Series
Bronchiectasis 1
Lancet 2018; 392: 866–79
This is the first in a Series of
two papers about bronchiectasis
This online publication has been
corrected. The corrected version
first appeared at thelancet.com
on October 4, 2018
See Perspectives page 811
Child Health Division, Menzies
School of Health Research,
Casuarina, NT, Australia
(Prof A B Chang PhD);
Department of Respiratory
Medicine, Children’s Health
Queensland, Brisbane,
Queensland University of
Technology, Brisbane, QLD,
Australia (Prof A B Chang); Head
of Section (Paediatrics),
Imperial College London,
London, UK (Prof A Bush MD);
National Heart and Lung
Institute, London, UK
(Prof A Bush); Royal Brompton
Harefield NHS Foundation
Trust, London, UK (Prof A Bush);
Menzies Health Institute
Queensland, Griffith
University, Gold Coast, QLD,
Australia (K Grimwood MD);
and Department of Infectious
Diseases and Department of
Paediatrics, Gold Coast Health,
Gold Coast, QLD, Australia
(K Grimwood)
Correspondence to:
Prof Anne B Chang, Department
of Respiratory Medicine,
Children’s Health Queensland,
Brisbane, QLD 4101, Australia
anne.chang@menzies.edu.au
866 www.thelancet.com Vol 392 September 8, 2018
Bronchiectasis in children: diagnosis and treatment
Anne B Chang, Andrew Bush, Keith Grimwood
Bronchiectasis is conventionally defined as irreversible dilatation of the bronchial tree. Bronchiectasis unrelated to
cystic fibrosis is an increasingly appreciated cause of chronic respiratory-related morbidity worldwide. Few randomised
controlled trials provide high-level evidence for management strategies to treat the children affected by bronchiectasis.
However, both decades-old and more recent studies using technological advances support the notion that prompt
diagnosis and optimal management of paediatric bronchiectasis is particularly important in early childhood. Although
considered to be of a non-reversible nature, mild bronchiectasis determined by radiography might be reversible at any
age if treated early, and the lung function decline associated with disease progression could then be halted. Although
some management strategies are extrapolated from cystic fibrosis or adult-based studies, or both, non-cystic fibrosis
paediatric-specific data to help diagnose and manage these children still need to be generated. We present current
knowledge and an updated definition of bronchiectasis, and review controversies relating to the management of
children with bronchiectasis, including applying the concept of so-called treatable traits.
Introduction the many children at risk of, or affected by, this condition.
Bronchiectasis unrelated to cystic fibrosis has gained High-quality evidence in this field is scarce, and unless
prominence in the past decade with the increasing otherwise specified, recom­ mendations are based on
appreciation that it is more common than previously expert opinion.
thought.1–3 Although the burden of bronchiectasis is
particularly high among Indigenous populations (one in Diagnosis and definition
63–68 children4) and low-income settings (wherein the Clinical diagnosis
epidemiology [the cause and burden of disease] is Awareness of the symptoms and signs of bronchiectasis
changing5), it is also present in major cities.2 Few is important for case ascertainment (table 1, figure 1).
reliable prevalence estimates exist for bronchiectasis; Presence of key symptoms should alert clinicians to
extrapolation of published data suggests its prevalence assess the child for bronchiectasis. When bronchiectasis
ranges widely (0·2–735·0 cases per 100 000 children).2 is identified, a minimum set of tests are warranted
Although the paediatric bronchiectasis knowledge to establish whether an underlying cause is present
base is increasing slowly, bronchiectasis remains and for clinical care. Chronic wet or productive cough,
neglected compared with other chronic respiratory the dominant symptom of bronchiectasis,2 can be
diseases (eg, cystic fibrosis).6 We provide an update of intermittent after treatment.1 Recurrent (>3 episodes per
data and controversies relating to the diagnosis and year) protracted bacterial bronchitis8 (adjusted odds ratio
management of paediatric bronchiectasis unrelated [OR] 11·5, 95% CI 2·3–56·0) and a wet or productive
to cystic fibrosis. This includes proposing an updated cough failing to respond to 4 weeks of oral antibiotics9
definition to raise awareness and encourage an evidence- (20·9, 95% CI 5·4–81·8) predicts the presence of chest
based approach, with the hope of improving the lives of CT-defined bronchiectasis. Among young Australian
Indigenous children, a persistent cough at 3 weeks after
hospital admission for treatment of bronchiolitis was
Search strategy and selection criteria significantly associated with bronchiectasis (OR 3∙0,
We searched PubMed and Cochrane databases with no 95% CI 1·1–7∙0) within the next 13 months.10
language or date restrictions but we prioritised publications Other clinical findings, dependent on disease severity,
since January, 2010. For the diagnosis component, we used the vary considerably among global cohorts and clinical
search terms: “bronchiectasis” or ”suppurative lung disease”, settings (table 1). In general, when the disease is mild
and “diagnosis” or “endotypes”, or “phenotypes”, or (usually in affluent settings where bronchiectasis is
“biomarkers”, and “children”. For the management diagnosed earlier), the symptoms and signs of severe
component, we used the search terms: “treatment” or disease (eg, haemoptysis) are rare.2 Comorbidities are
“management”, or “trials” and “bronchiectasis” or ”suppurative important and might not relate directly to markers of
lung disease”, and “children”. In the management sections, we bronchiectasis severity. These include airway hyper-
placed more weight on randomised controlled trials, responsiveness, malnutrition, cardiac dysfunction, sleep-
systematic reviews, and clinical practice guidelines where related disorders, gastro-oesophageal reflux disease,
evidence was assessed and used. We included studies relevant psychosocial elements, and quality of life (QoL).1,11
to the topic but excluded single case reports. The presence of any of the features above should trigger
a management pathway (figure 1).
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Radiological diagnosis
Proportion of cohort with symptom (%) Odds ratio* (95% CI)
Features of bronchiectasis seen on chest high-resolution
CT, the objective method of diagnosing bronchiectasis, are High-income countries Low-income
from non-Indigenous countries
shown in figure 2. The main features of bronchiectasis settings
in CT scans are: (1) increased broncho-arterial ratio
Chronic wet or productive cough 35 28–100 527 (45·4–6102)†
(defined as inner diameter of airway as a ratio to outer
Wet cough not resolved after 4 weeks ·· ·· 7·5 (0·3–161·5)
diameter of the accompanying vessel, within 5 mm and
Recurrent protracted bacterial bronchitis ·· ·· 18·4 (1·0–349·7)†
in a non-tangential plane), the signet-ring appear­ance;
Recurrent pneumonia ·· 46 22·8 (1·2– 424·3)†
(2) bronchial wall thickening; (3) lack of bronchial tapering
Previous pneumonia 4–47 23–100 Not examined
(from central to periphery) that can also be seen as
Haemoptysis 0 5–41 Absent in cohort
tramlines depending on the orientation plane; (4) presence
Wheeze or reversible airway obstruction 10–40 20–66 Absent in cohort
of bronchial structures in the lung periphery; (5) mucus
plugging; and (6) mosaic perfusion reflecting air-trapping, Chest pain 3 3–43 Absent in cohort

particularly in expiration scans. In the acute state, tree-in- Dyspnoea or exertional dyspnoea 1 9–81 4·3 (0·2–109·7)

