Expert Review of Respiratory Medicine

ISSN: 1747-6348 (Print) 1747-6356 (Online) Journal homepage: http://www.tandfonline.com/loi/ierx20

An Update on Pediatric Bronchiectasis

Danielle F Wurzel & Anne B Chang

To cite this article: Danielle F Wurzel & Anne B Chang (2017): An Update on Pediatric
Bronchiectasis, Expert Review of Respiratory Medicine, DOI: 10.1080/17476348.2017.1335197

To link to this article: http://dx.doi.org/10.1080/17476348.2017.1335197

Accepted author version posted online: 25

May 2017.

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Download by: [The UC San Diego Library] Date: 26 May 2017, At: 22:20
Publisher: Taylor & Francis

Journal: Expert Review of Respiratory Medicine

DOI: 10.1080/17476348.2017.1335197
REVIEW

An Update on Pediatric Bronchiectasis

Authors: Danielle F Wurzel, MBBS, PhD, FRACP,1 Anne B Chang, MBBS, MPHTM,

PhD, FRACP, FAPSR, FThorSoc, FAHMS2

Affiliations: 1Paediatric Respiratory Physician, The Royal Children’s Hospital;

Honorary Fellow, Murdoch Childrens Research Institute, Parkville, Australia 3052

2
Paediatric Respiratory Physician and Professor, Lady Cilento Children’s Hospital,

Queensland University of Technology, Brisbane, Australia and Head of Child Health

Division, Menzies School of Health Research, Charles Darwin University, Darwin,

Australia.

Corresponding author: Dr Danielle F Wurzel, Murdoch Children’s Research Institute,

Melbourne, Victoria 3052, Australia. Email: danielle.wurzel@rch.org.au, telephone: +61

3 9345 5818 fax: +61 3 9345 9154.

1
2
Abstract
Introduction: The prevalence and awareness of bronchiectasis not related to cystic

fibrosis (CF) is increasing and it is now recognized as a major cause of respiratory

morbidity, mortality and healthcare utilization worldwide. The need to elucidate the early

origins of bronchiectasis is increasingly appreciated and has been identified as an

important research priority. Current treatments for pediatric bronchiectasis are limited to

antimicrobials, airway clearance techniques and vaccination. Several new drugs targeting

airway inflammation are currently in development.

Areas covered: Current management of pediatric bronchiectasis, including discussion on

therapeutics, non-pharmacological interventions and preventative and surveillance

strategies are covered in this review. We describe selected adult and pediatric data on

bronchiectasis treatments and briefly discuss emerging therapeutics in the field.

Expert commentary:

Despite the burden of disease, the number of studies evaluating potential treatments for

bronchiectasis in children is extremely low and substantially disproportionate to that for

CF. Research into the interactions between early life respiratory tract infections and the

developing immune system in children is likely to reveal risk factors for bronchiectasis

development and inform future preventative and therapeutic strategies. Tailoring

interventions to childhood bronchiectasis is imperative to halt the disease in its origins

and improve adult outcomes.

Keywords: bronchiectasis, children, cough, treatment

1. Background

3
Worldwide, bronchiectasis is increasingly diagnosed [1-3]. Thus, elucidating the early

origins of the disease has been identified as a research priority in both children [4, 5] and

adults [6]. Indeed, bronchiectasis is regarded by the European Respiratory Society (ERS)

as one of the most neglected lung diseases [6]. The role of childhood respiratory tract

infections in the aetio-pathogenesis of chronic suppurative lung diseases such as

bronchiectasis is well-known [7] [3] and first described as early as the mid 20th century

[8-10]. Until today the exact mechanisms leading to the development of bronchiectasis

remain poorly understood, although is believed to be related to persistent infection and

inflammation of the airways [11, 12].

An appreciation of the aetio-pathogenesis of bronchiectasis is crucial in order to

understand the role of current and potential future treatments for the disease. In

bronchiectasis, a vicious cycle phenomenon is believed to exist, whereby impairment in

mucociliary clearance facilitates the establishment of airway infection and the subsequent

inflammatory response further impairs mucosal function and mucociliary clearance

creating a feedback loop as first described by Cole [13]. Treatment for the condition is

thus multimodal, with antibiotics and airway clearance as mainstays. Lifestyle factors

such as exercise, nutrition, environmental pollutant (e.g. tobacco smoke) exposure and

vaccinations are additional modifiable factors that likely influence the disease [14]. Host

innate immune factors (generally non-modifiable) are likely to have additional impact on

the likelihood of disease developing and its severity.

4
Although significant advancements have occurred with respect to our understanding of

bronchiectasis risk factors and treatments, major knowledge gaps remain. The paucity of

clinical trials in pediatric bronchiectasis unrelated to CF has resulted in extrapolation

from adult and CF data. In recent years, the pitfalls of this approach have been

recognized [15] although the number of clinical trials specifically relating to

bronchiectasis treatment in children remains exceptionally low [16, 17] and out of

proportion to the burden of disease worldwide [18]. This review outlines current

recommendations on the treatment of bronchiectasis unrelated to CF in children and

highlights the need for further well-designed interventional studies in this field.

In recent years as the burden of bronchiectasis is now recognized and larger than that of

CF on a global scale, a concerted effort to abandon the term non-CF bronchiectasis is

being made. This review focuses on bronchiectasis and, unless specifically mentioned,

refers to bronchiectasis unrelated to CF.

1.1 Diagnosis

Bronchiectasis is a possible late consequence of a large number of different pathological

conditions resulting in a common outcome with respect to airway dilatation and damage.

Prior to the advent of CT in the 1970s, the diagnostic criteria for bronchiectasis was

based on contrast bronchography. Today, chest CT definitions used by most centers are

based on adult data [19, 20]. Indeed, this has remained essentially unchanged for several

decades. The radiological conventional high-resolution CT (c-HRCT) scan definition of

bronchiectasis is irreversible dilatation of one or more bronchi with bronchi larger than

their accompanying vessel and/or failure of one or more bronchi to taper within the

5
periphery of lung [20]. However, in children particularly, there is increasing awareness of

the fact that a diagnosis of bronchiectasis requires clinical and radiological correlation.

Further, the current adult-based radiological criteria for bronchiectasis diagnosis is

inappropriate for children for many reasons [12]. The key reasons, as outlined in an

Australian guideline [21] were “(a) extrapolating c-HRCT findings of bronchiectasis

from adult studies may be inappropriate for children, as morphology of the airway and

lungs changes with age; (b) at least two c-HRCT scans (separated by an undefined

period) are required to confirm irreversible airway dilatation; and (c) c-HRCT scans

performed in different clinical states yield different results.”

The applicability of a broncho-arteriolar ratio of 1:1, used to define airway ectasia in

adults, under-estimates the presence of bronchiectasis in children as was demonstrated in

a study by Kapur et al [22]. Airway measurements in this study were taken from the inner

wall as is the classical approach used since the 1980s and currently used in adults. Recent

studies in children with CF have suggested that outer wall measurements may be

arguably more accurate as this accounts for bronchial wall thickening and is less prone to

parallax error [23]. Further, a ratio of 1.11 has been proposed as the optimal threshold for

differentiating CF patients from controls using this outer wall (AA-ratio) method [24].

The applicability of this finding to children with bronchiectasis unrelated to CF is

unknown and warrants investigation.

