Bronchiectasis - Monograph 2011

Guest Editors
R.A. Floto
C.S. Haworth
R.A. Floto is a Principle Investigator and Wellcome Trust Senior Clinical Fellow
at the Cambridge Institute for Medical Research, University of Cambridge
(Cambridge, UK). His laboratory, funded by the Wellcome Trust and Medical
Research Council (UK), is focussed on understanding how the immune system
interacts with bacterial and mycobacterial pathogens to trigger inflammatory
lung damage. He is head of research at the Cambridge Centre for Lung Infection
directing clinical and translational studies on CF and non-CF bronchiectasis
and is an Honorary Consultant at Papworth Hospital and Addenbrookes
Hospital (both Cambridge). Recent honours received include the BUPA
Foundation Researcher of the Year award (2010) and the European Respiratory
Society Maurizio Vignola Award for Innovation in Pulmonology (2007).
C.S. Haworth is Director of the Cambridge Centre for Lung Infection
(incorporating The Adult Cystic Fibrosis Centre, The Lung Defence Clinic and
The Immunology Clinic) at Papworth Hospital (Cambridge, UK). He is also an
Honorary Consultant at Addenbrookes Hospital in Cambridge. The Lung
Defence Clinic oversees the care of more than 1,000 patients with bronchiectasis
associated with primary and secondary immunodeficiency syndromes,
nontuberculous mycobacterial (NTM) disease, Aspergillus-related lung disease,
rheumatoid arthritis, serious childhood infection, chronic aspiration and
primary ciliary dyskinesia. C.S. Haworth trained at the Royal Brompton
Hospital and the Hammersmith Hospital in London (UK), before moving to
Cambridge in 2003. He is a co-author of the North American Cystic Fibrosis
Foundation/the UK Cystic Fibrosis Trust/European Cystic Fibrosis Society
Bone Health Guidelines and is co-chair (with R.A. Floto) of the European
Cystic Fibrosis Society NTM working group. He collaborates with several
research groups at the University of Cambridge and is the chief investigator of
multicentre, novel therapy, clinical trials in cystic fibrosis (CF) and non-CF
bronchiectasis.
Eur Respir Mon 2011. 52, v.

Printed in UK all rights reserved.
Copyright ERS 2011.
European Respiratory Monograph;
ISSN: 1025-448x.
DOI: 10.1183/1025448x.10004811
Preface
B
ronchiectasis has been a well-known disease for a long time. Following

the introduction of antibiotic treatment in clinical practice for
respiratory tract infections, the problem of bronchiectasis appeared to be
solved, with some exceptions, e.g. in diseases such as cystic fibrosis. However,
bronchiectasis is associated with a number of immunological diseases and
occurs as a long-term complication of chronic lung diseases. These types of
diseases, mainly chronic obstructive pulmonary disease, have become more
and more prevalent, which has again made bronchiectasis a disease of
interest. Unfortunately, most of the evidence regarding bronchiectasis is
from case series and uncontrolled studies. Bronchiectasis has not been a
focus of the pharmaceutical industry and randomised controlled studies have
never been performed. Specific guidelines focusing on bronchiectasis are yet
to be published.
Over the past few years the scene has changed dramatically. Bronchiectasis is
now a hot topic for epidemiological, basic and clinical research. A number of
drugs, such as inhaled antibiotics and substances improving sputum
clearance, are now available in a clinical development programme, the first
results of which will be presented later this year. Therefore, now is the time to
summarise the current knowledge about bronchiectasis.
The Guest Editors of this Monograph have succeeded in attracting leading
experts within the field to write chapters which provide an overview from
current pathophysiology, diagnostics and treatment to future developments
that are on the horizon.
I want to congratulate the Guest Editors for this excellent Monograph, which
will be of interest and use to basic scientists and clinicians in their daily
practice.
Editor in Chief
T. Welte
vi
Eur Respir Mon 2011. 52, vi. Printed in UK all rights reserved, Copyright ERS 2011. European Respiratory Monograph;
ISSN: 1025-448x. DOI: 10.1183/1025448x.10005111
Introduction
R.A. Floto*,# and C.S. Haworth#
*Cambridge Institute for Medical Research, University of Cambridge, and #Cambridge Centre for Lung Infection, Papworth Hospital, Cambridge, UK.
Correspondence: R.A. Floto, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK, Email: arf27@cam.ac.uk
ince its first description in the 19th century, bronchiectasis remains a clinically important, but
poorly understood condition. This issue of the European Respiratory Monograph (ERM) brings
together contributions from leading international experts on the subject of non-cystic fibrosis
(CF)-associated bronchiectasis in adults. This issue of the ERM discusses the epidemiology and
aetiology of the condition and describes the associated changes in histopathology and radiology. It
explores the basic mechanisms controlling lung inflammation and immunity and how these can be
disrupted to trigger bronchiectasis. In this Monograph, we define appropriate investigation
algorithms, explore the role of bacteria, viruses, fungi and nontuberculous mycobacteria, and
discuss the specific features of bronchiectasis associated with ciliary dyskinesias, channelopathies,
inflammatory bowel disease, immunodeficiencies and autoimmune disease. This Monograph
details the various treatment modalities available for bronchiectasis, including antibiotic regimens,
the use of macrolides and other anti-inflammatory agents, airway clearance strategies and the role
of surgery.
This issue of the ERM offers a comprehensive and cutting edge review of non-CF-associated
bronchiectasis and provides a definitive guide to the management of this challenging condition.
vii
Eur Respir Mon 2011. 52, vii. Printed in UK all rights reserved, Copyright ERS 2011. European Respiratory Monograph;
ISSN: 1025-448x. DOI: 10.1183/1025448x.10004911
Chapter 1
Bronchiectasis:
epidemiology and
causes
D. Bilton*,#," and A.L. Jones*,#,"
Summary
Keywords: Aetiology, bronchiectasis, epidemiology, non-cystic

fibrosis
*Dept of Cystic Fibrosis, Royal

Brompton Hospital,
#
NIHR Biomedical Research Unit
into Advanced Lung Disease, Royal
Brompton Hospital, and
"
Dept of Cystic Fibrosis, National
Heart and Lung Institute, Imperial
College London, London, UK.
Correspondence: D. Bilton, Royal
Brompton Hospital, Sydney Street,
London, SW3 6NP, UK, Email
D.Bilton@rbht.nhs.uk
D. BILTON AND A.L. JONES
Bronchiectasis remains a significant cause of morbidity and

mortality in the developed world. The true prevalence of the
condition remains elusive, in part, because of the innate
difficulty in determining causation, when more than one
respiratory condition exists in the same patient, but also due to
the increasing rate of diagnosis by radiological means where no
clinical symptoms are present. The wide ranging aetiology of
bronchiectasis will be discussed in this chapter; however, some
aspects will be discussed in greater detail throughout this
Monograph.
The diagnosis of bronchiectasis should be the beginning of a
targeted search for causation, which may lead to directed
treatment, thereby limiting the disease progression. Over the
next 5 years a reduction in the number of cases labelled as
idiopathic bronchiectasis should be expected, as the continual
expanding knowledge of immunology and immunogenetics,
with respect to large studies of patients with bronchiectasis, can
be applied.
Eur Respir Mon 2011. 52, 110.

Copyright ERS 2011.
ISSN: 1025-448x.
DOI: 10.1183/1025448x.10003110
ronchiectasis was first described by Laennec [1] in 1819 as part of a wider work describing the
use of his novel invention, the stethoscope. In his book De lAuscultation Mediate ou Traite du
Diagnostic des Maladies des Poumons et du Coeur [1], he described the condition through the use of
case reports, detailing clinical examination and correlating this with post mortem findings. He
identified that any illness characterised by chronic sputum production could lead to bronchiectasis
with tuberculosis and pertussis infection identified as the most likely causative conditions.
A century later, in 1919, A. Jex-Blake delivered a lecture at the Hospital for Consumption
(London, UK) on the condition of bronchiectasis [2]. He examined the case records for the
hospital over a 20-year period and gave a detailed account of the condition and its causes. He
identified that bronchiectasis itself was a secondary condition to a preceding disorder of the lung and,
as such, its frequency was likely to be underestimated as the preceding condition was of such
severity that the presence of bronchiectasis was overlooked. He also identified that the condition
was apparent in 2% of the hospitals admissions over the same 20-year period, but estimated that
the true figure could be as high as 5%. Perhaps, unsurprisingly, in this pre-antibiotic era a third of
patients were identified as having bronchiectasis secondary to an episode of pneumonia or pleurisy,
a third due to chronic bronchitis and a further third due to bronchial obstruction, the majority of
which were malignant tumours.
Since the introduction of antibiotic therapy the incidence of bronchiectasis due to tuberculosis or other
infections decreased markedly from the beginning of the 20th century. Perhaps the most striking
evidence for the effect of antibiotic introduction was a report in 1969 by FIELD [3] into childhood
admissions for the condition. The author reported a reduction from 2499 per 10,000 hospital
admissions to 613 per 10,000 admissions for five large childrens hospitals between 1952 and 1960.
Despite this decline in cases in the antibiotic era of medicine, non-cystic fibrosis (CF)
bronchiectasis remains a significant cause of morbidity.
EPIDEMIOLOGY AND CAUSES
Epidemiology
Remarkably the current knowledge of the true incidence of bronchiectasis has changed very little
from when A. Jex-Blake gave his lecture almost a century ago. In part, the reason for this remains
similar to what was perceived in 1919. Bronchiectasis is often noted as a secondary phenomenon
to a more severe pulmonary pathology, as is the case of asthma or chronic obstructive pulmonary
disease (COPD), and as such goes unreported. Conversely, the widespread use of computer
tomography (CT) as a diagnostic tool in respiratory medicine has resulted in the identification of
an increased number of radiological bronchiectasis cases in patients who showed no symptoms
and who would have otherwise not been classified as having it. Future studies of the prevalence of
bronchiectasis should not be confined to radiological evidence alone but should include the
assessment of clinical symptoms.
One of the first large-scale studies to determine the incidence of bronchiectasis was performed in
1953 and examined the population of Bedford, a town in the UK [4]. The authors identified an
incidence of bronchiectasis as 1.3 per 1,000 people. The relevance of this data, collected prior to
the widespread use of antibiotics and where the authors excluded patients with bronchiectasis as a
consequence of other pulmonary pathology, is perhaps limiting. However, more recent data has
been collected from cohorts in Finland, New Zealand and the USA [57]. The data from Finland
suggested an incidence of 2.7 per 100,000 people, while in New Zealand an overall incidence in
children of 3.7 per 100,000 was noted but showed wide variations with regards ethnicity. For
example, children from a Pacific Island descent had an incidence of 17.8 per 100,000 compared
with an incident of 1.5 per 100,000 for those of a Northern European descent.
Unsurprisingly, given the often chronic nature of its development, the prevalence of bronchiectasis
and hospital admission related to bronchiectasis increased with age. Studies from the USA
estimate a prevalence of 4.2 per 100,000 people in those aged 1834 years, increasing to 271.8 per
100,000 in people aged .75 years [7].
Aetiology
There are a wide range of conditions that can cause bronchiectasis and there are a number of ways
in which one could classify these aetiological factors; however, an approach based on pathological
processes appears to be the most logical and is described in table 1.
Bronchial dilatation can be caused by a structural defect in the wall itself, an effect of abnormal
airway pressure on the bronchial wall or by damage to the airway elastic tissue and cartilage as a
result of bronchial wall inflammation.
The lungs are continuously exposed to

inhaled pathogens and have developed
an advanced mechanism for trapping
and removing them. The human airways
are lined with ciliated epithelium with
submucosal goblet cells secreting mucus
that makes up the top layer of the airway
surface liquid, the lower layer being the
periciliary fluid that bathes the cilia and
ensures they function appropriately. In
healthy individuals the mucus traps
inhaled pathogens and the continuously
motile cilia transport the mucus and its
contents out of the lung. Any defect in
this mucociliary clearance mechanism
can lead to the retention of pathogens
resulting in the progression of airway
infection, inflammation and ultimately
bronchiectasis.
Structural lung conditions

The effect of obstructions within the bronchus itself was identified by LAENNEC [1]
as a significant cause of bronchiectasis.
Obstruction of the bronchi with foreign
objects or tumours is now a relatively rare
cause of bronchiectasis. Unsurprisingly
most patients with bronchiectasis secondary to retained objects are young children.
Congenital disorders affecting the structure of the bronchial tree can lead to
bronchiectasis through a direct effect on
the bronchial wall itself, although impaired clearance of sputum through the
abnormally dilated structures can further compound the condition.
Table 1. Aetiology of bronchiectasis

Structural lung conditions
WilliamsCampbell syndrome
MounierKuhn syndrome
EhlersDanlos syndrome
Toxic damage to airways
Inhalational injury
Aspiration secondary to neuromuscular disease
GERD
Obstruction of single bronchus
Tumour
Foreign body
Obstructive airways disease
Asthma
COPD
AAT deficiency
Defects of mucociliary clearance
Ciliary dyskinesia
Primary ciliary dyskinesia
Secondary ciliary dyskinesia
Channelopathies
CFTR dysfunction
ENaC dysfunction
ABPA
Immunodeficiency
CVID
XLA
CGD
Antibody deficiency with normal Ig
Secondary immunodeficiency
Haematological malignancy
Post-allogeneic bone marrow transplant
Drug-induced immunosuppression
Infections
Childhood infections
Tuberculosis
Pneumonia
Measles
Whooping cough
Nontuberculous mycobacteria
Bronchiectasis in systemic diseases
Inflammatory bowel disease
Connective tissue diseases
Yellow nail syndrome
Idiopathic bronchiectasis
Inflammation within the bronchial wall

can be the result of an infection within
the airway, inhalation of injurious agents
or an endogenous condition such as an
autoimmune disease.
GERD: gastro-oesophageal reflux disease; COPD: chronic

obstructive pulmonary disease; AAT: a1- antitrypsin deficiency; CFTR: cystic fibrosis transmembrane conductance
regulator; ENaC: epithelial sodium channel; ABPA: allergic
bronchopulmonary aspergillosis; CVID: common variable
immunodeficiency; XLA: X-linked agammaglobulinaemia;
CGD: chronic granulomatous disease; Ig: immunoglobulin.
WilliamsCampbell syndrome was first

described in 1960 after the case reports of
five children were studied by WILLIAMS
and CAMPBELL [8]. Histological examination of the bronchial wall revealed a deficiency or absence of
cartilage, mostly from the third division of the bronchi down. WILLIAMS and CAMPBELL [8] went on to
describe a further 11 children with the same clinical findings of bronchiectasis and cartilage
deficiency.
MounierKuhn syndrome (tracheobronchomegaly) is characterised by dilatation of the trachea

and large bronchi, usually presenting in young adults. Its underlying pathology is not clearly
understood but histological examination has shown atrophy of airway cartilage and smooth muscle.
Case reports suggesting an association with EhlersDanlos syndrome, and the appearance of the
condition in siblings, could point to an unidentified genetic cause for the condition.
Obstructive airways disease

To carry on the theme of defects in the gross airway structure itself, perhaps a continuation of this
is to consider whether obstructive airways diseases, namely asthma and COPD, could lead to
bronchiectasis. It is natural to assume that these conditions would lead to bronchiectasis as both
have clearly been shown to cause airway inflammation and structural blockage of airways, either
through bronchospasm or fixed airways obstruction, in the case of COPD.
Asthma
A number of studies have highlighted the presence of airway remodelling in chronic asthma
patients using high-resolution CT (HRCT) scanning techniques. The airway remodelling can vary
from mild airway wall thickening to blatant bronchiectasis. Bronchial wall thickening has been
found in up to 82% of asthmatic patients in a cohort [9] and in patients with mild asthma [10]. As
bronchial wall thickening is indicative of airway inflammation this suggests that a significant
number of patients with asthma are at risk of developing bronchiectasis.
The prevalence of bronchiectasis in these studies is estimated at 17.540% [911]. In the largest of
these studies, which comprised of 463 patients with severe asthma, 40% of patients were shown to
have evidence of bronchiectasis on HRCT scans [11]. However, study participants were selected for
HRCT on the basis of clinical indication, the most common being a suspicion of bronchiectasis.
The studies suggest that bronchiectasis is associated with a more severe obstruction and is more
apparent in patients who present with a longer history of asthma symptoms, consequently a
subgroup of severe asthma patients appear to be at risk of developing bronchiectasis [911].
COPD
COPD is a term encompassing a number of pathological processes including chronic bronchitis,
asthma, emphysema and bronchiectasis. Therefore, it is difficult to fully attribute COPD as the cause
of bronchiectasis as in some cases bronchiectasis may be the primary diagnosis. Certainly it is
probable that bronchiectasis in COPD is common. A study of moderate-to-severe COPD patients
demonstrated the prevalence of bronchiectasis to be 50% [12]. The COPD patients with
bronchiectasis were found to have more severe exacerbations and increased sputum inflammatory
markers. Further studies are required to elucidate the mechanisms that predispose COPD patients to
developing bronchiectasis; severity of airflow obstruction may be a key driver in this mechanism.
a1-antitrypsin deficiency
a1-antitrypsin (AAT) deficiency is classically associated with predominantly lower lobe emphysema. Bronchiectasis has also been associated with the enzyme deficiency, whether this is a
direct consequence of the deficiency or secondary to the emphysema-associated airways
obstruction is less clear. In a study of patients with severe AAT deficiency the vast majority of
subjects had some evidence of bronchiectasis on a HRCT scan (70 out of 74 subjects), with 27%
having clinically significant bronchiectasis with a correlation between forced expiratory volume in
1 second (FEV1) and bronchial wall thickness [13]. In a study of the distribution of AAT alleles in
a population of bronchiectasis patients, there was no difference in AAT allele distribution between
healthy controls and bronchiectasis patients [14]. However, there was an over representation of
hetero- and homozygote AAT deficiency alleles in those patients with bronchiectasis and
coexistent asthma. Therefore, the evidence would suggest that AAT deficiency is related to airway
obstruction rather than a direct effect of the enzyme deficiency on the bronchial wall structure.
Defects of mucociliary clearance

Ciliary dyskinesia
Abnormalities of cilia structure and/or motility cause a decreased mucus clearance from the lungs.
These abnormalities can be due to a primary defect in the structure or function of the cilia or
secondary damage to the cilia from external agents, such as bacteria or inhaled noxious agents.

Airway cilia are complicated structures containing more than 250 proteins. The ciliary structures
are composed of microtubules which are mobilised by structures known as dynein arms, these are
divided into two groups the outer and inner dynein arms. This complicated polypeptide structure
can be affected by numerous genetic mutations and, as such, primary ciliary dyskinesia (PCD) is a
genetically heterogenous disorder. Among the most commonly identified mutations are those of
the genes DNAI1 and DNAH5, which code for proteins responsible for the assembly of outer
dynein arms.
As cilia are present throughout the body, patients with PCD will often present with multiple
symptoms such as sinusitis, recurrent otitis media, infertility and defects of organ lateralisation
with situs inversus or situs ambiguus. The triad of bronchiectasis, chronic sinusitis and situs
inversus is also known as Kartageners syndrome.
A number of noxious agents, both organic and inorganic, have been shown to affect the function
of cilia in human airway epithelia. Certain bacteria, such as Pseudomonas aeruginosa and
Haemophilus influenzae, have been shown to disable mucociliary clearance by releasing products
that inhibit ciliary beat frequency, allowing them to persist and propagate infection [15, 16].
Inhaled inorganic substances such as diesel particles [17] and cigarette smoke [18] have also been
shown to have a direct effect on ciliary function, inhibiting ciliary beat frequency. It is important
to note here that no causal role for tobacco smoking and the development of bronchiectasis has
been made, indeed outside of COPD bronchiectasis appears to be a disease of the nonsmoker.
Aspiration of gastric contents is a well recognised, but perhaps under diagnosed, cause of
bronchiectasis. Whilst aspiration of both acid and nonacid stomach contents leads to direct
inflammation of the bronchial wall, ciliary function may also be affected by these agents.
Secondary ciliary dyskinesia
Channelopathies
As previously mentioned, the epithelial lining of the airway is coated in a liquid known as the
airway surface liquid. It contains two layers, the outer mucus layer and an inner periciliary layer.
Ion channels within the apical surface of the epithelial levels regulate the fluid content of this layer
to ensure adequate hydration. This enables the cilia to move in a liquid layer but also prevents the
desiccation of the mucus into a thick, sticky substance that is difficult to mobilise.
Defects in the ion channels of the epithelial layer can lead to dehydration of the airway surfaces,
thereby affecting the depth of the periciliary layer and bringing the cilia into contact with the
viscous mucus layer, further impeding its function. The most widely recognised of these defects is
that found in CF. Here, the loss of a chloride channel known as the CF transmembrane regulator
(CFTR) protein leads to the inability of the epithelial cells to excrete chloride. The dysregulation of
the ion transport is further compounded by the effect of CFTR on another ion channel, that of the
epithelial sodium channel (ENaC). CFTR is an inhibitor of the ENaC channel and therefore the
loss of CFTR is postulated to lead to hyperactivity of the sodium channel, resulting in a large
increase in the transport of sodium into the epithelial cell with a corresponding movement of
water out of the airway liquid.
In theory, genetic defects of the ENaC channel could lead to bronchiectasis if such a mutation led to
over activity of the channel. Whilst mutations of ENaC genes have been identified in patients with
idiopathic bronchiectasis [19], a significant number of these were also carriers of a CFTR mutation.
Furthermore, a single CFTR mutation is frequently observed in patients with diffuse bronchiectasis.
A study comparing patients with either none, one or two CFTR mutations suggested a continuum of
CFTR dysfunction (as measured by nasal potential differences) existed and that this may lead to the
development of bronchiectasis in some patients who are CFTR heterozygotes [20].
Allergic bronchopulmonary aspergillosis
Allergic bronchopulmonary aspergillosis (ABPA) is a pulmonary condition caused by a hypersensitivity reaction to the ubiquitous environmental fungus Aspergillus fumigatus. It is most
commonly seen in patients with pre-existing asthma or CF and is clinically characterised by
recurrent wheeze, pulmonary infiltrates and the development of bronchiectasis. The hypersensitivity reaction has mixed features of immediate hypersensitivity (type I), antigenantibody
complexes (type III) and inflammatory cell responses (type IV) [21].
The inflammatory cell response seen in ABPA shows a predominance of T-helper cell type 2 (Th2)
cells leading to a release of cytokines mediating allergic inflammation (as opposed to the Th1,
cytotoxic pathway) [22]. The type I hypersensitivity reaction causes local degranulation of mast
cells and histamine release leading to bronchoconstriction. The combination of airway inflammation, which leads to viscous, eosinophil-laden mucus, plugging and airway obstruction,
and bronchospasm leads to a reduction in mucociliary clearance and the development of
bronchiectasis. As such bronchiectasis in ABPA is common. In three large case studies it was found
that central bronchiectasis was present in 6976% of patients with ABPA [2325].
Immunodeficiency
Defects in the immune system leave the lungs vulnerable to infection and in some cases the
development of bronchiectasis can be the first indication of immunodeficiency.
The most common forms of primary immune deficiencies observed in patients with bronchiectasis
are common variable immune deficiency (CVID), X-linked agammaglobulinaemia (XLA) and
chronic granulomatous disease (CGD).
Common variable immune deficiency

CVID is characterised by reduced levels of immunoglobulins (Igs) with associated recurrent bacterial
infections. An increased risk of autoimmune conditions and malignancy has also been identified. The
majority of patients present with recurrent pulmonary infections at a mean age 29 years [26]. CVID is
the most common primary immune deficiency to cause bronchiectasis. A case series undertaken in a
UK population identified 68% of the patients with CVID as having evidence of bronchiectasis [27].
The most likely cause of this high rate of incidence could be the delay in the diagnosis of CVID, with a
mean duration of 4 years between reporting of symptoms and diagnosis [27].
X-linked agammaglobulinaemia
XLA is caused by a mutation of a tyrosine kinase gene that is involved in the development of Blymphocytes, leading to an absence of circulating B-lymphocytes and the absence of Igs. Given the
severity of the immune deficiency it usually presents much earlier than CVID, usually being
diagnosed in early childhood [28]. Despite treatment with replacement Igs, chronic lung disease
can still develop with the risk of developing bronchiectasis increasing with age [29].
Chronic granulomatous disease

CGD is a group of disorders characterised by a loss of phagocytic NADPH oxidase, without which
phagocytes are unable to produce the reactive oxygen species required to kill ingested bacteria.
Infections are mainly due to Staphylococcus aureus, Serratia marcescens, Salmonella sp., Klebsiella
sp. and Burkholderia cepacia.
Antibody deficiency with normal Igs

In a study of patients with bronchiectasis and normal IgG levels, 11% were shown to have specific
antibody production deficiencies with an inability to respond to pneumococcal and H. influenzae
vaccines [30].
Secondary immunodeficiency
The development of bronchiectasis in HIV-infected patients has been noted in a number of case
series. While recurrent pulmonary infection is likely to be the major factor in the development of
bronchiectasis in these patients, the development of lymphocytic interstitial pneumonia may also
be implicated [31].
Infections
A number of childhood respiratory infections have been implicated in the pathogenesis of

bronchiectasis. The most widely recognised infectious causes of bronchiectasis are measles and
pertussis infection in the West [32], with tuberculosis being a major cause elsewhere.
Nontuberculous mycobacterial infection

Globally, Mycobacterium tuberculosis infection remains a major cause of morbidity and mortality
and a significant cause of bronchiectasis. In developed countries with screening programmes and
adequate access to treatment, the incidence of new infections remains low. However, the incidence of
nontuberculous mycobacterial (NTM) pulmonary infections is increasing. These mycobacteria vary
in pathogenecity with Mycobacterium avium complex (MAC) being the most pathogenic whilst
other organisms, such as Mycobacterium gordonae and Mycobacterium abscessus, act as opportunistic
pathogens and are only found in patients with underlying lung diseases. NTM is commonly present
in one of three clinical forms; 1) a tuberculosis-like pattern with a predominant upper lobe
fibrocavitatory disease, mostly found in older males with COPD; 2) nodular bronchiectasis, most
commonly seen in middle-aged females; and 3) hypersensitivity pneumonitis [33].
Childhood infections
The second of these clinical forms is also known as Lady Windermere syndrome, and was first
described in 1992 in a case series of 29 predominately elderly, female patients [34]. The patients had
MAC infection with bronchiectasis predominantly affecting the middle lobe and lingula. The
authors postulated that persistent voluntary cough suppression could lead to chronic inflammatory
processes in these poorly draining lung regions which are susceptible to MAC infection [34].
Bronchiectasis in systemic diseases

Inflammatory bowel disease
The development of bronchiectasis in patients with ulcerative colitis is a well recognised

phenomenon and the subject of a number of case series [35]. Classically, bronchiectasis develops
after resection of the large bowel, suggesting a common immune system response that becomes
concentrated on the bronchial wall after the bowel is removed. The common embryonic origin
and similar structures of bowel and bronchial wall (columnar epithelial and submucosal glands)
add weight to this theory.
The link between Crohns disease and bronchiectasis is less clear with only a small number of case
reports detailing their coexistence [36], perhaps too few to determine a definite association.
Connective tissue diseases

A number of connective tissue diseases have been noted to be associated with bronchiectasis,
largely based on case series reviews of small numbers of patients. The clearest association is that
between rheumatoid arthritis and bronchiectasis. Studies have estimated the incidence of
bronchiectasis in rheumatoid arthritis patients to be as high as 41% with a significant number of
them being asymptomatic [37]. Again no clear pathological process has been identified as the
cause of this association, although studies have suggested common genetic predisposition with an
association between human leukocyte antigen sub-groups [38]. An effect of the immunosuppressive agents used in rheumatoid arthritis treatment has also been postulated, although a
significant number of patients develop bronchiectasis prior to the onset of arthropathy.
Associations between bronchiectasis and Sjogrens syndrome [39], systemic sclerosis [40], systemic
lupus erythematosus [41], ankylosing spondylitis [42, 43] and relapsing polychondritis [44] have
all been made in small case series reviews.