bud appearance can also be visualised. False positives can Faltering growth 4 10–66 Absent in cohort
occur at high altitude, with asthma, and reduced Feeding difficulties ·· ·· 22·8 (1·2–424·3)†
pulmonary flow, while false negatives are mentioned Digital clubbing ·· 4–73 7·5 (0·3–161·5)
below. The relative sizes of the airway (from cylindrical Chest deformity ·· 15–29 4·3 (0·2–109·7)
to varicose then cystic) are well accepted markers of Differential airway sounds (on chest ·· ·· 7·5 (0·3–161·5)
auscultation)
severity and form components of the various paediatric
Crackles ·· 47 10·8 (0·5–218·9)
radiographically-based bronchiectasis scales.1 However,
Abnormal chest radiograph ·· ·· 41·6 (2·3–750)†
imaging techniques and interpretation are controversial
and radiographic images alone are usually insufficient to Median forced expiratory volume in 1 s 71–95 52–80 4·3 (0·2–109·7)
(% predicted)
diagnostically label childhood bronchiectasis.
Median forced vital capacity (% predicted) 77–96 58–82 ··
Controversies in diagnostic and radiographic labelling
exist. There are four key reasons why the current labelling Data summarised from several publications.2,5 Only data published in the last 20 years were included. *The odds ratio of
for paediatric bronchiectasis needs revising. First, the key having bronchiectasis reported in a study of 346 Australian children with chronic cough, comparing those who were
newly referred to a respiratory paediatrician with children whose cough resolved without any specific treatment.7
radiographic feature of bronchiectasis, namely increased †Depicts significant values.
broncho-arterial ratio (BAR; inner airway compared with
outer vessel diameter, figure 2) of more than 1∙0 to 1·5, was Table 1: Prevalence of symptoms and signs related to bronchiectasis
based on six adults with severe bronchiectasis.12 Currently a
single cutoff to define abnormality is used for all ages. endobronchial suppuration is requested and carried out,
However, BAR correlates with age (r=0·77, p<0·0001) in neutrophilic endobronchial suppuration is present. Use
adults (aged 21–90 years) without cardiopulmonary of paediatric specific rather than the adult derived
disease.13 In children aged 0–5 years without evidence of definitions (ie, irreversibility and a single higher BAR
bronchial sepsis, BAR is 0·49–0·58,14 and the upper limit of value) is important in the context of stimulating efforts to
normal (mean plus twice the standard deviation) is 0·76, prevent disease progression or even reverse the changes
suggesting that a lower cutoff of 0·80 or more should be with early and intensive treatment in children.
used to define abnormality12 when the clinical history is
consistent with bronchiectasis. Airway diameter also Underlying causes and investigations
increases with increasing lung volumes; thus, uncontrolled Bronchiectasis is the end consequence of many conditions
inspiration depth is a potential source of error. Second, related to recurrent or persistent respiratory infections, or
some clinicians and authors use the outer airway diameter both. The findings, in terms of cause and comorbidities
when measuring BAR as opposed to the inner diameter.15 will differ, depending on the region, country, and depth of
Third, sensitivity varies with the type of CT scan used investigations undertaken (table 2). For example, in-depth
to diagnose bronchiectasis.1,12 Fourth, the radiographic testing for rare genetic immunodeficiency disorders could
definition of irreversible airway dilation requires at least be required (such as when consanguinity exists).16 As
two CT scans,12 which is associated with an increased underlying causes (eg, immunodeficiency) affect clinical
radiation exposure. Strictly speaking, in clinical medicine management, a search for a possible underlying condition
irreversibility cannot be defined rigorously, the reversibility is mandatory. A minimum set of diagnostic tests (all
can only be documented (see appendix for further details). children should have these tests) with additional tests, See Online for appendix
We thus recommend that childhood bronchiectasis is dependent on the clinical setting, is recommended
defined as a clinical syndrome (persistent or recurrent (figure 1, table 2). Some of these possible causes have
[>3] episodes of chronic [>4 weeks] wet or productive suggestive clinical features and initial investigation
cough, sometimes with coarse crackles and digital results. More than one contributing cause might be found.
clubbing), confirmed radiographically using paediatric Spirometry and bronchoscopy findings are summarised
BAR data (abnormal when >0∙80). If an investigation for in table 3.

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least in a substantial proportion of patients) and the

Key symptoms initiating (or perpetuating) events include infection and
• Chronic productive or wet cough unresponsive to 4 weeks of antibiotics
• Recurrent (>3 times per year) protracted bacterial bronchitis inflam­ mation. Without intervention, the unrelenting
• Recurrent pneumonia or lower respiratory tract infections infection or inflammation, or both, leads to ongoing
• Haemoptysis
• Severe asthma
damage manifested clinically (pending treatment) as an
• Digital clubbing over­lapping continuum of protracted bacterial
• Persistent chest signs, pneumonia, or chest radiograph changes bronchitis,31 chronic suppurative lung disease,33 and
• Positive sputum culture for unusual organisms (eg, Pseudomonas
aeruginosa) eventually bronchiectasis (figure 3). Chronic cough
• Respiratory symptoms after infection with certain organisms (eg, Bordetella (>4 week’s duration) in children is the dominant
pertussis, adenovirus pneumonia, and Mycobacterium tuberculosis)
symptom after having acute lower respiratory
infections.10,34 Bacterial infection and inflammation are
Evaluate for bronchiectasis present in children with chronic wet cough,35 including
protracted bacterial bronchitis, and are injurious to the
lung.36 These issues are likely to be more important in
Chest CT scan (multidetector with high-resolution reconstruction) the developing lung than the matured lung (ie, events
No Yes
in the first years of life are most likely to have long-term
adverse effects).37,38
Chronic cough duration correlates with increased
airway inflammatory dysfunction,39 poorer lung function,
Reconsider diagnosis, assess for Assess in all children Assess in selected children
chronic suppurative disease, • Bronchoscopy and worse radiographic bronchiectasis scores in children
For possible underlying causes
and manage patients • Full blood count • Tuberculosis and adults.23,40 In 93 children, the duration of wet cough
accordingly • HIV
• IgA, IgM, IgG, IgE
• Other in-depth immune tests
correlated with markers of bronchiectasis severity (ie,
• Vaccine responses
• Sweat test • Tests for aspiration Bhalla radiology score, bronchoscopic appearance, and
• Tests for primary ciliary neutrophilia).23 107 (59%) of 182 Australian adults with
For clinical care dyskinesia
• Lower airway specimen* • Cystic fibrosis genotypes bronchiectasis had a chronic cough from childhood or
• Lung function*
• Exacerbating factors
• Other genetic assessment adolescence;40 those symptomatic from childhood had
(pollution, tobacco exposure) substantially worse disease (ie, poorer radiographic scores,
• Immunisation, including worse lung function, more exacerbations, and more
annual influenza
• Nutrition status hospitalisations for treatment) than those who did not
• Psychosocial have symptoms in childhood.40
• Other comorbidities (eg,
previous tracheoesophageal
The link between protracted bacterial bronchitis and
fistula, prematurity-associated bronchiectasis is reflected in the microbiology1,31 and
conditions) microbiota41 of the lower airway, the inflammatory
• Indoor and outdoor pollution
profile (eg, airway neutrophilia, elevated interleukin-1β
concentration, and matrix metalloproteinases),1,39 and
Figure 1: Suggested diagnosis pathway when a child is suspected of having bronchiectasis supported by longitudinal studies.8 Also, pathobiological
*A lower airway specimen should be obtained and in young children this usually warrants a bronchoscopy; lung studies describe impaired efferocytosis42 and elevated
function should be investigated if the child is age appropriate. The optional tests depend on the clinical setting.
expression of genes32 related to macrophage function and
impaired resolution of inflammation in both protracted
Framework of pathogenesis of chronic bacterial bronchitis and bronchiectasis; and the values of
suppurative lung disease and bronchiectasis the above in children with protracted bacterial bronchitis
Except for congenital tracheobronchomegaly (Mounier- were intermediate between controls and individuals with
Kuhn syndrome), the presence of underlying conditions bronchiectasis.
associated with future development of bronchiectasis Our framework emphasises the importance of pre-​
(eg, hypogammaglobulinaemia) do not always result vention, early diagnosis, and optimal management, since
in bronchiectasis, provided treatment is initiated early (cylindrical) bronchiectasis is potentially reversible
early. This theory is supported by several cohorts show­ in children, as described by earlier bronchogram-based
ing that with optimal treatment, and irrespective of the studies28–30 and later substantiated by CT-based data.43
underlying cause, lung function improves init­ially and Thus, in children, clinicians can hope to reverse the
does not decline 3–5 years later.24,25 Our proposed disease (when possible) and limit disease progression.
framework (figure 3) is based on Cole’s widely accepted
“vicious cycle” hypothesis27 supported by indirect Biomarkers, phenotypes, endotypes, and traits
evidence and biological plausibility, as obtaining Airway neutrophilia is the dominant airway inflam­
randomised con­trolled trial (RCT) level evidence is not matory profile in bronchiectasis, but several cohorts
possible. showed additional eosinophilic inflammation (up to
As suggested by astute clinicians more than 34% of the cohort).1,22 Many possible biomarkers
six decades ago,28–30 bronchiectasis is preventable (at (eg, neutrophilic inflammation) exist,1,44 but none are