A diagnosis of bronchiectasis is generally made in the context of clinical symptoms

and/or signs of bronchiectasis in addition to characteristic radiological findings. In

6
pediatrics, a smaller broncho-arterial ratio of >0.8 rather than the adult definition of 1 is

sometimes used [25].

Clinically, recurrent or persistent episodes of wet cough are the hallmark clinical feature

in children with bronchiectasis [26]. Unlike adults with bronchiectasis, in children with

mild or early bronchiectasis, the wet or productive cough may resolve after initial

treatment and only recur during acute exacerbations [26]. Other symptoms that may be

present include wheeze (often reflective of the presence of airway secretions and oedema

rather than bronchospasm). Increased sputum production or change in colour of sputum,

chest pain, breathlessness, haemoptysis or auscultatory signs of crackles or wheeze may

also occur during exacerbations of bronchiectasis [27]. Chronic signs can include growth

failure, digital clubbing, hyperinflation and chest wall deformity, the later occurring more

frequently with increasing severity of bronchiectasis [28].

The above are common symptoms and signs suggestive of bronchiectasis. The absence of

any of the symptoms (other than cough) or signs above does not indicate absence of

disease. In addition to these, a child with bronchiectasis may also have symptoms and

signs of the underlying cause of the bronchiectasis. For example, naso-otitis problems or

markers of heterotaxy may be present in primary ciliary dyskinesia or dysmorphism

associated with genetic syndromes (e.g. Cri du Chat syndrome or Trisomy 21) may

underlie neurological symptoms with associated dysphagia and aspiration.

Bronchiectasis is diagnosed when a child presents with a clinical history suggestive of

7
bronchiectasis (e.g. recurrent episodes of antibiotic responsive protracted wet cough,

usually >3 per year) in conjunction with a HRCT chest showing abnormal dilatation of

one or more bronchi [14]. A child who presents with clinical symptoms but that has a

normal CT chest, is usually given a diagnosis of chronic suppurative lung disease

(CSLD) [14]. CSLD may progress to bronchiectasis over time if left untreated [29]. In

protracted bacterial bronchitis (PBB), the mildest form of endobronchial suppuration,

while the majority of children with PBB fully recover [5], there is a small minority where

those with recurrent (>3 per year) episodes are later diagnosed with bronchiectasis [30].

1.2 Burden and prevalence

The prevalence of non-CF bronchiectasis worldwide appears to be increasing,

particularly in adults [1, 2]. Studies in high-income countries have investigated the socio-

economic, geographic and ethnic factors that influence the disparity in observed rates of

bronchiectasis between different populations [2, 31]. Pediatric bronchiectasis is a major

health issue for socially disadvantaged Indigenous populations in developed countries

e.g. Maori and Pacific Islanders in New Zealand, Australian Aboriginal and Native

Alaskan children living in the US [31-34]. However, it has now been recognized as a

major issue in non-Indigenous settings in affluent societies.

The global burden of bronchiectasis in children is extremely difficult to quantify as the

diagnosis is dependent on case ascertainment with radiological confirmation using chest

CT that has limited accessibility outside of major cities in affluent settings. The

prevalence estimates in high-income countries range from 0.5 child years per 100,000 in

Finland (1983-1992) to 1,470 per 100,000 in Aboriginal children (<15 years) from

8
Central Australia [32] and 1,600 per 100,000 in South-West Alaskan Native children

living in the US [35] (data from the early 2000s). Prevalence in low-income countries is

likely to be substantially higher (although no data is available from these regions)

underlining the association between low socioeconomic status and bronchiectasis.

Further, the prevalence of bronchiectasis appears to be increasing in all populations,

irrespective of the country’s affluence.

In a recent study by Quint et al, from a UK-based primary care database of predominantly

adult patients, a substantial increase in the incidence and prevalence of bronchiectasis

was observed between 2004-2013 [2]. More notably, within the same population, age-

adjusted mortality rates were dramatically higher in those with bronchiectasis compared

to those without (e.g. in males, mortality rate was 1914.6 per 100,000 vs 895.2 per

100000 in general population, comparative mortality rate of 2.14) [2]. Further, these data

suggested that bronchiectasis was associated with higher, rather than lower, socio-

economic status [2]. However, this latter finding may be confounded by access to high-

resolution CT scans. Although data on bronchiectasis in children is scarce, we have

observed an increasing number of children with bronchiectasis in our clinics over the last

15 years, whereby the total number of children with bronchiectasis now outnumber those

with CF.

A study by Munro et al [36] in Auckland, New Zealand, reported that in the period

between 2000 and 2008, the number of children with bronchiectasis under active review

had increased 280% [36]. Once again this may be due to increased use of HRCT scan and

9
heightened recognition of disease, nevertheless it is likely that the true burden of disease

is under-estimated worldwide. Mortality from bronchiectasis also occurs in children.

In high-income countries, the overall number of childhood fatalities from bronchiectasis

is low [37] but deaths do occur (as shown in Figure 1). In a New Zealand study

examining deaths in children with and without CF over a similar period (in children <14

years) showed no deaths related to CF, compared to several deaths in children with

bronchiectasis [38, 39]. Similarly, a UK study in 2010 [37] reported mortalities in

children with bronchiectasis. In less affluent countries, where healthcare access is

marginal, mortality in children with bronchiectasis is estimated to be around 10%

(unpublished). Despite this, awareness of, and availability of resources for children with

bronchiectasis is limited and substantially lower than that related to CF.

In adults with bronchiectasis, mortality is significantly increased compared to the normal

population. A study in England and Wales showed an increased mortality rate of 3% per

year between 2001 and 2007 in those with bronchiectasis [37]. This is compared to a

study of hospitalized Indigenous Australian adults in Central Australia that showed an

88.5% survival rate at 1-year [40] and further demonstrated in a Turkish study published

in 2007 that showed even lower survival of 58% at 4 years [41]. Despite these figures,

there has been a significant improvement in survival over time, with a study of 400

patients with bronchiectasis published in 1940 suggesting that most patients died before

the age of 40 years [42]. This improvement in survival over time is likely due to factors

such as antimicrobials, vaccination and overall improvements in healthcare.

10
Overall, the prevalence of bronchiectasis unrelated to CF is substantially higher than that

of CF (US data showed 30,000 [43] with CF compared to an estimated >190,000 cases

with bronchiectasis [44]).

1.3 Pathophysiology

A knowledge of the basic pathophysiological mechanisms underlying the development of

bronchiectasis is necessary in order to understand its management. This involves an

interplay between the host (airway and systemic) inflammatory response, pathogens and

the environment [45]. A comprehensive review of the pathophysiology is beyond the

scope of this article. Readers are referred to a recent pediatric review [4].

Histologically, in bronchiectasis, the bronchial walls (elastic and muscular components)

become damaged by an acute or chronic insult (often infection) leading to progressive

bronchial wall dilatation and airflow obstruction. As described by Cole [46] such injury is

believed to initiate a vicious cycle phenomenon whereby muco-ciliary clearance is

impaired contributing to ongoing infection, inflammation and bronchial wall damage. It

has been suggested that pediatric bronchiectasis may be reversible when diagnosed early

and managed intensively [4, 47-49].

Reversibility of bronchiectasis on imaging has been shown in several studies in children

with cylindrical bronchiectasis [47-49], questioning the relevance of the current

definition of bronchiectasis to children (that refers to permanent dilatation of the

11
airways). The ability to definitively ascertain reversibility is reliant upon clearly defined

imaging protocols to ensure appropriate image comparison. Radiological features

however are believed to resolve or improve in some cases of foreign body aspiration

(after removal) and when bronchiectasis is mild or post-pneumonia in a segment of

atelectatic lung [47]. In children with an underlying progressive cause for their

bronchiectasis e.g. immunodeficiency, reversibility may still be seen (Table 1).