Yellow nail syndrome is a rare syndrome that was first described in 1964 by SAMMAN and WHITE
[45] and is characterised by bronchiectasis, lymphoedema and a characteristic appearance of the
nails. The underlying pathological defect is not clear, although a recent study revealing an
association with chronic rhinosinusitis suggests a possible defect in an inflammatory pathway or
mucociliary clearance rather than a structural defect within the lung itself [46].
In two large studies [47, 48], which identified the cause of bronchiectasis in adults, a significant
proportion of patients (26% and 53%, respectively) were found to have no identifiable cause and
were labelled as having idiopathic bronchiectasis, the majority of whom were found to be female
and nonsmokers. As all the patients studied had undergone rigorous clinical testing and their
history had been reported, leading to the exclusion of all known causes, including genetic
disorders, it is unlikely under recognition of known causes of bronchiectasis could have occurred.
Even in paediatric studies, with much shorter follow-up periods and clear exposure histories, no
cause could be found for bronchiectasis in 25% of the patients [32]. It is clear, therefore, that there
is still much to learn about bronchiectasis and its underlying pathogenesis.
Statement of interest
None declared.
References
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Chaude, 1819.
2. Jex-Blake AJ. A lecture on bronchiectasis: delivered at the Hospital for Consumption Brompton, November 19th,
1919. Br Med J 1920; 1: 591594.
3. Field CE. Bronchiectasis. Third report on a follow-up study of medical and surgical cases from childhood. Arch Dis
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10
39. Uffmann M, Kiener HP, Bankier AA, et al. Lung manifestation in asymptomatic patients with primary Sjogren
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40. Andonopoulos AP, Yarmenitis S, Georgiou P, et al. Bronchiectasis in systemic sclerosis. A study using high
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48. Pasteur MC, Helliwell SM, Houghton SJ, et al. An investigation into causative factors in patients with
bronchiectasis. Am J Respir Crit Care Med 2000; 162: 12771284.
Chapter 2
Pulmonary defence
mechanisms and
inflammatory pathways
in bronchiectasis
B.N. Lambrecht*,#, K. Neyt* and C.H. GeurtsvanKessel*,"
Over recent years there has been a tremendous increase in the

understanding of pulmonary immunity, mostly driven by large
research efforts in understanding the basis of asthma and
chronic obstructive pulmonary disease. Bronchiectasis is well
understood. In this article, an overview of pulmonary defence
mechanisms as well as inflammatory mechanisms is given as a
basis to understand the pathogenesis of bronchiectasis.
Keywords: Bronchiectasis, inflammatory mechanisms,

immunity, pulmonary defence
*Dept of Pulmonary Medicine,

Laboratory of Immunoregulation and
Mucosal Immunology, Ghent
University, Ghent, Belgium.
#
Dept of Pulmonary Medicine, and
"
Dept of Virology, Erasmus
University Medical Center,
Rotterdam, The Netherlands.
Correspondence: B.N. Lambrecht,
Dept of Pulmonary Medicine,
Laboratory of Immunoregulation and
Mucosal Immunology, Ghent
University, De Pintelaan 185, B-9000
Ghent, Belgium, Email
bart.lambrecht@ugent.be
B.N. LAMBRECHT ET AL.
Summary

Copyright ERS 2011.
ISSN: 1025-448x.
DOI: 10.1183/1025448x.10003210
11
ronchiectasis is a chronic disorder characterised by permanent dilatation of the bronchi

accompanied by inflammatory changes in their walls and in the adjacent lung parenchyma.
The pathogenesis is related to recurrent inflammation of the bronchial walls combined with
fibrosis in the surrounding parenchyma. The resultant traction on weakened walls leads to
eventual irreversible dilatation [1]. Bronchiectasis can result from defective pulmonary defence
mechanisms that lead to recurrent, severe and tissue-damaging microbial insults or chronic
bacterial colonisation with persistent inflammation leading to structural changes to the airway
wall. Given the fact that restoration of inflammation and return to immune homeostasis is crucial
in the lung to protect the delicate gas exchange machinery, it is also possible that bronchiectasis
results from defective anti-inflammatory pathways that serve to dampen chronic inflammation.
Therefore, in this chapter we provide a brief overview of lung defence mechanisms and how these
immune defence mechanisms can contribute to chronic inflammation and structural changes to
the airway wall if not properly counter-regulated by anti-inflammatory pathways. The major
inflammatory cell types found in bronchiectasis are neutrophils in the airway lumen causing
purulent sputum and macrophages, dendritic cells (DCs) and lymphocytes in the airway wall [2, 3].
The latter cells often occur in lymphoid aggregates or so-called tertiary lymphoid follicles, and are
typically seen in patients with tubular bronchiectasis and are a major cause of small airway
obstruction [4].
Mechanical and physical pulmonary defence mechanisms
PULMONARY DEFENCE AND IMMUNITY
The inspired air is contaminated with toxic gases, particulates and microbes. The first line of
defence of the lung is made up of the complex physical shape of the conducting upper and lower
airways, causing a highly turbulent airflow that facilitates the impaction, sedimentation and
deposition of particulate matter and microorganisms on the mucosa, followed by the removal of
these deposited particles by the mucociliairy blanket and/or the physical expulsion from the
respiratory tract by sneezing, coughing or swallowing. Reductions in the cough reflex are
associated with increased frequency of respiratory infections, but it is not known at present
whether this would also predispose to development of bronchiectasis [5]. The presence of isolated
middle lobe bronchiectasis and colonisation with nontuberculous mycobacteria (the so-called
Lady Windermere syndrome) has been proposed to be caused by cough suppression [6].
The action of the mucociliary blanket is a dynamic and complexly regulated escalator for bringing
inhaled particles to the throat so that they can be swallowed. Defects in the function of the
mucociliary blanket can cause bronchiectasis. The conducting airways are lined with ciliated
epithelium and the structure and function of the cilia in propulsing mucus has been extensively
studied [79]. Genetic defects in the structure of the outer dynein arm proteins that connect
microtubules in cilia are the cause of primary ciliary dyskinesia [10]. Other mutations involve the ktu
gene, which is involved in the assembly of both the outer dynein and the inner dynein arm [11].
Defects in radial spoke head proteins are associated with abnormalities of the central microtubule pair
of the cilium (presence of only one microtubulus rather than two) [10]. Ciliary disturbances
(sometimes associated with situs inversus; Kartagener syndrome) almost always lead to bronchiectasis
and are often also associated with chronic rhinosinusitis. The correct movement of cilia and function
of the mucociliary escalator also depend on the low viscosity of the periciliary fluid layer, physically a
hydrated sol layer, allowing sufficient separation between the apical side of the epithelium and the
viscous mucous blanket covering the cilia. If the periciliary fluid layer is concentrated (i.e. like in cystic
fibrosis (CF)), the periciliary fluid layer becomes thinner and the cilia become entangled in the mucus
layer, thus impeding normal ciliary propulsion of the mucus [12, 13].
Humoral innate immune mechanisms in the lung

Innate immune defences are evolutionary conserved pathways of defence that kill microbes in a
generic pathway, often relying on the recognition and antagonism of common motifs in microbial
proteins or lectins, the so-called pathogen-associated molecular patterns (PAMPs), which are so
crucial for the function of the microbe that their antagonism leads to loss of pathogenicity. Just
like acquired or adaptive immunity, innate immunity consists of a humoral and a cellular part.
12
Humoral innate defence mechanisms are elaborate in the lung and consist of lactoferrin, lyzozyme,
defensins, complement, cathelicidins and collectins [14]. These molecules can be produced by
airway structural cells or by recruited innate immune cells such as neutrophils and macrophages
(see later). Lactoferrin chelates Fe2+ molecules that are crucial for the growth of some bacteria but
also stimulates the function of neutrophils. Lyzozyme degrades Gram-positive cell walls. Defensins
are made by neutrophils (a-defensins) and epithelial cells (b-defensins). They serve to make pores
in bacterial cell walls, and thus are truly antibacterial peptides but also neutralise viruses and fungi
and recruit DCs via activation of the CCR6 chemokine receptor on these cells [15]. The proper
function of defensins depends on the correct salt concentration in the airway surface liquid [16].
Thus, in CF patients defensin function against Staphylococcus aureus is defective, possibly
explaining the susceptibility to colonisation, although this theory has also been questioned. LL37 is
a well-known airway cathelicidin that is also salt sensitive and has broad antimicrobial activity but
also has effects on innate and adaptive immune cells [17]. Surfactant protein A and D are
collectins that opsonise bacteria and viruses such as influenza. A closely related collectin family
member is mannose binding lectin (MBL), it is not secreted into the lung lining fluid but is an
important circulating factor that can activate the complement cascade. Deficiency of MBL is a
cause of recurrent bacterial infections and could be a cause of bronchiectasis. Low MBL levels in
CF patients and other forms of bronchiectasis are also associated with a more rapid decline in lung
function [18].
Cellular innate immune mechanisms in the lung

The cellular arm of innate immunity in the lung is primarily made up of alveolar macrophages and
recruited neutrophils (fig. 1). Alveolar macrophages serve an important function in the
phagocytosis, killing and/or neutralisation of inhaled particulate antigens. Resident alveolar
macrophages continuously encounter inhaled substances due to their exposed position in the
alveolar lumen. These cells are packed with enzymes, metabolic products and cytokines that are
vital to defence of the alveolar space but can potentially damage the alveolocapillary membrane.
To avoid collateral damage to type I and type II alveolar epithelial cells (AEC) in response to
harmless antigens, they are kept in a quiescent state, producing few inflammatory cytokines [19].
It has been estimated previously, that the pool of alveolar macrophages can handle up to 109
Stimulus
Ingestion by
alveolar
macrophages
Direct triggering
of epithelial cells
Activation of
dendritic cells
Secondary
neutrophil
influx
TNF-, IL-1,
G-CSF, GM-CSF,
chemokines (IL-8)
13
Figure 1. When a pathogen enters the lung, it triggers both epithelial cells, macrophages and dendritic cells.
The epithelial cells make chemokines that subsequently attract neutrophils that help in phacocytosing the
pathogens. All recruited cells together with epithelial cells then make cytokines and growth factors that further
enforce innate immune responses to the pathogen by further recruitment of inflammatory cells. TNF: tumour
necrosis factor; IL: interleukin; G-CSF: granulocyte colony-stimulating factor; GM-CSF: granulocyte-macrophage
colony-stimulating factor.
14
intratracheally injected bacteria before there is spill-over of bacteria to DCs and before adaptive
immunity is induced [20]. Elegant studies have demonstrated that in vivo elimination of alveolar
macrophages using clodronate filled liposomes lead to overt inflammatory reactions to otherwise
harmless particulate and soluble antigens [21], but also to an increased sensitivity to bacterial,
fungal and viral infection. In their exposed position, alveolar macrophages serve as the first line of
defence against inhaled pathogens not only by directly acting as the main phagocytes, but also as
an important producer of pro-inflammatory chemokines, cytokines and lipid mediators; bioactive
mediators that recruit other cell types to the lung.
In contrast to alveolar macrophages that reside in the lung and serve as an immediate line of
innate defence against inhaled pathogens, neutrophils are recruited within minutes following
inoculation of microbes into the lung. The main function of neutrophils is phagocytosis and
killing of microbes, particularly fungi such as Aspergillus sp. and Pneumocystis jeroveci. They can
also kill microorganisms through the release of a-defensins and lyzozyme. Neutrophil killing
function depends on oxidative enzymes such as those of the NADPH oxidase system and
myeloperoxidase. Chronic granulomatous disease is caused by missense, nonsense, frameshift,
splice or deletion mutations in the genes for p22(phox), p40(phox), p47(phox), p67(phox)
(autosomal chronic granulomatous disease) or gp91(phox) (X-linked chronic granulomatous
disease), which result in variable production of neutrophil-derived reactive oxygen species [22].
Neutrophil extravasation is also a highly organised process requiring the rolling, arrest and
diapedesis of cells on the vessel wall. Defects in certain integrins, selectins or their activator can
cause defective neutrophil recruitment and cause recurrent pulmonary infections [23]. Once
recruited, neutrophils can also further enhance more neutrophil recruitment through production
of cytokines (interleukin (IL)-1, tumour necrosis factor (TNF)-a and IL-6) as well as through
release of calcium binding proteins of the S100 family (S100A8, A9 and A12) that act on the RAGE
(receptor for advanced glycation end products) receptor.
Induction of innate immune responses in the lung

The above mechanisms of innate defence act in a coordinated fashion. Although a single aspect of
the innate defence system can be triggered directly through recognition of foreign PAMPs, the
innate defence mechanisms are often induced simultaneously via triggering of common receptors
on both phagocytes (for cellular defences) and epithelial cells (for inducing the production of
humoral innate defence mechanisms). The most famous pattern recognition receptors belong to
the family of Toll-like receptors (TLR)1-11, NOD-like receptors, RIG-I-like receptors and C-type
lectin receptors [24]. These receptors recognise particular conserved PAMPs on specific groups of
microbes. The archetypical TLR4 is expressed at the cell surface and recognises the Gram-negative
cell wall component lipopolysaccharide, whereas TLR2 recognises peptidoglycan and TLR5
recognises bacterial flagellin. The endosomal TLR receptors TLR3 recognise double-stranded RNA,
TLR7 and TLR8 single-stranded RNA and TLR9 unmethylated CpG motifs [24]. The exact cellular
localisation and downstream signalling mechanisms of these pathways have been studied
extensively over the past few years and several clinical primary immunodeficiency syndromes have
been brought back to deficiencies in one of the signalling intermediates of these pathways.
Deficiency of IRAK4, a critical intermediary in TLR4 signalling causes recurrent bacterial
infections, particularly at a young age [25]. Deficiency of the C-type lectin receptor dectin-1 or the
downstream signalling intermediate molecule CARD9 causes immunodeficiency to candida and
P. jeroveci, most probably due to reduced induction of T-helper cell (Th)17 responses [26].
Conversely, over activity of these signalling cascades, for example caused by small polymorphisms
in or mutations of negative regulators of these pathways are associated with auto-immunity and
overzealous inflammatory pathways. As one example, polymorphisms in the ubiquitin editing
enzyme TNF-a-induced protein 3 (TNFAIP3, also known as A20), cause hypersensitivity of TLR
and cytokine receptors and are often found in patients with systemic lupus erythematosus [27].
Our own unpublished data also show that genetic deficiency of A20 in epithelial cells causes severe
mucosal inflammation in response to inhalation of intrinsically harmless proteins, but it is
unknown at present how this could be implicated in the regulation of inflammatory pathways
relevant to bronchiectasis.
Adaptive cellular immunity

Like innate immunity, adaptive or acquired immunity consists of a cellular and a humoral arm.
Cellular adaptive immunity is made up of different types of T-lymphocytes, whereas humoral
immunity is made up of B-lymphocytes and plasma cells and their secreted product;
immunoglobulins (Ig).
DCs are potent antigen presenting cells that have emerged as key regulators of adaptive immunity
(see [28] for a more detailed review on the biology of lung DC function). The general function of
lung DCs is to recognise and pick up foreign antigens at the periphery of the body, and
subsequently migrate to the draining mediastinal lymph nodes where the antigen is processed into
immunogenic peptides and displayed on major histocompatibility complex (MHC)I and MHCII
molecules for presentation to nave T-cells. In fact, these cells should be seen as specialised cells of
the mononuclear phagocyte system, which have evolved from the cells of the innate immune
system to control adaptive immunity that came later in evolution [29]. DCs express all the pattern
recognitions receptors shared with phagocytes of the innate immune system, yet at the same time
also have the machinery to talk to T-cells and B-cells and relay information about the type of
antigen to these cells, so that a tailor-made adaptive response is induced and long-term memory is
initiated. As these cells respond to many noxious stimuli from both the outside world (PAMPs)
and from within (danger-associated molecular patterns) and at the same time closely
communicate with lung structural cells such as alveolar epithelial cells, endothelial cells and
fibroblasts, it has been proposed that they could be crucial players in many lung diseases,
particularly where T-cell responses are involved in initiation of maintenance of the disease [30].
Very recently the first case reports of patients presenting with defects in the DC system have been
reported. These DC-deficient patients are at risk of severe viral skin infections and pulmonary
infections with atypical mycobacteria, which also leads to bronchiectasis [31, 32]. Our own
experiments employing DC-deficient mice have elucidated a crucial role for these cells in the
induction of antiviral immunity to influenza virus, via induction of both CD4 and CD8 T-cell
responses [33]. Similar conclusions have been reached in models of tuberculosis and bacterial lung
infections [34]. Conversely, DCs are also heavily involved in maintaining immunopathology in
which T-cells play a predominant role, the best example being the mucosal inflammation seen in
asthma and chronic obstructive pulmonary disease (COPD) [35]. In humans with bronchiectasis,
as well as in a rat model of bronchiectasis, there is an increased infiltration of the airway wall with
DCs [2, 3]. The airways of patients with diffuse panbronchiolitis, a disorder of the small
bronchioles that can also lead to bronchiectasis, contain increased numbers of DCs that have a
clearly activated phenotype, while treatment with neomacrolides reduces the antigen presenting
capacities of these DCs [36, 37].
Induction of adaptive cellular immunity by DCs
Constituents of adaptive cellular immunity
15
Adaptive cellular immunity consists of defined subsets of CD4+ Th cells and CD8+ cytotoxic Tcells. Once DCs transport their antigenic cargo to the draining lymph nodes, they induce the
proliferation and differentiation of nave T-cells into particular types of T-cell responses (fig. 2).
Discrete types of Th cells provide crucial help for different parts of the innate and adaptive
immune response [38]. Th1 cells make interferon (IFN)-c and mainly provide help to monocytic
cells, including macrophages and DCs, thus enforcing killing of intracelullar pathogens, and at the
same time enforcing opsonisation of these through provision of B-cell help. Conversely, Th2 cells
make IL-4, IL-5 and IL-13 providing help to eosinophils, mast cells and basophils to eliminate
IL-4
Th2
Gata-3
c-maf
STAT6
IL-10
TGF-
Th0
Treg
IL-4
IL-5
IL-13
TNF-
IL-10
TGF-
Foxp3
IL-6
TGF-
IL-1
IL-23
IL-12
Th17
IL-17
IL-22
ROR
STAT3
Th1
T-bet
STAT4
STAT1
IFN-
TNF-
complex helminths, and at the same

time induce IgG1 and IgE from Bcells to arm the basophils and mast
cells with effector potential. For a
long time since the original description of the Th1/Th2 concept, it has
been unclear which subtype of TAnti-inflammatory
Suppresses lymphocytes cell help was important for induProfibrotic?
cing neutrophilic responses and
protection from extracellular pathogens such as fungi. This gap has
Antifungal
been breached recently by the disStimulates neutrophils
covery of the cytokines IL-17 and
Autoimmunity
IL-22 which are produced by Th17
cells that induce neutrophilic inflammation and production of defensins
Intracellular pathogens
Stimulates macrophages by epithelial cells and are important
Stimulates lgG2a
for clearance of fungi and extracelDelayed hypersensitivity
lular bacteria [39].
Antihelminthic
Stimulates eosinophils
Stimulates lgE, lgG1
Allergy
The precise signals that induce

different types of Th lineage-comtheir secreted cytokines. When a T-helper cell (Th) type 0 encounters
mitment of nave T-cells has been
antigen on a DC, it will be induced to differentiate into various
intensely studied [38]. Antigen premutually exclusive cell fates. Each T-cell differentiation programme is
senting cells can provide different
controlled by transcription factors such as Gata-3, forkhead box P3
levels and quality of signal one
(Foxp3), RAR-related orphan receptor gamma (RORc) or T-bet,
which enforce Th cell lineage choice. Eventually Th cells emerge
(peptide-MHC), signal two (cothat are specialised for performing various antimicrobial tasks.
stimulatory molecules) and signal
IL: interleukin; Treg: T-regulatory cell; TGF: transforming growth
three (instructive cytokines) to
factor; TNF: tumour necrosis factor; IFN: interferon; Ig: immunoglonave T-lymphocytes upon antigen
bulin; STAT: signal transducer and activator of transcription.
encounter and triggering of their
pattern recognition receptors [29]. When stimulated through the unique T-cell receptor (TCR),
nave CD4+ T-cells differentiate into Th1 cells in the presence of high amounts of IL-12. IL-12
instructs Th1 development via activation of signal transducer and activator of transcription (STAT)4
and the lineage instructing transcription factor T-bet. IL-17 producing cells are induced when
exposed to a cocktail of cytokines including transforming growth factor (TGF)-b, IL-6, and IL1a/b,
while IL-23 further enhances the proliferation of these cells. The Th17 lineage specific transcription
factor RAR-related orphan receptor ct enforces Th17 characteristics in nave T-cells, and is induced
by the cocktail of cytokines instructive to their development. The mechanisms leading to Th2 cell
differentiation in vivo are still poorly understood, but in most instances require a source of IL-4 to
activate the transcription factors STAT6 and GATA-3, and a source of IL-2, IL-7 or thymic stromal
lymphopoietin to activate the transcription factor STAT5 [4044]. Despite the overwhelming
evidence that IL-4 is necessary for most Th2 responses, DCs were, however, never found to produce
IL-4 and it was therefore assumed that Th2 responses would occur by default, in the absence of
strong Th1 or Th17 instructive cytokines in the immunological DC T-cell synapse, or when the
strength of the MHCII-TCR interaction or the degree of co-stimulation offered to nave T-cells was
weak [4548]. In this model, nave CD4 T-cells were the source of instructive IL-4. In an alternative
view, IL-4 is secreted by an accessory innate immune cell type, such as natural killer T-cells,
eosinophils, mast cells or basophils, that provide IL-4 in trans to activate the Th2-differentiation
programme [49]. In the lung allergic response to house dust mite allergen, we have recently found
that basophils help DCs to induce Th2 immunity by providing an important, but not essential source
of IL-4 [50].
Figure 2. T-cell polarisation induced by dendritic cells (DCs) and
16
Lung DCs are also essential in instructing the selection and expansion of CD8 cytotoxic T-cells
that recognise virus-infected cells, cells infected with intracellular bacteria and tumourally
transformed cells via presentation of endogenous cellular antigen on the MHCI complex [33]. An
important conceptual point is that DCs do not have to be infected themselves to perform this task,
but can phagocytose virally infected or transformed cells and use the process of cross-presentation
to present the exogenous antigen into their MHCI loading machinery. Once activated by DCs and
CD4 T-cell help, cytotoxic T-cells can lyse and kill infected cells in a process requiring granzyme
and/or perforin, or kill target cells in a FasL- and/or TNF receptor-like apoptosis inducing liganddependent manner, causing apoptotic cell death in targets [51].
Humoral immune mechanisms in the lung

Humoral immunity plays a predominant role in protection from severe infections with
encapsulated bacterial strains. Antibodies are well known for their neutralising effects on
secondary infections and this is the principle of most vaccinations against childhood infections.
During a primary infection, however, antibodies, some of which have broad-spectrum specificity
(so-called natural antibodies), also have the capacity to activate complement and opsonise
bacterial cell walls and capsules, thus facilitating clearance of the pathogens. Antibodies of the IgA
and IgG class are actively secreted into the airway lumen via the action of the polymeric Ig
receptor. Airway luminal IgA is an important defence against viral entry. Maybe the most
prevalent cause of bronchiectasis is deficiencies in humoral immunity, such as common variable
immunodeficiency (CVID), a group of disorders characterised by low to absent Ig and various
degrees of T-lymphocyte abnormalities [18, 58]. CVID can be caused by mutations in the proteins
involved in TB-cell communication such as ICOS, BAFF, TACI and APRIL [59, 60]. This is a
rapidly evolving field and it is only a matter of time before all these mutations can be diagnosed on
a routine basis.
Several defects in adaptive immunity are associated with increased susceptibility to lung infection
and can be an important risk factor for later development of bronchiectasis. Defects in the IL-12/
IFNcSTAT1 axis are a well-known risk factor for mycobacterial infections and invasive
Salmonellosis [52]. Defects in the IL-23//Th17 axis are associated with increased risk of fungal
infections and P. jeroveci infections [53]. Patients with sporadic or autosomal dominant forms of
the hyper IgE syndrome (Jobs syndrome when associated with connective tissue abnormalities)
have mutations in STAT3, and hence deficient differentiation of Th17 cells [54, 55]. These patients
are at risk for severe recurrent Staphyloccal infections, pneumatocoeles and mucocutaneous
candidiasis. In recessive forms of the hyper IgE syndrome, mutations in DOCK8 have been
described, and these patients are similarly at risk for recurrent sinopulmonary infection and have
defects in Th17 generation [56]. The few biopsy studies that have been performed in
bronchiectasis have seen increased infiltration of the bronchial wall with CD4 and CD8 T-cells.
The neutrophilic inflammation seen in CF and other forms of bronchiectasis is typically associated
with the increased presence of Th17 cells [57]. In bronchiectasis associated with allergic
bronchopulmonary aspergillosis, one has also observed increased numbers of Th2 cells, thus
explaining the association with sputum eosinophilia.
Organised lymphoid structures and bronchiectasis
17
The organised accumulation of lymphocytes in lymphoid organs serves to optimise both

homeostatic immune surveillance, as well as chronic responses to pathogenic stimuli [61]. During
embryonic development, circulating haemopoietic cells gather at predetermined sites throughout
the body, where they are subsequently arranged in T- and B-cell specific areas, leading to the
formation of secondary lymphoid organs, such as lymph nodes and spleen. In contrast, the body
has a limited second set of selected sites that support neo-formation of organised lymphoid
aggregates in adult life. However, these are only revealed at times of local, chronic inflammation
when so-called tertiary lymphoid organs (TLO) appear. Just like in lymph nodes and spleen, areas
of TLO are characterised by formation of specialised high endothelial venules and the organised
production of chemokines leads to cellular organisation of T-cells and B-cells in discrete areas. In
humans, TLO has been observed in the joint and lung of rheumatoid arthritis [62], around the
airways of COPD patients [63] and in the thyroid [64]. Certain infectious diseases are also
accompanied by the formation of TLO. Influenza virus infection of the respiratory tract leads to
formation of inducible bronchus-associated lymphoid tissue (iBALT) that supports T- and B-cell
proliferation and productive Ig class switching in germinal centres [65, 66]. Tertiary lymphoid
follicles or iBALT is frequently seen in tubular bronchiectasis, and the close association with
bronchi might explain the obstruction of small bronchioles and airway obstruction that is often
seen. This is certainly the case in rheumatoid arthritis-associated bronchiectasis, in which
bronchial obstruction is often caused by strongly enlarged TLOs that impinge on the lumen of the
airway, an entity known as follicular bronchiolitis by pathologists and reflecting the presence of
B-cell follicles inside TLO structures [62]. Formation of TLO could be the result of chronic
colonisation of bronchiectatic airways by microbes, and indeed it has been proposed that latent
adenoviral infection is a cause of follicular bronchiectasis [4]. However, in one school of thought,
TLO formation can also be seen as a source of self-specific autoantibodies and a reflection of an
underlying auto-immune component of the disease. In TLO associated with rheumatoid arthritisbronchiectasis, one has indeed seen the production of pathogenic antibodies to citrullinated
proteins [62].
18
Anti-inflammatory pathways
With its large surface area, the lung is a portal of entry for many pathogens as inhaled air is
contaminated with infectious agents, toxic gases and (fine) particulate matter. At the same time,
inhaled microbes and toxic substances can gain easy access to the bloodstream across the delicate
alveolarcapillary membrane. Innate and adaptive immune defence of this vulnerable barrier is not
easy and needs to be tightly controlled as too much oedema, inflammation and cellular
recruitment will lead to thickening of the alveolar wall and will jeopardise the diffusion of oxygen
vital to life. Considering the large surface area of the respiratory epithelium and the volume of air
inspired on a daily basis it is remarkable that there is so little inflammation under normal
conditions, suggesting the presence of regulatory mechanisms that act to protect the gas-exchange
mechanism. Even following severe bacterial or viral infection, a return to homeostasis is the usual
outcome. Understanding the conditions by which lung immune homeostasis is regulated might be
crucial to advance our insight into the pathogenesis of inflammatory lung diseases such as
bronchiectasis. One type of cell that has received particular attention in suppressing immune
responses in the lung is the alveolar macrophage. Alveolar macrophages adhere closely to AECs at
the alveolar wall and are separated by only 0.20.5 mm from interstitial DCs. In macrophagedepleted mice, the DCs have a clearly enhanced antigen presenting function [67]. When mixed
with DCs in vitro, alveolar macrophages suppress T-cell activation through the release of nitric
oxide (mainly in rodents), prostaglandins, IL-10 and TGF-b. Alveolar macrophages also express
CD200R, an inhibitory receptor that regulates the strength of innate immunity to inhaled
pathogens. Another cell type that has received a lot of attention is the regulatory T-cell (Treg).
Natural Tregs express high levels of CD25 and express the lineage specific transcription factor
Foxp3 [68]. These cells are generated in the thymus and have a natural reactivity for self antigens
as well as some foreign antigens, and mainly suppress autoimmunity [69]. Induced Tregs are
generated when DCs encounter self antigen in the periphery or upon chronic immune stimulation.
It is assumed that these induced Tregs serve to dampen overt immune activation to stimuli that
cannot be fully eliminated, a typical example being chronic helminth infections or mycobacterial
infections [70]. As bronchiectasis is a disorder of chronic inflammation accompanied by microbial
colonisation, it is very likely that increased Tregs are found inside lesions, although this has not
been formally addressed. It is also possible that failure of Treg function at a certain stage of the
disease contributes to ongoing inflammation, which might ultimately progress to fibrosis. In this
regard it is a striking observation that Tregs also make TGF-b as part of their suppressive
programme. TGF-b might be at the crossroads of immunoregulation and fibrosis initiation.
Immune regulation might also stem from changes in stromal cells of the airways, such as epithelial
cells. Airway epithelial cells play a predominant role in deciding whether or not an acute or
chronic stimulus like endotoxin is recognised or not [71]. Epithelial cells express many pattern
recognition receptors and the sensitivity of these can be regulated through negative regulators of
signalling. Finally, some epithelial derived cytokines, such as IL-37, have an intrinsically antiinflammatory effect on innate immunity in the lung [72]. It is currently unknown if defects in
these counter-regulatory mechanisms are involved in the maintenance of inflammation in patients
with bronchiectasis.
Conclusion
There has been great progress in our knowledge of innate and adaptive immune responses in the
lung. Immune defects in innate and adaptive cellular and humoral immunity can all lead to
bronchiectasis. In contrast to other obstructive airway diseases, such as asthma and COPD, we
have not yet fully grasped the immunopathogenesis of chronic inflammation in this disorder.
Support statement
None declared.
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Chapter 3
Histopathology of
bronchiectasis
M. Goddard
HISTOPATHOLOGY
Summary
The clinical presentation of bronchiectasis occurs after initial
irreversible damage to the airway has occurred. The clinician then
has to control symptoms and limit the progression of the disease.
A clearer understanding of the pathogenesis of this disease will
enable the development of better treatment strategies.
Bronchiectasis is a multi-factorial disease process in which
there are a number of key steps, although they are not always
clinically identifiable. There is often an initiator or damaging
event such as a viral infection which, in an individual with a
predisposing risk such as a degree of immune dysfunction or an
impaired mucociliary clearance system, leads to persistent
and damaging bacterial infections. These infections go on to
provoke an inappropriate and self-damaging inflammatory
response in which neutrophil activity leads to progressive tissue
damage and a relentless cycle of infection, inflammation and
bronchial wall injury. Persistent infection and chronic inflammatory cell infiltration further amplify the local inflammatory
milieu and may lead to systemic complications.
Keywords: Aetiology, bronchiectasis, histopathology,
inflammation, neutrophils, pathogenesis
Correspondence: M. Goddard, Dept

of Pathology, Papworh Hospital NHS
Foundation Trust, Papworth Everard,
Cambridge, CB23 3RE, UK, Email
Martin.Goddard@papworth.nhs.uk

Copyright ERS 2011.
ISSN: 1025-448x.
DOI: 10.1183/1025448x.10003310
ronchiectasis was first described at the beginning of the 19th century by LAENNEC [1]. He
ascribed the term to the pooling of secretions in the airways leading to wall weakening and
dilatation. Whilst the term is often used loosely by radiologists to describe any airway dilatation,
pathologically the term is used to describe an irreversible dilatation of the airway often associated
with chronic suppuration.
Aetiology and classification

Aetiologically, bronchiectasis may be divided into obstructive and nonobstructive types (table 1).
22
In the obstructive type of bronchiectasis airway dilation may develop from obstruction due to any
cause. The disease is confined to the airways distal to the obstruction. Causes of obstruction may
be luminal, such as the inhalation of foreign bodies. This is most common in children and shows a
The pathogenesis of obstructive bronchiectasis is

relatively straightforward, as bronchial secretions accumulate distal to the obstruction and become
infected producing inflammation and damage to
the bronchial wall which becomes weakened and
dilated. This was recognised by LAENNEC [1].
Table 1. Causes of bronchiectasis

Bronchial obstruction
Foreign bodies
Tumours
Carcinoid tumours
Endobronchial chondromas and lipomas
Mucous plugs
ABPA
Nonobstructive
Post-infective
Measles
Adenovirus
Pertussis
Tuberculosis
Mucociliary abnormalities
Cystic fibrosis
Ciliary dysmotility syndromes
Immunological abnormalities
Hypogammaglobulinaemia IgA and IgG
sub-class deficiencies
Neutrophil function abnormalities
Ataxia telangiectasia
Associated with systemic diseases
Rheumatoid arthritis
Sjogrens syndrome
Ankylosing spondylitis
a1-antitrypsin deficiency
Pulmonary fibrosis
ABPA: allergic bronchopulmonary aspergillosis;
There have been several attempts to classify nonIg: immunoglobulin.