868 www.thelancet.com Vol 392 September 8, 2018


well accepted or used clinically. Among adults with
bronchiectasis, latent cluster-analysis suggests
phenotypes exist and endotypes have been proposed.3
However, these phenotypes and endotypes have not
been validated and there are no comparable data for
children. Indeed, the lower airway microbiota of children
with bronchiectasis is more like that of children with
protracted bacterial bronchitis and substantially different
from adults with bronchiectasis.41 The long-term aim
should be to progress from the airway phenotype of
chronic infection and neutrophilic inflammation, which
has limited non-specific therapeutic avenues, to specific
endotypes as in cystic fibrosis thus allowing molecular-
based treatments (eg, ivacaftor). The concept of
paediatric treatable traits (figure 4) might be useful, but
requires clinical validation. The proposed treatable trait
approach is derived from asthma and COPD;45,46 both of
which are also heterogeneous conditions that overlap
with adult bronchiectasis.3
Management
With few RCTs assessing children with bronchiectasis,
treatment recommendations are based largely on expert
opinion and extrapolation of studies done in patients
with cystic fibrosis and in adults with bronchiectasis.47–49
The possible dangers of some of these approaches were
highlighted previously elsewhere.48 Nevertheless, cystic
fibrosis-based data show that good clinical care alone
(attention to infection and nutrition) before availability of
CFTR-targeted therapy substantially improved clinical
outcomes (increased forced expiratory volume in 1 s of
children aged 6 years [91% in 1987–91 cohort to 98% in
2007–11 cohort] and median life expectancy [25 years in
1982 to 50 years in 2014]).50
Goals of management
Management goals centre around preventing further
airway damage, and include optimising postnatal
lung growth; preventing premature respiratory decline;
optimising QoL; minimising exacerbations and; pre­
venting complications. Ideally a team approach with
incorporation of allied health expertise (ie, nursing,
physiotherapy, nutrition, and social work) is used as this
model improves outcomes of chronic diseases (table 4).62
Infection and antimicrobial therapy
Microbiology and principals of antibiotic selection
The type and specimen quality is important for
interpretation for clinical use (table 3). Suggested
empirical antibiotics are based upon bronchoalveolar
lavage data from children in a stable clinical state
(appendix p 4). Infection is often polymicrobial with
Haemophilus influenzae, Streptococcus pneumoniae, and
Moraxella catarrhalis dominating. In contrast with cystic
fibrosis, Staphylococcus aureus, Pseudomonas aeruginosa,
Aspergillus, and non-tuberculous mycobacterial species
are rarely detected in children. S aureus or P aeruginosa
www.thelancet.com Vol 392 September 8, 2018 869
Series
A B
C D
Figure 2: Features of bronchiectasis seen in chest high resolution CT scans
reconstructed from multidetector CT scans ranging from mild (cylindrical)
to severe (cystic)
See Radiological diagnosis section for description of features. (A) Cylindrical
bronchiectasis. Early bronchiectasis that is likely to be reversible if diagnosed early
and treated aggressively. This CT scan of a 4 year old child shows in the left and
right lower lobes and feature 3 in the right middle lobe. (B) Cylindrical
bronchiectasis. A repeat CT scan 2 years later shows resolution of the
bronchiectasis, but with linear fibrosis within the inferomedial aspect of the right
middle lobe. Clinically the child was asymptomatic. (C) Varicose or fusiform and
cystic bronchiectasis. A CT slice from a 22 month old child with previous pulmonary
tuberculosis who migrated to Australia. This CT scan shows varicose bronchiectasis
in the right upper lobe and the more severe cystic bronchiectasis in the left. In the
left upper lobe, increased broncho-arterial ratio, bronchial wall thickening, lack of
bronchial tapering, and presence of bronchial structures in the lung periphery are
present with centrilobular densities with tree-in-bud appearances also visible.
(D) Varicose or fusiform and cystic bronchiectasis. Following aggressive treatment,
the repeat CT scan undertaken 3 years later shows improvement in the cystic
bronchiectasis where some cystic areas have become varicose. Asymmetry is
shown in the lung volumes with the right lung appearing hyperinflated relative to
the left, suggesting impaired growth of the left lung.
are detected more often in older patients with advanced
disease with comorbidities, unrecognised cystic fibrosis,
or primary ciliary dyskinesia.19,63
Where some viruses (eg, adenoviruses) can initiate
bronchiectasis, others precipitate exacerbations. Patients
with bronchiectasis might have impaired antiviral
defences. One study found more than 100-times higher
rhinovirus loads in bronchoalveolar lavage fluid from
patients with bronchiectasis than in controls infected
with rhinovirus.64 Another study followed up 69 children
with bronchiectasis (900 child-months of observation),
performing naso-​ pharyngeal aspirates during 77 acute
exacerbations.65 A respiratory virus was detected in 48% of
samples, mainly rhinoviruses (n=20) and parainfluenza
viruses (n=6).65 However, as there were no control
samples, the virus attributable risk remains unknown.
Our understanding of the pulmonary microbiome is
evolving. A longitudinal study of 76 adults (381 sputum
samples) underscores the complexity of lower airway
microbial communities, whereby the patient character­
istics correlated poorly with the clinical state, antibiotic
treatments, and underlying cause.66 Studies in children
 Series

