B ro n c h i e c t a s i s f rom 2 0 1 2

to 2022
James D. Chalmers, MBChB, PhD, FRCPE, FERS

KEYWORDS
 Bronchiectasis  Epidemiology  Clinical trials  Guidelines

KEY POINTS
 Bronchiectasis is a disease with an increasing prevalence and substantial clinical and economic
burden
 Once regarded as a neglected disease, bronchiectasis has experienced a renaissance in recent
years with an increase in clinical research
 International guidelines now provide a framework for high-quality care and are increasingly
informed by randomized clinical trials of high quality.
 Major developments in the past 10 years include international registries, clinical trials, guidelines,
and translational research

INTRODUCTION concerted effort by researchers across different

The last issue of Clinics in Chest Medicine dedi-
cated to bronchiectasis was published in 2012,
edited by my colleagues and friends Mark Meter-
sky and Anne O’Donnell.1 The challenge they
faced in 2012 was considerable. Bronchiectasis,
famously described as “the most neglected dis-
ease in respiratory medicine” is a disease that
has historically been overshadowed by conditions
that have a greater evidence base and a wider
awareness among the general public.2 The
comprehensive review series published in 2012,
comprising each of the key areas of assessment
and therapy, served as a high-quality clinical
guide, a state of the art review on pathophysiology
and a call to arms with each chapter highlighting
the paucity of evidence and the need for further
research.1
Where do we find ourselves 10 years later, with
an updated series on bronchiectasis published in
Clinics in Chest Medicine? While there remains a
great deal of work still to do to improve the care
of bronchiectasis patients globally, here I will
argue that the field of bronchiectasis has been
transformed in the past 10 years thanks to a
fields to address gaps in our knowledge.
EPIDEMIOLOGY-A GROWING PROBLEM AND
GROWING AWARENESS
Bronchiectasis was previously regarded as a rare
or orphan disease, defined by European regula-
tors as a disease with a prevalence of less than
50 per 100,000 individuals. Recent studies have
documented an increase in the prevalence of
bronchiectasis of up to 40% more than 10 years
to 2015 and the most recent estimate of preva-
lence in the United Kingdom is up to 566 per
100,000 in women, far exceeding the threshold
of a are disease.3 Similar data from other Euro-
pean countries and the United States have also
been reported.4,5 Historically, the public aware-
ness of bronchiectasis has been extremely low
relative to its prevalence and this remains the
case. Bronchiectasis has, however, gained sub-
stantially in terms of awareness within the medi-
cal profession and particularly within respiratory
medicine.6 Bronchiectasis clinical and scientific
sessions are now a regular feature of all of the
chestmed.theclinics.com

major respiratory congresses, and also con-

growing recognition of its high prevalence and a gresses for primary care. The first World

Division of Molecular and Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School,
Dundee, Scotland, UK
E-mail address: jchalmers@dundee.ac.uk
Twitter: @profjdchalmers (J.D.C.)

