for asthma and bronchiectasis outreach subgroups, and for children with asthma in the hospital-based group. INTERPRETATION: Comparable significant lung function improvement of children was seen in Indigenous-focused outreach remote/regional clinics and paediatric tertiary hospitals. This suggests that effective clinical care is achievable within the outreach setting.

Culturally Appropriate Outreach Specialist Respiratory Medical Care Improves the Lung Function of Children in Regional and Remote Queensland.

BACKGROUND AND OBJECTIVES: Indigenous Respiratory Outreach Care (IROC) is a culturally appropriate specialist respiratory service established to deliver multidisciplinary respiratory care to regional and remote Queensland communities. Our objective was to evaluate the impact of an outreach specialist respiratory service on the spirometry of children attending IROC clinics, particularly Indigenous children with asthma and bronchiectasis. METHODS: Retrospective single-arm cohort study of 189 children who performed spirometry at twelve sites across regional and remote Queensland between October 2010 and December 2017. Each child's baseline spirometry was compared to their best spirometry at follow-up visit occurring within (1) 12 months of their most recent visit with at least 12 months of specialist care and; (2) each year of their first 3 years of care. RESULTS: Forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) z-scores improved significantly across the whole group from baseline to follow-up (change in z-scores (Δz) of FEV1 = 0.38, 95% CI 0.22, 0.53; ΔzFVC = 0.36, 95% CI 0.21, 0.51). In subgroup analyses, lung function significantly improved in Indigenous children (n = 141, ΔzFEV1 = 0.37, 95% CI 0.17, 0.57; ΔzFVC = 0.36, 95% CI 0.17, 0.55) including those with asthma (n = 117, ΔzFEV1 = 0.41, 95% CI 0.19, 0.64; ΔzFVC = 0.46, 95% CI 0.24, 0.68) and bronchiectasis (n = 38, ΔzFEV1 = 0.33, 95% CI 0.07, 0.59; ΔzFVC = 0.26, 95% CI - 0.03, 0.53). Significant improvements in FEV1 and FVC were observed within the first and second year of follow-up for Indigenous children, but not for non-Indigenous children. CONCLUSION: The IROC model of care in regional and remote settings leads to significant lung function improvement in Indigenous children with asthma and bronchiectasis.

ERS statement on tracheomalacia and bronchomalacia in children.

Tracheomalacia and tracheobronchomalacia may be primary abnormalities of the large airways or associated with a wide variety of congenital and acquired conditions. The evidence on diagnosis, classification and management is scant. There is no universally accepted classification of severity. Clinical presentation includes early-onset stridor or fixed wheeze, recurrent infections, brassy cough and even near-death attacks, depending on the site and severity of the lesion. Diagnosis is usually made by flexible bronchoscopy in a free-breathing child but may also be shown by other dynamic imaging techniques such as low-contrast volume bronchography, computed tomography or magnetic resonance imaging. Lung function testing can provide supportive evidence but is not diagnostic. Management may be medical or surgical, depending on the nature and severity of the lesions, but the evidence base for any therapy is limited. While medical options that include bronchodilators, anti-muscarinic agents, mucolytics and antibiotics (as well as treatment of comorbidities and associated conditions) are used, there is currently little evidence for benefit. Chest physiotherapy is commonly prescribed, but the evidence base is poor. When symptoms are severe, surgical options include aortopexy or posterior tracheopexy, tracheal resection of short affected segments, internal stents and external airway splinting. If respiratory support is needed, continuous positive airway pressure is the most commonly used modality either via a face mask or tracheostomy. Parents of children with tracheobronchomalacia report diagnostic delays and anxieties about how to manage their child's condition, and want more information. There is a need for more research to establish an evidence base for malacia. This European Respiratory Society statement provides a review of the current literature to inform future study.

Towards developing a valid scoring tool for bronchitis during flexible bronchoscopy.

BACKGROUND: A valid bronchoscopic scoring tool for bronchitis would be useful for clinical and research purposes as currently there are none in children. From 100 digitally recorded flexible bronchoscopies (FB), we related the various macroscopic features to airway neutrophil % to develop a FB-derived bronchitis score (BScoreexp ). We aimed to develop a FB-derived bronchitis tool. METHODS: FB recordings for six visualised features: secretions (amount and color) and mucosal appearance (erythema, pallor, ridging, oedema) based on pre-determined criteria on a pictorial chart were assessed by two physicians independently, blinded to the clinical history. These features were used to obtain various models of BScoreexp that were plotted against bronchoalveolar lavage (BAL) neutrophil % using a receiver operating characteristic (ROC) curve. Inter- and intra-rater agreement (weighted-kappa, K) were assessed from 30 FBs. RESULTS: Using BAL neutrophilia of 20% to define inflammation, the highest area under ROC (aROC) of 0.71, 95%CI 0.61-0.82 was obtained by the giving three times weightage to secretion amount and color and adding it to erythema and oedema. Inter-rater K values for secretion amount (K = 0.87, 95%CI 0.73-1.0) and color (K = 0.86, 95%CI 0.69-1.0) were excellent. Respective intra-rater K were 0.95 (0.87-1.0) and 0.68 (0.47-0.89). Other inter-rater K ranged from 0.4 (erythema) to 0.64 (pallor). CONCLUSION: A repeatable FB-defined bronchitis scoring tool can be derived. However, a prospective study needs to be performed with larger numbers to further evaluate and validate these results.