Proportion reported for Suggestive clinical feature Confirmatory test

underlying cause based on
income* (%)
High Low
Idiopathic 18–55 0–52 Diagnosis of exclusion None
Post-infection 4–36 10–40 History of infection None
Post-tuberculosis 0 3–20 History of tuberculosis ··
Post-infectious bronchiolitis obliterans 0–3 8 History of severe respiratory infection, inspiratory crackles CT scan features, nuclear medical scan
Recurrent protracted bacterial bronchitis ·· 23 History of protracted bacterial bronchitis8 ··
Immunodeficiency16 10–34 0–19 Recurrent severe and persistent or atypical infections, ··
family history, consanguinity, faltering growth
Agammaglobulinaemia or hypoglobulinaemia ·· ·· ·· IgA, IgG, IgM values
Selective hyperglobulinaemia (eg, hyper IgE, ·· ·· ·· Immunoglobulin levels, genetics
hyper IgG4, hyper IgM) (eg, CD40 mutations)
Specific antibody deficiency16 ·· ·· ·· Immunoglobulin concentrations to vaccines
Neutrophil abnormalities (function with or ·· ·· Chronic granulomas, recurrent pyogenic or fungal In-depth immune tests
without movement)16 infections
Others ·· ·· Many rare causes (eg, bare lymphocyte syndrome, Genetics and in-depth immune tests
STAT1 mutations
Secondary 4–11 1 History of immunosuppressant chemotherapy, Serology
post-oncology HIV: clinical risk factors
Associated with syndromes 2 ·· Trisomy 21 and velocardiofacial syndrome Genetics (eg, 22q11, homozygous for ATM
(facial features)†; ataxia-telangiectasia gene), α-fetoprotein
(movement disorder)†
Congenital malformations 1–15 0–10 ·· ··
Tracheobronchomegaly† ·· ·· Unusual cough or respiratory noises Bronchoscopy
Tracheomalacia ·· ·· Brassy-type cough, history of associations Bronchoscopy; controversy regarding whether
(eg, tracheo-oesophageal fistula or atresia, vascular ring or tracheomalacia is secondary to airway
slings) suppuration or the primary cause†
Foreign bodies 0–2 4–10 History of acute aspiration Bronchoscopy
Obstructive airway lesions ·· ·· Risk factors—eg, active tuberculosis, lymphadenopathy Bronchoscopy
Lung injury ·· ·· ·· ··
Aspiration† 4–22 0–10 Dysphagia, neurological abnormality Assessment of swallow (eg, video fluoroscopy)
Gastro-oesophageal reflux disease ·· 4 ·· ··
Pollution† ·· ·· History of exposure NA
Mucociliary clearance apparatus or epithelial disease
Primary ciliary dyskinesia17 2–24 0–26 Tachypnoea or oxygen requirement at birth (full term Nasal fractional nitric oxide, cilia biopsy and
babies), congenital cardiac disease, heterotaxy, early onset motility, genetics, see guidelines17
wet cough, and nasal disease
Cystic fibrosis† Excluded in all 6 Family history, growth faltering, diarrhoea Sweat test and genotype
studies
Concomitant lung disease
Asthma or airway hyper-responsiveness† 40‡ 2–22 Response to β2 agonists Spirometry, airway hyper-responsiveness
challenges
Prematurity4 ·· ·· History of preterm birth ··
Non-post-infectious bronchiolitis obliterans† 3 ·· Risk factors (eg, post-transplantation, medications) CT scan pattern, lung biopsy
Allergic bronchopulmonary aspergillosis18 0 6–8 Dyspnoea and wheeze; minimum criteria in guidelines Elevated aspergillus IgG and IgE, total IgE
requires presence of asthma or cystic fibrosis18
Interstitial lung or connective tissue disease† 0–1 0–46 Risk factors (eg, medications, autoimmune diseases) Disease-specific serology
Other syndromes
Marfan syndrome† ·· ·· Body habitus, pectus excavatum FBN-1 gene
Yellow nail syndrome† 1 ·· Yellowish nail discolouration and dystrophy, ··
lymphoedema, and pleural disease
Polycystic kidney disease and other kidney ·· ·· Renal cysts Renal ultrasound, genetics
disease†

High-income country data are limited to non-Indigenous settings as data from Indigenous settings are similar to low-income countries.2 NA=not applicable. *Data summarised from a review2 and other papers
(see appendix for references). †Reference in appendix. ‡Cohorts in high-income countries rarely report asthma as the underlying cause once the patients have been evaluated; cause and effect is controversial.

Table 2: Most common underlying causes associated with development of bronchiectasis in children

870 www.thelancet.com Vol 392 September 8, 2018

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Indication Key findings Additional comments

Spirometry Routine when age
appropriate (usually when
aged >3 years in specialist
centres and >6 years in
other centres)
Lower airway Routine for assessment of
specimen airway microbiology
Bronchoscopy Focal disease, suspected
airway lesions, foreign
body inhalation,
non-response to antibiotic
treatment, especially if
sputum unavailable or
unexplained deterioration
Normal in mild disease; in later-stage disease, spirometry is
predominantly obstructive, but some children might have
primarily restrictive or mixed obstructive and restrictive
patterns1
Respiratory pathogens identified; summarised from review19
and supplementary table (excluding study with unclear
denominator): Haemophilus influenzae 32–55%; Streptococcus
pneumoniae 10–37%; Moraxella catarrhalis 2–20%;
Staphylococcus aureus 0–17%; Pseudomonas aeruginosa 0–16%;
Mycoplasma pneumoniae 0–2%; Klebsiella species 0–6%;
non-tuberculous mycobacteria 0; Aspergillus 0; respiratory
viruses up to 12%; no pathogens, up to 51%
Airway suppuration; this amount and type of airway
suppuration, and airway changes seen during bronchoscopy
correlate with disease severity23
Spirometry is insensitive both for detection and monitoring of disease severity
compared with CT scans.1
Obtaining suitable respiratory specimens to guide antibiotic therapy is difficult in
non-expectorating preschool children. Upper airway samples and induced sputum
in preschool children are unreliable at predicting lower airway microbiology in
young children with bronchiectasis.20,21 Although bronchoalveolar lavage enables
collection of lower respiratory specimens, it is invasive and is restricted to initial
investigations for bronchiectasis or if patients fail therapy and atypical or
antibiotic-resistant pathogens are suspected.22 Various specimen types and
different diagnostic thresholds were used between studies (see appendix).
Obtaining suitable respiratory specimens to guide antibiotic therapy is difficult in
non-expectorating preschool children. Upper airway samples and induced sputum
in preschool children are unreliable at predicting lower airway microbiology in
young children with bronchiectasis.20,21 Although bronchoalveolar lavage enables
collection of lower respiratory specimens, it is invasive and is restricted to initial
investigations for bronchiectasis or if patients fail therapy and atypical or
antibiotic-resistant pathogens are suspected.22 Various specimen types and
different diagnostic thresholds were used between studies (see appendix).

Table 3: Summary of spirometry and lower airway microbiology

Treatable traits (factors affecting Chronic infection,

outcomes and consequences) persistent biofilms,
• Quality care, access, service, and inflammation, and
family factors immune
• Microbial virulence factors dysregulation
• Host susceptibility factors (some
might not be treatable)
• Modifiable factors (see section on
Predisposing factors Airway remodelling
modifiable features)
• Genetics and ongoing
• Epigenetics disease progression
• Low birthweight or prematurity
• In-utero tobacco smoke
Acute respiratory Early persistent Epithelial and Airway wall matrix
infections infection, endobronchial injury; damage
Modifiable factors inflammation with or mucociliary disruption
• Vaccinations without atelectasis
• Malnutrition (macro or micro)
• Hygiene practices
• Health education Protracted bacterial Chronic suppurative Radiographic bronchiectasis
• Socioeconomic bronchitis lung disease Reversible Irreversible
• Environmental tobacco
smoke or pollutants
• Housing conditions Clinical manifestation of disease process

Figure 3: Framework for the development of paediatric bronchiectasis

This adapted framework26 is based on a combination of Cole’s vicious cycle theory (appendix),27 and both old28–30 and recent studies on protracted bacterial
bronchitis,31,32 chronic suppurative lung disease,33 and bronchiectasis.1 The diagnostic criteria and features of protracted bacterial bronchitis are described in recent
reviews from the past 3 years (appendix). The framework emphasises the importance of early detection and treatment of endobronchial suppuration (reflected by
chronic wet cough), which halts the vicious cycle of infection-inflammation.

