Vikas Goyal

Pediatric bronchiectasis: No longer an orphan disease

Bronchiectasis is described classically as a chronic pulmonary disorder characterized by a persistent productive cough and irreversible dilatation of one or more bronchi. However, in children unable to expectorate, cough may instead be wet and intermittent and bronchial dilatation reversible in the early stages. Although still considered an orphan disease, it is being recognized increasingly as causing significant morbidity and mortality in children and adults in both affluent and developing countries. While bronchiectasis has multiple etiologies, the final common pathway involves a complex interplay between the host, respiratory pathogens and environmental factors. These interactions lead to a vicious cycle of repeated infections, airway inflammation and tissue remodelling resulting in impaired airway clearance, destruction of structural elements within the bronchial wall causing them to become dilated and small airway obstruction. In this review, the current knowledge of the epidemiology, pathobiology, clinical features, and management of bronchiectasis in children are summarized. Recent evidence has emerged to improve our understanding of this heterogeneous disease including the role of viruses, and how antibiotics, novel drugs, antiviral agents, and vaccines might be used. Importantly, the management is no longer dependent upon extrapolating from the cystic fibrosis experience. Nevertheless, substantial information gaps remain in determining the underlying disease mechanisms that initiate and sustain the pathophysiological pathways leading to bronchiectasis. National and international collaborations, standardizing definitions of clinical and research end points, and exploring novel primary prevention strategies are needed if further progress is to be made in understanding, treating and even preventing this often life‐limiting disease. Pediatr Pulmonol. 2016;51:450–469.

Bronchiectasis: the arrival of better evidence

12 www.thelancet.com/respiratory Vol 2 January 2014 Bronchiectasis unrelated to cystic fi brosis is increasingly recognised as a major contributor to respiratory morbidity and mortality in children and adults living in countries of all income levels. Despite its importance, bronchiectasis has attracted little research. As a result, the management of bronchiectasis is often extrapolated from research on cystic fi brosis. However, this extrapolation might have unintended consequences. For example, recombinant human DNase, a mucolytic agent used successfully in cystic fi brosis, leads instead to increased exacerbations and hospital admissions, and accelerated pulmonary decline in adult patients with bronchiectasis. In 2013, improved high-level evidence for managing children and adults with bronchiectasis fi nally arrived with publication of several multicentre, randomised placebo-controlled trials. Three pharmaceutical industry based multicentre trials were published in 2013, although only one was a phase 3 study. In this trial, participants aged 15–80 years with a predicted forced expiratory volume in 1 s (FEV1) of 50% or greater received either inhaled dry powder mannitol (320 mg twice-daily, n=231) or placebo (n=112) for 12 weeks (with a subsequent open-label phase for 52 weeks in a subset of participants). Mannitol provided minimal benefi t; surprisingly, sputum expectoration at 12 weeks in the placebo group was signifi cantly less than in the mannitol group (mean diff erence 4·5 g, 95% CI 1·64–7·00; p=0·002). 82 participants also underwent high-resolution CT scans, which showed signifi cantly reduced mucous plugging in the mannitol group. However, there were no signifi cant betweengroup diff erences in exacerbation frequency, St George Respiratory Questionnaire (SGRQ) score, spirometry, microbiology, and infl ammatory variables. This contrasts with data in cystic fi brosis, where 24 weeks of mannitol (400 mg twice daily for 26 weeks; compared with control dose of 50 mg) improved FEV1 and reduced exacerbation frequency by 29%. A possible explanation for these confl icting results is a Hawthorne eff ect because the placebo group received substantially more antibiotics during the fi rst 6 weeks of the study. Other multicentre trials published in 2013 were not industry based. The Bronchiectasis and Long-term Azithromycin Treatment (BAT) study enrolled 83 adults (from 14 hospitals) with three of more bronchiectasis exacerbations in the previous 12 months. Consistent with data from the fi rst published multicentre trial (EMBRACE) of azithromycin effi cacy (500 mg, threetimes per week for 6 months) in bronchiectasis, those participants allocated daily azithromycin (250 mg) for 12 months in the BAT study had signifi cantly fewer exacerbations (absolute risk reduction 33·5%, 95% CI 14·1–52·9) compared with placebo. Unlike EMBRACE, the azithromycin group in the BAT study had signifi cant improvements in SGRQ scores (12 vs 4 points in the placebo group, p=0·046) and spirometry (FEV1 +1·03% predicted per 3 months in the azithromycin group vs –0·10% in the placebo group, p=0·047; FVC +1·33% vs –0·30%, p=0·02). However, there were signifi cant between-group diff erences favouring placebo for diarrhoea (relative risk 8·36, 95% CI 1·10–63·15) and sputum macrolide-resistant bacteria (placebo 25·9%, azithromycin 88·3% of pathogens tested, p<0·001). The fi rst multicentre trial in children with bronchiectasis, the Bronchiectasis Intervention Study (BIS), was published recently and involved 89 Indigenous children from four regions of New Zealand and Australia. The authors reported that onceweekly azithromycin (30 mg/kg) for a mean duration of 20·7 months (SD 5·7) reduced exacerbation frequency by 50% (95% CI 35–71) compared with placebo (p<0·0001). At the end of the study, the mean weight-for-age Z-score was signifi cantly better in the azithromycin group (1·03, SD 1·91) compared with placebo (0·20, 1·25, p=0·003). Similar to the studies in adults, an increase in nasopharyngeal carriage of macrolideresistant bacteria occurred in the azithromycin group (46% vs 11% in the placebo group, p=0·002). However, despite harbouring more macrolide-resistant bacteria, post-hoc analysis showed acute non-pulmonary infections needing antibiotics were also reduced by 50% in the azithromycin group (95% CI 31–81, p=0·005). BIS also included children with chronic suppurative lung disease, a disorder that probably precedes radiographically confi rmed bronchiectasis in children. Inclusion of this group highlighted both the limitations associated with making a purely radiographically based diagnosis for bronchiectasis, and the feasibility of early intervention programmes. Bronchiectasis: the arrival of better evidence