obstructive bronchiectasis, which are variably based
on a mixture of historic bronchographic and, more
recently, high-resolution computed tomography (HRCT), appearances (saccular or cystic,
fusiform or cylindric) [10] and histological appearances (follicular) with lymphoid follicles in
the wall, as defined by WHITWELL [11]. Nonobstructive bronchiectasis is typically more widespread, affecting more than one lobe and most commonly affecting the basal segments of the lower
lobes [1113]. The left lung is more frequently affected than the right and the disease process
typically involves the middle-order bronchi (fourth to ninth generations).
M. GODDARD
predilection for the right lower lobe and posterior

segment of the right upper lobe [25]. The risk of
developing bronchiectasis following foreign body
inhalation has been assessed as 316% [6]. However,
other causes of obstruction include mucus inspissation in allergic bronchopulmonary aspergillosis
(ABPA) [7], with central or upper lobe bronchiectasis, and distal to broncholitis. Tumours may also
cause obstruction and bronchiectasis but this is more
prevalent in the slower growing often polypoid tumours, such as carcinoid tumours, endobronchial
lipomas and chondromas [8]. Extrinsic compression
of the bronchus may also lead to obstruction, and
typically hilar tuberculous lymphadenopathy can
lead to bronchiectasis, particularly of the right
middle and lower lobes. The middle lobe, because
of its relatively narrow lumen, is at particular risk of
compression or obstruction, a condition sometimes
referred to as middle lobe syndrome [9].
23
This classification is now probably unsatisfactory and of little pathological significance; although
the distribution of changes may provide a clue to the underlying aetiology. Post-infective
bronchiectasis is traditionally the most common underlying cause, is most often basal and may
be confined to a single lobe. However, nonobstructive bronchiectasis may occur in association
with a number of other conditions. In diseases where mucociliary clearance is impaired,
bronchiectasis frequently, if not inevitably, develops. In cystic fibrosis [14] and ciliary
dysmotility syndromes, such as primary ciliary dyskinesia arising from a defect in the dynein
arms [15], bronchiectais is more widespread, sometimes with upper lobe predominance. The
association of bronchiectasis with disturbances in mucociliary clearance mechanisms highlights
the importance of local defence mechanisms within the airways in aetiological terms and in
terms of the pathogenesis of the disease. There may be primary defects in the immune system
with abnormalities of neutrophil function, hypogammaglobulinaemia [16], immunoglobulin
(Ig)A and IgG sub-class deficiencies [17], and in ataxia telangiectasia. Bronchiectasis may also be
associated with some autoimmune conditions including ulcerative colitis [18], rheumatoid
disease [19], Sjogrens syndrome [20] and ankylosing spondylitis. Bronchiectasis is also associated with several noninflammatory conditions within the lung, such as a1-antitrypsin
deficiency, and is reported in some cases of pulmonary fibrosis but in these cases may be due to
traction effects of the surrounding fibrosis.
Of the known causes or associations of bronchiectasis, childhood infection is probably the most
common accounting for up to 30% of cases, with immunodeficiencies present in up to 18%.
However, in some studies, no underlying abnormality can be detected in .50% of cases.
Histopathological appearances
Histopathologically, bronchiectatic airways appear dilated and on examination have a crosssectional area that is much larger than the accompanying pulmonary artery (fig. 1). The airway
lumen is often filled with a mucopurulent exudate with neutrophils and macrophages (figs 2 and 3).
The respiratory epithelium lining shows variable changes from a reserve cell hyperplasia to
squamous metaplasia (fig. 4) with active inflammation shown by epithelial and mucosal infiltration
by neutrophils and in severe exacerbations, ulceration (figs 5 and 6). The bronchial wall is often
destroyed due to loss of fibromuscular tissues and the elastic framework, and may show erosion and
loss of cartilage [21]. There is usually a reduction in submucosal glands. The wall may be thin but is
more often greatly thickened with extensive peribronchial fibrosis extending into the adjacent lung
parenchyma (fig. 7) [22]. There is an associated chronic inflammatory cell infiltrate within the wall,
predominantly lymphocytes and plasma cells, and in some cases lymphoid follicles with germinal
centres may be prominent [23]. The presence of B-cell immune activation through the presence of
germinal centres and plasma cells in the walls of bronchiectatic airways, would support the role of
antibodies in the immune response to persistent infection. However, bronchiectasis is associated
with some autoimmune connective tissue diseases, in particular rheumatoid arthritis [19, 24, 25],
and a role for autoimmunity in the destruction of the airway has also been suggested.
HISTOPATHOLOGY
Eosinophils may be seen as part of

the infiltrate as with any chronic
airways inflammation. Whilst nonspecific, they raise the possibility of
an associated fungal infection such
as Aspergillus. Although eosinophils
are commonly seen in the mucus
plugs of ABPA, their presence
within the airway wall inflammation is nonspecific. Granulomas and
multinucleate giant cells may be
seen in the wall and might be a
reaction to the inspissated luminal
material but the possibility of concomitant fungal or mycobacterial
infection should always be considered. In established bronchiectasis,
the histological pattern of chronic
inflammation within the airway wall
with superimposed active inflammation, most likely reacting to
concomitant infection, has a fairly
uniform appearance and provides
little insight into the underlying
aetiology or pathogenesis.
24
Figure 1. Low-power view of a bronchiectatic airway; note the

airway lumen is much larger than that of the accompanying
pulmonary artery. Magnification64.
The surrounding lung parenchyma

may show a number of changes.
Where there is distal luminal obliteration of bronchi and bronchioles, the lung parenchyma may
The airways are supplied by the

bronchial arteries and the inflammatory destruction and healing processes
result in the formation of bronchopulmonary anastamoses, probably due
to a mixture of new vessel formation
and the re-opening of pre-existing,
pre-capillary bronchopulmonary connections (fig. 8). Ulceration of the airways can lead to severe haemorrhage
and haemoptysis. The formation of
anastamoses and the loss of some of
the alveolar capillary bed leads to the
development of pulmonary hypertension [27].
Figure 2. Bronchiectatic airway wall with dense chronic

inflammatory cell infiltrate, which includes lymphocytes, plasma
cells and eosinophils. Magnification620.
M. GODDARD
show atelectasis due to absorption

and collapse. Obliterative changes in
small airways are important in contributing to airflow obstruction in
bronchiectasis [10, 11]. Destructive
inflammation may lead to the formation of an abscess cavity, although
this may be difficult to distinguish
from a distended, ulcerated airway.
There may be accompanying interstitial pneumonitis, particularly in
cases of follicular bronchiectasis, and
also changes of an organising pneumonia. Small airway changes, such
as bronchiolectasis, may be seen as
part of the whole disease process or
may be part of an underlying disease
leading to more proximal dilatation, as has been seen with small
airways disease, such as bronchiolitis
[18, 26].
Focal proliferations of neuroendocrine

cells are also seen and may lead to
the formation of multiple tumourlets,
small aggregates of neuroendocrine
cells in the walls of small airways.
These are not specific to bronchiectasis and may be seen in a number of
chronic lung conditions [28].
Figure 3. Bronchiectatic airway wall with luminal pus, neutrophil

infiltration of the airway epithelium and a dense chronic
inflammatory cell infiltrate. Magnification640.
25
It has also been recognised that the

persistent chronic activation of the immune system in the wall of the airway may lead to the development of
bronchus-associated lymphoid tissue
(BALT), especially in bronchiectasis
associated with Sjogrens syndrome
[29]. Increased incidence of BALTomas,
low-grade, B-cell lymphomas, is associated with Sjogrens syndrome

but not specifically related to bronchiectasis [20].
In chronic disease, further complications may arise. Locally, the lung
may develop abscesses and even empyema, although this is less common
as the pleural space is often obliterated by fibrous adhesions. Bronchiectatic spaces may become colonised
by saprophytic fungi, most commonly
Aspergillus sp.
HISTOPATHOLOGY
Systemic dissemination of infection

may lead to abscesses in other organs,
notably the brain, and chronic suppuration may be complicated by
systemic amyloidosis (type AA). The
incidence in bronchiectasis is unclear
but in one study of patients with
systemic amyloidosis requiring haemodialysis, 40% had underlying bronchiectasis [30].
Figure 4. Squamous metaplasia of the epithelium lining in
bronchiectasis. Magnification640.
Pathogenesis
The pathogenesis of bronchiectasis

is complex and a number of different mechanisms contribute to the development of a similar
morphological appearance and different factors act together to set up a cycle of inflammation and
destruction that leads to damage and destruction of the bronchial wall [31].
The initiator to this sequence is usually damage to the bronchial epithelium. This may be due to an
external insult or to an intrinsic deficiency within the patient. The most common predisposing
factor to the development of bronchiectasis is a severe childhood respiratory infection, which may
be viral, such as measles or adenovirus, or bacterial, such as Bordetella pertussis [3234]. The
resultant permanent dilatation of
the airways is thought to be due
not only to inflammation and destruction of the bronchial wall but
also, in part, to a traction effect
produced by collapse of the surrounding lung parenchyma. However, the persistence of infection
and inflammation are of paramount
importance in the progression of the
disease.
Figure 5. Severely inflamed ulcerated bronchiectatic airway with
26
no epithelium and surface granulation tissue. Magnification620.
Whilst an underlying cause is not

established in all cases, the number
and type of associations for bronchiectasis gives us some indication
of what the important underlying
pathogenetic mechanisms may be.
In post-infectious causes, the initiating viral infection appears to be

transitory and, in the case of adenoviruises, it has not been possible to
demonstrate the persistence of the
virus within bronchiectasis by in situ
hybridisation [35]. However, some
respiratory viruses have been shown
to lead to abnormalities in ciliary
function, which may persist for several
weeks [36].
In the early stages of bronchiectasis, the most common bacterial isolate is Haemophilus influenzae,
which has the capacity to directly damage the airway epithelium and induce the production of
inflammatory mediators [37]. The typical immune response to H. influenzae is a T-helper (Th)1
response. However, some bronchiectasis patients with persistent infection have been found to have
a Th2 response with a cytokine profile of interleukin (IL)-4 and IL-10. The release of cytokines
contributes to the inflammatory response within the airway and at the same time may also result
in a failure of the response to satisfactorily remove the organism [38].
Figure 7. A bronchiectatic airway showing an attenuated inflamed

epithelium with surrounding inflammation and fibrosis extending into
the peribronchial lung parenchyma. Magnification620.
27
Over time, a number of other organisms have been found to be

established within the airways, particularly Streptococcus pneumoniae
and Pseudomonas aeruginosa. The
initial damage to the epithelium
lining allows this secondary bacterial colonisation to occur, which further inhibits ciliary clearance and
promotes the persistence of infection and damaging inflammation
[39]. The importance of this persistence in bacterial colonisation may
be related to the production of heatlabile products by the bacteria,
which further damage ciliated cells
and inhibit ciliary activity. P. aeruginosa can be a particular problem
as it is protected from cellular and
humoral attack because it survives
in a biofilm on the mucosal surface
[40]. Pseudomonas has been shown
M. GODDARD
Clinically, it is the recurrence and

persistence of bacterial infections
in the airways with which most
patients present that are of most
importance and are linked to the
progression of the disease. There is a
Figure 6. Ulcerated airway with surrounding fibrosis of the wall.
prevailing view that bacterial infecMagnification610.
tion in the lower respiratory tract
provokes an exaggerated and uncontrolled neutrophilic response and that the complex interplay between bacterial infection and airway
inflammation, along with the release of tissue damaging substances, leads to the progressive damage
which typifies bronchiectasis.
to produce phenazine pigments that

can inhibit ciliary action through a
mechanism which leads to a reduction in cellular cAMP and ATP.
Furthermore, pseudomonal pyocyanin can lead to epithelial disruption
and rhamnolipids have a ciliostatic
effect [41, 42]. Alveolar macrophages are an important mediator of
defence against Pseudomonas and
stimulated macrophages secrete cytokines that both recruit and activate
neutrophils, thus potentially amplifying both the inflammatory response
and the potential for further tissue
damage [43, 44].
The resultant inflammatory reaction
is an important pathogenic mechanwall. Magnification620.
ism in the weakening of the bronchial wall. Much of the damage
appears to relate to the release of proteolytic enzymes and oxygen free radicals from neutrophils.
The severity of an inflammatory response is dependent on the interplay of several cytokines, which
may be both pro- and anti-inflammatory [45]. In a well-regulated system, the inflammatory
cascade is proportionate to the triggering bacterial stimulation and is switched off. There is
evidence that in bronchiectasis the inflammatory response is disproportionate to the infective
burden and that the inflammatory response persists [43, 46]. Indeed, in the early phases of
bronchiectasis, active airway inflammation has even been reported in the absence of identifiable microbial infection, suggesting a dysregulation of the cytokine network independent of
infection [47].
HISTOPATHOLOGY
Figure 8. Thick-walled bronchial artery in a bronchiecatic airway
Neutrophils are potent effectors in inflammatory responses and secrete anti-microbial substances,
as well as reactive oxygen free radicals [48]. Bronchoalveolar lavage (BAL) studies have demonstrated that neutrophils are consistently present in patients with bronchiectasis, even when
sterile and clinically stable, but increase in the presence of potential pathogens [49, 50].
Recruitment and migration of neutrophils in airways is facilitated by the activation of neutrophils
and the upregulation of adhesion molecules on endothelial cells [5153]. These changes are
regulated by cytokines, particularly IL-1 and tumour necrosis factor (TNF)-a, as well as
lipopolysaccharide (LPS), which have been shown to be increased in the airways of patients with
bronchiectasis [54, 55]. Activated neutrophils secrete potentially tissue damaging enzymes such as
neutrophil elastase, proteinase 3 and metalloproteinases. Levels of these enzymes in BAL samples
have been shown to correlate with neutrophil numbers and markers of disease activity such as 24hour sputum production [56]. These enzymes can directly damage the structural integrity of the
airway via damage to the basement membrane and elastin framework [5760]. Neutrophils are
also an important source of oxygen free radicals. Release of oxygen free radicals are an important
part of the defence against infection and are regulated by a protective anti-oxidant system.
However, the excessive release of these oxidants can overwhelm the defence mechanisms and cause
tissue damage via lipid peroxidation. Furthermore, reactive oxygen species may amplify the
inflammatory response through the induction of cytokine and chemokine production by the
stimulation of genes regulated by nuclear factor-kB. Studies in bronchiectatic patients have shown
increased levels of exhaled H2O2 correlating with neutrophil counts and disease activity [61, 62].
28
Macrophages also play a role in the disease progression as they secrete TNF-a, which promotes
neutrophil recruitment, as well as other inflammatory mediators including IL-8, monocyte
chemotactic protein-1 and chemokines [23, 63]. Lymphocytes are also typically present in
bronchial biopsies within the lamina propria and may also infiltrate the overlying epithelium.
Studies assessing the relative proportions of CD4+ and CD8+ have produced mixed and, at times,
conflicting results. Nonetheless, their presence indicates a cell-mediated immune response
contributing to the overall inflammatory process [22].
Whilst the epithelial layer may be seen as a protective barrier through mucociliary clearance and
generation of anti-bacterial substances, it also contributes to the inflammatory process through the
direct generation of pro-inflammatory cytokines [64]. Exposure to LPS leads to the generation of
IL-8 and TNF-a which, as stated previously, are important in neutrophil recruitment. Bronchial
epithelial cells are also able to upregulate surface adhesion molecules, such as intracellular
adhesion molecule-1, aiding the migration of neutrophils [65, 66].
Thus, a number of pathways lead to the activation and recruitment of neutrophils into the airways
which, if not adequately regulated and controlled, results in the destruction of local tissue and the
persistence and progression of bronchiectasis. Individual variability in this innate response may
help to explain why not all individuals exposed to predisposing triggers will go on to develop
bronchiectasis and offers potential targets for therapeutic intervention.
None declared.
29
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31
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Chapter 4
Assessment and
investigation of adults
with bronchiectasis
M. Drain and J.S. Elborn
ASSESSMENT AND INVESTIGATION
Summary
The diagnosis of bronchiectasis is made on the basis of highresolution computed tomography (HRCT) scan findings. A
diagnosis of bronchiectasis should be considered in all
patients with persistent cough productive of sputum, where
another clear diagnosis has not been made. This includes
patients with an initial diagnosis of chronic obstructive
pulmonary disease or severe asthma. Once bronchiectasis
has been confirmed by HRCT scanning, patients should
undergo a range of investigations to determine whether or not
there is an underlying cause. This can usually be determined
in approximately 50% of patients with bronchiectasis. The
common conditions which should be sought are cystic
fibrosis, immunodeficiency syndromes, primary ciliary dyskinesia, and autoimmune diseases, such as rheumatoid arthritis
and ulcerative colitis. For many of these conditions, there is
specific treatment to improve symptoms and reduce lung
injury but, without an accurate diagnosis, appropriate therapy
may not be instituted.
Keywords: Bronchiectasis, computed tomography scan, cystic
fibrosis, primary ciliary dyskinesia, primary immunodeficiency
Centre for Infection and Immunity,

School of Medicine, Dentistry and
Biomedical Sciences, Queens
University Belfast, Belfast, UK.
Correspondence: J.S. Elborn, Centre
for Infection and Immunity, School
of Medicine, Dentistry and
Biomedical Sciences, Queens
University Belfast, 97 Lisburn Road,
Belfast, BT9 7BL, UK, Email
s.elborn@qub.ac.uk

Copyright ERS 2011.
ISSN: 1025-448x.
DOI: 10.1183/1025448x.10003410
32
ronchiectasis is a generic diagnostic term that describes the pathological dilation of the airways
found in a number of chronic lung conditions. The aetiology of bronchiectasis is varied
(table 1), and, in most series, an underlying cause can only be definitively identified in 50% of
cases [1, 2]. The importance of determining a cause lies in facilitating treatment that may improve
symptoms, reduce exacerbations and alter the course of the disease by preserving lung function. In
one series in children, extensive investigation detected a specific cause in 74% of those
investigated, and this led to a change in treatment in 56% [3]. In an adult series from the same
geographical area, a diagnosis was again reached in 74%, and the treatment of 37% of these was
affected by knowledge of the diagnosis [4].
Congenital
Acquired
Cystic fibrosis#
Primary ciliary dyskinesia#
a1-Antitrypsin deficiency
Congenital anatomical defects
Tracheo-oesophageal fistula
Bronchotracheomalacia
Tracheomegaly
Pulmonary sequestration
Marfans syndrome
Cystic fibrosis#
Primary ciliary dyskinesia#
Following infection#
Bacterial#
Whooping cough
Tuberculosis
Nontuberculous mycobacteria
Viral
Measles
HIV#
Fungal
ABPA#
Immunodeficiency
Primary
Common variable immunodeficiency#
X-linked agammaglobulinaemia#
IgA deficiency
MHC class II deficiency
B-cell deficiency
Hyper-IgE syndrome
Secondary
Following chemotherapy#
Haematological malignancy#
Graft-versus-host disease
Interstitial lung disease# (traction bronchiectasis)
Autoimmune disease
Rheumatoid arthritis#
Ulcerative colitis
Sjogrens syndrome
Sarcoidosis
Following surgery
Inhaled foreign body
Chronic GORD
ABPA: allergic bronchopulmonary aspergillosis; Ig: immunoglobulin; MHC: major histocompatibility complex;
GORD: gastro-oesophageal reflux disease. #: more common conditions that should be considered when
making an initial diagnosis [2].
Childhood respiratory infection, e.g. whooping cough, measles, tuberculosis (TB) or severe
bacterial pneumonia, is cited as being responsible for a large proportion of cases of bronchiectasis,
i.e. up to 50% [46]. This potential cause, however, is subject to recall bias, particularly since the
majority of cases present in the fifth and sixth decades of life. Many people of this age have had
measles, whooping cough or other childhood infections associated with respiratory infection,
including pneumonia. In addition, the first episode of pulmonary infection could represent the
first exacerbation of bronchiectasis. Bronchiectasis is found in association with numerous
multisystemic diseases, such as cystic fibrosis (CF) [7], immunodeficiencies [8], a1-antitrypsin
(a1-AT) deficiency [9], primary ciliary dyskinesia (PCD) [10], rheumatoid arthritis and
inflammatory bowel diseases, especially ulcerative colitis [1, 7, 11].
M. DRAIN AND J.S. ELBORN
Table 1. Causes of bronchiectasis in adults
Prevalence
The prevalence of bronchiectasis is almost certainly underestimated. This is because it is a
condition that many healthcare practitioners are unfamiliar with, and it is frequently misdiagnosed as asthma or chronic obstructive pulmonary disease (COPD) due to the similarities in
clinical findings (table 2).
33
In the USA, the prevalence of bronchiectasis has been estimated at 4.2 per 100,000 population
among those aged 1834 years, rising to 272 per 100,000 population in those aged .75 years [12].
Table 2. Clinical findings in chronic obstructive pulmonary disease (COPD), asthma and bronchiectasis
Symptom
Cough
Sputum production
Dyspnoea
Wheeze
Haemoptysis
Fever
Lethargy
Recurrent infection
Clinical signs
Finger clubbing
Breath sounds
Added sounds
Lung function
Spirometry
Reversibility
Lung volumes
Transfer factor
Hypoxia
Radiology
Chest radiography
CT findings
COPD
Bronchiectasis
Asthma
+
+
++
+
+/+/+
+
++
+/+/+
+
+
++
+
+/+
++
+
No
Q/wheeze
Wheeze
Extensive disease
Normal/Q
Crackles
No
Normal/wheeze
Wheeze
FEV1Q, FVCQ FEV1/

FVCQ
15%
Q/q
Normal
Yes
FEV1Q/normal FVCQ/normal
FEV1/FVCQ/normal
40%
Normal/Q
Normal/Q
Yes/no
FEV1Q/normal, FVC
normal FEV1Q/normal
Yes
Normal
Normal
No
Chronic inflammatory
changes, hyperinflation
Hyperinflation, airtrapping, bullae, may
have mildly dilated
airways or thickened
bronchial wall
Tramlines, ring shadows/normal
Normal/
hyperinflation
Normal/air-trapping,
may have mildly dilated
airways or thickened
bronchial wall
Dilated bronchi, thickened

bronchial wall, lack of
tapering of bronchi,
bronchi visible in outer
12 cm, air-trapping
CT: computed tomography; FEV1: forced expiratory volume in 1 second; FVC: forced vital capacity;
-: uncommon; +/-: occurs sometimes; +: common; ++: very common; Q: decrease; q: increase.
However, these values are derived from a database of claims from 30 different healthcare insurance
plans made over a 2-year period. They are likely to underestimate the true prevalence as they
exclude not only the uninsured population but also those who use alternative plans. It cannot,
therefore, be claimed that they are truly representative of the real population prevalence. The
prevalence of non-CF bronchiectasis in Northern Ireland is estimated at around 5,000 in a
population of approximately 2 million [13], leading to 300400 admissions per annum for the
treatment of an infective exacerbation.
In children, bronchiectasis is less common. It can be extrapolated that the prevalence should be
falling following the advent of improved antibiotic therapies and vaccination of children during
the first year of life. Only two national studies have been reported with very different rates, 0.5 per
100,000 population in Finland [14] and 3.7 per 100,000 population in New Zealand [15]. In
certain indigenous population groups, the prevalence is much higher, e.g. the New Zealand figure
doubles among the Maori and Pacific Islander populations [11, 15], Aboriginal rural communities
have 14.7 per 1,000 population affected among those aged ,16 years [16] and 16 per 1,000
population in Alaskan natives [17]. This is thought to occur due to an increased rate of severe
pulmonary infection in early childhood, due to a combination of socioeconomic factors rather
than solely a genetic predisposition.
Approach to diagnosis
34
The diagnostic approach to a patient with bronchiectasis should first establish that there is radiological evidence of airways dilatation and secondarily consider possible underlying conditions [1].
People presenting with a chronic productive cough lasting for .4 weeks or recurrent episodes,
with two or more episodes occurring over 8 weeks, should have the diagnosis of bronchiectasis
considered [2]. In the scheme outlined in figure 1, all of the first-line investigations should be
considered as routine in patients being investigated for bronchiectasis. Most people have already
undergone some investigations prior to referral, such as a sputum culture, chest radiography or
computed tomography (CT), which may guide further investigations.
Symptoms and physical findings

Cough productive of sputum is the most common symptom associated with bronchiectasis [1, 1821].
In some studies, 25% of patients do not report excessive daily sputum production, but describe a
marked increase in volume during an exacerbation [1, 18]. Occasional haemoptysis is a frequent
symptom and is reported by half of all patients. This is often associated with a pulmonary exacerbation.
Shortness of breath, fever and chest pain are also common complaints among non-CF bronchiectasis
patients [18], although they are common symptoms in other chronic inflammatory lung disease that
may coexist, e.g. COPD and asthma (table 2). Patients presenting with such symptoms who do not
respond as expected to usual therapy should raise the possibility of bronchiectasis and this should be
investigated. Some symptoms point to specific diagnoses (table 3).
Physical examination
Diagnostic suspicion of bronchiectasis
Consider other Negative

diagnosis
Chest
HRCT scan
Sputum culture
(including mycobacteria)
Spirometry
Chest
radiography
Assessment of
functional status
and infection in all
patients
Positive
Sweat [Cl-]
(CF)
Genetics
Nasal PD
Igs
(CVID)
1-AT levels
and phenotype
(1-AT)
Vaccination
studies: Pneumovax
and tetanus
Genetics
Nasal NO RF/autoantibodies
(PCD)
(CTD)
EM studies
Genetics
Functional studies
Aspergillus
IgE and IgG and
eosinophilia
(ABPA)
Physical findings are of modest help in the assessment of patients with bronchiectasis. The classic
findings of wet crackles and finger clubbing are now uncommon and should trigger investigation
for conditions associated with severe bronchiectasis, such as CF. Crackles with some associated
First-line diagnostic
investigations to
be considered in
all patients
Further studies in case of

diagnostic suspicion or doubt
Figure 1. Diagnostic approach to bronchiectasis. HRCT: high-resolution computed tomography; [Cl-]: chloride
35
ion concentration; CF: cystic fibrosis; Ig: immunoglobulin; a1-AT: a1-antitrypsin; PCD: primary ciliary dyskinesia;
NO: nitric oxide; RF: rheumatoid factor; CTD: connective tissue disease; ABPA: allergic bronchopulmonary
aspergillosis; PD: potential difference; EM: electron microscopy; CVID: common variable immunodeficiency.
Table 3. Specific historical features suggestive of a particular diagnosis in adults

Cystic fibrosis
Common variable immunodeficiency
Neonatal respiratory distress, middle ear disease, infertility

Culture of Staphylococcus aureus, Pseudomonas aeruginosa or
Burkholderia cepacia complex, malabsorption symptoms,
infertility, recurrent pancreatitis, nasal polyposis
Recurrent respiratory, urinary, gastrointestinal and skin infections
wheeze are the most common findings, with finger clubbing now a rare feature, and usually
associated with severe disease. Other aspects of examination should focus on clinical signs of
associated diseases, such as CF, immune deficiency or a connective tissue disease.
Diagnostic tests
Blood tests
A complete blood count, although nonspecific, is important in monitoring the ongoing condition
of each individual patient. Haemoglobin level can be low secondary to anaemia of chronic disease,
and, conversely, patients may be polycythaemic secondary to chronic hypoxia. An elevated white
cell count may indicate the presence of acute infection. The differential white cell count can reveal
lymphopenia, which may prompt further investigation for immunodeficiency syndromes or
eosinophilia, which can occur in but is not diagnostic of allergic bronchopulmonary aspergillosis
(ABPA).
C-reactive protein (CRP) is an acute-phase reactant commonly measured in respiratory patients
with acute exacerbations in order to assist in determining whether or not there is a systemic
inflammatory response [1, 22, 23]. In bronchiectasis patients in a stable state, it has been shown
that CRP levels are elevated from baseline [22]. The CRP level also correlated with decline in lung
function and severity of disease on high-resolution CT (HRCT) in the same series [22].
Radiology
Although suspected with a history of recurrent lower respiratory tract infection on a background
of chronic cough and sputum production, the diagnosis of bronchiectasis can only be confirmed
radiologically [2]. The gold-standard investigation is HRCT. This was first described in 1982 [16],
and permits a detailed examination of the lung architecture using a noninvasive technique.
Historically, the diagnosis was based on bronchography, which involved instillation of a radioopaque dye into the airways and fluoroscopic screening. This technique has been superseded due
to the greater detail available in a safer more easily tolerated imaging method and is now obsolete.
Volumetric HRCT has some advantages over conventional HRCT as it provides more-detailed
images, but it is more prone to image degradation due to motion artefact and requires a higher
radiation dose. Standard HRCT is appropriate for the majority of patients.
Findings on HRCT are bronchial wall thickening with dilatation of the bronchi to a diameter
greater than that of the accompanying arteriole (the signet-ring sign); lack of normal tapering of
bronchi/bronchioles on sequential slices; and visualisation of bronchi in the outer 12 cm (fig. 2)
[1, 23, 24]. The bronchiectatic changes in CF have been quantified using a number of scoring
systems, but the value of these in diagnosis or follow-up care has not been established.
36
The histopathological appearance of bronchiectasis has been further subcategorised as cylindrical,

saccular and varicose, depending on the shape of the bronchi [25]. The true clinical significance of
these subdivisions is unclear. However, cystic bronchiectasis has been associated with an increased
frequency of exacerbation and more-clinically significant disease [24]. HRCT appearance can also
be used to confirm any other parenchymal or bronchiolar pathology, such as interstitial lung
a)
b)
c)
changes in bronchiectasis. a) Signet-ring sign, i.e.

dilatation of the bronchi to a diameter greater than
that of the accompanying vessel. b) Visualisation of
the bronchi in the outer 12 cm. c) Thickened
bronchial walls. The circled areas indicate ring
shadows.
disease [25, 26]. The distribution of ectatic airways throughout the lung fields can be used to guide
investigation of underlying causes, but most changes are nonspecific (table 4) [27, 28].
Although the diagnosis is confirmed radiologically using HRCT, a posteroanterior chest
radiograph should be obtained as a baseline with which to compare future films in the event of
acute exacerbation. Depending on the distribution of the bronchiectasis and the degree of damage,
the chest radiograph may show minimal change from normal or be markedly abnormal.
Traditionally, the radiographic changes associated with bronchiectasis are tramlines and ring
shadows [18]; these markings correspond to the thickened mucosa of the more-severely inflamed
airways in transverse or cross-section.
Figure 2. High-resolution computed tomography
Table 4. High-resolution computed tomography features of bronchiectasis

General features
Bronchial dilatation (bronchus diameter greater than that of adjacent vessel)
Bronchial wall thickening
Bronchial plugging
Areas of reduced attenuation (mosaic pattern)
Specific features
ABPA: upper-zone central bronchiectasis
Cystic fibrosis: upper-zone bronchiectasis
NTM/MAC: Middle-lobe irregular branching and tree-in-bud appearance
37
ABPA: allergic bronchopulmonary aspergillosis; NTM: nontuberculous mycobacteria; MAC: Mycobacterium

avium-intracellulare complex.
Once the diagnosis of bronchiectasis has been confirmed, a detailed clinical work-up should be
undertaken in order to determine the extent of the impact on lung function, morbidity and
prognosis, the underlying cause of the existing structural lung damage and the most prevalent
infecting organisms. The benefits of this are that not only can treatment be tailored to the
individual, but also a potentially treatable underlying condition may be uncovered [1, 24, 25].
A comprehensive clinical assessment, including a detailed history and physical examination, are
required to illicit any pointers towards a specific diagnosis. This should be followed up by extensive
investigation to allow determination of baseline functional status and lung function and to permit
guidance of treatment. During the course of investigation, underlying conditions which are known
to have an association with bronchiectasis, albeit not a causative one, may be discovered.
Pulmonary function testing and other physiological factors

Forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) should be measured
at the time of the diagnostic evaluation and at least annually, more frequently in the setting of
PCD, immunodeficiency or connective tissue disease [21, 24]. Spirometric results may be normal
in some patients, although usually show a pattern of airflow limitation, with a decreased FEV1 and
a reduced FEV1/FVC ratio. FVC may be normal or slightly reduced, although this finding alone
may be indicative of mucous impaction [2, 24]. Airway hyperresponsiveness has also been
demonstrated. In 40% of patients, an FEV1 reversibility of .15% following administration of
b-agonist can be demonstrated [29]. In addition, 3069% of patients who do not exhibit a reduced
FEV1 at baseline, show a 20% decrease in FEV1 following histamine or methacholine challenge
[30, 31], indicating clinically significant hyperresponsiveness. FEV1 has the strongest correlation
with severity of structural abnormality on HRCT [32, 33]; however, it correlates poorly with
clinical fluctuations in disease course.
Full pulmonary function testing, including lung volumes and gas transfer coefficient, should be
carried out at the outset in adult presentations in order to give a picture of the overall functional
status of the lungs and also to assist in the diagnosis of underlying conditions [2]. Reduced lung
volumes and transfer factor should prompt consideration of underlying interstitial lung disease.
Elevated lung volumes can be secondary to air-trapping or indicate mucous impaction of smallcalibre airways.
Exercise testing, such as the incremental shuttle test and 6-minute walking test, are widely used
tools for the assessment of functional capacity in chronic pulmonary disease patients and can be
applied to bronchiectatic patients [34]. However, such tests have no value in diagnosis and there
are no data to support their use outside of clinical studies [35]. Limitation of exercise capacity has
not been shown to correlate with severity of airway damage on HRCT [36].
Studies in post-resection patients have shown that exercise testing is more informative as an
ongoing assessment of lung function than static spirometry, particularly in patients whose
performance or symptoms do not correlate with spirometric results [37].
Specific investigations
Cystic fibrosis
38
CF is the single most common cause of structural bronchiectasis in children and a reasonably
common diagnosis in adults [2, 7, 24]. Increasingly, CF is diagnosed later in life, with many patients
now being diagnosed in their third and fourth decades of life, and some even later [3843]. Given
this, all adults presenting with bronchiectasis and other features of CF should undergo
comprehensive investigation in order to rule out CF. Pilocarpine iontophoresis for sweat chloride
ion concentration ([Cl-]) measurement, should be carried out in all patients with bronchiectasis and
a clinical suspicion of CF [2, 44]. The results should be interpreted as detailed in table 5. A sweat [Cl-]
of ,30 mM effectively excludes CF as a diagnosis, although one CF-disease-causing mutation has been
described with normal sweat [Cl-] [44]. If the sweat [Cl-] is .60 mM, a diagnosis of CF is confirmed. If
the sweat test result is 3060 mM, the identification of one or more disease-causing mutations
determines which diagnostic category the patient falls into, CF or CF transmembrane conductance
regulator (CFTR)-related disorder (table 5) [44]. The diagnostic category of CFTR-related disorder
has recently emerged and describes single-organ disease, most frequently bronchiectasis, with an
associated sweat [Cl-] of 3060 mM or one or two disease-causing mutations of the CFTR. In some
cases of diagnostic uncertainty, measurement of nasal potential difference may help to determine
CFTR dysfunction. This may help to distinguish CF from a CFTR-related disorder [44].
Immunological investigations
Specific IgG subclass deficiency can be detected in serum or by checking the antibody response to
vaccination with either pneumococcal or Haemophilus influenzae and tetanus toxoid vaccines.
This is performed by measuring antibody levels prior to administration of a dose and again
4 weeks later in order to investigate whether or not the individual has mounted an appropriate
response [45]. Specific antibody response studies should be undertaken in consultation with an
immunologist as interpretation of responses is complex, and a decision to treat patients with
specific deficiencies with Ig replacement requires a range of considerations and should undertaken
by an immunologist with expertise in this area [2]. Replacing deficient IgG is usually effective in
reducing the frequency of infection and preventing further lung damage [4547]. Neutrophil, Tcell, B-cell and complement disorders are a rare cause of bronchiectasis, and functional studies
should be discussed with a specialist immunologist. All patients with an identified immunodeficiency should be managed with a specialist immunologist [2].