are limited by low bacterial loads and difficulties accessing
lower airway samples.67 So far, none of the aforementioned
studies have resulted in improved clinical care.
Principles of antibiotic use
High bacterial density in the lower airways is associated
with more severe and more frequent symptoms,
exacerbation frequency, and inflammatory indices.68
Antibiotics aim to reduce airway bacterial loads,68 thereby
interrupting the cycle of infection and inflammation
(figure 3). Antibiotics can be prescribed to prevent and
treat acute exacerbations, and to eradicate P aeruginosa
(table 5, figure 5).70
Exacerbations: flare-ups or lung attacks
Like with other chronic airway diseases, exacerbations are
common. Exacerbations are associated with increased
psychological stress, impaired QoL, lung function decline
(–1·9% forced expiratory volume in 1 s predicted per
hospitalised exacerbation), and substantial health-care
costs.1,25 Without being able to visualise sputum purulence
and quantity, defining exacerbations in non-expectorating

www.thelancet.com Vol 392 September 8, 2018 871

 Series
Infections
• Pseudomonas aeruginosa
• Haemophilus Influenzae
• Biofilm
Generic modifiable factors†
• Hygiene practices
• Malnutrition
• Vaccinations, etc
Figure 4: Treatable traits in children with bronchiectasis
A suggested approach based on asthma or chronic obstructive pulmonary disease data.45,46 These traits overlap—
ie, children can have more than one trait and examples are listed for each trait (see table 4 for details of possible
interventions). *For more information, see table 2. †For more information, see figure 4. ‡For more information,
see table 4.
For ACTRN12612000011886
trial details see https://www.
anzctr.org.au/Trial/Registration/
TrialReview.aspx?id=347862
For ACTRN12612000010897
trial details see https://www.
anzctr.org.au/Trial/Registration/
TrialReview.aspx?id=347879
872 www.thelancet.com Vol 392 September 8, 2018
Underlying disease*
• Immunodeficiency
• Aspiration
• Structural airway lesions
Inflammation and airway
secretions
• Eosinophilic, neutrophilic
• Airway clearance
• Mucolytics
Comorbidities‡
• Airflow obstruction
• Extra-pulmonary (eg,
sleep-related disorders,
and upper airway disease)
children is not as straightforward as in adults, but it can be
validly predicted by use of a standard assessment of clinical
features (major factors such as increased cough or change
in cough characteristics for ≥3 days; minor factors such as
chest pain, dyspnoea, haemoptysis, and chest signs), with
or without systemic markers (appendix). Although there
are no published RCTs, to the best of our knowledge, of
antibiotics treating acute exacerbations in children, two
clinical trials finished in the past year. One was a placebo-
controlled trial (ACTRN12612000011886), the other was a
non-inferiority study of azithromycin versus amoxicillin-
clavulanate (ACTRN12612000010897),71 both with children
with non-severe exacerbations.
Although exacerbations are often triggered by viruses
(about 48%),65 adult and paediatric guidelines recommend
treatment with antibiotics for at least 10–14 days,48,49
prescribed according to expert opinion (table 5).47,48
Antibiotic selection is determined by known or suspected
lower airway pathogens, local antibiotic availability and
susceptibility profiles, age of patient, severity of the lung
disease, comorbidities, antibiotic tolerance, and previous
responses to treatment.70 Ideally, sputum should be sent
for culture and, if a non-severe exacerbation, oral
antibiotics active against the most common pathogens
should be used. Those with severe episodes, not
improving with oral agents, or featuring drug-resistant
pathogens, such as P aeruginosa, might need intravenous
antibiotics.
Treating respiratory virus infections that trigger an
exacerbation is limited to neuraminidase inhibitors
for influenza viruses. However, their use remains
controversial given that they do not prevent lower
respiratory complications in healthy children or improve
outcomes in those with asthma.72 Furthermore, there
are no RCTs in cystic fibrosis and bronchiectasis
populations,73 and a meta-analysis of individualised data
from 1725 children admitted to hospital with severe
influenza showed no mortality reduction.74 High-quality
RCTs are needed to establish whether children with
bronchiectasis benefit from antiviral agents.
P aeruginosa eradication
The association of P aeruginosa with exacerbation
frequency, admission to hospital for treatment, and
reduced QoL75 in patients with cystic fibrosis and adults
with bronchiectasis means various eradication strategies
are recommended, although there are no RCTs to guide
this practice, to our knowledge.47–49 Cystic fibrosis studies
show that eradication is possible by use of 4 weeks of
nebulised antipseudomonal antibiotics alone or combined
with oral ciprofloxacin.76 However, we do not know in any
context which regimen is best and whether it improves
long-term outcomes. Until clinical trial results are
available, it seems reasonable to offer eradication therapy
to newly infected children using cystic fibrosis-based
regimens.
Long-term use of antibiotics
Long-term use of antibiotics (>3 months) is recommended
for those experiencing frequent exacerbations of more
than three per year.47–49 Three broad approaches are
available: macrolides, other oral antibiotics, and inhaled
antibiotics. Macrolides have antibacterial, immune-
modulating, and mucus-modulating properties,53 and it is
often unclear which of the properties has the most
important effect in clinical situations. Azithromycin, the
most widely studied macrolide, is well tolerated by
children, and its long half-life allows convenient dosing
schedules. A Cochrane review77 analysing four RCTs (all
had low risk of bias) comparing macrolides with placebo
reported that macrolides administered for 6–12 months
reduced exacerbation frequency in 341 adults with
bronchiectasis (OR 0·34, 95% CI 0·22–0·54), but not in
children. However, there was a misinterpretation of the
data extracted for the review,77 whereby they identified
those who were exacerbation free during the study rather
than the actual incidence rate of exacerbations. In a single
study of 89 Indigenous children from Australia and
New Zealand aged 1–8 years receiving azithromycin once
per week for up to 2 years, those taking azithromycin had
a significantly lower exacerbation rate (incidence rate
ratio 0·50, 95% CI 0·35–0·71).51 However, increased
carriage of macrolide-resistant bacteria occurred
(OR 7·39, 95% CI 2·15–25·39), including macrolide-
resistant strains of S aureus, which persisted after ceasing
azithromycin.51,78 Adherence proved crucial, and when
greater than 70%, carriage of respiratory bacterial
pathogens and macrolide-resistant organisms were
statistically significantly lower than in those taking
 Series