1.4 Impact and significance of bronchiectasis in children

As the prevalence of bronchiectasis diagnoses are rising the substantial cost of

hospitalizations, school and/or work absenteeism and declining quality of life (QoL) in

children and families is increasingly appreciated [50-53]. Child-rated QoL physical

health scores are lower in children and adolescents with bronchiectasis compared to

controls [54]. The burden on parents of children with bronchiectasis, particularly during

exacerbations, has been shown using a parent-proxy cough-specific QoL (PC-QOL)

questionnaire [52] and the depression, anxiety and stress scale (DASS) [51]. This latter

study showed that younger age of children is associated with impairment in QOL for

parents (using PC-QOL and DASS) and that QOL is significantly reduced during

exacerbations [51]. The strong correlation between QoL measures and disease severity in

children with bronchiectasis [53] underpins the importance of early recognition and

prompt and aggressive treatment of bronchiectasis in childhood.

With advancing bronchiectasis, impacts on general health and QoL increase with

breathlessness and fatigue as prominent symptoms. In end-stage disease, chronic hypoxia

12
contributes to the development of pulmonary hypertension that may progress to cor

pulmonale and eventually death from respiratory failure [55].

1.5 Treatable underlying diseases

Specific underlying disease processes render an individual at increased risk of

bronchiectasis. Such a diagnoses should be sought in all patients known to have

bronchiectasis or demonstrating clinical symptoms of signs of the condition. This is

especially important as treatment of the underlying disease e.g. immunodeficiency, may

alter the natural history of their lung disease. In children with bronchiectasis, an

underlying disease process is identified in 63% of cases as shown in a systematic review

of 12 studies including 989 children [56]. The most common causes were: infectious

(17%), primary immunodeficiency (16%), aspiration (10%), ciliary dyskinesia (9%),

congenital malformation (3%) and secondary immunodeficiency (3%)[56].

The prevalence of an underlying disease causing bronchiectasis may be influenced by the

setting (e.g. HIV common in some African countries) and depth of tests available (e.g.

nasal ciliary brushing for PCD). In addition to routine treatment of bronchiectasis,

treating an underlying disease may reduce the rate of progression of bronchiectasis. The

table below summarizes potentially treatable conditions in which bronchiectasis is a

complication. This highlights the importance of investigating for and identifying an

underlying cause of bronchiectasis.

Table 1: Causes of bronchiectasis where Specific treatment of the underlying

13
underlying disease is treatable disease

Primary or secondary immunodeficiency eg Immunoglobulin replacement therapy [57],

hypogamaglobulinaemia, HIV [58], anti-retroviral therapy

Aspiration disease – primary or secondary, Dietary modification or non-oral feeding

including oral disease [59], Nissen’s fundoplication, improved

oral care, repair of tracheoesophageal

fistula

Foreign body inhalation causing bronchial Removal of foreign body - bronchoscopic

obstruction or surgical [60]

Allergic bronchopulmonary aspergillosis Oral glucocorticoids [61, 62] + anti-fungal

therapy [63]

Autoimmune diseases eg sarcoidosis Oral glucocorticoids [64] and/or disease

modifying anti-rheumatic drugs

IgG4 related disease Oral glucocorticoids [65] and/or disease

modifying anti-rheumatic drugs

Treatment of bronchiectasis can thus be broadly divided into: (i) treatment of the

underlying disease where possible; and (ii) generic treatment. There are several recent

comprehensive reviews on medications for bronchiectasis [66-68]. The remainder of this

review focuses primarily on generic management of bronchiectasis in children. Specific

references to CF or adult-related data are included where relevant.

1.6 The need for early diagnosis

14
Early management of bronchiectasis, such as prompt initiation of airway clearance and

appropriate antibiotics during exacerbations, is likely to reduce the rate of progression in

those with an underlying disease. This was shown in children with primary

immunodeficiency who were treated early [69]. These reasons underpin the notion that

early diagnosis and treatment for bronchiectasis is vital in order to reduce long-term

morbidity and prolong survival of patients with this condition.

Although it is accepted that early recognition and treatment of bronchiectasis ensures the

best outcomes for children with bronchiectasis, in reality, delays in diagnosis are

common. A recent study in children suggested delays of several years before diagnosis

[70]. Moreover, a study in adults with newly-diagnosed bronchiectasis showed that 59%

had chronic cough dating back to childhood [71]. This data should be interpreted in the

context of evidence suggesting there may be a linear relationship between duration of wet

cough and lung function decline in adults with bronchiectasis [71]. A study by King et al

showed that with each additional year of wet cough, FEV1 %predicted decreased by

0.51% in non-smoking adults with bronchiectasis [71]. In children, spirometry data is

unavailable but a Greek study showed that the longer the duration of wet cough, the more

severe the radiological findings, as determined by CT score [72]. Early recognition of

bronchiectasis, and identification of those at greatest risk, is needed in order to target

primary and secondary prevention strategies.

Awareness amongst primary care physicians regarding the risk factors for bronchiectasis,

and when to refer for specialist opinion, is important to facilitate early diagnosis. An

15
Australian multi-center study evaluating the etiology of chronic cough in children found

that 9% of the 346 children enrolled had bronchiectasis [73]. A recent study suggested

that children with recurrent episodes (>3 per year) of protracted bacterial bronchitis

(PBB) and those with lower airway infection with H. influenzae may be at increased risk

of a later diagnosis of bronchiectasis [30]. The findings were based upon the hypothesis

that PBB and bronchiectasis represent a common clinical spectrum as they share many

similarities e.g. chronic wet cough, lower airway bacterial infection and neutrophilic

inflammation [12]. Further studies evaluating this hypothesis, and research aimed at

identifying key risk factors for bronchiectasis in children are needed to inform monitoring

and surveillance interventions.

2. Therapies

After a diagnosis of bronchiectasis is made and an underlying cause investigated, the aim

of treatment is several fold: (i) improve QoL; (ii) reduce frequency and/or severity of

exacerbations; (iii) prevent progression of disease and/or achieve resolution; and (iv)

minimise complications. The justification for early and aggressive treatment of children

with, or at risk of, bronchiectasis is that it may preserve lung function [74] and improve

or reverse changes in those with mild disease [47].

2.1 Airway clearance

Regular airway clearance tailored to an individual child by a physiotherapist with

respiratory expertise, is considered standard treatment for bronchiectasis [75]. There are

several different physiotherapy techniques, many of which are age-dependent. Airway

clearance techniques employed may include use of a device (e.g. an oscillatory positive

16
expiratory pressure (PEP) device), autogenic drainage and/or manual techniques such as

chest percussion. Although there are no supportive studies on optimal frequency of

physiotherapy, daily airway clearance is generally recommended with intensification

during exacerbations. Studies comparing physiotherapy techniques are limited. Readers

are referred to a recent review [76].