PCD is an autosomal recessive disorder leading to immotile cilia, and occurs in 1 in 15,000 to 1 in
40,000 of the population. It results in bronchiectasis and sinusitis and, in around half of cases,
Kartageners syndrome (bronchiectasis, sinusitis and situs inversus) [10]. Diagnosis is based on exhaled
nasal nitric oxide levels and electron microscopy of nasal biopsy specimens [48]. Reduced nitric oxide
level has a specificity of 98% and a positive predictive value of 92% for PCD [48], and may be used as a
screening tool to select those in whom nasal mucosal biopsy for electron microscopy is required. The
diagnostic gold standard is transmission electron microscopy of nasal biopsy specimens to view the
ultrastructural defects in the dynein arms within individual cilia [10]. Recent studies suggest that
15% of patients with functional PCD show no ultrastructural defects and so there is a high falsenegative diagnostic rate [10]. Genetic testing is now becoming more readily available and may go
some way towards overcoming limitations to ultrastructure as a diagnostic method [10].
A range of immunological abnormalities are associated with non-CF bronchiectasis [24]. The
prevalence of each in bronchiectasis varies from study to study. Humoral immunity can be
affected by low levels of any of the major immunoglobulin (Ig) classes, IgM, IgG and IgA [1, 24,
45, 46]), and, in some cases, IgG subclasses, IgG1, IgG2, IgG3 and IgG4. The specific antibody
response to polysaccharide and peptide vaccines provides additional information about the innate
immune response to antigenic stimulus [11].
Table 5. Sweat test diagnostic criteria for cystic fibrosis (CF)

Sweat [Cl-] mM
Diagnostic conclusion
o60
3060
f30
CF confirmed
Equivocal: further investigation required: CFTR DNA test
Not CF
39
[Cl-]: chloride ion concentration; CFTR: CF transmembrane conductance regulator.
Allergic bronchopulmonary aspergillosis

IgE is a sensitive marker for ABPA if levels are .1,000 IU?L-1. Aspergillus precipitins or specific
IgG directed against Aspergillus confirm the diagnosis. This condition responds well to a
combination of high-dose oral corticosteroid and oral antifungal therapy [2, 4951].
a1-Antitrypsin deficiency
In order to diagnose a1-AT deficiency, serum levels of a1-AT should be checked with the
biochemical phenotype requested in those patients with low levels, particularly if there is a family
history of respiratory disease of young onset, or in family members who have never smoked or
show evidence of bullous disease on HRCT [9]. Genetic tests for the different genotypes (M, Z and
S) are also now available.
Connective tissue disorders
Autoimmune disease covers a spectrum of conditions, which, although rare individually, can cause
bronchiectasis and, depending on the condition, may respond to directed treatment. These conditions
can be screened for by thorough history-taking and measurement of rheumatoid factor and other
specific autoantibodies, such as antineutrophilic cytoplasmic antibody and cryoglobulin [2]. More
common autoimmune conditions with a strong association with bronchiectasis are rheumatoid
arthritis and ulcerative colitis. It is recommended that patients attending specialist rheumatology or
gastroenterology clinics for monitoring of these conditions who develop chronic cough or respiratory
symptoms should undergo lung function testing and HRCT in order to rule out bronchiectasis.
Gastro-oesophageal reflux
Gastro-oesophageal reflux disease has been associated with bronchiectasis, although it is unclear
whether or not there is a direct causal relationship. If suspected, barium studies and fluoroscopy
are indicated [2, 24].
Infection and sputum microbiology

Sputum microbiology is a key investigation in the diagnosis of patients with bronchiectasis [52].
H. influenzae is the most-frequently isolated pathogen, being found in up to 35% of patients.
Staphylococcus aureus, Streptococcus pneumoniae, Moraxella catarrhalis and Pseudomonas aeruginosa are also commonly identified organisms [53]. Aspergillus sp. may also be found, and may be
related to a diagnosis of ABPA. The presence of P. aeruginosa in sputum from people with
bronchiectasis is associated with more-severe lung disease and may also have a negative impact
upon prognosis [54, 55].
Monitoring disease activity

Monitoring disease activity in bronchiectasis can be difficult as there is little fluctuation in lung
function as measured by spirometry [2]. The inflammatory response to infection in bronchiectasis
has been shown to be compartmentalised, with higher concentrations of inflammatory mediators
being found in the airways than in the systemic circulation [3, 56].
Patients symptoms are a very important guide to pulmonary exacerbations, with increased cough,
sputum volume and purulence, and haemoptysis and reduced energy all being common symptoms.
40
Sputum analysis plays a pivotal role in the assessment of bronchiectasis, with antibiotic therapy
being directed by the results of sputum culture and antibiotic sensitivity testing. Sputum culture
should be performed at all outpatient reviews and when symptoms deteriorate.
Although exacerbation rate does not clearly correlate with particular organisms, it has been shown
to increase with increasing resistance of organisms to antibiotics [54]. Longitudinal studies
demonstrate that subjects who carry the same organism after a 5-year period tend to carry
increasingly resistant organisms, making exacerbations more difficult to treat successfully [54].
Recent studies using molecular identification techniques in the sputum of CF patients have
revealed a wider spectrum of organisms in significant quantities than culture alone [57]. This has
led to the discovery that the CF microbiome is much more extensive and diverse than was
previously suspected. This is also likely to be the case in non-CF bronchiectasis. Molecular
diagnostic methods are considerably more expensive than culture-based methods and not freely
available in most clinical microbiological laboratory settings.
Exacerbations are often associated with new isolates of bacteria and respond to antibiotic
therapies. However, in many such episodes, no clinically significant organism can be identified as
the precipitating factor. Although it may be some time before molecular diagnostics enter clinical
practice, it is worth bearing in mind, in the case of an infection not responding to standard
antibiotic therapy, that there are other potentially pathogenic organisms present that may require
alternative treatment. As a rule of thumb, sputum culture is more likely to underestimate the
prevalence of bacterial infection, and each positive culture should be treated with appropriate
antibiotics.
A thorough structured approach to the investigation of patients with suspected bronchiectasis will
enable further learning about the natural history of the condition and improve patient outcomes
by appropriate direction of treatment.
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Chapter 5
Radiological features
of bronchiectasis
P.L. Perera* and N.J. Screaton#
RADIOLOGICAL FEATURES
Summary
Imaging plays a crucial role in the diagnosis and monitoring of
bronchiectasis and the management of complications. Chest
radiography is useful as an initial screening tool and during
acute exacerbations, but has limited sensitivity and specificity.
High-resolution computed tomography (HRCT) is the reference standard for diagnosis and quantification of bronchiectasis, providing detailed morphological information. Computed
tomography (CT) is also valuable in diagnosing and managing
complications. Routine surveillance using HRCT has been
mooted, particularly in cystic fibrosis (CF), where advances in
treatment have increased life expectancy considerably, but
cumulative radiation dose remains a concern.
Pulmonary magnetic resonance imaging is an evolving
technique that provides both structural and functional information. Its advantage is the lack of ionising radiation. Limitations include cost, availability and its inferior spatial resolution
compared to CT. The technique requires further evaluation, but
has potential benefits where serial follow-up imaging is being
considered, such as in CF. Evaluation of mucociliary clearance
using radionuclide scintigraphy may be of value, particularly in
drug development.
Keywords: Bronchiectasis, cystic fibrosis, diagnostic imaging,
magnetic resonance imaging, mucociliary clearance, spiral
computed tomography
*Dept of Radiology, Norfolk and

Norwich University Hospital,
Norwich, and
#
Diagnostic Imaging Dept, Papworth
Hospital, Papworth Everard, UK.
Correspondence: N.J. Screaton,
Diagnostic Imaging Dept, Papworth
Hospital, Papworth Everard, CB23
3RE, UK, Email
nicholas.screaton@papworth.nhs.uk

Copyright ERS 2011.
ISSN: 1025-448x.
DOI: 10.1183/1025448x.10003510
44
ronchiectasis is characterised by irreversible dilation of bronchi, which may be focal or diffuse,

and usually occurs with associated inflammation. Its pathogenesis is complex and often
multifactorial, with bronchial wall inflammation, bronchial wall weakness and infection often
occurring in parallel and with numerous aetiological factors. Since it was first described by
LAENNEC [1] in 1819, there have been considerable advances in the understanding, diagnosis and
treatment of bronchiectasis. Imaging now forms the cornerstone of diagnosis of bronchiectasis and
its complications and plays an increasing role in disease monitoring and therapeutic planning. The
present review focuses on imaging features in bronchiectasis and their role in diagnosis and
monitoring of disease. Several imaging modalities are available, with varying strengths and
limitations, which are outlined below. The choice of diagnostic/monitoring strategy shows some
variation depending on access to each modality and interpretive expertise. Image-guided
intervention, such as percutaneous pleural aspiration/drainage and angiography with embolisation
play important roles in treating complications, but are beyond the scope of the present review.
Chest radiography
Chest radiography (CXR) is usually the initial study performed in both suspected bronchiectasis
and the evaluation of nonspecific respiratory symptoms, such as dyspnoea and haemoptysis, when
bronchiectasis may be identified incidentally. Signs on CXR include the identification of parallel
linear densities, tram-track opacities, or ring shadows reflecting thickened and abnormally dilated
bronchial walls. These bronchial abnormalities form a spectrum from subtle or barely perceptible
5-mm ring shadows to obvious cysts. Tubular branching opacities conforming to the expected
bronchial branching pattern may result from fluid or mucous filling of bronchi. Peribronchial
fibrosis results in a loss of definition of vessel walls (fig. 1) [25].
The radiograph may raise the initial suspicion of bronchiectasis, triggering more definitive imaging.
However, its projectional nature and limited contrast resolution lead to limited sensitivity and
specificity, particularly in mild disease. CXR also plays a role in the follow-up of bronchiectasis and
management of exacerbations, although, again, the relative insensitivity to change is highlighted by
proponents of computed tomography (CT) and magnetic resonance (MR) imaging (MRI) [25].
The reported accuracy of CXR has changed over the years as the management emphasis has shifted
from being reactive to complications to one of early detection and proactive management, and as the
diagnostic reference standard has shifted from bronchography to CT. In 1955, GUDJBERG [6]
reported only 7.1% of 114 bronchiectatic patients having a normal CXR, perhaps reflecting the more
florid nature of the condition during this period. In 1987, CURRIE et al. [7] reported an overall
sensitivity of 47%, and only 13% on a lobar basis, in 19 patients with bronchographically proven
bronchiectasis. The same study confirmed significant interobserver variation in CXR interpretation,
with two experienced readers disagreeing on the diagnosis of bronchiectasis in 22% of cases [7].
In comparison to CXR, CT is both more sensitive and provides more specific information. BHALLA
et al. [8] showed that, out of a total of 162 bronchopulmonary segments reviewed, bronchiectasis
was detected in 124 on high-resolution CT (HRCT) and only 71 on CXR.
P.L. PERERA AND N.J. SCREATON
Signs of complications/exacerbations, such as patchy densities due to mucoid impaction and

consolidation, volume loss secondary to bronchial mucoid obstruction or chronic cicatrisation,
are also seen. In the more diffuse forms of bronchiectasis, such as cystic fibrosis (CF), generalised
hyperinflation and oligaemia are often present, consistent with severe small airways obstruction.
Radiographic scoring systems, such as those of CHRISPIN and NORMAN [9] and BRASFIELD et al. [10],
have been developed and subsequently modified for patients with CF. These can be useful clinically,
but are more commonly used for comparison in research. CLEVELAND et al. [11] showed that a score
based on the scoring system of BRASFIELD et al. [10] could be used to assess the longitudinal
progression of lung disease in CF, and was at least as effective as spirometry in this regard.
Although CXR has limitations in specificity in diagnosing bronchiectasis and in detecting early or
subtle changes, it is useful for assessing more florid cases of bronchiectasis, in CF and in follow-up
of bronchiectatic patients.
Computed tomography
45
The CT signs of bronchiectasis were first described by NAIDICH et al. [12] in 1982. Although initial
studies using 810-mm slice thickness showed low sensitivity [1315], the advent of HRCT led to
markedly improved sensitivity, resulting in HRCT replacing bronchography as the diagnostic
reference standard. GRENIER et al. [16] showed that HRCT with 1.5-mm collimation at 10-mm
a)
b)
intervals was accurate in the recognition of bronchiectasis using bronchography as the gold standard in 36
patients.
Multidetector CT (MDCT) with volumetric acquisition further increases
the sensitivity in detection of subtle
nontapering airways. DODD et al. [17]
compared contiguous 1-mm MDCT
with 1-mm incremental HRCT with
10-mm interspaces in 61 bronchiectatic patients and 19 normal controls.
Using MDCT as the gold standard,
the sensitivity, specificity and positive
and negative predictive values of incremental HRCT in detecting bronchiectasis were 71, 93, 88 and 81%,
respectively. Interobserver agreement
for the presence, extent and severity
of bronchiectasis was also better for
MDCT (kappa 0.64, 0.5 and 0.48,
respectively) than for incremental
HRCT (kappa 0.65, 046 and 0.25,
respectively).
Optimal HRCT technique is important for maximising diagnostic accuracy. Importantly, thin slices of
12 mm and a high-resolution lung
reconstruction algorithm are used
to optimise spatial resolution. Incremental imaging with 10-mm slice
interspace reduces radiation dose,
but helical MDCT permits volumetric acquisition in a single breathhold, which is often the preferred
technique. Electronic images should
be viewed in stack/cine mode using the appropriate window settings (centred -400 -950 HU; width
1,0001,600 HU). Difficulties in diagnosing bronchiectasis can arise from
cardiorespiratory motion artefact, use
Figure 1. Chest radiography showing a) cystic bronchiectasis with
multiple cystic airspaces and b) cylindrical bronchiectasis and tramof inappropriate window widths and
track opacities in a cystic fibrosis patient.
levels, and the relatively thick-walled
appearance of bronchial walls on
expiratory scans. Tractional airway dilation associated with pulmonary fibrosis has a characteristic
corkscrew appearance and should be differentiated from pathological bronchiectasis.
CT signs of bronchiectasis
46
Bronchial dilation, the cardinal sign of bronchiectasis, is characterised on HRCT by a

bronchoarterial ratio (BAR) of .1, lack of bronchial tapering, and visibility of airways within
1 cm of the pleural surface or abutting the mediastinal pleural surface [2, 12, 16, 18, 19].
The different morphological types of bronchiectasis

corresponding to the bronchographic classification of
REID [20] show differing radiological features [16, 21],
but this is of little relevance in terms of aetiology and
rather reflects varying severity of the disease. Although,
in cylindrical bronchiectasis, there is uniform dilation
of airways with nontapering walls, in varicose bronchiectasis, dilated bronchi have a beaded appearance and,
in cystic bronchiectasis, grosser bronchial dilation gives
the appearance of cysts (fig. 2).
The BAR refers to the ratio of the internal bronchial
diameter to the diameter of the accompanying pulmonary artery at an equivalent branching level. A BAR
of .1 is considered abnormal [14, 15, 19] and is otherwise known as the signet-ring sign (fig. 3).
Figure 2. High-resolution computed tomography image showing cystic bronchiectasis

(same patient as in fig. 1a).
Physiological influence on BAR was highlighted by LYNCH et al. [23], who showed that 59% of 27
normal volunteers living in Colorado, USA (1,600 m above sea level) had at least one bronchus
that had an internal diameter larger than its accompanying artery. KIM et al. [18] confirmed this
environmental influence on BAR by demonstrating that residents living at 1,600 m exhibited
significantly higher BARs than those living at sea level (0.76 and 0.62, respectively; p,0.001).
Physiological variation can also occur due to regional hypoxia, and so secondary vasoconstriction
causing apparent bronchial dilation must be recognised in order to prevent a spurious diagnosis
of bronchiectasis. Conversely, if there is arterial dilation (e.g. due to pulmonary arterial
hypertension), bronchiectasis could be missed. A practical problem in assessing BAR is the need to
identify the accompanying artery, which may be difficult in the presence of other lung pathology,
such as consolidation. In the setting of consolidation, the presence of bronchial dilation may be a
reversible phenomenon and so caution should be observed when interpreting CT data during an
acute illness.
Although objective measurement may be performed, visual inspection is the usual method of assessing
bronchial dilation. DIEDERICH et al. [24] showed this to
have good interobserver agreement for detection (kappa
0.78) and severity assessment (kappa 0.68).
Figure 3. High-resolution computed tomography image demonstrating signs of

bronchiectasis, the signet-ring sign (short
arrow) and peripheral airway visible within
1 cm of the pleural surface (long arrow).
47
Lack of bronchial tapering or tram-track appearance of

the parallel bronchial walls is a sensitive feature of
bronchiectasis often identified in more horizontally
orientated airways in the mid-zones. KANG et al. [25]
showed that lack of tapering on HRCT was more
sensitive than bronchial dilation in bronchiectasis (79
and 60%, respectively) using pathology as the reference
standard. However, the sign can be difficult to
interpret in nonvolumetric CT studies. KIM et al. [18]
demonstrated lack of tapering on HRCT in 95% of
patients with bronchiectasis, but also in 10% of normal
subjects. It has been suggested that bronchial diameter
should remain unchanged for at least 2 cm distal to a
branching point for this sign to be robust (fig. 4) [26].
The accuracy of the BAR can be limited by a number of factors, including physiological
variation and orientation of the bronchovascular bundle with respect to the imaging plane
[16, 22, 23]. Comparison is best performed on perpendicularly orientated airways. When
oblique to the acquisition plane, airways and vessels appear ovoid and their short axis should
be compared.
Visibility of peripheral airways is another important

direct sign of bronchiectasis [17]. Current HRCT
techniques permit visualisation of airways of up to
2 mm in diameter and walls of around 0.2 mm in
thickness. KIM et al. [18] showed that normal bronchi are
not visualised within 1 cm of the costal pleura, but may
be seen within 1 cm of the mediastinal pleura. Visible
bronchi within 1 cm of the costal pleura or abutting the
mediastinal surface were seen in 81 and 53% of HRCT
images of known bronchiectatic patients (fig. 4).
Ancillary signs commonly identified in bronchiectatic
patients include bronchial wall thickening, mucoid
tomography image showing nontapering
impaction and air-trapping. Minor volume loss can be
bronchi, in keeping with bronchiectasis.
seen in the early stages of bronchiectasis. Larger areas of
collapse secondary to mucous plugging may be seen in more advanced disease. Patchy
consolidation is sometimes seen reflecting superimposed infection.
Figure 4. High-resolution computed
Bronchial wall thickening is often seen in the presence of bronchiectasis [25], but is a variable
nondiagnostic feature. It may result from reversible airway wall inflammation [27] or smooth
muscle hypertrophy and fibroblastic proliferation. Minor bronchial wall thickening has, however,
also been described in normal individuals, asthmatics, asymptomatic smokers and during lower
respiratory tract infections [23, 28].
Identification of bronchial wall thickening on HRCT is often made subjectively and is associated
with significant interobserver variation, with no universally agreed definition. REMY-JARDIN and
REMY [28] defined a thickened bronchus as being twice as thick as a normal bronchus; however,
this definition is difficult in diffuse disease DIEDERICH et al. [24] defined a thick-walled bronchus
by an internal diameter of ,80% of its external diameter and showed good interobserver
agreement (kappa 0.66). However, this can lead to overdiagnosis of thickening in the presence of
bronchoconstriction and underestimation with marked bronchodilation. An alternative approach,
used by BHALLA et al. [8] in CF and subsequently modified by REIFF et al. [29], is to compare
bronchial wall thickness to the diameter of the adjacent artery. As with assessment of BAR,
peribronchial fibrosis and consolidation pose practical difficulties in identifying accompanying
vessels (fig. 5).
Mucous plugging of dilated bronchi is readily identified, causing either complete or partial
luminal filling (fig. 5). Plugging of the smaller peripheral airways and peribronchiolar inflammation are characterised by a tree-in-bud appearance, with V- and Y-shaped branching
nodular opacities [30]. Mucous plugging was scored in
terms of number and generation of involved bronchopulonary segments using the scoring system of BHALLA
et al. [8], and may be reversible.
Figure 5. High-resolution computed tomo-
48
graphy image demonstrating bronchiectasis

with bronchial wall thickening (asterisk) and
mucous plugging (arrow) in the right lower
lobe.
Air-trapping results either from mucous plugging and

abnormal bronchial compliance [31] or inflammation/
fibrosis of the small airways [2]. On HRCT, airtrapping is characterised by patchy lobular areas of
low attenuation with regional vasoconstriction, which
causes a mosaic attenuation pattern, accentuated on
expiratory images, although inspiratory images are
usually characteristic (fig. 6). Air-trapping and bronchiectasis coexist in the same lobe in approximately
half of cases [25]. Whether it is the bronchiectasis and
recurrent infections driving obliterative bronchiolitis
(OB) or primary small airways disease that precedes the
onset of bronchiectasis is debated, and may vary [31].

The latter is supported both by the observation that, in
patients with CT-proven bronchiectasis, expiratory
HRCT identifies air-trapping in 17% of lobes with no
bronchiectatic features and that, in patients with
rheumatoid arthritis (RA)-associated OB, the onset of
symptoms and obstructive function may predate the
onset of bronchiectasis by several years [32].
Imaging and aetiology of bronchiectasis
However, in a large study comparing HRCT features in bronchiectasis of defined aetiology with
idiopathic bronchiectasis, REIFF et al. [29] concluded that, although some HRCT features were
more common in some aetiological groups, the differences were not sufficient to be diagnostic. LEE
et al. [40] reinforced this observation in a study of 108 bronchiectatic patients in whom the correct
cause was identified on CT in only 45% of cases. A confident diagnosis was asserted in a minority
(9%) and was correct in only 35%. Interobserver agreement in likely aetiology was also poor
(kappa 0.2) [40]. However, more recently, CARTIER et al. [41] obtained accurate diagnoses on the
basis of HRCT in 61% of 82 patients with bronchiectasis of known cause, with moderately good
agreement (kappa 0.53). Confident and accurate diagnosis was made in 44% of patients (kappa
0.53). Accuracy was highest in CF (68%), previous tuberculosis (67%) and ABPA (56%). Part of
the reason for the higher number of accurate diagnoses was attributed to the exclusion of patients
in whom the aetiology of bronchiectasis was not known. They concluded that the combination of
radiological pattern and clinical scenario would have improved the accuracy of the evaluation.
HRCT is important in the assessment of mycobacterial infection. This is particularly true of
nontuberculous mycobacteria (NTM), where the diagnosis is often first suggested on HRCT. CT
signs of NTM include bronchiectasis, nodules, tree-in-bud opacity, patchy consolidation and
cavities, often affecting the upper lobes and superior segments of lower lobes in the classic subtype
and middle lobe/lingula in the nonclassic subtype [42]. The presence of this combination of
features with a middle lobe and lingual predominance, especially in the setting of elderly females
with no underlying malignancy or immunocompromise, is particularly suggestive of nonclassic
NTM [43, 44]. Bronchiectasis is more common in NTM infection, being seen in up to 94% of
patients with Mycobacterium avium complex and 27% of patients with M. tuberculosis [45].
There are many aetiologies associated with bronchFigure 6. Inspiratory high-resolution computed tomography image showing bronchiectasis, but a specific underlying cause is found in
iectasis and widespread areas of low
,40% of patients [33]. In some cases, the distribution
attenuation, representing air-trapping.
and pattern of bronchiectasis on HRCT may suggest
the aetiology. Allergic bronchopulmonary aspergillosis
(ABPA) typically demonstrates an upper zone and central predominance [3437], hypogammaglobulinaemia may be associated with bronchiectasis with disproportionate bronchial wall
thickening, middle lobe predominance is common in immotile cilia syndrome [38] and idiopathic
bronchiectasis often has a lower lobe distribution [39].
Bronchiectasis in CF usually has a bilateral, proximal, parahilar and upper lobe predominance.
Other findings include bronchial wall thickening, peribronchial interstitial thickening, mucous
plugging, tree-in-bud opacification, superadded consolidation and mosaic attenuation. SHAH et al.
[27] assessed the CT changes in 19 symptomatic adult CF patients before and after 2 weeks of
therapy and identified airfluid levels in bronchiectatic airways, mucous plugging, centrilobular
nodules and peribronchial thickening as potentially reversible signs.
49
Bronchiectasis with a central or proximal predominance is the characteristic finding in ABPA

(fig. 7a). REIFF et al. [29] showed that the prevalence of central bronchiectasis was higher in ABPA
(11 out of 30) than in idiopathic bronchiectasis (26 out of 179) (p,0.005). However, the sensitivity of the observation of central bronchiectasis in diagnosing ABPA was only 37%. PANCHAL et al. [46]
a)
b)
Figure 7. High-resolution computed tomo-
demonstrated central bronchiectasis in 85% of lobes

and 52% of lung segments in a series of 23 patients
with ABPA. Other common findings in ABPA include
mucous plugging, high-attenuation mucus, tree-inbud opacities, atelectasis, peripheral consolidation or
ground-glass opacification, mosaic perfusion and airtrapping. The bronchiectasis is often cystic or varicose.
WARD et al. [47] assessed CT images from 44
asthmatic patients with ABPA and 38 without and
found much higher levels of bronchiectasis, centrilobular nodules and mucous impaction in ABPA.
They concluded that randomly distributed predominantly central moderate-to-severe bronchiectasis
affecting three or more lobes, bronchial wall thickening and centrilobular nodules in asthmatics is highly
suggestive of ABPA (fig. 7b).
High-attenuation mucous plugs are reported to occur
in 1828% of patients with ABPA, and, if observed, are
thought to be characteristic [4850]. In a study of 155
patients with ABPA, AGARWAL et al. [48] found this
sign in 29 patients, and that it correlated with greater
severity and greater likelihood of relapse.
graphy showing a) proximal bronchiectasis

affecting segmental airways and b) highattenuation mucous plugs in patients with
allergic bronchopulmonary aspergillosis. No
intravenous contrast medium was used in (b).
In summary, there are some recognised clinical

conditions in which assessment of bronchiectasis forms
an important part of management. CT images in
bronchiectatic patients should be examined for features
suggesting ABPA, CF, immotile cilia, opportunist
mycobacteria and tracheobronchomegaly, but these observation need to be correlated with
clinical and laboratory findings.
CT scoring of bronchiectasis
Although the extent, severity and distribution of bronchiectasis may be evaluated subjectively,
more-robust objective scoring systems have been developed particularly for use in the research
arena. With the development of novel software tools, it is now possible to objectively quantify
parameters, such as airway wall area and volume, in a semi-automatic manner. Both subjective
and objective quantification permit correlations between structure and function to be evaluated.
CT scoring systems are based on collective scores for the extent and distribution of a range
of morphological abnormalities, including bronchial dilation, bronchial thickening, abscesses,
mucous plugging, emphysema, collapse and consolidation.
The HRCT score of BHALLA et al. [8] was devised to evaluate the severity of CF in an objective
manner. Severity of bronchial dilation and thickening were defined relative to the adjacent
pulmonary artery, and other parameters were scored according to the number of bronchopulmonary segments involved, as shown in table 1.
50
This scoring system has been modified many times, and has also been adapted for use in MRI
assessment of CF. Modifications have included incorporation of additional findings, such as airtrapping/mosaic attenuation, ground-glass opacification, acinar nodules and septal thickening,
with some scores being per segment and others based on lobar scoring. Each scoring system
attempts to produce both a total score, by combining features, and specific morphological scores.
These have been demonstrated to be more sensitive to disease and show better correlation with
both clinical features and lung function than the CXR-based scoring systems. OIKONOMOU et al. [51]
Table 1. Summary of computed tomography scoring system