Evaluation and possible interventions Evidence Experimental

Underlying diseases
General See table 2 (eg, immunoglobulins in some immune- See table 2 (eg, immunoglobulins in some immune-deficiency states16 and CFTR-modulating drugs
deficiency states16 and altering feeding mechanisms altering feeding mechanisms when primary aspiration present)
when primary aspiration present)
Infections
Bacteria Antibiotics, see text and table 5 (oral, inhaled, acute, Limited except for long-term treatment with azithromycin;51 see text Various inhaled antibiotics
long term)
Fungal Antifungal therapy Rare in children outside of immunodeficiency ··
Viruses Antiviral therapy No evidence of benefit, see text Antiviral therapy under
development
Microbiome Probiotics and other modulators52 (eg, short chain Animal studies (not currently recommended) Modulators52
fatty acids in gut)
Biofilm Higher dose and longer-term treatment with In-vitro studies* Targeted extracellular polymeric
antibiotics substance strategies
Inflammation or airway immune modulators
Neutrophilic Macrolides53,54 Low level evidence for direct effect Neutrophil elastase inhibitors44
Eosinophilic Inhaled corticosteroids Other chronic diseases;45 no evidence for routine use55 Biologics—eg, benralizumab
Other Modulators to improve efferocytosis—eg, Efferocytosis impaired in children with bronchiectasis;42 azithromycin improves Low-dose theophylline
azithromycin efferocytosis in in-vitro chronic obstructive pulmonary disease studies*
Increased airway secretions
Airway clearance Multiple techniques (eg, active cycle breathing, use of Observational evidence in children;56 adults with bronchiectasis showed ··
devices such as Acapella, flutters, and others) improved clinical outcomes57,58
Mucolytics Mannitol, hypertonic saline No RCT evidence, see text ··
Muscarinic antagonist Tiotropium In-vitro study showing that tiotropium might reduce mucus hypersecretion ··
through reducing the effect on neutrophil elastase*
Airflow obstruction
Variable Increased airway hyper-responsiveness in some, Good evidence for asthma; single RCT in children that found 12 weeks of ··
inhaled corticosteroids and bronchodilators roxithromycin reduced airway hyper-responsiveness (methacholine)
associated with bronchiectasis59
Fixed Prevent further respiratory infections Observational* Unknown
Extra-pulmonary comorbidities
Nasal or sinus, sleep, See respective guidelines for management of these See respective guidelines for management of these comorbidities; no RCTs ··
gastro-oesophageal comorbidities specific to bronchiectasis
reflux disease, obesity
Generic modifiable factors
Adherence Reminders (eg, SMS and other technologies); Adults with bronchiectasis: low adherence associated with poorer ··
self-management plans outcomes,60 but no RCTs; Adults with bronchiectasis: Low level evidence61
Nutrition and Vitamin D deficiency or insufficiency, vitamin D Observed in adults with bronchiectasis;3 no RCTs; other chronic diseases ··
malnutrition supplementation; growth faltering, given
supplements
Tobacco Prevent exposure and uptake Other chronic lung diseases* ··
Vaping Prevent exposure and uptake In-vitro and animal studies (enhances pneumococcal adherence to airway ··
epithelial cells and other lung effects)*
Pollution Reduce indoor and outdoor exposure Adults: associated with increased exacerbations and mortality, also in other ··
chronic lung diseases; reduced risk of respiratory infections and other
disorders with pollution reduction*
Allergen and fungal Reduce exposure to allergens and environmental Other chronic lung diseases* ··
exposure fungal exposure
Psychosocial Various techniques—eg, cognitive behavioural therapy RCTs: weak evidence for other chronic diseases* ··
Hygiene Improving practice and behaviour Generalised infectious diseases* ··
Exercise Promote exercise including specific programmes Adults: improved exercise capacity, reduced dyspnoea, fatigue, and fewer Approaches to improve and
exacerbations over 12 months* maintain level of physical activity
Others Prevent recurrent infections (eg, breastfeeding) Breastfeeding was a protective factor for bronchiectasis in a case-control Strategies to reduce recurrent
study (adjusted odds ratio 0·2, 95% CI 0·1–0·7)* respiratory infections—
eg, maternal vaccination

For further information see figure 4. RCT=randomised controlled trial. *Reference in appendix.

Table 4: Proposed scheme for possible interventions for children with bronchiectasis based on treatable traits

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 Series

Initial empirical therapy†
Specific pathogens
Haemophilus influenzae
β-lactamase negative
β-lactamase positive
Streptococcus pneumoniae
Moraxella catarrhalis
Staphylococcus aureus
Methicillin resistant
Pseudomonas aeruginosa
Non-tuberculous mycobacteria Seek specialist advice§
Non-severe exacerbation (oral antibiotics)* Severe exacerbation or no response to oral therapy (intravenous antibiotics)*
Amoxicillin, amoxicillin-clavulanate, or doxycycline Ampi(amoxi)cillin, amoxicillin-clavulanate, cefuroxime, cefotaxime, or ceftriaxone; Piperacillin-
(restricted to children aged ≥8 years); ciprofloxacin tazobactam or ceftazadime plus tobramycin if P aeruginosa present; dual anti-pseudomonal antibiotic
with or without inhaled antibiotics if Pseudomonas therapy is controversial; benefits of possible improved bacterial clearance and reduced selection of
aeruginosa in recent cultures antibiotic-resistant strains versus risks recorded in adults of increased adverse effects of dual
anti-pseudomonal antibiotics compared with single β-lactam therapy are yet to be determined in children
Amoxicillin Ampi(amoxi)cillin
Amoxicillin-clavulanate or doxycycline (restricted Amoxicillin-clavulanate, cefuroxime, cefotaxime, or ceftriaxone
to children aged ≥8 years)
Amoxicillin Benzylpenicillin G, ampi(amoxi)cillin.
Amoxicillin-clavulanate Amoxicillin-clavulanate, cefuroxime, cefotaxime, or ceftriaxone
Di/Flucloxacillin Flucloxacillin
Seek specialist advice‡ Seek specialist advice‡
Ciprofloxacin (see figure 5 if new isolation) with or Anti-pseudomonal β-lactams (eg, piperacillin-tazobactam or ceftazidime) plus tobramycin‡
without inhaled antibiotics
Seek specialist advice§

Reproduced from Chang and colleagues,69 by permission of The Medical Journal of Australia. *Seek specialist advice when there is a history of severe antibiotic intolerance, hypersensitivity, or potential drug
interactions. British guidelines recommend clarithromycin if there has been an immediate hypersensitivity reaction to penicillin.47 †Initial antibiotic therapy is guided by local antibiotic availability (eg, parenteral
cefuroxime is not licensed in some countries), previous lower airway cultures (sputum or bronchoalveolar lavage), local antibiotic susceptibility patterns, disease severity, antibiotic tolerance, and previous
response to therapy. In children too young to expectorate or when previous culture results are unavailable, antibiotic therapy should be active against the common respiratory pathogens (H influenzae,
S pneumoniae, and M catarrhalis). ‡Specialist advice is needed to treat meticillin-resistant S aureus according to local susceptibility patterns and infection control policies. §Specialist advice is needed when treating
non-tuberculous mycobacterial infection because of regular difficulties distinguishing between colonisation and infection, intrinsic antibiotic resistance, and choosing between various complex, potentially toxic,
and prolonged antibiotic regimens.

Table 5: Antibiotics for managing children with a bronchiectasis exacerbation

Other oral antibiotics (eg, co-trimoxazole, tetracycline)