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.

Carers' perspectives on an effective Indigenous health model for childhood asthma in the Torres Strait.

OBJECTIVE: To describe parents'/carers' views of the characteristics of a clinical service model shown to improve asthma outcomes. DESIGN: A randomised controlled study on education intervention for childhood asthma by Indigenous health care workers. SETTING: Thursday Island, Horn Island and Bamaga. PARTICIPANTS: Thirty-five children received the intervention and 53 were in the control group. At the last study visit 12 months after enrolment, carers were asked to give feedback about the clinical service delivered by paediatric respiratory physicians and the asthma education intervention. INTERVENTION: Additional asthma education. MAIN OUTCOME MEASURES: Carers' responses to the open-ended questions were analysed separately by three Indigenous investigators who assigned codes and developed the themes. These were then cross-checked and combined to develop an overall interpretation of the data. RESULTS: The carers (n = 81) of 88 children in the Torres Strait region of North Queensland reported positively to the clinical service delivery. Service was rated as excellent = 26.8%, very good = 51.2%, good = 19.5% and poor = 2.4%. Parents'/carers' views about the clinical service model were grouped into seven themes: clear communication by health professionals, service delivery, professional approach, clear transfer of knowledge and education/clinical knowledge of asthma, established rapport/caregiver satisfaction, importance of coming into the local community, and areas of concern for the carers/parents. CONCLUSION: Community-based perspectives of an effective health service model include empowered Indigenous health care workers currently attached to the medical specialist service with elements of high expertise and appropriate cultural awareness that enabled clear communication and transfer of knowledge.

Paediatric hospitalisations for lower respiratory tract infections in Mount Isa.

OBJECTIVE: To compare the rates of acute lower respiratory tract infection (ALRI) among children in north-west Queensland, according to age, sex and Indigenous status. DESIGN, SETTING AND PATIENTS: Retrospective chart review of hospitalisations at Mt Isa Base Hospital, Queensland, from 1 January 2007 to 31 December 2011 among children < 15 years of age. MAIN OUTCOME MEASURES: Rates of admission for bronchiolitis, pneumonia and bronchiectasis, calculated using population data from the Australian Bureau of Statistics. RESULTS: There were 356 admissions for ALRI, involving 276 children. Of the 162 children aged < 12 months old, 125 (77.2%) were Indigenous. Hospitalisations increased over the study period, and rates were significantly higher among Indigenous children compared with non-indigenous children (24.1 v 4.5 per 1000 population per year). There were 195 admissions of 164 children with pneumonia, 126 (76.8%) of whom were Indigenous. Annual rates for Indigenous children were higher than for non-Indigenous children (13.7 v 2.3 per 1000 population). Multiple admissions were common. One-third presented with gastrointestinal symptoms and signs. Pneumococcal disease persisted despite vaccination. There were 160 hospitalisations for bronchiolitis; 114 occasions (71.3%) involved Indigenous children. Seven children had bronchiectasis; all were Indigenous. CONCLUSION: Rates of ALRI in Mt Isa are comparable to those in the Northern Territory, which is reported to have rates of pneumonia among the highest in the world for children < 12 months of age. Multiple admissions are common, suggesting an even higher rate of bronchiectasis. Pneumonia may present as gastrointestinal disease, and invasive pneumococcal infection must be suspected despite vaccination.

Respiratory viruses in exacerbations of non-cystic fibrosis bronchiectasis in children.

BACKGROUND: Respiratory viral infections precipitate exacerbations of chronic respiratory diseases such as asthma and chronic obstructive pulmonary disease though similar data in non-cystic fibrosis (CF) bronchiectasis are missing. Our study aimed to determine the point prevalence of viruses associated with exacerbations and evaluate clinical and investigational differences between virus-positive and -negative exacerbations in children with bronchiectasis. METHODS: A cohort of 69 children (median age 7 years) with non-CF bronchiectasis was prospectively followed for 900 child-months. PCR for 16 respiratory viruses was performed on nasopharyngeal aspirates collected during 77 paediatric pulmonologist-defined exacerbations. Clinical data, systemic (C reactive protein (CRP), IL-6, procalcitonin, amyloid-A, fibrinogen) and lung function parameters were also collected. FINDINGS: Respiratory viruses were detected during 37 (48%) exacerbations: human rhinovirus (HRV) in 20; an enterovirus or bocavirus in four each; adenoviruses, metapneumovirus, influenza A virus, respiratory syncytial virus, parainfluenza virus 3 or 4 in two each; coronavirus or parainfluenza virus 1 and 2 in one each. Viral codetections occurred in 6 (8%) exacerbations. HRV-As (n=9) were more likely to be present than HRV-Cs (n=2). Children with virus-positive exacerbations were more likely to require hospitalisation (59% vs 32.5% (p=0.02)) and have fever (OR 3.1, 95% CI 1.2 to 11.1), hypoxia (OR 25.5, 95% CI 2.0 to 322.6), chest signs (OR 3.3, 95% CI 1.1 to 10.2) and raised CRP (OR 4.7, 95% CI 1.7 to 13.1) when compared with virus-negative exacerbations. INTERPRETATION: Respiratory viruses are commonly detected during pulmonary exacerbations of children with bronchiectasis. HRV-As were the most frequently detected viruses with viral codetection being rare. Time-sequenced cohort studies are needed to determine the role of viral-bacterial interactions in exacerbations of bronchiectasis.

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.