Score
0
Severity of bronchiectasis
Absent
Moderate (luminal
diameter 23 times
that of adjacent
blood vessel)
Severe (luminal
diameter .3 times
that of adjacent
blood vessel)
Peribronchial thickening
Absent
Mild (luminal
diameter slightly
greater than that
of adjacent
blood vessel)
Mild (wall
thickness equal
to diameter of
adjacent vessel)
Severe (wall
thickness .2 times
the diameter of
adjacent vessel)
Extent of bronchiectasis
BP segments n
Extent of mucous plugging
BP segments n
Sacculations or abscesses
BP segments n
Bronchial divisions
involved (bronchiectasis/
plugging) generations
Bullae
Bullae n
Emphysema
BP segments n
Collapse/consolidation
Absent
Present
15
Present
15
Present
15
Up to 4th
Moderate (wall
thickness greater
than and up to
twice the diameter
of adjacent vessel)
Present
69
Present
69
Present
69
Up to 5th
Unilateral
not .4
Present
15
Subsegmental
Bilateral
not .4
Present
.5
Segmental/lobar
Absent
Absent
Absent
Absent
Absent
Absent
Present
.9
Present
.9
Present
.9
Up to 6th and distal
Present
.4
BP: bronchopulmonary. Reproduced from [8] with permission from the publisher.
suggested a simplified scoring system evaluating severity of bronchiectasis, bronchial wall thickening
and atelectasis consolidation. They found strong correlation between the simplified scores and the
complete scores.
SHAH et al. [27] used a modified Bhalla score in bronchiectatic patients undergoing HRCT at
baseline and 2 weeks after exacerbation in order to identify reversible findings, and showed that
airfluid levels, centrilobular nodules, mucous plugging and peribronchial thickening improved
following treatment in 100, 36, 33 and 11% of cases, respectively.
DE JONG et al. [52] compared the original scoring system of BHALLA et al. [8] and four modified
Bhalla systems [5356]. Three observers reviewed thin-slice CT images of 25 children with CF
using the various scoring systems. Interobserver variability was analysed using kappa coefficients
and found to be generally good (kappa .0.76; p,0.05). However, inter- and intra-observer
agreement was less for mild disease, as well as for parameters such as mosaic perfusion, acinar
nodules and airspace disease. All five scoring systems correlated strongly with forced expiratory
volume in 1 second (FEV1), forced vital capacity (FVC), forced expiratory flow between 25 and
75% of vital capacity (FEF2575), FEV1/FVC ratio and each other.
Category
Quantitative computerised evaluation of the airways presents a number of challenges, including

obtaining a plane perpendicular to the airway, exclusion of the adjacent artery, determining the
borders of the bronchus, artefacts and partial volume averaging. Three different methods have
been used to obtain airway measurements, full width at half maximum, model fitting approaches
and boundary fitting approaches [19]. A detailed description of these techniques is beyond the
scope of the present chapter.
51
GORIS et al. [57] looked at automated evaluation of the extent of air-trapping in 25 patients with
mild CF compared to 10 controls; six anatomically matched CT slices were obtained during
inspiration and expiration. Computerised lung segmentation was performed and automated
software used to quantify air-trapping, using analysis of a histogram of the distribution of densities
in the lung, and assessing contiguous low-attenuation voxel regions. In mild CF, air-trapping did
not correlate with global pulmonary function test (PFT) results, except for the ratio of residual
volume (RV) to total lung capacity (TLC); however, the size of the air-trapping defects was the
best discriminator between patients and control subjects (p,0.005).
KIRALY et al. [58] looked at fully automated methods of obtaining three-dimensional (3D) images
and quantification of airway abnormalities. Working from thin-slice image acquisition and using
computerised segmentation techniques, they obtained 3D images of the airways with colour-coded
maps showing BAR, wall thickness and mucous plugging. These have, however, not been fully
clinically validated.
Although these objective tools are interesting, further studies are required to evaluate the
various computerised imaging parameters and their relation to functional and clinical findings
in bronchiectasis. A note of caution was raised by MATSUOKA et al. [59], who used semiautomatic image processing to assess the airways of 52 asymptomatic patients with no
cardiopulmonary disease. They found that luminal area and wall area increased in 10 and 29%
of subjects, respectively, suggesting caution in over-reliance on changes in airway calibre in
disease monitoring.
Structurefunction relationships
Relationships between HRCT data and functional and clinical characteristics have been widely
explored. WONG-YOU-CHEONG et al. [60] showed a clear negative correlation between FEV1 and
extent of bronchiectasis on HRCT (p,0.002; r5 -0.43). SMITH et al. [61] showed correlation
between extent of bronchiectasis on HRCT and both dyspnoea (p,0.01; r50.38) and FEV1
(p,0.01; r5 -0.43). More recently, DE JONG et al. [52] showed strong correlations between five
scoring systems [8, 5356] and FEV1 (r5 -0.69 -0.73), FEF2575 (r5 -0.76 -0.82) and FEV1/
FVC ratio (r5-0.72 -0.78). Correlation with FVC was moderate (r5 -0.54 -0.58).
Authors have investigated which morphological abnormalities are most strongly associated with a
functional deficit. LYNCH et al. [62], in a study of 261 bronchiectatic patients, found significant
correlation between severity of bronchiectasis, FEV1 (r5 -0.362) and FVC (r5 -0.362), and
between bronchial wall thickening and FEV1 (r5 -0.367) and FVC (r5 -0.239). Cystic bronchiectasis was found to show worse PFT results than cylindrical or varicose disease.
In a study of 100 patients with bronchiectasis, ROBERTS et al. [63] found good correlation between
FEV1 and bronchial wall thickening (r5 -0.51; p50.00005) and extent of decreased attenuation on
expiratory HRCT (r5 -0.55, p50.00005) on univariate analysis. These were the only factors that
independently correlated with degree of airflow limitation on multivariate analysis. In this study,
obstructive lung function was not strongly associated with severity of bronchiectasis,
bronchodilation, or retained sections in bronchiectasis (r5 -0.42, -0.35 and -0.19, respectively,
on univariate analysis). Bronchial dilation as an independent factor was positively associated with
airflow obstruction on regression analysis (r250.42). The authors concluded that airflow
limitation in bronchiectasis occurred mainly due to inflammatory or obstructive/constrictive
bronchiolitis. They also suggested that areas of low attenuation attributed to emphysema in
bronchiectatic patients in previous studies (e.g. [64]) should be interpreted with caution,
suggesting that the emphysema demonstrated was often due to air-trapping related to intrinsic
small airways disease rather than emphysema, as evidenced by preserved gas transfer in the both of
these studies.
52
HRCT scoring can also be correlated with clinical parameters. In a study of 61 CF children,
baseline and follow-up PFT and HRCT scores were compared to the number of respiratory
exacerbations over 2 years. Only the HRCT score (r50.91; p50.001) and bronchiectatic score
(r50.083; p50.01) correlated significantly with exacerbation frequency. All HRCT parameters
progressed over this time period except for bronchial wall thickening and mucous plugging,
suggesting that these are reversible features [65]. OOI et al. [66] studied 60 patients with stable
bronchiectasis with HRCT. They showed good correlation between the extents of bronchiectasis, bronchial wall thickening and mosaic attenuation and FEV1 (r5 -0.43 -0.60), FVC
(r5 -0.36 -0.46), FEF2550 (r5 -0.38 -0.57) and FEV1/FVC (r5 -0.31 -0.49). Regression
analysis showed that extent of bronchiectasis and wall thickening were the most significant
determinants of airflow obstruction, correlating with all PFT parameters This study also
demonstrated associations between bronchial wall thickening and clinical factors, such as
exacerbation frequency and 24-hour sputum production (r5 -0.32 and -0.30). ALZEER [67] found
that the HRCT score correlated well with FEV1 (r5 -0.51), as well as with systolic pulmonary
artery pressure (Ppa,sys) (r50.23), in a study of 94 bronchiectatic patients.
The validity of the use of PFTs as the gold standard in evaluating HRCT has been questioned by
several authors. BRODY et al. [69] and HELBICH et al. [53] have shown that early HRCT changes,
including mosaic attenuation and bronchial dilation, can be seen early in disease in the presence
of normal PFT results. LONG et al. [70] showed HRCT changes, including wall thickening and
bronchial dilation in CF infants with a mean age of 2 years, further emphasising the sensitivity
of HRCT.
Regular low-dose HRCT for the surveillance of CF has been adopted by several centres since
the late 1990s [71]. This was initially in the form of 1-mm slice incremental HRCT (with 10mm interspaces), but, more recently, of full-lung volumetric HRCT. CT is performed as early
as an age of 2 years, when it is performed as controlled-ventilation CT (CVCT), requiring
sedation or general anaesthesia. The rationale for using this imaging-intensive approach is that
PFT results may lag behind structural CT changes, difficulty in reliably performing PFTs in
young children and the ability of imaging to follow relevant objective structural markers, such
as bronchiectasis, bronchial wall thickening, air-trapping and mucous plugging. Furthermore,
in the modern era, improved therapy has slowed the annual decline in PFT results such that
individual variability and changes due to other factors, such as technique, puberty and
infections, have made PFTs even less reliable for disease monitoring. However, the benefit has
to be viewed in the setting of radiation risk. DE JONG et al. [72] used a computational model to
estimate mortality effects of regular CTs. The mean radiation dose for the published CT
protocol was 1 mSv. Survival reduction associated with annual scans from the age of 2 years
until death for CF patients with a median survival of 26 and 50 years, were approximately
1 month and 2 years, respectively. Cumulative cancer mortality was approximately 2 and 13%
at age 40 and 65 years, respectively. Biannual CTs exhibit half the risk. This highlights the
increasing reduction in survival with increasing age, an important point given the increasing
life expectancy of CF patients.
Studies on the utility of HRCT in the follow-up of non-CF bronchiectatic patients have been
limited. In a study of 48 patients, SHEEHAN et al. [68] compared serial CT studies with PFTs,
showing correlation of changes in PFT results with air-trapping due to mucous plugging. Greater
severity of mucous plugging, bronchiectasis and bronchial wall thickening were predictive of
decreased FEV1. In a study evaluating morphological features in bronchiectasis at baseline and
2 weeks after exacerbation, SHAH et al. [27] showed that changes in HRCT score during
exacerbation of bronchiectasis also correlate with improvement in FEV1/FVC (r50.39;
p50.049). Severity of bronchiectasis was the component most strongly associated with PFT
results (r50.4 for FEV1 and r50.5 for FVC), whereas tree in bud and mucous plugging were not
strongly correlated.
53
DE JONG et al. [73] studied 48 young patients with CF using serial low-dose HRCT and PFTs
2 years apart. In all children, there was progressive structural HRCT change with deterioration in
HRCT scores by 2.23.5% overall, but particularly with peripheral extension of bronchiectasis and
mucous plugging, despite stable (or, in some cases, improved) lung function. This may reflect
poor PFT technique in young CF children, the use of predicted FEV1 (with reference to a global
population) and/or the greater sensitivity of HRCT for detection of early and regional changes.
JUDGE et al. [74] assessed serial HRCT performed 18 months apart in 39 consecutive CF patients
and found that the modified HRCT score declined faster (2.7% per year; p,0.001) than did FEV1
(2.3% per year). Six patients demonstrated worsening HRCT score with no change in PFT result.
DE JONG et al. [75], in a study of 119 children and adults with CF, showed that PFT results,
component and CT scores deteriorated over 2 years. The CT score (and its components) and PFT
results showed similar rates of deterioration in adults and children (p.0.09). Peripheral
bronchiectasis worsened by 1.7% per year in children (p,0.0001) and by 1.5% per year in adults
(p,0.0001).
In view of the potential for discordance between morphology and function and the complementary nature of these variables, authors have attempted to create more-robust clinically
useful composite scoring systems combining PFT results and HRCT findings [76].
Studies on assessment following therapy have been limited. ROBINSON et al. [76] used a composite
scoring system using many of the HRCT parameters described above and combining them with
PFT measures of obstructive function (FEV1 and FEF2575). They showed the composite
measurement to be more sensitive for assessing response to treatment in 25 CF children who were
randomised to a treatment arm and a nebulised saline arm; FEF2550 showed 13% improvement,
global HRCT 5% and composite score 30%. Small studies have shown some HRCT features to be
useful in post-treatment evaluation. NASR et al. [77] showed a significant improvement in total
HRCT score following recombinant human (rh) deoxyribonuclease (DNAse) therapy compared to
placebo. GORIS et al. [57] compared 25 CF patients with 10 age-matched controls using PFTs and
automated quantitative assessment of lung density. No significant difference was seen in PFT
results, but significant differences in air-trapping were seen, with the size of defects being the best
discriminator. There was a significant decrease in mean HRCT score from 25 to 22 (p50.014),
with improvement in peribronchial thickening (p50.007), mucous plugging (p50.002) and
overall appearance (p50.025).
There have been some differences in the degree of correlation between PFT results and HRCT
findings of bronchiectasis in the various studies, which could be attributed to several causes,
including the scoring system used, radiological interpretation, parameters assessed, population
studied, reliability of PFTs and data analysis (multivariate versus univariate). However, the link
between measures of obstructive lung function (FEV1 and FEF2550) and bronchial wall thickness/
total HRCT score has been consistently shown.
Role of HRCT in bronchiectasis

CT is invaluable in the diagnosis of bronchiectasis, but also plays an important role in the
evaluation of complications and assessment and monitoring of disease severity. HRCT provides
good clinical correlation, and the use of scoring systems holds promise for monitoring of
bronchiectasis. The more robust CT scoring systems have been formulated in CF patients. HRCT
is sometimes of value in identifying the aetiology of bronchiectasis. Advantages of HRCT over
PFTs include its ability to identify focal changes as well as provide a global score, in addition to
assessing multiple parameters, some of which are reversible and others irreversible (fig. 8).
Current British Thoracic Society guidelines recommend HRCT at diagnosis and during exacerbations,
but not for routine follow-up. An exception is in bronchiectasis secondary to humoral immunodeficiency, where follow-up HRCT may be beneficial [78].
54
HRCT is now widely regarded as part of the standard clinical evaluation of patients with CF. The
ability to quantify extent and severity of disease and to serve as a useful outcome marker, and the
potential for assessing treatment response, make this a particularly valuable investigation.
However, although HRCT provides valuable information on initial assessment, the role and
periodicity of serial imaging in CF remains controversial in view of increasing life expectancy and
cumulative radiation exposure. Some authors suggest that HRCT should form part of the routine
monitoring of CF, but with due consideration to the excess radiation [71]. With appropriate
scanning technique, it is estimated that a chest CT

every other year from birth to age 30 years would
involve an effective dose of 15 mSv compared to the
mean background radiation dose over this period of
90 mSv [79].
Thus HRCT forms an important part of the investigation and diagnosis of bronchiectasis and exacerbations.
It is particularly useful in CF, where it has been shown
to be a good marker of outcome and has demonstrated
the ability to pick up subtle and early changes with
greater sensitivity than PFTs.
Interest in the use of MRI for lung imaging arose in

Figure 8. Coronal reconstruction from
the mid-1980s. The inherent difficulties in pulmonary
high-resolution computed tomography
MRI are well documented. Lungs have an intrinsically
showing a bronchial collateral vessel.
low proton density, which results in poor signal
generation. This low signal is further degraded by susceptibility artefact resulting from the
innumerable airtissue interfaces and cardiac and respiratory motion. However, the advent of
parallel imaging and new rapid imaging sequences have permitted marked improvement in
temporal and spatial resolution. Although spatial resolution using conventional proton MRI is
less than that using CT, MRI offers significant morphological information and has advantages in
enabling improved tissue characterisation and providing functional imaging, including vascular
flow and respiratory mechanics. The use of novel imaging techniques, such as oxygen-enhanced
MRI and hyperpolarised helium-3 MRI, potentially permits derivation of further functional
parameters, including regional ventilation, regional oxygen concentration and evaluation of lung
microstructure using the apparent diffusion coefficient (ADC).
Although application of this technique currently lies largely in the research arena, a significant
advantage of MRI is the lack of radiation, which is particularly important in patients who require
recurrent imaging and the younger population group. This is pertinent when considering the
potential cumulative lifetime radiation dose from annual/biannual low-dose CT examination in the
CF population that are currently advocated by some groups [71], especially in view of the rapid
improvement in life expectancy in this patient group, which is projected to continue. Thus it is
unsurprising that much of the work on thoracic MRI imaging has been focused on patients with CF.
Conventional proton MRI features
Magnetic resonance imaging
Owing to the limited spatial resolution of MRI, assessment of bronchial wall thickness and
bronchiectasis are dependent upon bronchial level, wall thickness and wall signal. Thirdgeneration bronchi and beyond are poorly visualised on MRI, except in pathological states, when
the wall and luminal signal are raised due to wall thickening, inflammation and mucus [80].
Inflammation and oedema contribute to wall thickening. Gadolinium-enhanced images may be
useful in demonstrating inflammatory change.
55
Mucous plugging on MRI results in homogeneous high T2-signal intensity in proximal airways or an
abnormal branching grape-like pattern more peripherally, equivalent to the tree-in-bud opacities
seen on HRCT. In contrast to CT, the improved tissue characterisation of MRI can also differentiate
between mucus, haemorrhage and bronchial wall thickening [81]. Airfluid levels may be identified
on MRI, particularly in cystic or varicose bronchiectasis. Unlike CT, using contrast-enhanced MRI
sequences, thickened airway walls can be differentiated from mucous plugging. Consolidation may
also be identified as high T2-signal inflammatory fluid contrasts with the low airway signal,
equivalent to the classical air bronchogram. Air-trapping and mosaic perfusion are not readily seen
on conventional proton MRI in the absence of gadolinium (figs 9 and 10).
a)
b)
Figure 9. a) Transverse magnetic resonance (T2-weighted half-Fourier acquisition single-shot turbo spin-
echo (HASTE)) image and b) corresponding computed tomography image in a 14-year-old female with cystic
fibrosis. In both images, bronchial wall thickening, bronchiectasis, peripheral mucous plugging and dorsal
consolidations are demonstrated, as shown by the arrows. Reproduced from [81] with permission from the
publisher.
An early study of 17 CF patients (aged 730 years) in 1995 [82] found MRI to be inferior to CT in
the assessment of bronchiectasis. Correlations between CT and MRI (r for each observer) were
good for bronchial dilation (r50.81 and 0.50), bronchial thickening (r50.82 and 0.60) and
mucous plugging (r50.93 and 0.70). Progress in MRI technique in recent years has led to marked
improvement in its accuracy. In a study of six paediatric patients with CF, HEBESTREIT et al. [83]
found that CXR and MRI provided equal information, and considered MRI suitable for follow-up.
In a more recent study in 2007, PUDERBACH et al. [84] evaluated 31 patients with CF using CXR,
MDCT and MRI. MRI and MDCT were assessed using a modified Helbich score, whereas CXR
was evaluated using a modified ChrispinNorman score. Mosaic perfusion was excluded from the
original scoring system as this cannot be quantified on MRI. They concluded that morphological
a)
b)
56
Figure 10. T1-weighted magnetic resonance imaging showing appearance a) before and b) after contrast
medium in a 43-year-old cystic fibrosis patient. The post-contrast images demonstrate extensive bronchial
wall enhancement and permit differentiation of a thickened wall from intrabronchial secretions, with
intrabronchial fluid having an airfluid level (arrow). Reproduced from [81] with permission from the publisher.
MRI showed comparable results to MDCT and CXR. Median extent scores for MRI, MDCT and
CXR scores were 13, 13.5 and 14, and correlation between modalities ranged 0.630.80 (MRI/CT
0.80, p,0.0001; MRI/CXR 0.63, p,0.0018; CXR/CT 0.75, p,0.0001). The median lobe-related
concordance was 80% for bronchiectasis, 77% for mucous plugging, 93% for sacculation/abscesses
and 100% for collapse/consolidation.
MONTELLA et al. [85] evaluated patients with primary ciliary dyskinesia using HRCT and MRI.
They used a modified Helbich score for both HRCT and morphological MRI assessment, showing
mean scores of 12 for both, good-to-excellent agreement between HRCT and MRI scores (r.0.8),
and good correlation between both CT and MRI scores and FEV1 and FVC.
Functional MRI
A significant advantage of MRI over CT is its superior ability to assess function. Within the lungs
this mainly involves evaluation of haemodynamic function and perfusion and ventilation studies.
Perfusion imaging
EICHINGER et al. [90] performed morphological and contrast-enhanced MRI sequences on 11

patients with CF; 198 lung segments were scored for morphological (3 point score of none,
moderate or severe) and perfusion defects (0 normal; 1 impaired perfusion). In 86% of segments
considered morphologically normal, homogenous perfusion was demonstrated, whereas 97% of
segments with severe morphological changes were associated with perfusion defects. Of segments
with moderate morphological changes, 53%showed normal and 47% impaired perfusion. Thus
contrast-enhanced MRI appears to be a feasible method of assessing regional perfusion defects as a
surrogate for small airways disease, although further work is required in order to improve
sensitivity in moderately affected areas of lung.
In bronchiectasis, increased blood flow though bronchial and nonbronchial systemic collateral
vessels results in a systemic arterial to pulmonary venous shunt. Using conventional proton MRI
and phase-contrast flow-sensitive sequences, aortic and pulmonary arterial flow can be readily
quantified. In a study of 10 patients with CF and 15 healthy volunteers, LEY et al. [91] found a
significantly increased shunt in CF patients (1.3 L?min-1) compared to healthy volunteers
(0.1 L?min-1).
In the presence of small airways obstruction, regional ventilation defects lead to impaired gas
exchange and reflex hypoxic vasoconstriction [86]. Perfusion imaging can thus serve as a marker
of airway obstruction. ITTI et al. [87] used radionuclide imaging to show that the degree of
abnormal lung perfusion correlates well with disease severity in CF, as measured by PFTs and the
Shwachman radiographic score. Contrast-enhanced pulmonary MRI imaging can be used to
acquire a 3D data set in just 1.5 seconds [88, 89]. This also has advantages over scintigraphy in
terms of radiation dose and provides regional information.
Oxygen-enhanced MRI exploits the weak paramagnetic properties of oxygen, which cause a
shortening of T1 at high concentration and can be used as a gaseous contrast agent. The solubility
of oxygen means that images represent a combination of ventilation and perfusion. A limitation is
the low signal-to-noise ratio [81]. JAKOB et al. [92] studied five CF patients and five healthy
volunteers using oxygen-enhanced MRI, showing inhomogeneity of the lung parenchyma in the
CF patients.
Hyperpolarised noble-gas-enhanced MRI
57
Imaging of hyperpolarised noble gases using MRI is a relatively new imaging technique that shows
promise in the research arena in the evaluation of several ventilatory functional parameters.
Hyperpolarised helium-3 and hyperpolarised xenon-129 are gaseous contrast agents that provide a
very high MR signal [35]. Since oxygen promotes depolarisation, the polarised helium-3 is mixed
with nitrogen rather than air before being administered by active inhalation via a device such as a
plastic Tedlar bag or respirator-driven gas delivery system. The bag method uses a mixture of
300 mL helium-3 and 700 mL nitrogen and requires a single anoxic breathhold. The respiratordriven system provides an accurate single dose followed by an air chaser and hence no anoxic
breathhold is required.
Polarisation is not renewable and has to be used carefully during the scan, with use of sequences to
maximise use of finite magnetisation [93]. Dedicated receiver coils for the relevant resonance
frequency of helium-3 and xenon-129 are also required.
The different physical properties of helium-3 and xenon-129 present different opportunities.
Although helium-3 provides a better signal and greater polarisation levels have been obtained, its
larger diffusion coefficient results in signal loss. In addition, although helium-3 is virtually
insoluble in water, xenon-129 is highly soluble and hence has potential for use in assessing
perfusion [93]. On a purely practical basis, the limited supply of helium-3, estimated at 200 kg
globally [94], compared to that of xenon-129 is likely to lead to xenon-129 eventually emerging as
agent of choice [95].
The main techniques used in hyperpolarised noble gas imaging are static ventilation imaging and
dynamic ventilation imaging, as well as assessment of lung microstructure using ADC and regional
oxygen tension imaging.
MCMAHON et al. [96] showed that static helium-3 MRI ventilation in CF correlated strongly
with HRCT assessment of structural abnormalities (R50.89; p,0.001), and that the
correlation was higher between helium-3 MRI and PFT results than helium-3 MRI and HRCT.
In a further observational study of 18 patients aged 517 years with CF undergoing
hyperpolarised helium-2 MRI, VAN BEEK et al. [97] confirmed moderate correlation between a
visual score of ventilation on MRI and global assessment of pulmonary function (FEV1 r5 -0.41
and FVC r5 -0.42).
In a study comparing healthy volunteers and CF patients, MENTORE et al. [98] performed
spirometry and hyperpolarised helium-3 imaging at baseline in all cases, and following various
interventions in the eight CF patients. Treatments in the CF group included bronchodilators,
DNAse and chest physiotherapy. The number of ventilation defects was scored. The helium-3
ventilation score correlated moderately with spirometry, and was higher in CF patients than
controls (mean 8.2 and 1.6, respectively). The helium-3 ventilation score was raised in comparison
to controls even in CF patients with normal spirometric results. Defects in the eight treated
patients decreased in response to bronchodilator therapy (p50.025). WOODHOUSE et al. [99]
demonstrated reproducibility of regional and total lung volume measurements using hyperpolarised helium-3 MR in two examinations performed 30 minutes apart in a group of five young
CF sufferers.
The ADC of helium-3 or xenon-129 in the lung and the paramagnetic effect of oxygen are two
novel methods with the potential for extracting clinically relevant data. The ADC provides a
measure of the diffusion of gas and thus an assessment of the degree to which free diffusion is
restricted. Helium-3 has a very high self-diffusion coefficient, but, in the lung, diffusion becomes
restricted by the boundaries of the airspaces, and thus the ADC can be used to interrogate the
microstructure of the lung [93].
58
The oxygen-induced depolarisation of helium-3 or xenon-129 results in signal decay proportional

to the concentration of oxygen [100], permitting estimation of regional oxygen concentration and
uptake and regional pulmonary perfusion, and providing a regional ventilation/perfusion (V/Q)
map at a much higher resolution than that of radionuclide imaging [101]. PATZ et al. [95]
measured regional oxygen concentrations using xenon-129, and, although this is inherently more
complex than with helium-3 due to diffusion into septal tissue and vasculature, an oxygen tension
(PO2) equivalent can be calculated, which can provide valuable functional information.
A limitation of hyperpolarised noble gas MRI is that the signal is also influenced by factors other
than ventilation, including the sensitivity of the MR coil and local oxygen concentration in the
lung. The need for noble gas isotopes and both polarisation hardware and additional MRI
hardware, together with considerable physical and technical support, mean that hyperpolarised
noble gas imaging remains expensive and limited to the research environment. However, the
potential to perform noninvasive evaluation of regional ventilation, diffusion, regional oxygen
concentration, lung microstructure and perfusion without the use of ionising radiation has
potential, especially in the research setting.
Summary
MRI has potential in the imaging of bronchiectasis, particularly in conditions such as CF, in which
young patients may require serial imaging for disease monitoring and assessment of response to
treatment. Compared to HRCT, the ability of MR to provide functional imaging and lack of
radiation could compensate for its limited spatial resolution. With improvement in MRI
techniques, recent studies have shown good reproducibility and good correlation with PFT results.
Further work is required to improve spatial resolution, develop robust validated scoring systems
and evaluate correlations with clinical outcomes.
Currently cost, limited availability and limited spatial resolution limit the use of MRI in
bronchiectasis largely to the research arena. Although hyperpolarised noble gas imaging has great
potential in terms of provision of functional data, technical issues and set-up and ongoing costs
suggest its role will be limited to research for the foreseeable future.
Prior to the advent of HRCT, ventilation (with or without perfusion) scintigraphy was used to aid
disease evaluation in bronchiectasis. DOLLERY and HUGH-JONES [102] studied the physiological
implications of bronchiectasis and found reduced blood flow and impaired ventilation in bronchiectatic
areas. V/Q scintigraphy typically demonstrates matched ventilation and perfusion defects, reflecting
abnormal ventilation secondary to bronchiectasis and associated small airways obstruction [103].
PIFFERI et al. [104] studied 16 children aged 418 years with clinical and CXR evidence of
bronchiectasis, performing HRCT and V/Q scintigraphy. The extent of bronchiectasis, degree of
air-trapping on expiratory HRCT and ventilation and perfusion scores from V/Q scintigraphy
were assessed. HRCT scores for bronchiectasis and air-trapping showed a strong correlation with
perfusion (r50.82; p,0.001) and ventilation scores (r50.72; p,0.01). There was a moderate
negative correlation between FEV1 and HRCT bronchiectatic scores (r5 -0.53; p50.02), airtrapping (r5 -0.64; p50.007) and atelectatic score (r5 -0.54; p50.03).
Scintigraphy
The authors concluded that HRCT provides a comprehensive assessment of children with
bronchiectasis, and V/Q scintigraphy and lung function are additive tools to aid diagnosis and
guide therapeutic management. The ongoing issue of radiation dose and absence of useful
anatomical information, however, limit the value of V/Q scintigraphy in routine practice.
Mucociliary clearance
59
The interaction between the cilia on respiratory epithelium and the periciliary mucous layer
(periciliary liquid (PCL))/overlying mucous layer, together known as the airway surface liquid
(ASL) layer, has been widely investigated. Coordinated function is responsible for the constant
clearance of foreign material, including microorganisms and other debris, towards the pharynx
and ultimate expectoration or swallowing. Impaired mucociliary function has been implicated in
many disease processes, but particularly bronchiectasis. Techniques to objectively measure
mucociliary clearance (MCC) in vivo have been sought in order to improve understanding of the
disease processes and evaluate therapeutic response.
Techniques for measuring MCC