Clin Chest Med 43 (2022) 1–6

https://doi.org/10.1016/j.ccm.2021.12.001
0272-5231/22/Ó 2022 Elsevier Inc. All rights reserved.
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2 Chalmers
Bronchiectasis Conference took place in Hann-
over, Germany in 2016 and this has now become
a regular biannual event supported by the major
global research consortia.6 A further reflection
of the growing interest in the disease is the emer-
gence of specialist clinics dedicated to bronchi-
ectasis, in settings whereby patients were
previously managed either in cystic fibrosis ser-
vices or general respiratory clinics.
REGISTRIES AND LARGE DATASETS
Perhaps the area of bronchiectasis research that
has seen the greatest transformation in the past
10 years is in epidemiology. Reports on the clinical
characteristics, outcomes, and prognosis of bron-
chiectasis before 2012 consisted primarily of
single-center, and almost exclusively of single-
country studies. An example of the paucity of
data is that in 2012, the largest prospective study
of mortality and its risk factors in bronchiectasis
was a single-center of 91 patients which while
high quality and informative, reflected the lack of
large scale multicentre data on the key clinical out-
comes such as exacerbations, hospitalizations
and mortality.7 There is no question these gaps
have now been filled. Large scale registries have
been established in Europe and in the United
States as well as in individual countries including
outside of Europe such as in India, Australia, and
Korea.2,8–10 The power of these registries has clar-
ified with greater power and accuracy the demo-
graphics of the patient population, the most
common underlying causes and the burden of dis-
ease including symptoms, quality of life, and fre-
quency of exacerbations. Risk factors for poor
outcome have been identified in datasets of
several thousand patients from different centers
and formulated in multidimensional severity tools,
the most widely used of which is the bronchiec-
tasis severity index.11–13 Recognition of the impact
of exacerbations on outcomes including mortality
has been key in prioritizing exacerbation preven-
tion in patient management.14 Epidemiologic
data have emphasized the key role of Pseudo-
monas aeruginosa in patient outcomes.15,16
Importantly, bronchiectasis has been recognized
as a global problem requiring global solutions
and the key role of tuberculosis as a cause of bron-
chiectasis in Asia, in particular has been recog-
nized in addition to global heterogeneity such as
a high prevalence of NTM in United States, a
high prevalence of bronchiectasis in indigenous
populations.10,17–20 The overlap between COPD
and bronchiectasis has become a key clinical
topic as the increasing use of CT scanning has
identified more and more patients with a diagnosis
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of COPD who also have radiological and clinical
bronchiectasis.21–23 Many of the key insights
described above has been supported by an inter-
national collaboration called EMBARC, a Euro-
pean Respiratory Society network that
representing several hundred centers working on
bronchiectasis research and which supports the
European registry.24,25
It is difficult to investigate and treat a disease we
do not fully understand and there is no question
the past 10 years has seen major advances in
our understanding of bronchiectasis epidemiology
and outcomes. Registries in themselves do not
change clinical outcomes, but provide a frame-
work for research and clinical progress.
GUIDELINES
The first widely recognized guidelines for bronchi-
ectasis were published in Spain in 2008 and the
United Kingdom in 2010.26 The 2017 European
Respiratory Society guidelines were an important
milestone reflecting the increasing international
cooperation that has characterized bronchiec-
tasis research in the past 10 years.27 Most of
the recommendations were conditional and
based on low-quality evidence. They have never-
theless provided a framework to improve the
quality of care by promoting standardized testing
for underlying conditions, airway clearance treat-
ment of all patients, and prophylactic antibiotic
treatment of patients with frequent exacerbations
among other recommendations. These recom-
mendations have been used as a way to bench-
mark care between centers.10 There remain
major areas of care that rely on evidence from
other diseases such as cystic fibrosis, a clear
example being eradication treatment of P. aerugi-
nosa.28 Nevertheless guidelines have, without
question, had a positive influence on standard-
izing care in Europe and beyond.
PATHOPHYSIOLOGY
Bronchiectasis is complex and challenging to
study from a basic mechanism perspective. Un-
like cystic fibrosis, it is not caused by a single
gene defect and unlike COPD, most of the pa-
tients do not have an identifiable common envi-
ronmental exposure. Understanding “the
pathogenesis of bronchiectasis” may be a
contradiction in terms, as bronchiectasis is likely
a final common pathway of multiple pathologic
processes.29,30 Understanding of the pathophys-
iology is further limited by the lack of animal or
other experimental models to test causal path-
ways in bronchiectasis.