A Cochrane review published in 2015 showed that airway clearance techniques

employing an oscillating positive-expiratory pressure (PEP) device improve QoL and

symptoms in adults with bronchiectasis with reductions in cough and sputum volumes,

when compared to other airway clearance techniques and controls [77]. Authors reported

on 7 small studies, 6 of which were cross-over in design, and only 1 in children [77]. The

single study in children included 9 children enrolled in a randomized cross-over trial

comparing an oscillatory PEP (flutter) device compared to a sham device, however

methodological factors precluded any robust conclusions from this study [77]. Further

well-designed, interventional studies evaluating airway clearance methods in children are

needed. Mucoactive agents are sometimes used as part of airway clearance technique and

are discussed in section 2.4.

Aerobic exercise is considered important in the overall management of bronchiectasis.

Although there are no studies in children with pediatric bronchiectasis a study of children

with CF showed significant benefit. A randomized controlled trial compared a 3-year

home exercise program to usual care in children with CF and demonstrated a significant

decrease in lung function (FEV1 and FVC) decline over time compared to controls [78].

17
Further, in a small study on 12 children with PCD, compared to controls without PCD,

authors found that exercise was a more potent broncho-dilator than beta2 agonists [79]. In

light of the additional known health benefits of exercise, children with bronchiectasis are

encouraged to participate in regular aerobic exercise as part of their overall management

plan.

2.2 Antimicrobials

Antibiotic therapy is a key component in the management of patients with bronchiectasis.

This is based upon recognition of the role of bacterial infection in bronchiectasis

pathogenesis. Historically, there has been a paucity of research into optimal antibiotic

prescribing in bronchiectasis, although there has been a recent surge in trials in this area,

particularly in adults.

Bacterial load is directly related to neutrophilic airway inflammation in children with

bronchiectasis [80]. The aim of antimicrobial therapy is to reduce pathogen load and

attenuate the infection-inflammation cycle. Antibiotics reduce morbidity and the risk of

exacerbations whilst also improving QoL in adults with bronchiectasis [81]. A recent

review [66] provides an in-depth summary of antimicrobials in adults and children with

bronchiectasis. Antibiotic selection is based upon many factors including known or

presumed lower airway pathogen, patient factors e.g. age and severity of lung disease and

clinical response to therapy.

However, there are inherent challenges in antimicrobial prescribing for bronchiectasis in

children. As most young children are unable to produce sputum, pathogen identification

18
and susceptibilities are often unknown. CF studies have shown that upper airway

sampling is a poor predictor of lower airway microbiota [82, 83] and is thus not routinely

used in children with bronchiectasis unrelated to CF. Lower airway sampling via

bronchoalveolar lavage (BAL) is relatively invasive and generally undertaken at the time

of diagnosis [84] and later reserved for children who are non-responsive to empiric

antibiotics. Where possible, sputum induction should be used. However, in the absence of

knowledge of an individual child’s lower airway bacteriology, empirical antibiotic

selection is frequently employed (Table 2).

Choice of empirical therapy is based upon studies of the lower airways of children with

bronchiectasis (Table 2). These have shown H. influenzae (NTHi), S. pneumoniae and M.

catarrhalis to be the major infecting lower airway organisms [80, 85]. One pediatric

study showed that H. influenzae was identified on BAL in significant bacterial loads

(defined as >=105 colony forming units per ml) being present in 32%, whilst 14%

cultured S. pneumoniae, 8% M. catarrhalis and 5% harboured S. aureus as the major

bacterial pathogen in BAL culture [80]. In contrast to adults with bronchiectasis, in

whom Pseudomonas aeruginosa is often identified, P. aeruginosa is uncommonly

isolated in children with bronchiectasis (approximately 6% of newly-diagnosed children

[80]), and, if present, raises suspicion of CF or more advanced lung disease.

In addition to bacteria, viruses, most commonly human rhinovirus (HRV), have also been

shown to be associated with exacerbations of pediatric bronchiectasis [86]. However, in

this study, assessment in the non-acute state was not undertaken and as HRVs are

19
commonly found in well children [87] it remains unknown whether HRV triggers

exacerbations of bronchiectasis or whether its presents simply represents asymptomatic

carriage. Identification of viruses in the nasopharynx is reported in up to 45% of

asymptomatic hospitalized children [88].

An association between adenovirus species C (genotypes 1 and 2) and chronic

endobronchial suppuration (protracted bacterial bronchitis and bronchiectasis) has also

been shown [89]. In this study, children with adenovirus were more likely to have

bacteria (primarily H. influenzae, most were non-typeable H. influenzae) co-infecting

their lower airways, compared to those without adenovirus, raising the possibility of

viral-bacterial interaction [89].

Use of antimicrobials for bronchiectasis is generally divided into short and long term use.

The table below provides a general overview of the approach to treating exacerbations

(short-term use), adapted from Australia and New Zealand guidelines also in keeping

with recommendations from the British Thoracic Society [3]. Readers should tailor

antimicrobial selection to their local context. Although there is a paucity of evidence for

optimal duration, antibiotics are usually continued for 14 days and dosing is as per severe

infection [90] [3].

Table 2: Antibiotic selection for management of bronchiectasis exacerbations in

children. Chang AB, Bell SC, Torzillo PJ, et al. Chronic suppurative lung disease

and bronchiectasis in children and adults in Australia and New Zealand Thoracic

20
 Society of Australia and New Zealand guidelines. Med J Aust 2015; 202 (1): 21-23.

© Copyright 2015 The Medical Journal of Australia – adapted with permission.

Mild-to-moderate exacerbation Severe exacerbation (IV

(oral therapy)^ therapy)^

Initial empiric therapy* amoxycillin, amoxycillin- ampicillin, cefotaxime or

clavulanate ceftriaxone (amoxycillin,

ciprofloxacin if P.aeruginosa in amoxycillin-clavulanate, or

recent cultures. cefuroxime)

piperacillin-tazobactam or

ceftazidime + tobramycin§ if

severe or P.aeruginosa in recent

cultures.

Specific pathogens

H.influenzae

β-lactamase–ve amoxycillin Ampicillin (amoxycillin)

β-lactamase+ve amoxycillin-clavulanate or Cefotaxime or ceftriaxone

doxycycline† (amoxycillin-clavulanate or

cefuroxime),

S.pneumoniae amoxycillin Benzylpenicillin G, ampicillin

(amoxycillin)

M.catarrhalis amoxycillin-clavulanate Cefotaxime or ceftriaxone

(amoxycillin-clavulanate or

cefuroxime)

S.aureus di-/flucloxacillin flucloxacillin

MRSA seek specialist advice¶ seek specialist advice¶

21
P.aeruginosa Ciprofloxacin (max 14 days) piperacillin-tazobactam or

ceftazidime + tobramycin§

Non-tuberculous mycobacteria Seek specialist advice¶ Seek specialist advice¶

(NTM)

* Initial empiric therapy is guided by previous lower airway cultures (e.g. from sputum or

broncho-alveolar lavage) and local antibiotic susceptibilities. In children without a lower airway

sample, antibiotic therapy should be targeted towards H. influenzae, S. pneumoniae and M.

catarrhalis.

^ Local specialist advice should be sought for known or suspected antibiotic hypersensitivity,

significant drug side effects or possible drug interactions. British guidelines recommend

clarithromycin as second line agent for infections with S. pneumoniae, H. influenzae and

Methicillin sensitive S. aureus.

§ Of note, there is no proven additional benefit of dual anti-pseudomonal antibiotics for

respiratory infections, as opposed to a single beta-lactam alone. Combination therapy should still

be used for multi-resistant P. aeruginosa strains.

† Doxycycline is only used in children over 8 years of age.