Chronic cough postacute respiratory illness in children: a cohort study.

Objective Data on the aetiology of persistent cough at the transitional stage from subacute to chronic cough (>4 weeks duration) are scarce. We aimed to (1) identify the prevalence of chronic cough following acute respiratory illness (ARI) and (2) determine the diagnostic outcomes of children with chronic cough. Design Prospective cohort study. Setting A paediatric emergency department (ED) in Brisbane, Australia. Patients Children aged <15 years presenting with an ARI with cough. Interventions Children were followed weekly for 28 days;those with a persistent cough at day 28 were reviewed by a paediatric pulmonologist. Main outcome measures Cough persistence at day 28 and pulmonologist diagnosis. Results 2586 children were screened and 776 (30%) were ineligible; 839 children (median age=2.3 years, range=0.5 months to 14.7 years, 60% male) were enrolled over 2 years. Most children (n=627, 74.8%) had cough duration of <7 days at enrolment. At day 28, 171/839 (20.4%, 95% CI 17.7 to 23.1) children had persistent cough irrespective of cough duration at enrolment. The cough was wet in 59/171 (34.5%), dry in 45/171 (26.4%) and variable in 28/171 (16.1%). Of these 117 children , 117 (68.4%) were reviewed by a paediatric pulmonologist. A new and serious chronic lung disease was diagnosed in 36/117 (30.8%) children; 55/117 (47.0%) were diagnosed with protracted bacterial bronchitis. Conclusions When chronic cough develops post-ARI, clinical review is warranted, particularly if parents report a history of prolonged or recurrent cough. Parents of children presenting acutely to ED with cough should be counselled about the development of chronic cough, as an underlying respiratory condition is not uncommon.

Upper airway viruses and bacteria and clinical outcomes in children with cough.

Background: Cough is symptomatic of a broad range of acute and chronic pediatric respiratory illnesses. No studies in children have tested for an extended panel of upper airway respiratory viruses and bacteria to identify whether they predict cough outcomes, irrespective of clinical diagnosis at the time of acute respiratory illness (ARI). We therefore determined whether upper airway microbes independently predicted hospitalization and persistent cough 28‐days later in children presenting with an ARI, including cough as a symptom. Methods: A cohort study of children aged <15‐years were followed for 28‐days after presenting to a pediatric emergency department with an ARI where cough was also a symptom. Socio‐demographic factors, presenting clinical features and a bilateral anterior nasal swab were collected at enrolment. Polymerase chain reaction assays tested for seven respiratory bacteria and 17 viruses. Predictors of hospitalization and persistent cough at day‐28 were evaluated in logistic regression models. Results: Eight hundred and seventeen children were included in the analysis; median age 27.7‐months. 116 (14.2%, 95%CI 11.8, 16.6) children were hospitalized and 163 (20.0%, 95%CI 17.2, 22.7) had persistent cough at day‐28. Hospitalized children were more likely to have RSV A or B detected on nasal swab than those not admitted (adjusted relative risk (aRR) 1.8, 95%CI 1.0, 3.3). M. catarrhalis was the only microbial difference between children with and without cough persistence (aRR for those with cough at day 28: 2.1, 95%CI 1.3, 3.1). Discussion: An etiologic role for M. catarrhalis in the pathogenesis of persistent cough post‐ARI is worth exploring, especially given the burden of chronic cough in children and its relationship with chronic lung disease. Pediatr Pulmonol. 2017;52:373–381.

Barium aspiration in an infant: a case report and review of management.

We describe a case of bilateral inhalation of barium in an infant following a barium swallow for investigation of dusky spells associated with feeds. A bronchoscopy subsequently revealed the presence of a mid-tracheal tracheo-esophageal cleft. To date, little has been reported on barium aspiration in children and there is no consensus for management. We review the literature on barium aspiration, its consequences, and make recommendations for management.

How children with asthma breathe: have we been overlooking a problem?