First or new isolation of Pseudomonas aeruginosa
(broncholaveolar lavage or sputum)
are sometimes used, but there is no RCT-level evidence
to support their role in clinical practice.
Inhaled antibiotics deliver high drug concentrations
to the lower airways with minimal systemic toxicity.
Oral ciprofloxacin* or inhaled Intravenous antibiotics* (eg,
No Yes There are several RCTs investigating inhaled antibiotics
antibiotics, or both, for 2 weeks Exacerbation piperacillin-tazobactam or ceftazidime
with tobramycin) for 2 weeks specifically in adults, but none in children. A meta-
Followed by Followed by analysis of eight trials and 590 participants receiving
Inhaled antibiotics for 4–12 weeks Inhaled antibiotics for 4–12 weeks
inhaled aminoglycosides, colistin, and ciprofloxacin for
(eg, tobramycin, gentamicin, or (eg, tobramycin, gentamicin, or 1–12 months found these either eradicated or reduced
colistin) colistin) sputum bacterial loads almost 1000-times, and reduced
the exacerbation risk by 28% (95% CI 6–45), although
Figure 5: Pseudomonas aeruginosa eradication treatment pathway this primary endpoint was not achieved by all studies.81
Suggested eradication therapy for newly infected children. *The antibiotic choice is established by availability,
Inhaled antibiotics did not statistically significantly
susceptibility profile, tolerance, and patient adherence factors. For intravenous antibiotics, a two-drug regimen is
suggested. reduce admission to hospital for treatment for exacer­
bations, improve QoL measures or lung function, and
azithromycin less than 70% of the time.78 There are sputum bacterial loads recovered rapidly once the drug
insufficient data to recommend the optimal dosing was discontinued. The most common adverse event was
regimen or duration. Further long-term studies are bronchospasm, which occurred in 10% of cases and
needed to show efficacy of macrolides in children was primarily from inhaled aminoglycosides. Increased
with bronchiectasis, including their effect upon QoL, antibiotic resistance did not emerge during treatment.
preserving lung function, and gauging the clinical sig­ Since the review by Brodt and colleagues,81 several
nificance of macrolide-resistant pathogens.77–79 Ideally, replicate placebo-containing RCTs of aztreonam and
these trials should be done in more homogenous popu­ different ciprofloxacin formulations did not find a
lations, (eg, patients with primary ciliary dyskinesia).80 consistent clinical benefit, and high discontinuation
Meanwhile, because of concerns over inducing antibiotic rates for aztreonam from treatment-related adverse
resistance, we recommend use of long-term macrolides events were observed.82–84 The results are likely to reflect
cautiously, and only in children with frequent the heterogeneity of bronchiectasis. Thus, relying
exacerbations and without evidence of non-tuberculous on evidence from adult and cystic fibrosis studies,
mycobacterial infection. paediatricians need to contemplate the potential benefits

874 www.thelancet.com Vol 392 September 8, 2018


of inhaled antibiotics from increased bacterial killing
versus cost, drug delivery logistics, and adverse effects,
especially bronchospasm. Guidelines conservatively
suggest considering treatment with inhaled antibiotics in
those with frequent exacerbations and P aeruginosa
infections, or when macrolides are contraindicated.47–49 A
supervised test dose with prebronchodilator spirometry
and postbronchodilator spirometry and prior inhalation
of a short-acting bronchodilator is also recommended.49
Inflammation or immune-modulation
Neutrophil granule products, especially neutrophil
elastase, can be tissue damaging and act as secretagogues,
as well as being anti-infective (table 4).44 There is
considerable interest in modulating inflammation in
paediatric cystic fibrosis, with trials of oral prednisolone
and ibuprofen showing benefit. The increased side-effects
from corticosteroids and when blocking leukotriene-B4
testify to the risks of this approach. There are no such
studies in paediatric bronchiectasis.
Antineutrophilic agents
It is possible that the beneficial effects of azithromycin,
as mentioned previously in this paper, could be mediated
at least in part by one or more antimodulation or
antineutrophilic actions, rather than simply from its well
known anti-infective properties,54 but this is speculative.
There is insufficient evidence to recommend oral or
inhaled non-steroidal anti-inflammatory agents in
bronchiectasis. Other anti-inflammatory therapies are
being explored, but are not yet in clinical use.
Corticosteroids
Inhaled corticosteroids (ICS) are frequently prescribed,
but there is no logical basis for their use in the absence of
airway eosinophilia. There is little theoretical reason to
expect benefit from ICS in neutrophilic inflammation,
and indeed they might prolong the neutrophil lifespan by
inhibiting neutrophil apoptosis.54 ICS should be reserved
for children with evidence of airway type 2 inflammation,
(eg, elevated airway or blood eosinophil count, or raised
exhaled nitric oxide) especially if the child is atopic; this is
an important treatable trait. Cochrane reviews show no
evidence for the generic use of ICS with or without long
acting β agonists.55,85 In addition to side-effects such as
adrenal suppression, ICS, at least in adults, increase the
risk of pneumonia, tuberculosis, and non-tuberculous
mycobacterial infection,86 and should only be used if there
is objective evidence of a clinically important benefit.
There is no role for oral corticosteroids in bronchiectasis,
other than for treating the very rare cases of allergic
bronchopulmonary aspergillosis.
Airway obstruction
Although airflow obstruction can be stabilised, fixed
obstruction persists24,25 and not over-treating these patients
is important. Intermittent wheeze merely means the
www.thelancet.com Vol 392 September 8, 2018 875
Series
airway lumen is sometimes narrowed, which could be by
secretions or bronchospasm: wheeze is not an indication
to prescribe β2 agonists. One adult study87 suggested long-
term improvement in spirometry with inhaled β2 agonists
even if there was no acute bronchodilator response.
In children, β2 agonists should be reserved for those
with documented physiological evidence for benefit of
acute administration. There are no RCTs of β2 agonists,
anticholinergics, theophylline, or leukotriene receptor
antagonists.85 Indeed, paradoxical bronchoconstriction in
response to short acting β2 agonists due to airway
instability has been described in primary ciliary dyskinesia,
and exercise might be a better bronchodilator.88
Physical techniques for airway clearance
Managing airway secretions is time consuming, again
with little evidence base in children;56 empirically, airway
clearance sessions are usually recommended twice a day.
There are numerous physical techniques, including
active cycle of breathing, autogenic drainage, external
chest wall oscillation, and positive airway pressure
devices.56 A skilled physiotherapist will tailor airway
clearance techniques to the individual child. Exercise
can be used as an adjunct but again there is paucity of
evidence for its use outside cystic fibrosis.56 Pulmonary
rehabilitation and exercise programmes in adults with
bronchiectasis result in clinical improvements,89 but
such improvements are difficult to maintain. Singing
can be useful but is not supported with evidence;
however, its simplicity makes it an attractive adjunctive
treatment option. Cough in-exsufflation is another non-
evidence-based option for those with weak expiratory
muscles (eg, patients with neuromuscular disease).
Mucolytics
Dornase Alfa, a recombinant human deoxyribonuclease,
is a highly effective mucolytic in cystic fibrosis, but is
actually harmful in bronchiectasis,90 providing a warning
against uncritical extrapolation between airway diseases.
7% hyper­tonic saline has not been studied extensively as
a treatment for bronchiectasis. Although ineffective in a
small, probably underpowered clinical trial,91 7% hyper­
tonic saline is the most commonly used mucolytic
clinically. There are no data on inhaled mannitol in
children with bronchiectasis, but studies in adults showed
reduced efficacy compared with cystic fibrosis.90 Other
agents (eg, recombinant human deoxyribonuclease) are
either harmful, have little evidence base, or are under
investigation (eg, acetylcysteine, erdosteine, and ambroxol
hydrochloride).92
Extrapulmonary comorbidities
Primary ciliary dyskinesia is characterised by chronic
infective rhinosinusitis.17 Whether early treatment of
the upper airways changes the history or the origin of
lower airway infection, or both, is unclear. The indi­
cations for, and optimal treatment of, chronic upper
 Series