¶ Specialist advice is recommended for treatment of MRSA and NTM. The decision of when to

treat NTM is complicated by high rates of antibiotic resistance, requirement for prolonged

courses and risk of serious toxicity and drug interactions.

Table adapted from: Chang AB, Bell SC, Torzillo PJ, et al. Chronic suppurative lung

disease and bronchiectasis in children and adults in Australia and New Zealand Thoracic

Society of Australia and New Zealand guidelines. Med J Aust 2015; 202 (1): 21-23. ©

Copyright 2015 The Medical Journal of Australia – reproduced with permission.

22
2.2.1 Short-term (Acute exacerbations)

Exacerbations of bronchiectasis invariably occur during follow-up. Exacerbations are

important as they impact on QoL and are associated with financial cost. Further,

frequency of exacerbations requiring hospitalization predict future lung function decline

in childhood [91] which is also seen in adult patients [92]. Aggressive and timely therapy

for exacerbations, with antibiotics and airway clearance, helps to preserve lung function

into adulthood [69, 74, 93]

There is no universally accepted definition of a bronchiectasis exacerbation but a study

by Kapur et al validated a clinical definition in children. This was based on a cohort of 69

children with pediatric bronchiectasis prospectively followed for 900 child-months [26].

In this study, most children had a wet cough with increased severity of cough over at

least a 72-hour period. Other common signs of an exacerbation included: a change in

sputum colour, chest pain, shortness of breath, haemoptysis and auscultatory findings

[26].

A recent study by Chalmers et al of 433 adult patients with bronchiectasis showed that

sputum neutrophil elastase was a good biomarker of severe exacerbations. Elevated

neutrophil elastase was associated with FEV1 decline and neutrophil elastase activity

increased significantly during exacerbations (P=0.001) responding to antibiotic treatment

[94]. Studies identifying potential biomarkers for exacerbations in children are needed.

23
There are no published RCTs evaluating the optimal antibiotic regimen for the treatment

of exacerbations of pediatric bronchiectasis. A multi-center study comparing amoxicillin-

clavulanate, azithromycin and placebo in children with mild-moderate exacerbations is

currently underway [16]. Currently, treatment choice is based upon local susceptibility

profiles and specialist opinion. Similarly, optimal antibiotic duration is unclear.

Compared to duration of antibiotics for acute infections in otherwise well children, longer

courses of antibiotics are sometimes needed. Pathogens tend to persist in damaged

(bronchiectatic) lungs. In addition, microbiological factors such as biofilm formation [95]

and hypermutations [96] further contribute to this. Longer term antibiotic therapy in

bronchiectasis aims to reduce bacterial loads with resultant (presumed) reduction in

airway inflammation and less frequent exacerbations [97] whilst protecting airway

mucosa from further proteolytic and oxidative damage. Suppression rather than

eradication of bacterial pathogens is usually the aim of treatment, with the exception of

certain pathogens e.g. P. aeruginosa and methicillin-resistant S. aureus (MRSA)[3].

Oral antibiotics are usually prescribed in an acute exacerbation if it is mild-moderate in

severity. Amoxycillin-clavulanate is often used as a first-line oral agent due to its beta-

lactamase inhibiting effect. If there is failure to improve on an oral agent or if an

exacerbation is more severe, then intravenous (IV) antibiotics are prescribed. A single

agent, such as a third generation cephalosporin, is often considered first line. Although

there is a paucity of evidence for duration, antibiotics are usually continued for 14 days

[90]. In general, anti-pseudomonal agents are only used if the child has isolated

pseudomonas (Table 2.)

24
2.2.2 Long-term therapy

Recent guidelines suggest that long-term antibiotics should only be considered in patients

with 3 or more exacerbations of bronchiectasis per year [3, 98]. A recent Cochrane

review examining the utility of long courses of antibiotics (4 weeks to 1 year) in adults

and children with bronchiectasis showed a small benefit in reduced exacerbations and

hospitalization rates at the expense of increased bacterial resistance [99]. There are

different antibiotic types used for long term therapy. Prior to commencement of long-

term antibiotics, respiratory or infectious diseases specialist consultation is usually

obtained.

2.2.2a Macrolides

Macrolides act as both anti-microbial and anti-inflammatory agents. In simplistic terms,

macrolides attenuate host inflammatory responses providing an anti-inflammatory effect

without immune system suppression [100]. Their anti-inflammatory effects range from

inhibition of biofilm production to modulation of leukocyte recruitment and function

[100]. The rationale for their use in bronchiectasis is based upon attenuation of the

inflammatory component of the vicious cycle.

Recently, the role of long-term oral macrolides in bronchiectasis has been investigated in

a number of RCTs in children [101, 102] and adults [103-105]. Three multi-center trials,

25
showed significant reductions in exacerbation frequency in adult patients receiving

macrolides, however this was balanced by an increase in adverse effects e.g. diarrhoea

and macrolide-resistant bacteria in sputum. A New Zealand based RCT (EMBRACE

study)[103] involved participants receiving 500mg azithromycin, three times per week, as

compared to placebo. The second RCT was the Bronchiectasis and Long-Term

Azithromycin Treatment (BAT)[105] study where patients were given daily azithromycin

(250mg) for 12 months compared to placebo. Both showed similar benefit in the

azithromycin group with respect to significantly fewer exacerbations (EMBRACE: rate

ratio 0.38, 95% CI 0.26-0.54; p<0.0001; BAT: absolute risk reduction 33.5% 95% CI

14.1-52.9). A third, Australian study (BLESS)[104], showed that 400mg of erythromycin

twice daily for 48 weeks results in a reduction in frequency of pulmonary exacerbations,

lung function decline and sputum production, however, in all studies, a significant

increase in macrolide resistance was observed [104].

An international multi-center trial of macrolides in children with bronchiectasis has

shown similar results to adult studies. The Bronchiectasis Intervention Study (BIS)[101]

included 89 Indigenous children from Australia and New Zealand. Children received

once-weekly azithromycin (30mg/kg) for a mean duration of 20.7 months with resultant

50% (95% CI 35-71) reduction in exacerbation frequency compared to placebo

(p<0.0001). Mean weight-for-age was also significantly higher in the azithromycin group

compared to placebo (1.03 vs 0.20, p=0.003). Similar to findings from adult studies,

nasopharyngeal carriage of macrolide-resistant bacteria was increased in those receiving

azithromycin [101]. A subsequent study examined the determinants of macrolide

26
resistance in these children and showed that poor adherence (<70%) and the remote

Australian setting were major independent risk factors for macrolide resistance in those

receiving azithromycin and hence improved adherence may reduce the likelihood of

emergence of some macrolide resistant strains [102]. Once weekly dosing, as opposed to

daily or second-daily dosing, may also impact upon likelihood of emergence of macrolide

resistance however this remains unstudied. Of note, macrolide resistant S. pneumoniae

declined significantly by the 6-month post-intervention follow-up [102].

The Australian and New Zealand guidelines on the management of bronchiectasis

currently recommend a therapeutic trial of daily or second-daily azithromycin (e.g. up to

12-24 months) in selected patients [e.g. ≥3 exacerbations and/or ≥2 hospitalizations in the

previous 12-months) [11]. Readers should be cognizant that exclusion of non-tuberculous

mycobacterium infection is recommended prior to initiation of long-term macrolide

therapy to avoid emergence of macrolide resistant strains [90].

