Advancing the knowledge, understanding and management of respiratory exacerbations of bronchiectasis in children

IntroductionBronchiectasis unrelated to cystic fibrosis (CF) remains an under-researched area and is often labelled a “neglected disease”. Yet, worldwide it is more common than CF and causes substantial morbidity and mortality in both children and adults.To reduce morbidity and premature mortality from bronchiectasis in adults, interventions should begin in childhood. Diagnosing bronchiectasis early and providing effective treatment, including treating exacerbations, can prevent significant morbidity. Although the importance of recognising and treating exacerbations effectively is well-accepted, there have been no prior randomised trials for managing exacerbations of bronchiectasis in children. The studies in my PhD address several important clinical and research gaps relating to children with bronchiectasis, including its early identification and antibiotic treatment of exacerbations.AimsThe overarching aim of my thesis is to improve knowledge of bronchiectasis, the pre-bronchiectasis state and management of bronchiectasis exacerbations in children.The specific main objectives were to:1.      Identify whether children with a poor response to at least 4-weeks of oral antibiotics predict an increased risk of finding bronchiectasis on a multi-detector computed-tomography (MDCT) scan of the chest.2.      Describe the clinical characteristics, investigations and treatment outcomes for children with chronic suppurative lung disease (CSLD) without radiographic evidence of bronchiectasis.3.      Determine in children with bronchiectasis the effect of oral azithromycin and oral amoxicillin-clavulanate (each compared to placebo) on symptom resolution after 14-days treatment of non-severe (non-hospitalised) acute respiratory exacerbations.4.      Asses in children with bronchiectasis whether oral azithromycin was non-inferior (within a 20% margin) to oral amoxicillin-clavulanate at achieving symptom resolution after21-days treatment of non-severe (non-hospitalised) acute respiratory exacerbations.5.      Estimate the cost of hospitalised bronchiectasis exacerbations.6.      Undertake a systematic review using Cochrane methodology to assess the effects of inhaled long-acting beta-2-agonists (LABA) combined with inhaled corticosteroids (ICS) in children and adults with bronchiectasis during (a) acute exacerbations and (b) stable state.An overview of the major findings for each objective is detailed below:Objective-1 was addressed by studying 144 children undergoing chest CT scans for a chronic wet cough. Among the 105 children with persistent cough despite at least 4-weeks of antibiotics, 88 (83.8%) had bronchiectasis. In contrast, of the 24 children whose cough resolved after 4-weeks of antibiotics, only six (25.0%) received this diagnosis (adjusted OR 20.9; 95%CI 5.36 to 81.8).1 The study addressing objective-2 is the first to describe children with CSLD. These 22 children lacked features of bronchiectasis on CT scans but had a wet cough unresponsive to oral antibiotics, which resolved with intravenous antibiotics and airway clearance therapy. Children with CSLD had broncho-alveolar lavage (BAL) characteristics similar to protracted bacterial bronchitis and bronchiectasis, but their poor clinical response to oral-antibiotics and non-specific chest-CT findings differentiated them from the other two disorders respectively.2 Objective-3 was accomplished by a multicentre three-arm, double-dummy, randomised controlled trial (RCT) involving 197 children. Compared to placebo, the relative risk of resolution by day-14 for amoxicillin-clavulanate was 1.50 (95%CI 1.08-2.09) and for azithromycin 1.41 (95%CI 1.01-1.97). However, azithromycin was associated with increased carriage of antibiotic-resistant bacteria.3Objective-4 was achieved by a multicentre double-dummy, double-blind, placebo-containing RCT comprising 179 children. By day-21, 61/73 (84%) exacerbations had resolved in the azithromycin group versus 73/87 (84%) in the amoxicillin-clavulanate group. The risk difference showed non-inferiority (–0.3%, 95%CI –11.8-11.1). Exacerbations were significantly shorter in the amoxicillin-clavulanate than the azithromycin group (median 10-days [IQR 6–15] versus 14-days [8–16]; p=0.014). Thus, azithromycin provides another option for treating exacerbations but must be balanced with the risk of treatment failure (within a 20% margin), longer exacerbation duration, and the risk of inducing macrolide-resistance.4For objective-5, a prospective study of hospitalisation costs for 100 children was undertaken. The cost of one hospital admission for bronchiectasis exacerbation was A$30,182 (SD 13998) with an average length-of-stay of 12.3 (SD 4.6) days. In planning this study, the absence of a Disease-Related-Group (DRG) classification for treating bronchiectasis exacerbations in Australia was evident. Thus, a public submission to the Australian Consortium for Classification Development for a bronchiectasis DRG was made and subsequently, hospitalisation for bronchiectasis was assigned a code from July 1, 2018.Objective-6 led to a systematic review showing no high-quality evidence exists for combined ICS and LABA therapy in paediatric bronchiectasis.5ConclusionsThe studies arising from this thesis provide new knowledge in relation to:1.      Identifying children with a wet cough who need further investigation for bronchiectasis.2.      Describing the clinical, bronchoscopic, BAL and treatment outcome findings for children with CSLD.3.      Proving for the first time, evidence for antibiotic efficacy compared to placebo for treating non-severe bronchiectasis exacerbations.4.      Establishing that azithromycin is non-inferior (within 20% margin) to amoxicillin-clavulanate for treating non-severe bronchiectasis exacerbations.5.      Providing data for the hospitalisation costs for bronchiectasis exacerbations in Australia.6.      Identifying the current lack of high-quality evidence for combined ICS and LABA in children and adults with bronchiectasis.References1.           Goyal V, Grimwood K, Marchant J, Masters IB, Chang AB. Does failed chronic wet cough response to antibiotics predict bronchiectasis? Arch Dis Child 2014;99:522-5.2.           Goyal V, Grimwood K, Marchant JM, Masters IB, Chang AB. Paediatric chronic suppurative lung disease: clinical characteristics and outcomes. Eur J Pediatr 2016;175:1077-84.3.           Goyal V, Grimwood K, Ware R, et al. Efficacy of oral antibiotics for non-severe exacerbations of bronchiectasis in children (BEST 1): A multi-centre, double-blind, double-dummy, randomised placebo-controlled trial. Lancet Resp Med 2019;7:791-801.4.           Goyal V, Grimwood K, Byrnes CA, et al. Amoxicillin-clavulanate versus azithromycin for respiratory exacerbations in children with bronchiectasis (BEST-2): a multicentre, double-blind, non-inferiority, randomised controlled trial. Lancet 2018;392:1197-206.5.           Goyal V, Chang AB. Combination inhaled corticosteroids and long-acting beta2-agonists for children and adults with bronchiectasis. The Cochrane database of systematic reviews 2014;6:CD010327.