In vivo assessment of MCC relies on the inhalation of radiolabelled particulate material that
becomes trapped in the mucous layer and can be imaged scintigraphically. Data acquired from the
gamma camera over time can be presented either as a series of images for visual inspection or,
more commonly, as timeactivity curves (fig. 11).
Technetium-99m-labelled human albumin, iron oxide and technetium-99sulfur colloid are some
of the aerosols used. Sulfur colloid is nondiffusible, remains extravascular and is expelled by MCC/
swallowing. Deposition of particles is affected by many factors. Some, such as particle size and
breathing pattern, can be controlled for, whereas others reflect the underlying lung condition (e.g.
obstruction and lung size). Thus, in order to make comparisons, it is important to standardise the
nature of the aerosolised particles (size and distribution) and provide a consistent nebulised flow
in order to produce a reproducible deposition rate [105].
In order to define the margins of the lung and differentiate central (C) and peripheral (P) lung
regions, an initial ventilation study utilising a xenon-133 or krypton-81 scan [106] can be
performed immediately prior to administration of particulate material. Following this, the patient
b)
c)
C
P
d)
e) 100
90
80
70
60
50
40
30
20
10
0
90
80
70
60 VCs
60
0
20
40
60
Time minutes
80
Retention at 120 minutes %
100
Retention %
a)
100
1.0
1.5
2.0
C/P ratio
2.5
3.0
Figure 11. Measurement of mucociliary clearance (MCC). a) A xenon-133 equilibrium scan was used to identify
60
the left (L) and right (R) lung boundaries in a normal subject, and assign central (C) and peripheral (P) regions of
interest (b). c) Deposition image obtained immediately after inhalation of technetiumsulfur colloid in the same
subject. d) Mean rate of clearance of technetiumsulfur colloid from 12 subjects with cystic fibrosis at baseline
(&)
h and immediately after inhalation of hypertonic saline ($) [16]. The fast phase (approximately 020 minutes;
), reflecting clearance from large airways, and slow phase (from 40 minutes to start of cough clearance
measurement; --------), reflecting smaller airway clearance, are highlighted. e) Effect of ratio of radioactive counts
measured in the C and P regions on rate of MCC, as denoted by particle retention at 120 minutes, in a cohort of
normal study subjects. VC: voluntary cough. Reproduced from [105] with permission from the publisher.
inhales nebulised radiolabelled aerosol. Various adjuncts are used during nebulisation in order to
provide consistent reproducible dosing, including pneumotachographic devices with visual
feedback to control inhalation flow rate and tidal volume within specific ranges, metronomes to
guide the timing of inhalation and exhalation, and aerosol dosimetric equipment to pulse aerosol
delivery during specific portions of the breathing cycle [105].
The rate of clearance from central airways is up to 1001,000 times faster than that from
peripheral airways [108, 109]. A two-phase MCC pattern is typically seen, with an initial rapid
phase lasting approximately 30 minutes and reflecting clearance from the central airways and a
prolonged slower phase. The latter occurs over 12 hours and is thought to represent movement
of particles to compartments that are more difficult to clear (e.g. absorption of PCL) or slow
clearance from peripheral airway/alveolar deposition. 24-hour measurement of clearance has also
been used to assess the pattern of clearance during the slower phase, which could also be of value
in assessing response to treatment. This, however, requires a higher administered radiation dose
due to the 6-hour half-life of technetium. A static measurement at 24 hours can be used as a
marker of deposition in the nonciliate airways or alveoli [110]. The relative contributions to the
24-hour measurement of slow clearance from peripheral airways, alveolar deposition and mixing
in a poorly cleared part of the ASL, are not fully understood [105]. The static 24-hour
measurement is useful in aiding calculation of other parameters, such as the tracheobronchial
retention (TBR) curve, which is derived by subtracting the 24-hour retention from the corrected
lung retention (LR) curve.
A potentially more accurate means of assessing peripheral clearance is inhaling particles of
different sizes, smaller (4 mm) particles being deposited more peripherally than larger (7.5 mm)
ones [111]. YEATES et al. [108] proposed labelling the differently sized aerosolised particles with
different radioisotopes to permit simultaneous measurement of central and peripheral regional
clearance. This method is not widely used due to practical difficulties.
Some authors [106] advocate measurement of activity solely in the lung periphery, where uptake
is more homogenous. This avoids the potential errors caused by differential uptake in central and
peripheral airways and confounding by variability of initial deposition. It is, however, limited by
a low signal-to-noise ratio due to lower deposition peripherally and intrinsically slower clearance
in these regions. It is also not possible to assess response to therapy in the central airways using
this method.
Following inhalation, the patient is positioned in front of the gamma camera and the gamma
radiation emitted is detected and recorded. The results are analysed graphically with reference to
the zones defined on the initial ventilation scan. At this stage of analysis, it is important to account
for decay of radioisotope and background radiation level. Given the variability of deposition of
radiolabelled aerosol in various parts of the airways, it is important to measure the initial
deposition pattern. The deposition pattern is usually presented as a ratio between C and P or as the
penetration index (PI), which is the ratio of radioactive counts per pixel in P to counts per pixel in
C [107]. A high initial C/P deposition ratio or low PI is associated with a higher clearance rate in
the central airways, making this a potential confounding factor in analysing final clearance data.
Additional imaging following various interventions, such as cough clearance (CC) assessed after
a standardised pattern of coughing, can also be performed. This has some limitations, as
performing this late in the study makes it less sensitive as the central airways would have been
largely cleared of radioisotope. A further normalisation measurement of C/P ratio must be
performed prior to CC.
Clinical applications
61
Measurement of MCC has important research applications in both understanding disease

processes and assessing therapeutic response. To date, the technique has not been broadly adopted
clinically, being cumbersome to establish.
Disorders that impair MCC can seriously affect respiratory function, with build-up of
thick mucus in the airways/lungs and inability to expel harmful material. This can predispose to complications, such as infection and structural lung disease. Other factors may influence
MCC, which is faster in nonsmokers and enhanced by b2-agonists, particularly in nonsmokers [112].
CF is a prominent example of a condition in which measurement of MCC could prove useful.
Scintigraphic evaluation has also been used to demonstrate impaired MCC in primary ciliary
dyskinesia [110] and following lung transplantation [113]. There have been limited studies in
idiopathic bronchiectasis [114].
In CF, disordered ion transport leads to dehydration of the ASL layer [115], impaired ciliary
motion and decreased mucus clearance, ultimately leading to degradation of cilia [105],
exacerbating the cycle of frequent infections. Ongoing research is focused on the earliest stages of
disease pathogenesis and therapeutic interventions to target defective mucus clearance.
Biomarkers objectively measuring MCC have the potential to assess response to treatment at
an early stage in contrast to longer-term end-points, such as clinical or functional parameters,
and thus to expedite drug development.
In a study of 24 patients with CF, DONALDSON et al. [116] showed improved MCC, measured using
technetium-99-labelled iron oxide, at both 1 and 24 hours after inhalation of hypertonic saline,
and that pretreatment with amiloride reduced the magnitude of this improvement. Using
radiolabelled iron oxide BENNETT et al. [106] demonstrated significantly reduced baseline MCC at
40 minutes in CF patients compared to healthy volunteers. In the CF group, treatment with
uridine 5-triphosphate and amiloride in combination improved peripheral MCC to near-normal
levels. Similar studies have used technetiumsulfur colloid to demonstrate improved MCC and CC
following inhaled hypertonic saline and mannitol in CF patients [117].
In summary, MCC can be measured using radiolabelled particulate materials, such as technetium99sulfur colloid. In the research setting, this provides a potential biomarker for evaluation of
mucociliary dysfunction and, in particular, assessment of the impact of targeted therapies. This is
especially true in conditions such as CF, in which impaired MCC plays a significant part in the
pathophysiology of the disease and where treatment is targeted at improving this.
Conclusions
Imaging plays a central role in the diagnosis, characterisation and quantification of disease severity
in bronchiectasis, as well as the evaluation of complications. Currently CXR and CT are the main
modalities. CXR is the initial screening tool, but has well-documented limitations in sensitivity
and specificity, particularly in early disease. Radiography also plays an important role in the
diagnosis of complications. HRCT is the reference standard in identifying airway dilation,
permitting detection of disease and quantification of extent. Routine surveillance CT has potential
for the diagnosis of structural disease at an early stage and impact on patient care, particularly
where these is discordance with functional parameters. Radiation dose, however, remains an
area of concern requiring further elucidation, particularly in the cohort of CF patients given their
ever-increasing life expectancy and the potentially large cumulative radiation dose. Although the
present review concentrates on the monitoring of disease, CT is an excellent problem-solving tool,
permitting the diagnosis of both infective complications, such as abscess, empyema and
aspergilloma, as well as identification of small pneumothoraces or enlarged systemic collateral
vessels (fig. 11) and aiding relevant image-guided intervention.
62
MRI offers opportunities to image the lung structure and its function without the use of ionising
radiation. The spatial resolution is inferior to that of CT but has improved substantially over
recent years. An increasing role for structural (proton) MRI is anticipated, but widespread
adoption will require further evidence to support its effectiveness. Although hyperpolarised noble
gases permit interrogation of a range of physiological parameters, the set-up costs of this technique
are likely to ensure it remains a predominantly research tool for at least the foreseeable future.
Evaluation of MCC using scintigraphy is another area in which there is great potential, particularly
in order to expedite and reduce costs of drug development.
None declared.
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Chapter 6
Microbiology of nonCF bronchiectasis

J.E. Foweraker* and D. Wat#
MICROBIOLOGY
Summary
Non-cystic fibrosis (CF) bronchiectasis is a complex disorder
characterised by recurrent chest infections and poorly regulated
respiratory innate and adaptive immunity. These lead to a
vicious cycle of impaired mucociliary clearance, chronic
infection, bronchial inflammation and progressive lung injury.
The most prevalent pathogenic bacteria are Haemophilus
influenzae, Pseudomonas aeruginosa, Streptococcus pneumoniae,
Staphylococcus aureus and Moraxella catarrhalis although
variations in sampling techniques and detection methods have
influenced their isolation rates. These organisms can inhibit
mucociliary clearance, destroy respiratory epithelium and
produce biofilms that promote persistent infection by blocking
innate immune defences and increasing antibiotic resistance.
While numerous studies have examined the role of different
bacteria in CF and chronic obstructive pulmonary disease, little
is known about how they contribute to the pathogenesis of nonCF bronchiectasis. There is also a paucity of data regarding the
role of respiratory viruses in this condition. This chapter
describes the microbiology of non-CF bronchiectasis, defines
the bacterial mechanisms that may contribute to persistent
infection and airway damage and discusses the potential role for
respiratory viruses in this condition. Understanding the
pathogenic properties of these microorganisms may allow the
development of novel therapies for the management of
respiratory exacerbations.
Keywords: Anaerobes, Haemophilus, Moraxella, Pseudomonas,
Streptococcus, viruses
*Dept of Microbiology, and

#
Lung Defence Unit, Papworth
Hospital, Cambridge, UK.
Correspondence: J.E. Foweraker,
Dept of Microbiology, Papworth
Hospital, Papworth Everard,
Cambridge, CB23 3RE, UK, Email
juliet.foweraker@papworth.nhs.uk

Copyright ERS 2011.
ISSN: 1025-448x.
DOI: 10.1183/1025448x.10003610
68
atients with bronchiectasis are commonly colonised with potentially pathogenic microorganisms in the airways [1]. These microorganisms can cause lung infections and may produce a
number of inflammatory mediators that can lead to progressive tissue damage and bronchial
obstruction. The phenomenon of chronic infection, bronchial inflammation and progressive lung
injury is a vicious cycle and is also the reason why prompt evaluation of infection is important [2].
Being able to identify the causative bacterium may allow appropriate antibiotic administration to
break this vicious cycle.
The most prevalent microorganisms found in non-cystic fibrosis (CF) bronchiectasis are discussed
in this chapter and we have included the role of viruses, as well as some recent studies that have
investigated microorganisms that are not usually considered to be pathogens in the respiratory
tract. Surprisingly, there is little published data on the epidemiology and pathogenesis of infections
in non-CF bronchiectasis. However, there are similarities with infections in CF bronchiectasis and
chronic obstructive pulmonary disease (COPD). Where the literature for non-CF bronchiectasis is
sparse, studies in CF and COPD have been drawn upon as these may aid the understanding of the
microbiology; in particular the adaptations that take place to enable microorganisms to establish
and maintain chronic infection and the role taken in the development of exacerbations.
Fungal infections, including allergic bronchopulmonary aspergillosis (ABPA), are discussed further
by HILVERLING et al. [3], while nontuberculous mycobacteria infections are discussed further by
DALEY [4] in this Monograph.
Several studies have reviewed the bacteria found in patients with non-CF bronchiectasis (table 1).
A similar range of organisms is found in most studies, but the prevalence of each varies. Age,
ethnicity, the underlying causes of bronchiectasis and the proportion of patients that were stable
or had cultures taken during an exacerbation varies between the different studies and would be
expected to affect the microbial flora found. The pattern of antibiotic usage, including long-term
prophylaxis, may vary between different centres and could also have an affect on the type of
microorganisms cultured. The type of respiratory specimen tested may also determine the rate of
positive cultures found. The use of a protected specimen brush to take samples at bronchoscopy
yielded the highest positivity rate when compared with sputum specimens in one study [7]. Finally
the methodology used for analysis (quantification, culture and identification techniques) will vary
between centres and could also affect the result.
Haemophilus influenzae and Pseudomonas aeruginosa were the most common bacteria found in the
majority of the studies and the most likely to cause long-term colonisation [12]. No potentially
pathogenic microorganisms were cultured from 1824% of the patients investigated and an
absence of a potentially pathogenic microorganism was associated with the milder disease [9, 13].
Haemophilus influenzae
J.E. FOWERAKER AND D. WAT
Range of bacteria in patients with non-CF bronchiectasis
H. influenzae has been reported in 1452% of patients with non-CF bronchiectasis. It is a Gramnegative coccobacillus with specific growth requirements, which can be difficult to isolate in the
laboratory if mixed with other flora. Some H. influenzae possess a polysaccharide capsule and can
be typed using type-specific anticapsule antisera. Those with the type B capsule (Hib) can cause
invasive infection with bacteraemia, and are most familiar as a cause of meningitis or epiglottitis.
The use of Hib vaccine has greatly reduced the incidence of these life-threatening conditions.
H. influenzae with capsule types other than type B are relatively rare and are far less pathogenic.
The nonencapsulated strains, referred to as nontypeable H. influenzae (NTHi), are also less
pathogenic than Hib and only rarely cause bacteraemia. They live as commensals in the human
upper respiratory tract but can cause otitis media, sinusitis and conjunctivitis, often following a
primary viral infection. NTHi are a common cause of lower respiratory infection in patients with
underlying respiratory abnormalities including non-CF bronchiectasis [9]. The Hib vaccine does
not prevent infection with NTHi as it only contains the H. influenzae type B capsule antigen.
69
NTHi could be an oral contaminant in expectorated sputum; however, studies using a protected
specimen brush (PSB) at bronchoscopy found NTHi in significant numbers in non-CF
bronchiectasis, confirming its presence in the lower respiratory tract [7]. In contrast
15 (10)
9 (6)
47 (33)
47 (33)
Colonised
subgroup"
13 (9)
21 (14)
39 (27)
30 (20)
39 (27)
20 (13)
42 (30)
46 (31)
62 (43)
52 (35)
75 (52)
ND
ND
Sputum
Sputum
PASTEUR [10]
MACFARLANE [11]
UK
UK
150
143
60.6
(1690)
3 (4)
7 (8)
6 (7)
11 (12)
42 (47)
Stable
Sputum
89
KING [9]
Australia
5714
9 (7)
3 (2)
13 (11)
38 (31)
37 (30)
ND
Sputum
123
USA
NICOTRA [8]
57.216.7
2 (3)
3 (4)
6 (8)
12 (16)
24 (32)
Stable
58 (1676)
PSB
75
Spain
ANGRILL [7]
Data are presented as mean (range), meanSD or n (%), unless otherwise stated. RTFlora: upper respiratory tract flora; PPM: potentially pathogenic microorganisms; ND: not described; K. pneumoniae: Klebsiella
pneumoniae; GNB: Gram-negative bacilli; GPB: Gram-positive bacilli; PSB: protected specimen brush; A. xylosoxidans: Achromobacter xylosoxidans: E. coli: Escherichia coli; S. maltophilia: Stenotrophomonas
maltophilia; #: some had more than one PPM cultured; ": bacteria were isolated on at least two occasions, 3 months apart, in 1 year.
7 (14) K. pneumonia
7 (14) GNB
2 (4) GPB
18 (24) RTFlora 1 (1) A. xylosoxidans
1 (1) E. coli
ND
16 (13) GNB
2 (3) Anaerobes
19 (21) no PPM
2 (2) E. coli
1 (1) A. xylosoxidans
ND
28 (20)
12 (8) S. maltophilia
42 (30) Coliforms
2 (1) S. maltophilia
13 (9) Coliforms
Sputum
Sputum
92
50
Ireland
Thailand
ZAID [5]
PALWATWICHAI [6]
,18
58 (3085)
ND
ND
50 (46)
7 (14)
8 (9)
10 (20)
34 (37)
3 (6)
9 (10)
2 (4)
14 (15)
ND
9 (18) RTFlora
Other
RTFlora/
no PPM
Haemophilus Pseudomonas Streptococcus Moraxella Staphylococcus

influenzae
aeruginosa
pneumoniae catarrhalis
aureus
Patients with organisms cultured from respiratory tract#

Stable or at
exacerbation
Age yrs
Sample
Subjects
n
Country
First author
[ref.]
Table 1. Range of microorganisms cultured from patients with non-cystic fibrosis bronchiectasis
MICROBIOLOGY
70
Haemophilus parainfluenzae, a common commensal organism found in

the upper respiratory tract, may be
cultured from sputum but was not
found in PSB samples. In patients
with COPD the presence of NTHi in
sputum was associated with raised
inflammatory cytokines, whereas patients with H. parainfluenzae in sputum had similar levels of cytokines to
those who had no microorganisms
cultured from their sputum, suggesting that even if present in the lower
tract it does not have a direct pathogenic role [14, 15].
There is little published data on the
epidemiology of H. influenzae in
non-CF bronchiectasis. It may be
cultured repeatedly from the same
patient over several years, but without typing data it is not known if
this is the persistence of a single
strain or repeated episodes of infection [9]. In COPD patients, NTHi
were found in higher numbers (.106
colony forming units (CFU)?mL-1)
during exacerbation compared with
when the patient was stable, and
exacerbations in COPD may be associated with the appearance of a new
strain [16, 17]. A prospective study in
COPD using molecular typing of
H. influenzae and direct analysis of
amplified DNA from sputum showed
persistence of the same strain over
prolonged periods [18]. This suggests
either long-term colonising infection
in the lung or persistence in the
upper respiratory tract with repeated
deposition followed by clearance from
the lung. In CF, sequential infection
with different strains of H. influenzae
was found in some patients and persistence of the same clone in other
individuals [19].
NTHi have various properties that
can help explain their pathogenicity
and ability to persist in the lung. They
can adhere to mucus and to various
cell types in the human respiratory
tract using pili and other adhesion
molecules. Virulence factors include
the endotoxin lipo-oligosaccharides
(LOS), and immunoglobulin (Ig)-A protease [20]. NTHi possess mechanisms to vary the structure
and activity of LOS and these may explain variations in the pathogenicity of different isolates [21].
Studies comparing the proteome of H. influenzae grown in vitro, either in pooled sputum or
chemically defined media, have shown that the organism is able to adapt to oxidative stress and
limited nutrients [22]. This is thought to be because H. influenzae has the ability to generate a diverse
population that allows rapid adaptation to changes in the environment by expansion of the clonal
members that express the phenotypic characteristics needed to survive. Mechanisms used by H.
influenzae to generate phenotypic diversity include altered gene expression, e.g. by phase variation,
and altered gene content by mutation or by horizontal gene transfer, e.g. direct DNA uptaketransformation, or via bacteriophage [23].
H. influenzae (along with other bacteria infecting a bronchiectatic lung) may exist in biofilms in the
respiratory tract. These are co-operative populations of bacteria surrounded by an amorphous matrix
and could help the organism to survive in a hostile environment by resisting both host defences and
antibiotics. The antibiotic resistance observed for bacteria growing in biofilms is in part attributable to
its electrolyte content but also by reduced bacterial growth or even dormancy within the biofilm
matrix. NTHi from patients with COPD can form biofilms in vitro, and NTHi biofilms were seen in
the chinchilla model of otitis media [28, 29]. NTHi cultured from CF patients could form biofilms in
vitro and on the surface of cultured airway epithelial cells. Structures consistent with biofilms
containing H. influenzae were also found in bronchoalveolar lavage (BAL) samples from children with
CF [30]. NTHi in biofilms were more resistant to antibiotics in vitro. Sub-inhibitory concentrations of
azithromycin were found to reduce the size of both growing and established biofilms [31].
The prevalence of antibiotic resistant NTHi increases over time in patients with non-CF
bronchiectasis [9]. Many are resistant to amidopenicillins (e.g. amoxicillin, ampicillin) either due
to production of b-lactamase or alteration of penicillin binding proteins. Quinolone resistance is
now recognised and resistance rates to trimethoprim and tetracycline are rising.
NTHi may be able to evade the immune response by varying its surface antigens. Mechanisms
include phase variation of LOS [24], and changes to outer membrane proteins (OMP) either by
horizontal gene transfer or point mutations of the immuno-dominant OMP, i.e. P2. Antigenic
drift, resulting from change in the P2 gene, has been observed in persistent infections in patients
with COPD [25]. NTHi could be protected within host cells as they have been found inside
macrophages in the chinchilla otitis media model and in macrophage-like cells in human
adenoids. NTHi were able to enter cultured nonciliated respiratory epithelial cells and cross the
respiratory epithelium [26]. Using in situ hybridisation, NTHi were identified inside cells in
bronchial biopsies taken from patients with COPD [27].
Antibiotic resistance may occur by horizontal transfer of genetic material from other organisms in the
complex polymicrobial environment of the mouth and upper respiratory tract. It may also take place
in the lower respiratory tract, which may be polymicrobial in non-CF bronchiectasis. Alternatively,
resistance may result from gene mutation. Some NTHi have a higher than usual mutation rate due to
a mutation in mutS, which is one of the methyl-directed mismatch repair genes (MMR) that corrects
errors in DNA. This hypermutability is not usually thought to be advantageous, as many random
mutations can reduce bacterial fitness. However, if mutations lead to antibiotic resistance, the
hypermutable state may become beneficial to the bacterial population. Hypermutators are generally
rare in acute infection but hypermutable H. influenzae have been found in patients with CF and these
strains have more resistance to antibiotics compared with normo-mutators [19, 32]. Hypermutability
is seen in other species causing chronic infection (as is discussed later in this chapter) and may be a
general adaptation to long-term survival in the lung. The prevalence and role of hypermutable
H. influenzae in non-CF bronchiectasis has yet to be assessed.
Pseudomonas aeruginosa
71
P. aeruginosa is a versatile nonfermentative Gram-negative bacillus that is found in a range of

environments. It is an opportunistic human pathogen that can cause severe, acute and invasive
infections, such as necrotising ventilator-associated pneumonia and infections in immunocompromised patients often with bacteraemia [33]. It is one of the most common causes of
infection in non-CF bronchiectasis and other chronic lung diseases, most notably CF, but may also
be important in severe COPD. The epidemiology of P. aeruginosa, the mechanisms of
pathogenicity and the genotypic and phenotypic changes in chronic infection have been
extensively studied in CF, with fewer publications in non-CF bronchiectasis and COPD. There are
many similarities between the infections in these different conditions, suggesting a common route
of adaptation to chronic infection in the lung.
MICROBIOLOGY
P. aeruginosa in CF
Early infections in CF are caused by genotypically distinct isolates, suggesting repeated episodes of
acquisition. These early P. aeruginosa have the typical phenotype of isolates causing acute
infections and environmental strains [34]. As chronic infection with P. aeruginosa can lead to an
accelerated deterioration in lung function, antibiotic treatment regimens were developed to clear
early infection and delay the onset of chronic infection [35]. CF patients eventually developed a
persistent infection that seldom cleared despite aggressive antibiotic therapy. While there are some
mixed infections, most CF patients carry a single genotype of P. aeruginosa, often for many
decades [36, 37], and exacerbations do not appear to be due to the acquisition of a new strain of
P. aeruginosa [38]. Early studies in CF showed that individual patients were infected with distinct
strains that were thought to have been acquired from the environment. Some siblings shared
strains but it was not known whether this was cross-infection or exposure to a common
environmental source. More recently there have been reports in several countries of crossinfection between CF patients with what are termed epidemic strains. Some, in particular the
Liverpool epidemic strain (LES), have been associated with increased morbidity [39, 40]. LES is
now the most common epidemic strain in the UK affecting as many as 11% of patients in England
and Wales [41].
P. aeruginosa in COPD
P. aeruginosa has been cultured from 415% of patients with COPD and was more prevalent in
patients with advanced disease, particularly those requiring mechanical ventilation for severe
exacerbations. P. aeruginosa infection was associated with steroid use, prior antibiotics and a low
forced expiratory volume in 1 second (FEV1) [42]. In a study of 126 patients with moderate-tosevere COPD over an 11-year period, 39 patients grew P. aeruginosa from one or more sputum
culture. There was a significant association with the culture of a new strain of P. aeruginosa and
symptoms of an exacerbation. However, of interest, two-thirds of new infections that later
cleared from the sputum, did so without the use of specific antibiotic treatment [43]. Only
13 patients had carriage of the same clone for more than 6 months with four patients infected
with mucoid strains. Chronic infection is therefore rare in COPD, but when it does occur
P. aeruginosa has a range of colony forms (morphotypes) and adaptations including increased
mutability, reduced motility, reduced protease production and increased antibiotic resistance,
similar to those seen in CF [44].
P. aeruginosa in non-CF bronchiectasis

P. aeruginosa is one of the most common isolates found in 1243% of non-CF bronchiectasis
patients (table 1). Stable patients with P. aeruginosa have poorer lung function and more sputum
production when compared with patients with other potentially pathogenic microorganisms
(PPM) [45] and it has been associated with a poorer quality of life and more frequent hospital
admissions [46]. There is debate over whether infection with P. aeruginosa leads to a faster decline
in lung function as is seen in CF, or whether it is a marker of more damaged lungs [47, 48].
72
A recent study compared long-term colonisation with P. aeruginosa in 21 patients, of which six
had CF, 10 had non-CF bronchiectasis and five had COPD. The authors typed 125 sequential
isolates from sputa taken at least 1 month apart. The authors found a similar pattern of
colonisation in all three diseases, with a dominant persistent clone, showing that the pattern of
infection found in CF could also be shown in other conditions [49].
There have been no studies using genomic typing methods to investigate whether patients with nonCF bronchiectasis share strains of P. aeruginosa, but there has been one report of a patient with nonCF bronchiectasis acquiring LES from a relative with CF [50]. Interestingly, early studies using
pyocin typing and examining mucinophilic and chemotactic properties of P. aeruginosa suggest that
specific subpopulations may have a predilection to infect bronchiectatic lungs [51, 52].
Pathogenicity of P. aeruginosa
P. aeruginosa possesses a range of virulence factors, although their expression may differ between
isolates that cause acute infection and those responsible for chronic infection. Flagella, type IV pili,
lipopolysaccharide and exopolysaccharides contribute to the adherence to cells and surfaces. Type
I and type II secretion systems export protein toxins, such as alkaline protease, elastase, exotoxin A
and phospholipase C, while type III secretion systems inject exoenzymes directly into eukaryotic
cells. Other extra-cellular virulence factors include rhamnolipids, pyocyanin and hydrogen cyanide
[53, 54]. Another pathogenicity factor is the ability to form alginate-enhanced biofilms [55], which
contributes to the persistence of the organism rather than acute tissue damage and, together with
other adaptations, promotes chronic infection (refer to later section).
P. aeruginosa is intrinsically resistant to many commonly used antibiotics and easily acquires
resistance by chromosomal mutation or the acquisition of new genes from other microorganisms
by horizontal transfer [56]. In addition, the biofilm mode of growth also protects P. aeruginosa
from antibiotics by a variety of mechanisms [57].
Little has been published specifically on antibiotic susceptibility of P. aeruginosa from patients
with non-CF bronchiectasis. In CF the prevalence of resistant P. aeruginosa is increasing as a result
of repeated antibiotic courses. Resistance rates are significantly higher than for strains originating
from patients without CF [58] and pan-resistant bacteria that are resistant to all antibiotics other
than the polymixins have been described.
P. aeruginosa can develop resistance by either: 1) producing enzymes that destroy the antibiotic,
such as AmpC b-lactamase, carbapenemases or aminoglycoside modifying enzymes; 2) modifying
the antibiotic target, such as gyrA for quinolone resistance; or 3) reducing exposure either by a
decrease in permeability or increased removal of the antibiotic from the bacterial cell (efflux).
Efflux mechanisms often affect more that one class of antibiotics and therefore contribute to
multi-drug resistance [56].
Antibiotic resistance
Antibiotic resistance and its regulation can be complex in P. aeruginosa and various mechanisms
that affect resistance to a single antibiotic may be present in the same organism. For example, low
level resistance to meropenem may be due to reduced permeability following changes to the
membrane porin OprD. More resistance can result from an increase in an efflux pump that can
remove the meropenem from the cell. Both mechanisms may be present and additive, leading to
high-level resistance. Enzymes that can destroy meropenem (penemases such as VIM) do occur
but are currently rare [56].
73
AmpC codes for an inducible cephalosporinase which, when production is increased, can result in
resistance to nearly all b-lactam antibiotics except the penems. Treatment with piperacillin or
ceftazidime can lead to the selection of bacteria that produce the enzyme constitutively rather than
just on induction. These are called derepressed mutants and offer a survival advantage. Imipenem
induces the AmpC b-lactamase, even though it is not affected by the enzyme, and it also induces
genes involved with alginate production [59]. The regulation of ampC is exceedingly complex and
is intimately linked to cell wall recycling [6062]. Some mutations can reduce biological
competitiveness and more work is needed to assess the link between antimicrobial resistance and
fitness [61]. AmpR does not just regulate ampC but is a global transcriptional regulator that
regulates another b-lactamase PoxB, as well as proteases, quorum sensing and other virulence
factors [63]. Antibiotic resistance may therefore be associated with a change in virulence and/or
fitness. This could explain why some CF patients respond to treatment for acute exacerbation,
even though some of the P. aeruginosa are resistant to the antibiotic used [64].
P. aeruginosa possesses multi-drug efflux pumps that can expel a wide range of antibiotics and are
responsible for much of the organisms intrinsic resistance to antimicrobials. For example,
substrates for efflux pump MexAB-OprM include ticarcillin, aztreonam, piperacillin, ceftazidime
and tetracycline [65]. MexXY uses the same exit duct OprM and can export aminoglycosides,
cefepime and ciprofloxacin. Antibiotic resistance may arise from an increase in the efflux pump
activity, e.g. MexXY-OprM over-expression may be due to mutation in the regulatory gene mexZ
and/or to mutations in the MexXY translocase genes [66].
MICROBIOLOGY
Conversely, P. aeruginosa may be hyper-susceptible in vitro to some anti-pseudomonal antibiotics

and susceptible to agents such as tetracycline and chloramphenicol to which P. aeruginosa would
normally be intrinsically resistant. This has been described in chronic infection in both CF and
non-CF bronchiectasis [67, 68], but the clinical relevance of these findings has not been
investigated. It was found that 25 out of 46 CF patients had strains hyper-susceptible to ticarcillin
due to deficiencies in MexAB-OprM efflux activity, resulting from various gene defects including
reduced or abnormal expression of MexB and OprM [66]. It is unclear why this phenomenon
exists. Efflux pumps do not just expel antibiotics and therefore reduced efflux may give a selective
advantage under certain physiological conditions in the chronically infected lung.
Adaptations to chronic infection