2.2.2b Inhaled antibiotics

Nebulised or dry-powder administration of antibiotics in CF bronchiectasis has been well

studied in adults with good evidence for their role, particularly tobramycin, in the acute

eradication of Pseudomonas aeruginosa and in decreasing bacterial density in the

airways, reducing exacerbation frequency and improving QoL and lung function in

patients with chronic P. aeruginosa infection [106]. The evidence in pediatric

27
bronchiectasis is less convincing however and adverse respiratory effects are reported to

be more common than in CF [107, 108].

A recent meta-analysis [109] of published trials examining the efficacy and safety of 6

inhaled antibiotics (amikacin, aztreonam, ciprofloxacin, gentamicin, colistin or

tobramycin) in the treatment of adults and children with stable bronchiectasis treated for

4 weeks to 12 months. Benefits of inhaled antibiotics compared to placebo were seen

with respect to reduction in bacterial load (5 trials), eradication of bacteria from sputum

(6 trials) and reduced risk of acute exacerbations (5 trials). Bronchospasm with

significantly more likely in the intervention, compared to the control group (7 trials)

however and no studies included children [109].

Long-term inhaled antibiotics are thus not currently considered part of routine

management in children [11] with the exception of children with P. aeruginosa infection.

2.3 Bronchodilators and inhaled steroids

Airway hyper-responsiveness and bronchiectasis often co-exist especially in those with

more advanced disease [110]. Differentiating asthma from bronchiectasis in children can

sometimes be difficult as both can present with wheeze. In bronchiectasis, wheeze is

more often caused by airway secretions and edema than bronchospasm [68]. Several

studies in adults examine use of inhaled corticosteroids and/or bronchodilators in

bronchiectasis however findings are conflicting. These are summarized in a Cochrane

review published in 2009 [111]. A subsequent prospective double-blinded RCT found no

significant benefit of inhaled corticosteroids compared to placebo in the management of

28
bronchiectasis in adults [112]. There are no RCTs on this topic in children with

bronchiectasis. Current practice in children is to only use inhaled steroids and/or

bronchodilators in children with comorbid asthma, it is thus not recommended practice to

use these medications for children with bronchiectasis alone.

With the exception of patients with co-existent asthma or ABPA, there is no clear

evidence that oral corticosteroids alter the rate of lung function decline in adults with

bronchiectasis. They are thus not routinely used in treating isolated bronchiectasis in

adults or children without asthma or ABPA [92].

2.4 Mucoactive agents

Mucoactive agents aim to assist in mobilizing airway secretions to relieve small and large

airway obstruction and/or reduce mucus hypersecretion. There are different types of

mucoactive medications. These are generally divided into expectorants, mucoregulators,

mucolytics and mucokinetics [113].

There is possibly some benefit associated with using expectorants such as inhaled

hyperosmolar agents. Earlier studies suggested a benefit in assisting mucous clearance in

patients with impairment of muco-ciliary function [114] and in an animal study [115].

However, a single-center double-blinded RCT over 12-months in adults with

bronchiectasis compared 6% hypertonic saline to isotonic saline used in conjunction with

chest physiotherapy and showed no significant difference between groups for the

outcomes of exacerbations, QOL, sputum colonization and respiratory function [103].

However, the study was small (total n=40) and likely under-powered [116]. Nevertheless,

29
inhaled hyperosmolar agents e.g. 6% hypertonic saline is sometimes used in conjunction

with chest physiotherapy in pediatric bronchiectasis.

In contrast, mannitol were initially promising in CF with good overall safety and efficacy

profile [117, 118], however, two RCTs of mannitol use for at least 12-weeks were

recently published in adults with bronchiectasis with less optimistic findings [119, 120].

The first was a phase-3 study [119] where subjects aged 15-80 years with FEV1 ≥50%

predicted received either inhaled dry powder mannitol (320mg twice daily, n=231) or

placebo (n=112) for 12-weeks, followed by open-label for 52-weeks in a subset. Mannitol

provided minimal benefit at 12-weeks and sputum expectoration in the placebo-group

was significantly less than those receiving the intervention (mean difference=4.5g,

95%CI 1.64-7.00; p=0.002) [119]. A subgroup (n=82) had HRCT scans which showed

significantly reduced mucous plugging in the mannitol group [119]. There were,

however, no between-group differences in exacerbation frequency, St. George

Respiratory Questionnaire (SGRQ) score, spirometry, microbiology or inflammatory

parameters [119]. The second RCT involved 461 patients randomized to 400 mg twice

daily of mannitol or low-dose mannitol control [120]. In this longer RCT with a higher

dose (same as CF studies) use of mannitol did not significantly reduce exacerbation rate

but increased the time to first exacerbation (HR 0.78, p=0.022) and improved SGRQ

score (-2.4 units, p=0.046) [120]. This contrasts with data in CF where 24-weeks of

mannitol improved FEV1 and reduced exacerbation frequency by 29% [121]. Until

further pediatric studies become available, mannitol is not recommended in the routine

management of pediatric bronchiectasis.

30
Mucolytic agents aim to reduce mucus viscosity by altering the mucin-containing

components and enable more effective mucociliary clearance. These agents include anti-

DNaseB, N-acetylcysteine, erdosteine and ambroxol. Randomised controlled trials

(RCTs) of these agents in bronchiectasis have shown equivocal or no benefit [4], with the

exception of anti-DNaseB which, in a study by O’Donnell et al, showed detrimental

effect in adult patients with bronchiectasis unrelated to CF, with increased exacerbations,

hospitalization rate and accelerated pulmonary decline [122]. Anti-DNase B is therefore

not recommended in the routine management of children with bronchiectasis.

2.5 Anti-inflammatories

Non-steroidal anti-inflammatories (NSAIDs), such as indomethacin, inhibit neutrophil

function and chemotaxis [123] and may reduce neutrophil elastase release thus

potentially reducing progression of bronchiectasis. There is limited evidence that non-

steroidal anti-inflammatories (NSAIDs) may be beneficial in adults with pediatric

bronchiectasis. A Cochrane review examining nebulized NSAIDs included a single study

in adults that showed inhaled indomethacin reduces sputum production and dyspnea in

adults with chronic lung diseases characterized by chronic sputum production (including

bronchiectasis)[124]. A second Cochrane review examined the use of oral NSAIDS and

found that there were no randomized controlled trials examining their utility in the

management of bronchiectasis [125].

Other anti-inflammatories currently under investigation include phosphodiesterase-4

inhibitor roflumilast, currently licensed in the United States for use in severe COPD and

31
chronic bronchitis [126] and CXC chemokine receptor 2 antagonists that inhibit

neutrophil mediated pulmonary damage and other lung injury induced cellular responses

such as angiogenesis [127], however a recent phase 2 study of this drug was discontinued

due to insignificant benefits and concerns re adverse effects [68, 128].

A comprehensive overview of current and emerging therapeutics in pediatric

bronchiectasis has recently been published (Figure 2 extracted from this manuscript

summarizes these interventions) [68].

2.6 Surgical management

In a small highly select group of children with localized severe disease, who either do not

tolerate conventional therapies or fail to respond, surgical evaluation for lobectomy or

segmental lung resection may be appropriate. The evaluation is usually undertaken in

specialized, tertiary care facilities involving respiratory and infectious diseases

consultation. A retrospective study by Otgal et al in 2004, of 54 children undergoing open

lung resection for bronchiectasis, found that most benefitted from surgery (approximately

85%) although the mortality rate was high (5.6%) from open surgery [129]. More recent

studies advocate a thorascopic approach which has been shown to minimize post-op

recovery in adults, with no intra-operative mortality [130, 131] [132]. Similar studies in

children are unavailable.