For more details on the trial see
https://www.anzctr.org.au/Trial/
Registration/TrialReview.
aspx?id=347907
airway infection is not evidence based; some groups use
long courses of oral antibiotics, nasal douching, or
inhalation of saline or antibiotics, decongestants, and
topical steroids. If upper airway disease is present, sleep
disordered breathing should be considered and actively
excluded.
Reflux might also complicate respiratory disease, or be
an association of no consequence93 (Berkson’s bias, a
selection bias in which the effect is seen when both the
exposure and the disease are selected). Lacking evidence,
it is probably reasonable only to screen and treat
symptomatic children, or those with an underlying
disorder predisposing them to reflux and aspiration.
Severe bronchiectasis can of itself lead to loss of fat
free mass and faltering growth,94 but worldwide, the
most common cause of stunting is child poverty and
poor living conditions, which are also associated
with developing bronchiectasis. Additionally, vitamin D
insufficiency is associated with disease severity in adults
with bronchiectasis,3 but has not been studied in children.
There are few data on obesity complicating bron-​
chiectasis. Obesity is a systemic, pro-inflammatory
condition, and whether obesity adversely affects bron-​
chiectatic airways is unknown. Likewise, obesity itself is
associated with dysanaptic airway growth;95 how much
this association is a factor in coincident bronchiectasis is
unknown, but optimising nutrition is another potentially
treatable trait.
Generic modifiable factors
Seasonal influenza and pneumococcal vaccines are
recommended according to national immunisation
programmes for people with bronchiectasis in their
respective countries.96 The need for a vaccine targeting
non-typeable H influenzae strains in those with
bronchiectasis and other chronic lung disorders is
recognised widely. The only licensed vaccine offering
potential protection against non-typeable H influenzae is
the ten-valent pneumococcal vaccine, (PCV10) which
uses protein D, a conserved H influenzae outer
membrane protein, as a conjugating agent. A 2018
observational study in Australian children undergoing
bronchoalveolar lavage for chronic cough found that
those who had received PCV10 (compared with other
pneumococcal conjugate vaccines) were significantly
less likely to have non-typeable H influenzae lower
airway infection (17% vs 31%, adjusted OR 0·22, 95% CI
0·14–0·33).97 In contrast, PCV10 did not affect non-
typeable H influenzae nasopharyngeal carriage. A
phase 2 RCT (ACTRN12612000034831) in children with
chronic suppurative lung disease was completed in the
past year and should inform future H influenzae vaccine
studies. Vaccines directed against other important
respiratory pathogens (eg, P aeruginosa and respiratory
syncytial virus) are undergoing development, entering
clinical trials, and could have a future role in patient
management.
The scarcity of evidence for cross-infection as a
common event and of infection control measures pre­
venting exacerbations, led European experts to recom­
mend that although individuals with bronchiectasis
should not have direct contact with patients with cystic
fibrosis, they do not need to be segregated from other
patients.96 Nevertheless, while in hospital, standard local
infection control precautions should apply, including
standard hygiene precautions (eg, handwashing and
avoiding those with current respiratory infections).
Probably the most challenging treatments, in terms of
adherence, are airway clearance and, if prescribed, inhaled
antibiotics. In adults with bronchiectasis, adherence is
low, which affects clinical outcomes.60 There are no studies
on adherence in children with bronchiectasis. Use of the
perceptions and practicalities approach,98 which promotes
an understanding of contributors to the complexities of
the regimen and the appreciation of the necessity of the
medication, could help improve adherence. Educating
the child and family is important, which could include
providing a management plan.47,48 However, there is
insufficient evidence to recommend any combination of
self-management strategies without supporting RCT
evidence to improve adherence.
Airway irritants, especially tobacco smoke, which
increase mucus production and impair airway defences
should be avoided. E-cigarettes contain hazardous
compounds not present in tobacco, and have different
effects on the airway proteome. E-cigarettes can also
cause increased bacterial adherence to airway epithelium
and therefore, should not be considered to be more
benign than tobacco smoke.99 It is essential to ensure that
children with bronchiectasis refrain from smoking or
vaping, and if their parents smoke, the parent should be
referred for smoking cessation interventions.
Allergen exposure is only relevant in atopic children
who are sensitised to a particular allergen, and in such
cases, reducing the allergen burden might help reduce
type 2 inflammation in the airway and improve outcomes.
In children, environmental fungal hypersensitivity
(allergic bronchopulmonary aspergillosis) is rare outside
the context of cystic fibrosis and largely absent in cohort
studies (table 2). Nevertheless, it is sensible to reduce the
environmental fungal burden.
In terms of psychosocial issues, a specific QoL tool for
primary ciliary dyskinesia exists, but not any tool specific
for paediatric bronchiectasis, although chronic cough QoL
scores have been used.11 Bronchiectasis has a considerable
effect on the child and their family, in terms of absences
from school and work, respectively. QoL is particularly
impaired during exacerbations and is compounded by
parental depression, anxiety, and stress.11 Parents of very
young children are particularly burdened.11
Other treatments
Surgery (usually lobectomy) can be beneficial in selected
patients100 but is generally reserved for localised, severe,

876 www.thelancet.com Vol 392 September 8, 2018


symptomatic bronchiectasis related to a non-recurring
cause (eg, from a foreign body). By analogy with cystic
fibrosis, it is probable that children with non-localised
disease or with a persistent underlying cause, or both,
could have initial improvement, but no real long-term
benefit. Moreover, mortality from surgery is around
2·5% (95% CI 1·2–5·3).100 Like for other end-stage lung
diseases, lung transplantation can be offered in
specialised centres.
Monitoring treatment response
Regular and frequent reassessment (every 3–6 months)
of the child is essential,48 including looking for new
features suggesting an underlying diagnosis. Height,
weight, and body-mass index should be plotted regularly.
Spirometry is frequently measured, but is relatively
insensitive in bronchiectasis.1 Unlike for cystic fibrosis,
whether multiple-breath washout tests are useful is
undetermined.101 Sputum should be cultured regularly.47–49
The utility of cough swabs is not established, although
used in many centres in non-expectorating children.
How repeated imaging informs management is also
unclear. Chest radiographs are insensitive and detect
only major structural changes, whereas repeat high-
resolution CT scans carry the risks of radiation exposure
and should only be considered if their use will change
management of the patient. MRI scans are being used
increasingly in airway disease, and could eventually have
a role in follow-up for children with bronchiectasis.
Conclusion
A myriad of heterogeneous risk or causative factors, or
both, can lead to bronchiectasis in children. These
factors and the various clinical symptoms vary among
settings and countries, but share the common thread of
cycles of chronic cough, recurrent respiratory infections,
and endobronchial suppuration with persistent in­fec­
tion and inflammation. Interrupting these processes
as early as possible is necessary to reverse or halt
disease progression, and prevent further tissue damage.
This interruption requires early diagnosis, which is
dependent on clinical awareness and use of paediatric
specific rather than adult derived definitions and
data. We have proposed a paediatric specific diagnosis
of bronchiectasis and suggest adopting the concept
of treatable traits when managing these children,
consistent with existing strategies to optimise the
manage­ ment of people with other chronic airway
diseases. However, a greater evidence base is required to
fully realise how these concepts would improve short-
term clinical outcomes and long-term prognosis of
children with bronchiectasis.
Contributors
ABC was invited to write the Review, gathered the coauthors, and
compiled and edited the different sections written by coauthors. AB and
KG wrote various sections of the Review and coedited the entire paper.
All authors undertook the relevant searches for their sections.
www.thelancet.com Vol 392 September 8, 2018 877
Series
Declaration of interests
ABC is an author and reviewer on a data safety monitoring board for an
unlicensed vaccine (GlaxoSmithKline) and an adviser for study design of
an unlicensed product for cough (Merck). ABC, AB, and KG declare no
competing interests.
Acknowledgments
ABC is funded by an Australian National Health and Medical Research
Council (NHMRC) Practitioner Fellowship. ABC and KG have received
multiple NHMRC grants related to bronchiectasis. AB is a National
Institute of Health Research (NIHR) Senior Investigator who has received
multiple grants from the NIHR and the European Union related to
suppurative lung disease. The funder of the Review had no role in study
design, data collection, data analysis, data interpretation, or writing of the
report. The corresponding author had full access to all the data in the study
and had final responsibility for the decision to submit for publication.
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