One of the characteristics of chronic infection with P. aeruginosa is the appearance in vitro of a
variety of colony forms (morphotypes) that differ from those seen in environmental strains or
those causing acute infection (fig. 1).
Several different morphotypes may be found in the same sputum, even though the isolates are
clonally related. These can include colonies lacking the typical pigmentation, mucoid forms, some
that look like coliforms, dwarf forms and very slow growing small colony variants. One of the
most easily recognised is the mucoid morphotype. This results from over-production of the
polysaccharide alginate, due to mutation in the
regulatory genes. Hyper-alginate producers were originally thought unique to CF but they are also found in
non-CF bronchiectasis and COPD [45, 49, 69]. They
are thought to be an adaptation to chronic infection
irrespective of the underlying cause. Alginate may
protect against phagocytosis [70] and contribute to the
formation of biofilms [71, 72]. Small colony variants
(SCVs) have enhanced ability to form biofilms and may
also contribute to persistence [73]. SCVs have only
been described so far in CF but are easily missed unless
cultures are prolonged.
Figure 1. Different pseudomonal morpho-
74
logical types of Pseudomonas aeruginosa

found in a single sputum sample taken from
a chronically infected individual.
The phenotypic changes found in chronic infection

have been studied extensively in CF but not in non-CF
bronchiectasis. They include loss of acute virulence
factors, such as toxin production (e.g. elastase, phospholipase C, pyoverdin, hydrogen cyanide) and type III
secretion [74]. Many virulence factors are regulated by
the quorum sensing (QS) system. These are signalling
molecules that act on the regulators of gene transcription. Some QS molecules depend on
population density, and only have their effect when the number of organisms reaches a critical
concentration (or quorum). P. aeruginosa QS molecules comprise acyl-homoserine lactones and
molecules of the PQS system. They can affect a large number of functions including pathogenicity,
metabolic adaptation and persistence [75]. P. aeruginosa with mutations in QS genes, most
frequently las R, do not respond to QS molecules and are surprisingly common, they were found
in 19 out of 30 CF patients in a study by SMITH et al. [76]. Las R mutants form characteristic
iridescent colonies and have also been cultured from patients with non-CF bronchiectasis (J.E.
Foweraker, Papworth Hospital, Cambridge, UK; personal communication). These mutants do not
produce the toxins elastase, phenazines or hydrogen cyanide. Las R mutants can use a more diverse
range of compounds as a source of carbon, nitrogen, phosphorus or sulphur and have a growth
advantage over the wild type when grown with phenylalanine, isoleucine or tyrosine. They
therefore appear to be less pathogenic but better able to adapt to the local environment. Again,
different phenotypes can co-exist so sputum may contain Las R mutants and organisms without
the mutation.
Longitudinal studies in CF have analysed strains from patients over several years. It is thought that
with time the bacteria adapt to a form that is less virulent but better able to persist in the damaged
lung [76]. Multiple phenotypic variants of the underlying clonal population of P. aeruginosa coexist and form a complex population in the chronically infected lung. This is described as
adaptive radiation and is thought to give the bacteria an advantage in that they can rapidly
respond to changes in the environment, as individual organisms that have the necessary
adaptation may already be present in the population.
P. aeruginosa is thought to grow in biofilms in chronic infections in both CF and non-CF

bronchiectasis. Biofilm formation is thought to be a general adaptation to a hostile environment
and may allow persistence of infection by protecting the bacteria from the host response and the
effects of antibiotics. Biofilm fragments have been seen in CF sputum [77] and may contain a
mixture of P. aeruginosa plus other bacteria and even fungi, such as Candida spp. The extracellular matrix comprises alginate produced by P. aeruginosa plus proteins and DNA from other
microorganisms and host cells. The biofilm contains a steep oxygen gradient and is anaerobic just
below the surface. Different concentrations of nutrients and waste products will also be found in
different areas of the biofilm. Therefore, the biofilm contains a wide range of physiological
conditions, by which the bacteria possess a variety of adaptations that enable them to survive
within these microniches [78].
Biofilms
Alginate protects P. aeruginosa in biofilms from interferon (IFN)-c activated macrophages [79].
Neutrophils have been observed immobilised in the extra-cellular matrix, unable to penetrate the
biofilm [80]. It is thought that neutrophils may actually enhance early biofilm formation, as
biofilms formed in vitro in the presence of neutrophils are thicker and contain more bacteria [81].
If P. aeruginosa and neutrophils are combined, the bacteria aggregate around necrotic dying
neutrophils. If neutrophil apoptosis is induced before the bacteria are added, the neutrophils are
intact and the P. aeruginosa remain dispersed. Neutrophils can release DNA and F-actin
complexed with histones and other cations, and these may form the framework for the biofilm.
The combination of DNAse and anionic polymers has a synergistic effect in clearing early
neutrophil-associated biofilms in vitro and is being studied as a potential treatment to prevent or
disrupt early biofilm formation [81]. Neutrophil lysis is thought to be caused by rhamnolipid, a
toxin produced by P. aeruginosa under QS control. Rhamnolipid may therefore help to protect the
biofilm from disruption by neutrophils, especially in the early stages of formation [82].
75
Azithromycin is a macrolide antibiotic that does not directly inhibit or kill P. aeruginosa, but it can
block QS and alginate polymer formation in vitro [83]. It can disrupt early biofilms formed by
nonmucoid strains but has less effect on early biofilms formed by hyper-alginate producers
MICROBIOLOGY
(mucoid strains) or on established biofilms [84]. Azithromycin also has an anti-inflammatory

effect in chronic lung infection and the relative importance of its diverse actions is yet to be
established. Other antibiotics may also influence bacterial virulence. For example ciprofloxacin can
suppress alginate biosynthesis at concentration well below minimum inhibitory concentration
(MIC) [85].
Bacteria cultured in biofilms in vitro are more resistant to most antibiotics than when they are
dispersed (planktonic). Several mechanisms have been proposed to explain this resistance [86]. It
was thought that the extra-cellular matrix formed a physical barrier but there are channels within
the biofilm through which most antibiotics can permeate. Positively charged antibiotics such as
colistin may bind to free anionic DNA and therefore not reach the bacteria, and an anionic
antibiotic, such as an aminoglycoside (e.g. tobramycin) may bind to the alginate. If the AmpC
b-lactamase is over produced by some P. aeruginosa it may form a high local concentration and
protect bacteria that can only produce basal levels of the enzyme. Mutability is increased in
biofilms, partly because of the presence of hypermutators but also because DNA can be damaged
by the increased amounts of reactive oxygen species within the biofilm. The range of metabolic
conditions in the biofilm may affect antibiotic susceptibility. P. aeruginosa can survive in the
anaerobic environment just below the surface of the biofilm by using nitrogen rather than oxygen
as a terminal electron acceptor and aminoglycosides, such as tobramycin, cannot act on organisms
that are metabolising anaerobically. Organisms within a biofilm may become dormant and
therefore resist quinolones and b-lactam antibiotics [87]. These affects have been shown in an in
vitro model of a young biofilm in a flow chamber using live/dead staining. Ciprofloxacin kills
organisms on the surface of the biofilm but cannot kill those deeply set within the biofilm, whereas
colistin can kill the non-dividing cells in the centre [88]. The two antibiotics appear to be very
effective against young biofilms in vitro and may explain why that combination is particularly
effective in eliminating early infection with P. aeruginosa in CF.
Hypermutators
One of the drivers of variability and adaptation seen in persistent infection in bronchiectasis is
thought to be the presence of hypermutator (HM) bacteria [89]. These are P. aeruginosa with a
higher than usual spontaneous mutation rate and are thought to accelerate bacterial evolution.
P. aeruginosa usually mutates at a frequency of one in 108109, while mutation rates in HM
bacteria can be as high as one in 100. HM P. aeruginosa were found in 37% of chronically infected
CF patients. This was the highest prevalence that had been described for a naturally occurring
population [90]. In comparison a HM prevalence of 1% in Escherichia coli and Salmonella spp. had
previously been considered high [91]. In a longitudinal study of CF patients in Denmark, none of
the bacteria from early infections were found to be HMs but after 20 years of colonisation 65% of
patients were infected with HM P. aeruginosa [92]. HM P. aeruginosa were described in 57% of
chronically infected patients with COPD or non-CF bronchiectasis, suggesting that hypermutability is a general adaptation to long-term survival in the lung [93]. KENNA et al. [94] suggests
that hypermutability is an extremely rare finding in environmental P. aeruginosa and in isolates
from newly infected CF patients.
Most of the information on HM P. aeruginosa comes from work on isolates from CF [95]. Hypermutability usually results from a primary mutation in genes of the MMR system, most commonly
mutS and mutL, or defects in the GO system (mut M, Y and T). The function of these systems is to
detect and repair DNA replication errors and repair oxidative damage. MMR also inhibits
recombination between moderately diverged sequences and therefore reduces the acquisition of
exogenous DNA through horizontal gene transfer [96].
76
HMs are uncommon in most bacterial populations because many of the mutations are deleterious.
HM P. aeruginosa had reduced virulence and fitness both in vitro and in an animal model [97, 98].
However, in changing environments or stressful conditions HM bacteria may be selected because
they have adaptive mutations, such as antimicrobial resistance (referred to as hitchhiking).
The sequential acquisition of resistance to multiple antibiotics is seen in infection with P. aeruginosa
in CF, and several studies in CF, non-CF bronchiectasis and COPD have shown that HM are more
likely to be antibiotic resistant than isolates with normal mutation rates [93, 99]. In a study of 29 CF
patients over a 5-year period, mutations accumulated at an average mutations rate of three per year
in HM P. aeruginosa compared with 0.25 per year in non-mutators. HM had more mutations
leading to antibiotic resistance but also more mutations in other genes such as lasR [89]. Therefore,
other adaptations may provide a selective advantage for HM isolates, not just antibiotic resistance.
Two recent studies have shown that CF patients with HM had poorer lung function (FEV1
predicted), but longitudinal studies are needed to determine if this was due to infection with a HM
or just an association, both being the result of prolonged infection [99, 100]. Work is needed on
the role of HM in non-CF bronchiectasis.
Chronic P. aeruginosa infection and the clinical microbiology laboratory

One practical implication of the range of phenotypic diversity of P. aeruginosa from non-CF
bronchiectasis is that some isolates may be difficult to identify. Colonies of P. aeruginosa from
chronic infection may lack pigmentation, grow very slowly and may mimic other species.
Another consequence of phenotypic diversity is that a range of antimicrobial susceptibility

patterns can be found in a population of P. aeruginosa in a single sputum sample (fig. 2). Bacteria
with the same morphotype may have different susceptibility and therefore resistant subpopulations may be missed, depending on which colony is picked for testing [68].
In CF, once a chronic infection is established the range in the antibiotic susceptibility of
P. aeruginosa in a single sputum is so diverse that susceptibility testing methods are unreliable
[102, 103]. It is currently unclear whether these findings can equally be applied to chronic infection in non-CF bronchiectasis.
Finally it has been questioned whether current methods used for testing antimicrobial
susceptibility are relevant for bacteria that may be present in biofilms in the chronically infected
lungs. A variety of methods are being developed for testing biofilm susceptibility; however, their
clinical relevance still needs to be determined.
Commercial identification schemes that use biochemical reactions and assimilation tests are not
reliable in identifying atypical P. aeruginosa and some of the other nonfermenting Gram-negative
bacilli found in chronic infection, and therefore identification methods, such as species-specific
PCR or sequencing of the 16S ribosomal RNA gene may be required [101].
Streptococcus
pneumoniae
Figure 2. Variation in antimicrobial susceptibility testing. The figure

shows the results from testing two bacteria with identical colony
form in sputum taken from a patient with non-cystic fibrosis
bronchiectasis. The same six different antimicrobial discs were
used for both cultures. The susceptibility is proportional to the
diameter of the zone of diffusion around the antibiotic disc.
77
S. pneumoniae is a Gram-positive
coccus appearing in pairs and in
short chains. It may be a harmless
commensal in the oro-pharynx but
can cause severe and invasive disease (pneumonia or meningitis).
It can also cause otitis media or
sinusitis, or lower airway infections
in patients with damaged lungs such
as non-CF bronchiectasis or COPD,
but it is rare in CF. Although
S. pneumoniae can be found in up
to 37% of patients with non-CF
bronchiectasis, very little has been published on its role in this condition. In COPD, S. pneumoniae
has been cultured from both stable patients and those with exacerbation [20, 104]. The patient with
non-CF bronchiectasis due to an underlying antibody deficiency may be particularly susceptible to
recurrent infections with S. pneumoniae [105]. Bronchiectasis in primary and secondary
immunodeficiency patients is discussed further in the chapter by BROWN et al. [106].
S. pneumoniae has a polysaccharide capsule that helps evade opsonisation, and isolates lacking the
capsule are avirulent. There are over 90 capsule types and the capsule type may be one of several factors
that determine the pathogenicity of an individual strain [107]. A polyvalent vaccine containing the
most common serotypes is available and recommended for use in patients with chronic lung disease.
S. pneumoniae can use a wide variety of molecules to adhere to host cells and produces an IgA
protease and a toxin, pneumolysin that can promote invasion, inflammation and tissue damage
[108]. Pneumolysin is proinflammatory and has many actions including cytolysis, inhibition of
cilial beating, and direct activation of the classical complement cascade. Although it is not a
common pathogen in CF, isolates of S. pneumoniae from CF sputum have characteristics that may
be associated with adaptation to persistence in the lung, i.e. hypermutability and the ability to
form biofilms [109, 110]. Further work is needed to clarify the role of the different virulence
factors in order to understand why S. pneumoniae may be a harmless commensal or cause noninvasive respiratory tract infection (in COPD or bronchiectasis) or produce severe invasive disease
with bacteraemia.
MICROBIOLOGY
The prevalence of antibiotic resistant S. pneumoniae has increased and in some countries very high
rates of resistance to penicillin, macrolides and tetracyclines limit the treatment options. Penicillin
resistance is due to modifications to penicillin binding proteins not by the production of a
b-lactamase and, therefore, amoxicillinclavulanate is ineffective.
Moraxella catarrhalis
M. catarrhalis is a Gram-negative diplococcus that was previously named Branhamella or Neisseria
catarrhalis. Like NTHi it is a common commensal organism in the upper respiratory tract and can
cause otitis media or sinusitis. It was not reported in studies of non-CF bronchiectasis in the 1960s
as it was considered an oral contaminant rather than a PPM. However, it can be cultured in
significant numbers from sputum or PSB in up to 27% of patients with non-CF bronchiectasis [7].
It is also considered a significant pathogen in COPD but is only rarely isolated in CF.
A longitudinal study of M. catarrhalis in 29 patients with non-CF bronchiectasis found that patients
were colonised with a variety of strains with average colonisation duration of 2.3 months for each
strain. No association between strain acquisition and exacerbation was found and as M. catarrhalis
was often in mixed culture with other PPMs (H. influenzae or S. pneumoniae), it was difficult to
determine whether it had an independent pathogenic role [111]. In a study of 50 patients with
COPD, the average time from acquisition to clearance of a new strain of M. catarrhalis was 1 month
and re-infection with the same strain was rare, suggesting that there was an effective immune
response. Of the new acquisitions, 47% were associated with an exacerbation [112]. Acquisition of
M. catarrhalis led to an increase in airway inflammation, characterised by a rise in sputum neutrophil
elastase, interleukin (IL)-8, tumour necrosis factor (TNF)-a and a reduction in secretory leukocyte
protease inhibitor (SLPI) [113].
Putative virulence factors of M. catarrhalis include several outer membrane proteins plus LOS and
these affect cell adhesion, epithelial cell invasion, serum resistance and biofilm formation [114].
More work is needed to understand the pathogenesis of infection in both COPD and non-CF
bronchiectasis.
78
More than 90% of M. catarrhalis produce a b-lactamase (BRO-1 or BRO-2) and are resistant to
ampicillin. Acquired resistance to other antibiotics is rare with most remaining susceptible to
macrolides, tetracyclines, amoxicillin-clavulanic acid and quinolones [115].
Staphylococcus aureus
S. aureus is a Gram-positive coccus found in clusters that may be part of the normal flora in the
anterior nares, throat and on moist skin sites such as groin and axilla. Infection is characterised
by abscess formation, particularly in skin and soft tissues. It is a rare cause of respiratory tract
infection, but can cause severe pneumonia after influenza. It is a common cause of early
infection in CF but is less common in non-CF bronchiectasis where its presence may indicate
undiagnosed CF [10]. There is also an association of S. aureus with ABPA in non-CF
bronchiectasis [116].
The ability of S. aureus to rapidly adapt and persist in the lung may be a result of genomic
instability due to mobilisation of bacteriophages. Isolates from the anterior nares of CF patients
had a higher frequency of genomic alterations than those from healthy controls [120]. A higher
proportion of hypermutable strains of S. aureus were found in CF patients when compared with
isolates from bacteraemia or other respiratory infections. As with other species with high mutation
rates, many of these had defects in mutS [121].
Meticillin resistant S. aureus (MRSA) are resistant to all penicillins, cephalosporins and penems
and are often also resistant to other classes of antibiotics (macrolides, fluoroquinolones and
aminoglycosides). They can be difficult to treat, partly because oral options are limited but
also because the active parenteral options (glycopeptides) may be less effective compared
with the use of a b-lactam antibiotic to treat a susceptible isolate. It may be difficult to clear
MRSA carriage from patients with bronchiectasis, but there is data from CF that shows
that a combination of systemic treatment with skin antisepsis and inhaled antibiotics may be
effective [122].
S. aureus produces a range of exotoxins that can cause tissue damage. It is also thought to form
biofilms on prosthetic devices and thereby evade the host response and resist antimicrobial
therapy [117]. Biofilm-like aggregates of S. aureus surrounded with the polysaccharide poly-Nacetyl-glucosamine have been observed in anaerobic conditions in CF mucus and can resist
nonoxidative killing [118]. Persistence of S. aureus in CF and prosthetic infections has also been
related to the presence of small colony variants. These tiny colonies are difficult to identify in vitro.
They are associated with treatment with trimethoprim/sulphamethoxazole or aminoglycosides,
are more antibiotic resistant than the typical forms in the same sputum and may survive within
host cells [119].
Burkholderia spp. and other non-fermenters

Burkholderia spp are plant pathogens and are a major cause of morbidity and mortality in CF but
are rarely encountered in other conditions. In spite of the frequent presence of these bacteria in the
environment, and their propensity for spread between CF patients, there are only two case reports
of infection in non-CF bronchiectasis, one with Burkholderia cepacia complex (not speciated) and
another with Burkholderia gladioli [123, 124].
79
A wide variety of other nonfermentative Gram-negative bacilli can occasionally act as opportunistic
pathogens in the human lung. Species of the genera Achromobacter, Stenotrophomonas, Ralstonia,
Pandoraea and Inquilinus can cause infection in the CF lung, and S. maltophilia and Achromobacter
(previously Alkaligenes) xylosoxidans have been reported in non-CF bronchiectasis (table 1). Many
are both intrinsically resistant to some antibiotics and easily acquire resistance. They can be difficult
to identify in the laboratory and molecular methods are recommended to ensure accurate
identification [101]. In particular it is important to differentiate these organisms from the
Burkholderia spp. because of the need to prevent cross infection. There is too little experience with
these microorganisms to comment on their propensity for colonisation, infection, or role in
exacerbation of non-CF bronchiectasis.
Anaerobes and other bacteria considered normal upper

respiratory tract flora
Sputum may contain microorganisms other than the PPM. These have been considered either
contaminants from the upper respiratory tract or harmless commensals colonising the sputum.
This assumption has been challenged following studies using both conventional culture methods
and culture-independent techniques.
Sputum is not routinely cultured for anaerobes partly because they are present in large numbers in
saliva and can easily contaminate expectorated sputum, but also because some are very difficult to
culture. Following the observation of a rapid drop in oxygen partial pressure just below the surface
of a CF sputum plug, investigators began to look for anaerobes in the sputum from CF and nonCF bronchiectasis [125]. Obligate anaerobes in particular Prevotella spp. were found in significant
numbers, far more than would be expected from oral contamination [126128]. Their significance
in disease has been questioned as high numbers of bacteria were found in a stable CF patient in
one study, and the numbers of anaerobes remained constant during successful treatment of a
clinical exacerbation [129].
MICROBIOLOGY
It has been proposed that members of the Streptococcus milleri group may have a role in chronic
lung infection. One study followed the changes in the microbial flora during and between
pulmonary exacerbations of CF using both culture and culture-independent methods. The group
identified members of the S. milleri group as of potential importance in exacerbations both in CF
and in two patients with non-CF bronchiectasis [130].
Following an observation that a range of upper respiratory tract flora were seen in large numbers
in sputum from CF patients, a Staphylococcus sp. (not S. aureus) and a viridans-type Streptococcus
sp. were further studied. While not intrinsically pathogenic, they were able to enhance the
virulence of P. aeruginosa in an animal model and increase the expression of certain virulence
genes of P. aeruginosa in vitro. This could be reproduced using an inter-species QS molecule, Auto
Inducer-2 (AI-2) [131]. Of interest, the oral anaerobe Prevotella also produces AI-2 [127]. The
complex pattern of interaction between microorganisms in ecosystems other than the lung has
been described and it is known that microorganisms can enhance or inhibit growth of other cohabitants [132]. The studies in CF show that interactions may also enhance pathogenicity [133].
The CF lung, therefore, may contain a mixture of microorganisms that includes those that are
directly pathogenic, those that behave as commensals and those that are not directly pathogenic
but may increase the virulence of other organisms. Although this has not been studied in non-CF
bronchiectasis, microorganisms other than PPMs are regularly observed in sputum cultures in
combination with PPMs and further work on these potential interactions is needed.
Culture-independent studies of microbial flora in the lung
80
There have been attempts to describe the composition and diversity of the microbes in the lung
irrespective of the ability to culture individual microorganisms. One approach is to analyse the
gene encoding 16S rRNA. This is present in all true bacteria and the sequence variation is sufficient
to identify most genera and many species. Genetic material can be extracted from a clinical sample,
and the 16S rRNA gene amplified by PCR. The product may be analysed looking at terminal
restriction fragment length polymorphisms (TRFLP). This compares the size of the terminal
fragment of rRNA after cutting with a restriction enzyme; the length of the fragment being
characteristic of certain species. Alternately the PCR product can be cloned, sequenced and
compared with databases containing sequence data from a wide range of microorganisms. These
methods and other variations have been applied to patients with CF and non-CF bronchiectasis to
describe the diversity of microorganisms, and have revealed species not previously found in
respiratory samples using traditional culture methods [12, 134136]. While the presence of nucleic
acid does not necessarily indicate the presence of viable organisms, a comparison of RT-TRFLP
with TRFLP showed that a high proportion of the bacterial species detected in CF sputum were
metabolically active [137].
There have been major technical advances facilitated by the development of next generation
sequencers plus developments in bioinformatics. These have allowed direct analysis of amplified
DNA without the cloning step, and greater depth of sequencing of 16S rRNA DNA [138, 139]. An
alternative approach is to attempt whole genome sequencing directly from the clinical sample [140].
This could include analysis of nucleic acid from eukaryotes and viruses in sputum as well as bacteria
[141]. Such techniques can provide an enormous amount of information that is a great challenge to
process. However, they offer the potential for a far more sophisticated analysis of the genetic
variability found in single species and the variety of microorganisms in chronic lung infection.
Respiratory viruses
The role of viruses in non-CF bronchiectasis is not known and remains an important area for
future research. Some data exists that viral infections in childhood may predispose to the
development of bronchiectasis in later life [142], whether it is through the development of
bronchiolitis, disruption of small airway associated innate/adaptive immunity, damage of airway
epithelia or compromise of mucociliary clearance, it is unclear.
Viral infections in asthma, COPD and CF

Viral exacerbation of asthma has been well published. In a study by JOHNSTON et al [143] using
PCR and viral culture, viruses were detected in 80% of episodes of wheeze or reduced peak
expiratory flow in children aged 911 years with asthma. Rhinovirus accounted for 61% of the
viruses detected, coronavirus 16%, influenza 9%, parainfluenza 9% and respiratory syncytial virus
(RSV) 5%. Similarly, NICHOLSON et al. [144] found that respiratory viruses accounted for 44% of
asthma exacerbations in adults. Respiratory viruses were also present in most patients hospitalised
for life-threatening asthma and acute not life-threatening asthma [145].
The application of molecular diagnostic methods has improved the understanding of viral
epidemiology. Respiratory viruses may induce asthma exacerbations via direct effects on the
airway epithelium as well as through a systemic immune reaction.
What is also unclear is the role that viral infection plays in triggering infective exacerbations and
progressive lung damage in patients with non-CF bronchiectasis where no studies have to date
been carried out. Therefore, only cautiously can parallels be drawn from studies examining the
role of viruses in asthma, COPD and CF.
Rhinovirus is the most common respiratory virus and represents two-thirds of all upper respiratory
tract infections. It also accounts for 50% of asthma exacerbations in children [146]. Traditionally,
rhinovirus is thought to infect the upper respiratory epithelium. However, rhinovirus is also capable
of replicating in the lower airway cells during experimental infection [147]. PAPADOPOULOS et al. [148]
showed that both rhinovirus genomic material and replicative strand RNA were detectable in
bronchial biopsies using in situ hybridisation in 50% of adult volunteers subjected to an experimental
rhinovirus upper respiratory infection.
81
The mechanism by which viruses cause bronchoconstriction is not fully understood, but it is likely
to involve cytokine production in response to viral replication in the lower airways, which includes
upregulating the expression of a range of proinflammatory mediators. The proinflammatory
cytokine IL-1b is detectable in experimental infected individuals. IL-8, a key mediator in
neutrophil-mediated acute inflammation, is also detected in naturally occurring infections
correlating with neutrophilia in blood and nasal samples in children with virally precipated asthma
or experimental infection [149]. Other mediators induced by rhinovirus infections include
neutrophil-activating peptide (which induces neutrophil migration), eotaxin and RANTES
(regulated on activation, T-cell expressed and secreted), IL-16 and monocyte chemoattractant
protein (MCP-1). All of these can lead to enhance airway inflammation.
RSV was detected in only 5% of asthma episodes in the study by JOHNSTON [143]. However, it is
known to be a potent cause of wheezing, particularly in infancy. It has been shown that Gglycoprotein of RSV appears to stimulate T-helper cell (Th) type 2 immune response in the upper
airway, whether or not if the infant is atopic [150]. Th2 cytokine patterns are known to be associated
with viral immunopathology and allergic-type responses, in contrast to Th1 cytokine patterns, which
are classically associated with viral elimination. Interestingly, the nasal cytokine responses to other
viruses are of the predominant Th1 type (except RSV). This could explain the tendency for RSV to
cause wheezing, but not the association between other respiratory viruses and wheezing.
MICROBIOLOGY
Influenza A infection induces large amounts of intrapulmonary IFN-c and enhances both later
allergen specific asthma and dual Th1/Th2 responses [151]. TERAN et al. [152] also demonstarted
that the eosinophil product, major basic protein (MBP), and RANTES increased with viral
infections, and there was a correlation in the concentration of RANTES with clinical symptoms. In
addition, epithelial cells infected with influenza in vitro were associated with an increase in eotaxin
[153]. Eotaxin can in turn lead to an exaggerated inflammatory response by being an agonist for
chemokine receptor 3, which can be found on eosinophils, T-cells and basophils. These are all key
factors in asthma exacerbation.
Patients with asthma are no more susceptible to upper respiratory tract rhinovirus infections than
healthy people, but suffer from more severe consequences of the lower respiratory tract infection.
Recent epidemiological studies suggest that viruses provoke asthma attacks by additive or
synergistic interactions with allergen exposure or with air pollution. An impaired antiviral
immunity to a rhinovirus may lead to impaired viral clearance and hence prolonged symptoms.
Indirect prevention strategies focus on the reduction of overall airway inflammation to reduce the
severity of the host response to respiratory viral infections. There is a lack of specific antiviral
strategies in the prevention or reduction of viral-triggered asthma exacerbations. Recent advances
in the understanding of the epidemiology and immunopathogenesis of respiratory viral infections
in asthma may provide opportunities or the identification of specific targets for antiviral agents
and strategies for management and prevention.
COPD is the fourth leading cause of mortality worldwide and is an important cause of global
burden of disease [154]. The disease is associated with intermittent exacerbations characterised by
acute deterioration in symptoms, lung function, and quality of life [155, 156]. Exacerbations have
major effects on health status and are associated with considerable morbidity and mortality that
can lead to hospital admission with high treatment costs [157].
Infectious agents are recognised as a major pathogenic factor in exacerbations. Bacteria have a role in
the pathogenesis [158, 159] and the exacerbations of COPD. However, bacteria are absent in about
50% of exacerbations and the frequency of isolation does not increase during exacerbation [160].
82
Early studies looking at respiratory viruses and COPD have stated a 20% detection rate in COPD
exacerbations [161, 162]. However, these studies were limited by using less sensitive methods in
viral detection. SEEMUNGAL et al. [163] detected respiratory viruses from nasal samples and blood
of patients with COPD using a combination of culture, serology and PCR. They showed that 64%
of COPD exacerbations were associated with a cold occurring up to 18 days before exacerbation.
In total, there were 168 episodes of COPD exacerbation in 53 patients and 77 viruses (39 were
rhinoviruses) were detected. Viral exacerbations were associated with frequent exacerbatons,
increased symptoms, a longer median symptom recovery period (up to 13 days) and a tendency
towards higher plasma fibrinogen and serum IL-6 levels. RSV has also been shown to be an
important virus in COPD exacerbations and was detectable in 11.4% of patients admitted into
hospital [164]. Patients with stable COPD may carry respiratory viruses. Non-RSV respiratory
viruses were detected in 11 (16%), and RSV in 16 (23.5%) out of 68 stable COPD patients, with
RSV detection being associated with higher inflammatory marker levels [161, 164].
Early studies looking at respiratory viruses in CF relied on repeated serological testing, either alone
[165], or in combination with viral cultures for viral detection [166170]. These methods are
relatively insensitive and more recent studies have utilised molecular based methodologies [171175].
All these studies produced different results in terms of prevalence of respiratory viruses in CF, these
differences could be due to the different methodologies utilised. It is also likely that there are
differences in the populations studied, as the prognosis for CF has improved with each successive
birth cohort.
More recent studies suggest no difference in the frequency of either upper respiratory tract illness
episodes [166] or proven respiratory viral infections [168] between children with CF and healthy
controls; however, children with CF have significantly more episodes of lower airway symptoms
than controls [166, 168]. RAMSEY et al. [168] prospectively compared the incidence and effect of
viral infections on pulmonary function and clinical scores in 15 school children with CF aged
521 years and their unaffected siblings. Over a 2-year period, samples were taken at regular
2-month intervals and during acute respiratory illnesses for pharyngeal culture and serology for
respiratory viruses. There were a total of 68 acute respiratory illness (ARI) episodes that occurred
in the patients with CF, in 19 of these episodes an associated virus identified. A total of 49 infective
agents were identified either during ARIs or at routine testing in the patients with CF; 14 were
identified on viral isolation (rhinovirus on 11 occasions), whilst 35 were isolated on
seroconversion (parainfluenza virus on 12, RSV on nine and Mycoplasma pneumoniae on six
occasions). There was no significant difference in the rate of viral infections between the patients
with CF and their sibling controls, as measured either by culture or serology. The rate of viral
infections was higher in younger children (both CF and controls), and the rate of decline in
pulmonary function was greater in the younger children with CF with more viral infections. At the
time of an ARI, the virus isolation and seroconversion (four-fold increase in titres) rates were 8.8%
and 19.1%, respectively, in children with CF compared with 15% and 15%, respectively, for the
siblings not affected. In contrast the rates for virus isolation and seroconversion at routine
2 monthly visits were 5.6% and 16.2%, respectively, for children with CF and 7.7% and 20.2%,
respectively, for the siblings not affected.
It has now been 25 years since WANG et al. [169] described the relationship between respiratory
viral infections and the deterioration in clinical status in CF patients. Viruses were identified
through repeated serology and nasal lavages for viral isolation in 49 patients with CF (mean age
13.7 years) over a 2-year period. Although the CF patients had more respiratory illnesses than the
sibling controls (3.7 per year versus 1.7 per year), there were no differences in virus identification
rates (1.7 per year). The rate of proven virus infection was significantly correlated with the decline
in forced vital capacity (FVC) and FEV1, Shwachman score, and frequency and duration of
hospitalisation.
Similarly HIATT et al. [166] assessed respiratory viral infections over three winters in 22 infants
less than 2 years of age with CF (30 patient seasons) and 27 age matched controls (28 patient
seasons). The average number of acute respiratory illness per winter was the same in the control
and the CF groups (5.0 versus 5.0). However, only four of the 28 control infants had lower
respiratory tract symptoms in association with the respiratory tract illness, compared with 13 out
of the 30 infants with CF (OR -4.6, 95% CI 1.316.5; p-value ,0.05). Seven of the infants with
CF cultured RSV, of whom three required hospitalisation. In contrast, none of the controls
required hospitalisation. Pulmonary function measured by rapid chest compression technique
was significantly reduced in the infants with CF after the winter months and was associated with
two interactions; RSV infection with lower respiratory tract infection and male sex with lower
respiratory tract infection.
83
From previous reports, two viral agents appear to have the greatest effect on respiratory status in
CF, namely RSV and influenza, possibly because the uses of viral culture and serology have
underestimated the effects of rhinovirus (due to the vast amount of serotypes). In younger
children, RSV is a major pathogen resulting in an increased rate of subsequent hospitalisation.
ABMAN et al. [176] prospectively followed up 48 children with CF diagnosed through newborn
screening and documented the effect of RSV infection. 18 of the infants were admitted into
hospital a total of 30 times over a mean follow-up period of 28 months (range 559 years). In
seven of these infants RSV was isolated, and their clinical course was severe with three requiring
mechanical ventilation and five necessitating chronic oxygen therapy. Over the next 2 years these
infants had significantly more frequent respiratory symptoms and lower chest radiograph scores
than non-RSV identified infants. In another prospective study of repeated BAL in 80 infants
identified through CF newborn screening over a 5-year period, 31 infants were hospitalised for a
respiratory exacerbation, 16 (52%) of which had a respiratory virus identified with the most
common being RSV (n57).
MICROBIOLOGY
In older children and adults with CF, influenza seems to have the greatest effect. PRIBBLE et al.
[167] assessed acute pulmonary exacerbation isolates from 54 patients with CF. Over the year of
the study 80 exacerbations were identified, of which 21 episodes were associated with an identified
viral agent (influenza A: five episodes; influenza B: four episodes; RSV: three episodes) with most
agents identified by serology. Compared with other agents, infection with influenza was associated
with a more significant drop in pulmonary function (FEV1 decreased by 26% compared with 6%,
respectively). A retrospective study in older patients with chronic P. aeruginosa infection reported
an acute deterioration in clinical status in association with influenza A virusl infection [177].
COLLINSON et al. [171] followed 48 children with CF over a 15-month period using a combination
of viral culture and PCR for picornaviruses alone [178]. 38 children completed the study and there
were 147 symptomatic upper respiratory tract infections (2.7 episodes per child per year), with
samples available for 119 episodes. Picornaviruses were identified in 51 (43%) of these episodes, of
which 21 (18%) were rhinoviruses. In those children old enough to perform spirometry there were
significant drops in both FVC and FEV1 in association with upper respiratory tract infection, with
little difference in the severity of drop whether a picornavirus was identified or not. Maximal mean
drop in FEV1 was 16.5%, at 14 days after onset of symptoms, but a deficit of 10.3% persisted at
2124 days. Those with more upper respiratory tract infections appeared to have a greater change
in total Shwachman and CrispinNorman scores over the study. Six children isolated a
P. aeruginosa for the first time during the study, five at the time of a upper respiratory tract
infection and only one was asymptomatic at the time of first isolation. The data from this study
has to be handled with care as the term upper respiratory tract illness (URTI) did not necessarily
imply a positive viral isolation.
PUNCH et al. [173] used a multiplex RT-PCR assay combined with an enzyme-linked amplicon
hybridisation assay (ELAHA) for the identification of seven common respiratory viruses in the
sputum of 38 CF patients. 53 sputum samples were collected over two seasons and 12 (23%)
samples from 12 patients were positive for a respiratory virus (influenza B n54, parainfluenza 1
n53, influenza A n53, RSV n52). There were no statistical associations between virus status and
demographics, clinical variables or isolation rates for P. aeruginosa, S. aureus or Aspergillus
fumigatus.
OLESEN et al. [174] obtained sputum/laryngeal aspirated from children with CF over a 12-month
period in outpatient clinics. They achieved a viral detection rate of 16%, with rhinovirus being the
most prevalent virus. However, this virus did not seem to have any devastating impact on lung
function. However, the other viruses detected were associated with significant reduction in lung
function. The authors failed to show a positive correlation between respiratory viruses and
bacterial infections in their studied population, as the type or frequency of bacterial infection
during or after viral infections were not altered. They also demonstrated that clinical viral
symptoms had a very poor predictive value (0.39) for a positive viral test.
84
WAT et al. [179] utilised real-time nucleic acid sequence-based amplification (NASBA) to
examine the role of respiratory viruses in CF. They achieved a rate of 46% for respiratory viruses in
their paediatric CF cohort during reported episodes of respiratory illness. The results compare
favourably with previous studies, this may be due to earlier studies relying heavily on repeated
serological testing either alone [165] or in combination with viral isolation [166170]. These traditional
methods are relatively insensitive and once again may have underestimated the prevalence of
viruses in CF.
Detection of respiratory viruses