3. Preventative and lifestyle

3.1 Exercise

32
Regular exercise improves exercise capacity and QoL in adult patients [133, 134].

Reasons for this include improved sputum clearance, reduced dyspnea and fatigue with

fewer exacerbations over a 12-month period as shown in an adult study [134]. There are

however no comparable studies in children. Nevertheless, due to the known benefits of

exercise with respect to general health, children should be encouraged to participate in

sports and exercise unless specific contra-indications exist (e.g. co-existent cardiac

abnormality).

3.2 Vaccines

Current evidence in pediatric literature indicates that the single predictor of lung function

decline in children with bronchiectasis is frequency of exacerbations requiring

hospitalization [91]. Each hospitalization is associated with a reduction in lung function

(as measured by drop in percentage predicted forced expiratory volume in one second

FEV1% adjusted for time) of 1.95% [91]. Vaccines aim to prevent acute respiratory

infections and reduce exacerbations and consequently acute hospitalizations. Readers are

referred to a recent review for a comprehensive overview of the subject [135].

Several currently licensed vaccines that confer protection against respiratory infections

and are currently recommended for children with bronchiectasis. These include

Streptococcus pneumoniae, Bordetella pertussis and influenza virus vaccines. There are a

number of candidate vaccines under development including those targeting Haemophilus

influenzae, Moraxella catarrhalis, additional serotypes of Streptococcus pneumoniae and

respiratory syncytial virus [135, 136]. These organisms are common respiratory tract

pathogens in children, hence vaccine development is an important priority as it has

33
potential to further reduce exacerbation frequency. A recent study [137] found that

children with bronchiectasis who received >/=3 doses of a pneumococcal conjugate

vaccine containing protein D from H. influenzae produced significantly more IFN-

gamma than children who received the alternative vaccines without protein D (median

939 versus 338pg/ml; p=0.007). The amount of IFN-gamma produced by those

vaccinated approached the levels observed in cells from healthy children [137]. An

interventional study (not yet published) in children with chronic suppurative lung disease

and bronchiectasis has shown benefit from this vaccine with a reduction in frequency of

exacerbations.

In the long-term it is likely that improvements in vaccine uptake amongst children with

bronchiectasis will improve clinical outcomes. However, to advance the field of

vaccinology for chronic lung diseases, further understanding of the different genotypes of

bacteria are also required. For example, in non-typeable Haemophilus influenzae (NTHi),

the most common bacteria cultured from the airways of children with bronchiectasis and

PBB [89, 138], NTHi from the lower airways has recently been found to be genomically

(on whole gene sequencing) different to that of the upper airways i.e. the NTHi in the

lower airways are more likely to lack the gene that codes for protein D [139].

3.3 Nutrition

Macro and micro-nutrient deficiencies may be a risk factor for exacerbations of

bronchiectasis and are an important predictor of acute and chronic respiratory disease in

children [140]. Studies in adults have described an association between Vitamin D

deficiency and worse outcomes in bronchiectasis [141]. However, there are no current

34
studies in children and there is discordance between data from association studies and

that from RCTs for other chronic respiratory diseases [142, 143].

3.4 Environmental pollutant avoidance

Tobacco smoke exposure and other environmental pollutants are known to exacerbate

chronic respiratory diseases [144, 145] and accelerate lung function decline [146].

Preventing children with bronchiectasis from taking up tobacco smoke is imperative.

Adolescents and all parents and guardians should be educated on the deleterious effects

of secondary smoke exposure. Referral to services facilitating smoking cessation should

be undertaken where children or parents smoke.

3.5 Self- or parent-management

Parent and patient education via provision of resources and literature regarding on-line

websites and support groups for families of children with bronchiectasis are an important

component of holistic management. Pictorial based education flipcharts are available and

may assist in education [147]. A self- or parent-management approach encourages

autonomy and promotes awareness amongst patients, families and their extended

communities to assist patients in managing their condition. Provision of bronchiectasis

management plans by respiratory specialists may assist families regarding when to seek

medical assistance and guide primary care physicians in ensuring optimal management of

a child with bronchiectasis.

4. Monitoring

35
Monitoring of children with pediatric bronchiectasis should consist of regular (e.g. 3

monthly) review by a respiratory physician, with lung function assessment when

appropriate (most children >/= 6 years are able to perform spirometry). Monitoring

should include assessment of: exercise tolerance; symptoms of cough, sputum, dyspnea

and wheeze; frequency of exacerbations; QoL measures and presence of clinical signs

e.g. persistent crepitations, clubbing or chest deformity, complications and overall

psychosocial aspects of caring for a child with a chronic illness. Growth and development

are important clinical indicators of disease severity and should be monitored closely [3].

Whilst spirometry is widely used, it is important to acknowledge that FEV1 is a poor

marker of disease severity in children with early bronchiectasis i.e. a child can have

radiological bronchiectasis even when spirometry is within population normal values.

This observation was documented in CF literature more than 15 years ago [148]. In the

early stages of bronchiectasis, FEV1 is entirely normal, this is assumed to be due to

disease being mild and/or localized [32, 149]. In contrast, when bronchiectasis is diffuse,

spirometric abnormalities, although insensitive to disease activity, better reflect disease

severity [150].

Frequency of chest imaging is clinician-dependent but may be indicated if there is

clinical evidence of disease progression. CXRs are very insensitive and rarely used for

monitoring. Whilst there is potential promise for the future use of chest MRI as a means

of monitoring small airways diseases such as bronchiectasis, its current utility is limited.

36
CT scan is considered the gold-standard for diagnosis and monitoring of bronchiectasis.

However, its current use is judicious in children due to the potential (albeit low)

increased cancer risk associated with exposure to ionizing radiation. However, in the

absence of an alternative imaging modality, the risk of CT must be balanced against the

risks of delayed diagnosis and management of bronchiectasis[151].

The use of CT chest as a monitoring modality is generally confined to patients with an

underlying diagnosis e.g. CF or PCD. In these children, bronchiectasis progression is

usually more rapid and in CF, life-expectancy is reduced. Hence, the potential benefits of

regular CT scans, in terms of tailoring treatment strategies and optimizing management

of lung disease, often outweigh the radiation risks associated with regular scanning. The

frequency of CT scanning for children with bronchiectasis needs to be tailored to the

individual child. This includes consideration of the child’s age, the severity and rate of

progression of their lung disease and any other relevant risk factors.

Further management and investigations in children with bronchiectasis is guided by

clinical symptoms and/or signs. If there is chronic deterioration with no clear cause then

investigations such as induced sputum or BAL in the non-expectorating child may assist

in identifying new lower airway infection with pathogens such as P.aeruginosa or NTM.

Investigation for allergic bronchopulmonary aspergillosis (ABPA) should also be

considered.

37
Ideally a multi-disciplinary team should be involved in the care of a child with

bronchiectasis. Effective communication with the child’s family doctor is essential to

achieve optimal care. Those with an underlying immunodeficiency require joint care

between a respiratory physician and immunologist [3].

5. Prognosis

Bronchiectasis severity scores e.g. FACED score [152] and Bronchiectasis Severity Index

(BSI) [153] have been shown to accurately predict morbidity and mortality as well as

hospitalizations, exacerbations and QoL in adults with bronchiectasis [154]. Poor

prognostic indicators in adults include decline in lung function, presence of P.aeruginosa

infection and reduced health questionnaire activity scores [155]. These scoring systems

were developed in adults and are not likely applicable to children as they incorporate

sputum and pulmonary function testing and most children <6 years of age cannot

expectorate sputum or perform spirometry. There are currently no scoring systems

available for children.