The vicious cycle proposed in the 1980s by Pe-
ter Cole has served us well as a framework for un-
derstanding the disease and its key
components—infection, inflammation, impaired
mucociliary clearance, and structural lung dis-
ease.31 Being able to name a problem is a long
way from understanding it, and treating it and
each of these components has been poorly char-
acterized. This is changing, however, with an ex-
plosion in translational research into the
condition. Infection research is being transformed
by the availability of molecular diagnostics, micro-
bial sequencing and techniques, and technologies
to look beyond the conventional bacterial
kingdom.32–35 This is the era of the microbiome.
In inflammation, advanced techniques such as
proteomics have extended our knowledge of in-
flammatory pathways associated with severe dis-
ease, biomarkers can predict disease outcomes
and stratify patients into inflammatory subtypes
of disease which may require different treat-
ments.36–38 Mucociliary clearance remains the
least well studied—a neglected area within a
neglected disease, but extraordinary progress in
gene discovery in the genetic bronchiectasis syn-
drome primary ciliary dyskinesia illustrates that
this is a tractable problem.39,40 The detailed un-
derstanding of pathophysiology is leading to new
drug development and repurposing, while the
concept of precision medicine is helping to over-
come disease heterogeneity in both research and
clinical practice.41 The development of CFTR
modulators and their transformational effect on
outcomes shows how understanding pathophysi-
ology can lead to major breakthroughs, and further
research into bronchiectasis pathophysiology is
the key to similar paradigm shifts in non-CF
bronchiectasis.
CLINICAL TRIALS
Randomized trials provide the highest level of ev-
idence to inform clinical practice and are critical
for the development of evidence-based guide-
lines. Before 2012, the negative trial of recombi-
nant DNAse represented a unique multicentre
international trial of a therapy in non-CF bronchi-
ectasis.42 Since 2012, however, multiple land-
mark trials have been published, providing key
insights into the opportunities and challenges of
managing the disease. Three trials of long-term
macrolide therapy, the EMBRACE, BAT and
BLESS trials were genuine landmarks in the field
demonstrating a reduction of approximately
50% in exacerbation frequency across the 3
studies.43–46 Further data in children also confirm
their efficacy.47 These drugs have proven to be
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Bronchiectasis 3
life-changing for some patients but do have
adverse effects including resistance. Interna-
tional trials of inhaled antibiotics including the
AIR-BX, RESPIRE, and ORBIT programs have
provided mixed results,48–50 but have collectively
demonstrated that inhaled antibiotics likely have
an important role in some patients with severe
bronchiectasis but that we also have not yet iden-
tified the optimal patient population or regimen to
provide consistent results.51 Even airway clear-
ance, perhaps the most important and most over-
looked aspect of care, has now been subject to
well-controlled randomized trials.52 The first
novel anti-inflammatory therapy targeting neutro-
philic inflammation, an inhibitor of dipeptidyl
peptidase-1 has also recently shown efficacy in
a phase 2 trial.53
Alongside these trials has been extensive work
to develop trial endpoints including new quality
of life measures, lung function endpoints, and a
deeper understanding of exacerbations and
responsive patient populations.54–57
These efforts will mean that future guidelines are
able to make recommendations with a higher level
of evidence, while future trials have the greatest
possibility of success by targeting the right patient
populations with the right therapies and measuring
efficacy with the right endpoints.
THE 2022 SERIES-MOVING FORWARDS
Bronchiectasis is a disabling disease, but one
whereby high-quality care can make a huge differ-
ence to exacerbation frequency and to patients’
quality of life. Few fields in respiratory medicine
have experienced such rapid development or
such growth in awareness as bronchiectasis has
experienced over the past 10 years.
Against this backdrop, I am excited to intro-
duce the 2022 edition of Clinics in Chest Medicine
dedicated to bronchiectasis. We have brought
together the world’s leading experts in their
respective field to share the cutting edge in bron-
chiectasis pathophysiology, assessment, under-
lying conditions, management, and future
directions. Our current state of the art is
explained and illustrated in detailed chapters,
and future directions are explored. Looking
ahead to the next 10 years, we have the opportu-
nity to once again transform bronchiectasis by
promoting higher quality care, greater public
awareness, and new therapies supported by
high-quality clinical trials and research. I am
excited to introduce this edition of Clinics in Chest
Medicine and I hope you find it a useful resource
for treating your patients and researching this
challenging disease.
4 Chalmers
CLINICS CARE POINTS
 Bronchiectasis is a growing clinical problem
 International guidelines for clinical practice
have been published by the European Respi-
ratory Society
 Airway clearance, antibiotic treatment and
exercise are key components of treatment
supported by randomized controlled trials
DISCLOSURE
Professor J.D. Chalmers has received research
grants from AstraZeneca, Boehringer Ingelheim,
GlaxoSmithKline, Insmed, and Novartis. Consul-
tancy and other fees from: AstraZeneca, Boeh-
ringer Ingelheim, Chiesi, GlaxoSmithKline,
Insmed, Janssen, Novartis, and Zambon.
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January 13, 2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.
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Bronchiectasis 5
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6 Chalmers

with Pseudomonas aeruginosa (ORBIT-3 and
ORBIT-4): two phase 3, randomised controlled trials.
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[Internet] 2019;28(151):180108. Available at:
https://pubmed.ncbi.nlm.nih.gov/30872400.

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