Asthma is one of the most common chronic diseases globally, with an estimated 300 million sufferers [1] and is diagnosed in up to 10% of paediatric populations in many developed countries. Despite many advances in the treatment of asthma, there remain a percentage of patients, including children, who do not respond, or respond poorly to current treatment. These are the patients for whom clinicians think of alternative diagnoses. THOMAS et al. [2] have investigated abnormal breathing patterns in adults with asthma using the Nijmegen questionnaire and have identified as many as 29% of patients as having dysfunctional breathing. Symptoms suggestive of dysfunctional breathing include: dyspnoea, deep sighing, chest pain, chest tightness, frequent yawning, hyperventilation and breathlessness during exercise [2]. The same authors also showed a positive response with breathing retraining in a randomised control trial [3]. Some others have reported some ongoing benefit of breathing retraining in patients with dysfunctional breathing in a 5-year follow-up [4]. Thus both the problem of dysfunctional breathing in adults diagnosed with asthma and the benefit such patients obtain from breathing retraining is reasonably well established. Psychological problems in children diagnosed with asthma have been described [5–8]. Various authors have suggested that the mainstay of the diagnosis of psychogenic and functional breathing disorders is a full and meticulously taken history

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

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

Does poor response to antibiotics in children with chronic wet cough predict the presence of bronchiectasis on a chest high resolution computerized tomography (HRCT) scan

Background : The current guidelines for acceptable levels of ambient PM ( Methods : The PM fraction was extracted from surface soil samples from 4 communities across Western Australia. BALB/c 10 mice were intranasally exposed to 100 µg of PM . Control mice received 100 µg of polystyrene beads (2.5 µm) or vehicle 10 alone. Mice were assessed for inflammation (cellular influx, MIP-2, IL-6 and IL-1β), lung volume (plethysmography) and lung mechanics (forced oscillation technique) 6, 24 or 168 hours post-exposure. The physical and chemical characteristics of the particles were assessed by cascade impactor and ICP-MS/OES respectively. Principal component analysis of the outcome measures were used to construct lung impairment scores. Multivariate linear regression models were then used to identify the characteristics of the particles driving the lung responses. Results : Exposure to geogenic particles caused an acute inflammatory response (6 hours post-exposure), an acute impairment in lung mechanics (24 hours post-exposure) and a long term deficit in lung volume (168 hours post-exposure). Both the inflammatory response and long term deficits in lung volume were associated with the concentration of Fe and variability in particle size (GSD) while the impairment in lung mechanics was associated with Fe and particle size (MMAD). Conclusions : Despite the complex physico-chemical characteristics of geogenic dusts we were able to identify the concentration of Fe and physical dimensions of the particles as the key drivers of lung responses. Using these data we may be able to predict which communities are at greatest risk of adverse respiratory health due to high geogenic particle loads.

The clinical, immunological and microbiological impact of the 10-valent pneumococcal-Protein D conjugate vaccine in children with recurrent protracted bacterial bronchitis, chronic suppurative lung disease and bronchiectasis: A multi-centre, double-blind, randomised controlled trial

ABSTRACT We aimed to determine the efficacy of the 10-valent pneumococcal-Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) in children aged 18-months to <18-years with recurrent protracted bacterial bronchitis (rPBB), chronic suppurative lung disease (CSLD) or bronchiectasis. In a multi-centre, double-blind randomised controlled trial, children received two doses, 2-months apart of the 10vPHiD-CV or quadrivalent meningococcal-ACYW135 conjugate vaccine. Active surveillance for acute exacerbations, respiratory symptoms and antibiotic use was undertaken through to 12-months after the second vaccine dose (clinical cohort only). Serum, saliva and nasopharyngeal swabs were collected to measure immunological and microbiological effects (immunology cohort). Between December 2012 and August 2015, 62 children were enrolled onto the clinical protocol (1 excluded from clinical analyses due to unblinding), while 74 contributed to the immunology cohort (overall mean age = 6.8-years (standard deviation = 3.7), 42 (56.8%) male). The absolute risk difference comparing the 10vPHiD-CV group (n = 31 children) to the MenACYW135 group (n = 30 children) for acute exacerbations was -0.5 exacerbations/100-weeks at risk (95% confidence interval (CI) -2.0, 0.9). Compared to the MenACYW135 group, children who received the 10vPHiD-CV were less likely to have respiratory symptoms in each fortnight of surveillance (incidence density ratio (IDR) 0.82, 95%CI 0.61, 1.10) and required fewer short-course (<14-days duration) antibiotics (IDR 0.81, 95% CI 0.61, 1.09). The vaccine was immunogenic and no serious adverse events related to the vaccine were reported. In conclusion, 10vPHiD-CV might have a future role in managing children with rPBB, CSLD and bronchiectasis, but larger multicentre trials are needed to confirm or refute findings from this preliminary study.

Burden and emergency department management of acute cough in children: Management of acute cough in children

In children presenting to an emergency department (ED) with an acute coughing illness, the aims of this study were to: (i) describe the frequency of doctor visits and medication use; and (ii) describe management and relate it to current evidence‐based guidelines.