38
6. Conclusion

Bronchiectasis is an important cause of respiratory morbidity in children but remains a

neglected field in research and allotment of clinical resources worldwide. The approach

to management is based largely upon evidence extrapolated from CF and adult data and

involves a combination of antibiotics, airway clearance techniques and vaccination. Well-

conducted interventional trials in children with bronchiectasis are urgently needed to

develop treatments to target the disease in its origins and to reduce childhood morbidity

and future adult disease.

7. Expert commentary

In tailoring management of bronchiectasis to children, as first priority, we need to revise

our current definition of pediatric bronchiectasis.

Since the advent of CT in the 1970s, an adult-based definition of bronchiectasis has been

extended to children and continues to be employed by most radiologists for the diagnosis

of pediatric bronchiectasis. Broncho:arterial ratio (BAR) and bronchial wall thickness

(diagnostic criteria) are both age-dependent [156], hence the lack of pediatric specific

criteria may be contributing to an under-estimation and under-appreciation of

bronchiectasis, especially in its early stages.

The importance of developing a pediatric-specific definition of bronchiectasis is

highlighted by mounting evidence to suggest that adult lung disease begins early in life

39
[71, 157]. This is particularly important in view of current knowledge of the potential

reversibility of bronchiectasis in its early stages [47-49]. A relationship between duration

of wet cough and lung function decline in adults with bronchiectasis has been shown

[71]. Further, early initiation of treatment for bronchiectasis may halt or even potentially

reverse the disease [47-49]. Despite this knowledge, the current armamentarium for

managing pediatric bronchiectasis remains very limited.

Antibiotics and airway clearance remain major strategies for managing pediatric

bronchiectasis, however, there is only one RCT currently underway (the first) comparing

options for oral antibiotic use in acute exacerbations [16] and a single pediatric trial

comparing a PEP device to a placebo as the optimal airway clearance technique. There is

promise with respect to future vaccine development in preventing or reducing

bronchiectasis exacerbations [135] however, currently no promising therapeutic

interventions exist.

A clinical spectrum uniting protracted bacterial bronchitis, chronic suppurative lung

disease and bronchiectasis, based upon clinical and laboratory characteristics in common

between these entities, has been proposed [12]. Chronic wet cough is the hallmark

symptom uniting all three conditions. Hence, early recognition of children with recurrent

episodes of protracted wet cough, who may be at risk of bronchiectasis [30], must be

achieved at primary care level. The pediatric population needs to become a major priority

for further research into bronchiectasis. Elucidating the early origins of bronchiectasis in

40
children will likely inform the development of future novel interventions to improve

outcomes from this important disease.

8. 5-year review:

There is increasing recognition of the significance of early life events and interest and

focus on the early origins of chronic respiratory disease, a major cause of morbidity and

mortality worldwide. Hence, we anticipate that there will be an increasing number of

studies on people with bronchiectasis and additional interventional and patho-biological

studies are likely to become available over the next 5 years. These will substantially

improve the evidence base in this field and provide novel ways to achieve better clinical

outcomes for individuals with bronchiectasis. Targeted interventions will include the

introduction of bronchiectasis specific management plans and QoL measures for pediatric

bronchiectasis and multi-center RCTs will provide further insight into effective

treatments.

Previous RCT data on rhDNAse clearly depicted that blind extrapolation of CF

management to bronchiectasis can be harmful [122] and more recent data on inhaled

aztreonam [108] has reinforced this. However, concerted work and support from

pharmaceutical companies in the research and development arena will be required to

advance knowledge and further improve management options.

The discordance between pediatric and adult bronchiectasis is currently only largely

appreciated by pediatric-focused clinicians. With time, an understanding of the key

41
differences will become more widespread. The importance of prevention and early

treatment in children, in whom bronchiectasis is reversible when mild [12], will gain

greater momentum, particularly as appreciation of the early origins of chronic lung

diseases affecting adults, increases.

The global epidemiology of bronchiectasis is unknown and the establishment of

bronchiectasis registries is needed to estimate the prevalence and burden of disease across

continents.

The importance of tackling health issues in childhood and the impact with respect to

improving health outcomes in adulthood is already gaining recognition [158]. Indeed,

future studies in adults may prove that bronchiectasis may be reversible with early

diagnosis and treatment. This would necessitate intense education of both the public and

health professionals of the potential significance of chronic wet or productive cough and

the need for aggressive and timely management. Earlier diagnosis would also require an

age-specific adjustment of the definition of the main HRCT feature of bronchiectasis

(increased broncho-arterial ratio) as opposed to a single cut-off throughout life that is

used currently, as broncho-arterial ratio increases with age in healthy adults. The link

between childhood and adult respiratory diseases need further research.

Bronchiectasis shares many common features with neutrophilic asthma, COPD and

protracted bacterial bronchitis (PBB), suggesting that therapies developed for one of

these diseases could be beneficial for others. PBB is now being recognized in adults

42
[159] and with increased interest from adult-based researchers, major advancement will

likely ensue.

A concerted, global approach to childhood bronchiectasis will likely have significant and

far-reaching effects into the future with potential to improve our understanding of adult

bronchiectasis and provide insights into future preventative and therapeutic interventions

for this increasingly common condition [45].

Key issues:

• Heightened recognition and improved access to high-resolution CT has likely

contributed to the increase in bronchiectasis diagnoses worldwide; further

research into the early origins and predictors of bronchiectasis are urgently

needed

• Recognition of the need for a pediatric-specific definition of bronchiectasis is

paramount to facilitate earlier diagnosis, timely management and improved

clinical outcomes in children with bronchiectasis

• There is a current deficiency in randomized controlled trials in pediatric

bronchiectasis unrelated to CF; extrapolating findings from adult and CF studies

can have limitations and may be detrimental

• Development of new vaccines for children and adults with bronchiectasis is

needed to achieve primary prevention goals

43
Funding

A. Chang is supported by a NHMRC practitioner fellowship (grant 1058213)

Declaration of Interest

A. Chang holds multiple grants awarded from the NHMRC related to diseases associated

with pediatric cough and bronchiectasis. The views expressed in this publication are

those of the authors and do not reflect the views of the NHMRC. D. Wurzel holds a

current grant awarded from Murdoch Childrens Research Institute related to respiratory

disease. The authors have no other relevant affiliations or financial involvement with any

organization or entity with a financial interest in or financial conflict with the subject

matter or materials discussed in the manuscript apart from those disclosed.

44
 ure Legend
Figu ds:

Figu
ure 1a:

Hospital Admisssions (20088-2012) andd Mortality ((2006-2010)) for New Z

Zealand Chilldren

and Young People with Cyystic Fibrosiis by Age. Reproduced

R with permisssion from [[38].

45
 ure 1b:
Figu

Acuute and Semii-Acute Hosspital Admissions (2006-2010) andd Deaths (20004-2008) for
f

New
w Zealand C
Children andd Young Peoople with Brronchiectasiis by Age. R
Reproduced with

perm
mission from
m [38].

46
 ure 2:
Figu

A siimplified schhematic diaagram of thee factors conntributing too the developpment of

bronnchiectasis. Reproducedd with perm

mission from
m [68].

47
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