The principal laboratory methods utilised for the diagnosis of respiratory viruses, rely upon the
detection of the virus in respiratory secretions and therefore an important factor in respiratory
viral diagnosis is the necessity for the submission of an appropriate sample for testing. Inadequate
or improper specimen collection and transport account for the largest source of error in the
accuracy of viral detection results [180]. Nasal swabs, nasopharyngeal aspirates, nasal wash and
sputum specimens are generally considered as the specimens of choice for the detection of
respiratory viruses [173, 180183]. A prospective study by HEIKKINEN et al. [184] showed that the
sensitivity of nasal swabs was comparable to nasopharyngeal aspirates for the detection of all major
respiratory viruses by tissue culture, with the exception of RSV.
Molecular techniques have superseded many conventional methods utilised for respiratory viral
detection, such as viral culture and serology analysis, due to the rapid turn-around time for the
results. Molecular assays have particular advantages where the starting material available is
acellular (swab) or where surveillance samples have a low copy number of the viral target. The
rapid turn-around time of results allows diagnostic virology to have an impact on patient
management, thereby avoiding prescribing the inappropriate use of antibiotics and allowing the
correct prescription for anti-virals. It may also play an important role in infection control in the
hospital setting.
There is very little known about the interaction between respiratory viruses and bacteria in non-CF
bronchiectasis but a number of publications suggest that respiratory viruses may precipitate
secondary bacterial infection in CF. In a 25-year retrospective review from the Danish CF clinic,
the most likely first isolation of P. aeruginosa was found to be occur between October and March
[185], coinciding with the peak of the RSV season. This observation implies a causal relationship
between respiratory viral and bacterial infection.
The first bacterial isolation of a given organism in CF has also been shown to often follow a viral
infection. In the 17-month prospective study reported by COLLINSON et al. [171], five of the six first
isolations of P. aeruginosa were made during the symptomatic phase of an upper respiratory tract
infection or 3 weeks thereafter. In contrast only one of the six initial infections with P. aeruginosa
was identified during the asymptomatic period. Similarly, H. influenzae was recovered for the first
time from three children within 3 weeks of an upper respiratory tract infection and the one new
S. aureus infection was identified immediately following a viral infection.
Interaction between bacteria and viruses
ARMSTRONG et al. [170] have reported that 50% of CF respiratory exacerbations requiring
hospitalisation are associated with the isolation of a respiratory virus. In their prospective study of
repeated BAL in infants over a 5-year period, a respiratory virus was identified in 52% of the
infants hospitalised for a respiratory exacerbation, most commonly RSV. 11 of the 31 hospitalised
infants (35%) acquired P. aeruginosa in the subsequent 1260-month follow-up period, compared
with three out of 49 (6%) non-hospitalised infants (relative risk 5.8).
85
Respiratory viruses can disrupt the airway epithelium and precipitate bacterial adherence. For
example influenza A infection results in epithelial shedding to basement membrane with submucosal
oedema and neutrophil infiltrate [186], while both influenza and adenovirus have a cytopathic effect
on cultured nasal epithelium leading to the destruction of the cell monolayer [187]. This epithelial
damage results in an increase in the permeability of the mucosal layer [188, 189], possibly facilitating
the bacterial adherence. Bacteria can also utilise viral glycoproteins and other virus-induced receptors
on host cell membranes as bacterial receptors, in order to adhere to virus infected cells [190, 191].
The lower respiratory tract is protected by local mucociliary mechanisms that involve the
integration of the ciliated epithelium, periciliary fluid and mucus. Mucus acts as a physical and
chemical barrier onto which particles and organisms adhere. Cilia lining the respiratory tract
propel the overlying mucus to the oropharynx where it is either swallowed or expectorated.
Influenza viral infection has been shown to lead to the loss of cilial beat, and shedding of the
columnar epithelial cells generally within 48 hours of infection [192]. PITTET et al. [193] showed
that a prior influenza infection of tracheal cells in vivo does not increase the initial number of
pneumococci found during the first hour of infection, but it does significantly reduce mucociliary
velocity, and thereby reduces pneumococcal clearance during the first 2 hours after pneumococcal
infection at both 3 and 6 days after an influenza infection. The defects in pneumococcal clearance
were greatest 6 days after an influenza infection. Changes to the tracheal epithelium induced by
influenza virus may increase susceptibility to a secondary S. pneumoniae infection by increasing
pneumococcal adherence to the tracheal epithelium and/or decreasing the clearance of
S. pneumoniae via the mucociliary escalator of the trachea, and thus increasing the risk of
secondary bacterial infection.
MICROBIOLOGY
DE VRANKRIJKER et al. [194] showed that mice that were co-infected with RSV and P. aeruginosa had
a 2,000 times higher CFU count of P. aeruginosa in the lung homogenates compared with mice
that were infected with P. aeruginosa alone. Co-infected mice also had more severe lung function
changes. These results suggest that RSV can facilitate the initiation of acute P. aeruginosa infection.
RSV has also been shown to increase adherence of NTHi and S. pneumoniae to human respiratory
epithelial cells in vitro [195]. This increase adherence could be explained by an upregulation of cell
surface receptors for bacteria, such as intercellular adhesion molecule-1 (ICAM-1), carcinoembryonic adhesion molecule 1 (CEACAM1) and platelet activating factor receptor (PAFr). Another
study also showed that NTHi and S. pneumoniae bind to both free RSV virions and epithelial cells
transfected with cell membrane-bound G protein, but not to secreted G protein. Pre-incubation with
specific anti-G antibody significantly reduce bacterial adhesion to G protein-transfected cells [196].
STARK et al. [197] showed that mice that were exposed to RSV had significantly decreased
S. pneumoniae, S. aureus or P. aeruginosa clearance between 1 to 7 days after RSV exposure. Mice
that were exposed to both RSV and bacteria had a higher production of neutrophils induced
peroxide, but less production of myeloperoxidase compared with mice that were exposed to
S. pneumoniae alone. This suggests that functional changes in the recruited neutrophils may
contribute to the decreased bacterial clearance.
More recently, CHATTORAJ et al. [198] demonstrated that acute infection of primary CF airway
epithelial cells with rhinovirus liberates planktonic bacteria from biofilm. Planktonic bacteria,
which are more proinflammatory than their biofilm counterparts, stimulate increased chemokine
responses in CF airway epithelial cells which, in turn, may contribute to the pathogenesis of CF
exacerbations.
Collectively, these findings suggest that respiratory viruses may lead to epithelial disruption,
destruction of mucociliary escalator, increased cytokine production, neutrophil influx and
increased neutrophil induced peroxide release, indirectly facilitating bacterial infection of the
airway. Whether these are the mechanisms for infective exacerbations in the context of non-CF
bronchiectasis remains to be seen.
Prevention and treatment of infection with respiratory viruses
86
Influenza associated death is between 13,000 to 20,000 incidents per year throughout the winter
months in the UK [199], though some of the deaths may be attributed to RSV. Influenza vaccines are
the only commercially available vaccines against respiratory viruses. Recent vaccines contain
antigens of two influenza A subtypes, strains of the currently circulating H3N2 and H1N1 (Swine
flu) subtypes, and one influenza B virus. The waning of vaccine-induced immunity over time
requires annual re-immunisation even if the vaccine antigens are unchanged. Influenza vaccination
is recommended to those with chronic respiratory diseases including non-CF bronchiectasis. Despite
this recommendation, there is neither evidence for, nor against, routine annual influenza vaccination
for children and adults with non-CF bronchiectasis from a recent Cochrane review [200].
Although there is no licensed RSV vaccine to date, prophylaxis using a humanised mouse
monoclonal antibody, Palizivumab, which has been shown to reduce the rate of RSV associated
hospitalisation in premature infants [201].
Amantadine has been the conventional anti-viral against of influenza. Its mode of action involves
interfering with viral protein M2, thereby inhibiting the replication of influenza viruses by
interfering with the uncoating of the virus inside the cell. However, it is strain specific as it is only
effective against influenza A and has common side-effects such as insomnia, poor concentration
and irritability. Amantadine has now been almost completely replaced by neuraminidase
inhibitors (NI), except for some NI-resistant influenza.
NIs such as Zanamivir and Oseltamivir are licensed for the treatment of influenza A and B, avian flu
(H5N1) and Swine flu (H1N1). They work by inhibiting the function of the viral neuraminidase
protein, thus preventing the release of the progeny influenza virus from infected host cells, a process
that prevents infection of new host cells and thereby halts the spread of the infection in the
respiratory. Early initiation of these therapies within 48 hours from the onset of symptoms can
reduce the duration of common cold symptoms by 12 days [202, 203]. Zanamivir has a poor oral
bioavailability and intranasal application has been shown to be effective in treating experimental
influenza infection, by the reduction in symptoms caused, virus shedding and the development of
otitis media [204]. A phase III study is currently underway that looks at the efficacy of intravenous
Zanamivir preparation. However, compassionate use of i.v. Zanamivir could be considered to treat
critically ill adults and children having a life-threatening condition, due to suspected or confirmed
pandemic Influenza A (H1N1) infection or infection due to seasonal Influenza A or B virus, who are
not responding to oral or inhaled neuraminidase inhibitors. A recent systematic review metaanalysis showed that neuraminidase inhibitors only have modest effectiveness (Oseltamivir and
Zanamivir 61 and 62%, respectively) against flu-like symptoms in previously healthy subjects [205].
Ribavarin
Ribavarin, a synthetic guanosine nucleoside that has a broad spectrum of antiviral activity, is
approved treatment for lower respiratory tract disease caused by RSV [206]. It can be incorporated
into RNA as a base analog of either adenine or guanine, it pairs equally well with either uracil or
cytosine, inducing mutations in RNA-dependent replication in RNA viruses. Controlled studies
also show that the use of ribavarin is effective in reducing the clinical severity score, duration of
mechanical ventilation, supplemental oxygen use and days of hospitalisation [207].
Neuraminidase inhibitors
Macrolides
Although rhinovirus is the major cause of colds, its vast amount of serotypes has made
development of anti-virals against it problematic. 90% of rhinovirus serotypes gain entry into
epithelial cells using ICAM-1 cellular receptors and blockade of these receptors in experimental
studies have shown reduced infection severity [208]. Macrolide antibiotics, bifilomycin A1 and
erythromycin, have been shown to inhibit ICAM-1 epithelial expression and hypothesis about
their potential as anti-virals have yet to be proven, more clinical proof is required [209].
Other anti-virals
87
Recently there has been a report regarding the use of an anti-rhinoviral agent known as Plecoranil.
This anti-viral binds to a hydrophobic pocket of the VP1, the major shell protein for the
rhinoviruses, thereby preventing the virus from exposing its RNA and also prevents the virus from
attaching itself to the host cell [210]. The rhinovirus 3C protease inhibitors, Ruprintrivir [211] and
soluble recombinant ICAM-1 Tremacamra [212], have shown promising results but they are
currently not widely available.
Conclusions
The role of bacteria and viruses in non-CF bronchiectasis is not presently fully understood.
Through necessity, evidence from studies in CF and COPD is used and applied to bronchiectasis.
More research using both conventional microbiological techniques as well as newer molecular
diagnostic approaches, is urgently required to address a number of important questions in non-CF
bronchiectasis. 1) What is the cause of infective exacerbations? 2) What is the role of anaerobic
bacteria and how do normal commensal bacteria interact with pathogenic bacteria? 3) How can we
clear chronic infection? 4) What proportion of exacerbations is triggered by viral infection?
5) How do viruses influence bacterial behaviour in chronically infected airways?
A greater understanding of bacterial communal behaviour and their interaction with epithelial
cells and viruses will be critical in further developments in the management of non-CF
bronchiectasis.
MICROBIOLOGY
J.E. Foweraker received a consultancy fee from Novartis Pharma AG for advice on a submission to
the European Medicines Agency for licensing of Tobramycin inhaled powder and a consultancy
fee from Gilead Sciences International Ltd for advice on an application to European Medicines
Agency for licensing of Aztreonam lysine.
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Chapter 7
Allergic
bronchopulmonary
aspergillosis and other
fungal diseases
B. Hilvering*, J. Speirs#, C.K. van der Ent# and J.M. Beekman#
Fungal spores are ubiquitously present in the air. Inhalation of

these spores by humans causes disease in susceptible patients;
most prevalent are invasive aspergillosis and allergic bronchopulmonary aspergillosis (ABPA). This chapter provides an
overview of the pathogenecity, clinical appearance, diagnosis
and treatment of ABPA.
ABPA is a hypersensitivity lung disease limited to patients
with asthma or cystic fibrosis (CF) with a prevalence of 12%
and 215%, respectively within these groups. It is triggered
by the exposure to Aspergillus fumigatus. Although it is
not clear what initiates this hypersensitivity response, polymorphisms in genes that drive innate and adaptive immune
mechanisms as well as loss-of-function mutations in the CF
transmembrane conductance regulator (CFTR) are associated
with ABPA development. The chronic inflammatory conditions
in ABPA eventually result in airway remodelling and functional
impairment.
The diagnosis of ABPA is based both on clinical symptoms,
laboratory testing and diagnostic imaging. Treatment consists
of a two tiered approach, glucocorticoids to control immunological activity and antifungal agents to suppress fungal load.
Keywords: ABPA, aspergillosis, Aspergillus fumigatus, CFTR,
hypersensitivity
*Dept of Pulmonology, University

Medical Center Utrecht, and
#
Dept of Paediatric Pulmonology,
Wilhelmina Childrens Hospital,
University Medical Center Utrecht,
Utrecht, The Netherlands.
Correspondence: C.K. van der Ent,
Dept of Paediatric Pulmonology,
University Medical Center Utrecht,
Lundlaan 6, 3584 EA Utrecht, the
Netherlands, Email
K.vanderEnt@umcutrecht.nl
B. HILVERING ET AL.
Summary
Eur Respir Mon 2011. 52, 97114.

Copyright ERS 2011.
ISSN: 1025-448x.
DOI: 10.1183/1025448x.10003710
97
umans continuously inhale fungal spores. Only some fungal species cause invasive, allergic or
toxic disease, most prevalent of which are invasive aspergillosis in immunocompromised
patients and allergic bronchopulmonary aspergillosis (ABPA) in asthmatics and patients with
cystic fibrosis (CF). This chapter provides an overview of the current knowledge concerning the
role of fungi in the pathogenesis of bronchiectasis and describes the clinical appearance,
immunological background, diagnosis and treatment of ABPA.
Centrally located, cylindrical bronchiectasis is a major characteristic of ABPA; however, 525% of
patients with ABPA are diagnosed without the presence of bronchiectasis [13]. ABPA is
predominantly observed in asthmatic and CF patients. Its prevalence among asthmatics and CF
patients is 12% [4] and 215% [511], respectively.
ABPA AND FUNGAL DISEASES
In patients with ABPA, Aspergillus fumigatus antigens provoke a strong allergic reaction,
characterised by the dominance of T-helper cell (Th) type 2 mediated responses, high numbers of
eosinophils, a high total immunoglobulin (Ig)E level and high levels of Aspergillus specific IgE and
IgG levels. Although it is not clear what initiates this hypersensitivity response, polymorphisms in
genes that drive innate and adaptive immune mechanisms as well as loss-of-function mutations in
the CF transmembrane conductance regulator (CFTR) are associated with ABPA development.
The chronic inflammatory conditions in ABPA eventually result in airway remodelling, which is
characterised by mucoid impaction, bronchial inflammation and obstruction. When left untreated
fibrosis bronchiectasis and eventually respiratory insufficiency are the final pathophysiological
stages in this remodelling process.
The diagnosis of ABPA is complex and difficult to discriminate from chronic inflammatory
episodes already observed in patients with asthma or CF. It has been estimated that on average
10 years elapse between the onset of ABPA and its eventual diagnosis [12]. Criteria for the
diagnosis ABPA in asthmatics include a history of asthma with immediate skin reactivity, elevated
serum IgE, precipitating antibodies against Aspergillus sp., peripheral blood eosinophilia, current
or previous infiltrates on chest radiographs and central bronchiectasis on high-resolution
computed tomography (HRCT) scans. CF patients are chronically exposed to multiple microorganisms and discrimination of ABPA is difficult in these patients. The main diagnostic criteria
are similar to those described above, except for higher total IgE levels.
ABPA treatment aims at reducing the fungal burden and dampening the immune response.
Antifungal agents are effective in reducing IgE levels and improving clinical outcome within a 16week period; however, their long-term clinical effects are unknown [13]. The role of antifungal
agents in the eradication of A. fumigatus hyphae is limited. Immune suppression is mainly
achieved by oral glucocorticoid therapy that reduces the total serum IgE levels and correlates
with a reduction in symptoms and radiological findings. However, the long-term use of steroids
is associated with serious side-effects. Therapy that targets individual components of the
hypersensitivity reaction is being developed and tested. The identification of crucial immunological components and associated molecular targets is essential for the design of novel drugs.
Bronchiectasis due to other fungal disease is mainly limited to the immunocompromised host.
Only limited studies are available on the role of fungi in otherwise healthy subjects. Both groups
are briefly summarised in this chapter.
Figure 1 shows the structure and appearance of A. fumagatis under light microscopy.
History and epidemiology of ABPA

In 1952, HINSON et al. [14] provided the term ABPA for the description of three patients who
suffered from pulmonary eosinophilia in the UK, and in 1969 ABPA was first reported in the USA.
In 1971, immunoserological features were discovered that supported hypersensitive immune
reactivity as a disease mechanism in ABPA. From that time onwards the diagnostic possibilities
rapidly improved and in the early 1980s ABPA was reported throughout the world.
98
Still, the true population prevalence of ABPA remains highly speculative: ABPA was not
acknowledged by the World Health Organization (WHO) as a disease entity in their 2007
International Classification of Disease (ICD-10) [15] and the diagnostic criteria for ABPA vary
greatly within international medical societies. It has been generally assumed that there is an
estimated population ABPA prevalence of 12% in

asthmatics [16, 17]. Overviews on the prevalence of
ABPA show a spectre of 1% prevalence in the general
population of asthmatics to 38.6% in patients with
acute severe asthma [18].
In patients with CF the prevalence is estimated to be
115% [16, 19]. NOVEY [16] found an average of 7%
among a total of 1,096 patients, taken from eight
studies. Despite the differences in diagnostic criteria,
laboratory methodology, demographical and geographical features, the range of prevalence was narrow in
these studies ranging from 311%. MASTELLA et al.
[20], on behalf of the European Registry of Cystic
Fibrosis, reported data for 12,447 patients with CF
in nine European countries. The overall prevalence
among the European CF patients was found to be
7.8%, with a range of 2.1% in Sweden and 13.8% in
Belgium. Age was found to be an important factor; in
the group aged ,6 years the prevalence was 6% and a
stable 10% thereafter [20].
Figure 1. Light microscopy of Aspergillus

fumigatus hyphae. The stalk is called a
hypha, the end of the hypha is swollen and
small strings emerge from it called philiades.
Chains of conidia (seen as small blue balls)
emerge from the philiades. Reproduced
with permission from K. Makimura (Teikyo
University Institute of Medical Mycobiology,
Tokyo, Japan; personal communication)
and the Pathogenic Fungi Database (www.
pfdb.net/).
Bronchiectasis is a morphological disorder, defined as the irreversible dilatation of the cartilage

containing airways or bronchi. Approximately half of the patients with bronchiectasis is classified
as having idiopathic bronchiectasis. In 78% of patients with bronchiectasis, ABPA is the causative
factor [21, 22]. ABPA can be subclassified into three groups based upon radiological features
indicating the presence or absence of central bronchiectasis and other radiological features.
Approximately 7595% of ABPA patients display both centrally located, cylindrical bronchiectasis
(ABPA-CB) with or without other radiological features (ABPA-CB-ORF). The remaining 525%
of the patients with ABPA are diagnosed without the presence of bronchiectasis, in these patients
the diagnosis is based on seropositivity (ABPA-S) [13].
B. HILVERING ET AL.
Bronchiectasis and ABPA
The presence of central bronchiectasis is associated with disease severity. The small group of
patients with ABPA-S appear to suffer from a less aggressive form of the disease when compared
with ABPA-CB and ABPA-CB-ORF patients. Whether ABPA-S is able to progress into ABPA-CB
or whether it is a pathogenetically different form of the disease is unclear. In a 3-year prospective
cohort study in 11 patients, KUMAR and CHOPRA [23] described better lung function and a lower
number of exacerbations in the ABPA-S group compared with an ABPA-CB control group.
GREENBERGER et al. [24] included 28 patients in a 2-year prospective cohort study and found
different immunological parameters in the ABPA-S group compared with the ABPA-CB group.
The study found significantly lower serum specific anti-A. fumigatus IgG subclasses in patients
with ABPA-S, and a trend towards lower levels of total serum IgE and specific anti-Aspergillus IgE
and IgA [24]. The radiological differences between the groups are, therefore, also reflected by
clinical and immunological differences. The question remains whether early recognition and
treatment of ABPA-S can prevent progression into ABPA-CB [23].
Pathogenesis of ABPA
99
The pathophysiological mechanisms underlying the development of ABPA are still poorly
understood, but clearly share important immunological mechanisms with other hypersensitivity
diseases. ABPA primarily develops in patients with asthma or CF, and is caused by an Aspergillusdriven strong hypersensitivity response [25]. Immunological features include highly elevated levels
of total IgE and Aspergillus-specific IgE and IgG, increased eosinophil numbers, and a Th2-dominated
antigen-specific CD4+ T-cell response. Hypersensitivity to Aspergillus and colonisation by Aspergillus
appear to be required but are not sufficient to develop ABPA alone. Between 31 and 59% of CF
patients display sensitisation towards Aspergillus and up to 40% are colonised; however, only 110%
of CF patients develop ABPA [26]. It appears that unique characteristics within Aspergillus itself in
combination with patient-specific environmental and genetic factors facilitate the chronic
colonisation and development of a deteriorating immune response, which ultimately induces the
irreversible airway remodelling associated with fibrosis, pulmonary obstruction and bronchiectasis.
A. fumigatus virulence
Fungal spores (fig. 2) or conidia are ubiquitously present in our environment. A cubic meter of air
typically contains approximately 104105 conidia, predominantly of the Cladosporium and
Alternaria genera, and of a lesser amount Aspergillus and Penicillium. The genus Aspergillus consists
of 250 subspecies of which A. fumigatus is considered the most prevalent airborne fungal human
pathogen, its conidia are present at approximately 1100 m-3 air [27]. A. fumigatus causes life
threatening, invasive disease in immunocompromised patients and is associated with multiple
hypersensitivity responses including allergic asthma, hypersensitivity pneumonitis and ABPA [28].
Many molecular subtypes of A. fumigatus exist, 85% of analysed A. fumigatus in air samples were
unique; however, in general none of these subtypes were found to be selectively enriched in
patients suggesting that most subtypes are equally pathogenic [29, 30]. The development of novel
antifungal reagents may, however, select for some subtypes [31, 32]. The presence of specific
subtypes of A. fumigatus in ABPA remains unknown, but these may be prime candidates to study
ABPA-related disease mechanisms.
In recent years insights into the mechanisms by which A. fumigatus regulates its pathogenic
potential or virulence have progressed significantly. These mechanisms regulate the rapid growth
characteristics of A. fumigatus at 37uC (A. fumigatus conidia germinate within 45 hours on
nutrient rich media in vitro), the overall mechanical fitness of conidia to withstand environmental
pressure, and its capacity to extract nutrients of dead organic matter for growth. Selective
mechanisms have also co-evolved. These selective mechanisms directly impair the epithelial barrier
function and host immune defence, facilitating its infection.
The particularly small size of a A. fumigatus conidia range between 1 mm and 3 mm, thereby
facilitating its ability to be airborne and allowing it to reach the alveolar spaces upon inhalation.
The cell wall of A. fumigatus conidia consists of a thick
internal layer of structural polysaccharides enriched for
branched b(1,3)/(1,6) glucans linked to chitin as
observed in most fungi [33, 34]. Additional bonds to
this backbone are species specific, in the case of
A. fumigatus this core polysaccharide backbone is
further linked to galactomannan and linear b(1,3)/
(1,4)-glucans. This large polysaccharide complex is
embedded in a cement-like mixture consisting of a1,3glucan, galactomannan and polygalactosamine. A thin
hydrophobic protein layer, termed surface hydrophobin, is composed of cross-linked proteins (including
RodA) that form a regular pattern of rodlet structures
and melanin that confers pigment, which further
Figure 2. Low temperature scanning
shields and protects the polysaccharide shell.
100
electron microscopy image illustrating a tuft

of Aspergillus spores arranged in rows. A
spore is approximately 1 mm in size (M.H.
Umar, Maasstad Hospital, Rotterdam, the
Netherlands; personal communication).
Germination initiates an asexual developmental growth

programme. It starts with conidial swelling followed by
a polar growth programme that results in the protrusion of an elongating germ tube, termed hyphae, from
the conidium cell [35]. Hyphae are covered by a newly synthesised polysaccharide coat without the
typical protein coat present on conidia [35]. Simultaneously with polar growth comes nuclear
division by mitosis, resulting in further elongating hyphae with each cycle. In immunocompromised patients, Aspergillus grows into large hyphal networks termed mycelia and forms
extracellular matrices termed biofilms that contain a1,3-glucan, galactomannan and galactosaminogalactan, and possibly other components that promote growth [36]. Interestingly, germination of A. fumigatus conidia is increased compared with Aspergillus flavus and Aspergillus niger at
37uC but not at 20uC [37]. This increased growth rate at 37uC likely contributes to the prevalence
of A. fumigatus in fungal diseases, such as ABPA.
Interestingly, when comparing fungal proteases of A. fumigatus with those of Alternaria alternata
and Cladosporium herbarum, KAUFFMAN et al. [41] reported an increase in the activity of
A. fumigatus-derived proteases, as indicated by the shrinking and desquamation of epithelial cells
and pro-inflammatory cytokine production. Although the role of isolated components from
A. fumigatus in conferring virulence as a human pathogen remains difficult to establish, it is clear
that their combined activity contributes to the strong association of A. fumigatus with fatal
human diseases.
Innate mechanisms underlying ABPA

The innate defence mechanisms involved in the clearance and inflammatory response to
A. fumigatus, and how these may impact on the development of ABPA will be discussed here. The
majority of conidia are cleared without inflicting a strong inflammatory response associated with
tissue destruction. Most inhaled conidia are efficiently trapped by mucus and removed by
mucociliary clearance systems that are affected in CF and asthma patients. Nevertheless, ABPA is
generally not observed in patients with primary ciliary dyskinesia in which impaired mucociliary
clearance leads to the accumulation of mucus and primarily bacterial infections, suggesting
additional mechanisms contribute to the development of ABPA [42].
B. HILVERING ET AL.
A. fumigatus expresses multiple factors to evade host immune defence mechanisms, which in total
contribute to the virulence of A. fumigatus in humans. These factors may be part of the growth
cycle of A. fumigatus, but may also be uniquely expressed as secondary metabolites during specific
phases of growth. For example, the binding of conidia to various extracellular matrix (ECM)
proteins prevents its mucociliairy clearance and the oxidative mechanisms of phagocytes are
counteracted by the production of superoxide dismutases, mannitol and three types of catalases.
A range of other toxins and proteases further inhibit immune responses and promote epithelial
cell penetration including ribotoxin [38], phospholipases [39], haemolysins, gliotoxins, metalloproteinase, alkaline proteinase and elastase [40].
Beyond the mucociliary system, resident cells of the lungs, such as alveolar macrophages (AM) and
type II pneumocytes, destroy conidia by phagocytosis and the production of reactive oxygen
species (ROS) upon activation of the membrane-bound NADPH-oxidase complex. It was recently
shown that RodA in the protein coat surrounding conidia inhibits the inflammatory response to
conidia by masking the highly immunogenic polysaccharide cell wall [43]. This may promote
survival of conidia by escaping host immunity, but may also be beneficial to the host by limiting
inflammatory responses upon inhalation of conidia.
101
However, during germination the extending hyphae expose their polysaccharide wall and start to
produce metabolites that trigger a strong inflammatory response. Pattern recognition receptors,
e.g. Toll-like receptors (TLRs) and carbohydrate-binding proteins termed C-type lectins, are
expressed by lung epithelial and resident immune cells, such as AM and dendritic cells (DCs),
which recognise the b-glucans, chitin and galactomannan of the cell wall. Controversy still exists
over the exact functional role of individual TLRs in the recognition of fungi, but it appears that
TLR2, TLR4 and TLR9 do signal in a fungal morphotype-specific manner [44]. Activation of TLR2
and inhibition of TLR4 signalling during hyphal growth has been proposed to promote the
development of a Th2 response [45, 46].
In addition to TLRs, members of the C-type lectin family, e.g. the mannose receptor, DC-specific
intercellular adhesion molecule-grabbing nonintegrin (DC-SIGN), Dectin-1, and Dectin-2,
recognise carbohydrate structures of the fungal wall and play an important role in fungal
recognition, killing, and inflammatory signalling. Dectin-1 binds b-(1,3)-glucan and is prevalent
on neutrophils, AM and DC. Neutrophils are the first cells to enter an inflammatory site and are
short-lived phagocytic effector cells. Neutrophils produce ROS and release proteolytic enzymes,
upon apoptosis their DNA traps pathogens but also increase mucus viscosity [47, 48]. Mice
lacking Dectin-1 are highly susceptible to A. fumigatus infection; their macrophages and DC
produce low levels of inflammatory cytokines and have limited recruitment of neutrophils to the
site of infection with reduced killing capacity [49].
Triggering these pattern-recognition receptors induces the release of multiple inflammatory

networks that recruit cells from the blood to the infected area, and play a crucial role in shaping
the adaptive immune response at later stages [5052]. Human polymorphisms in these systems
can affect fungal load, growth properties and the balance of inflammatory mediators produced by
innate cells that can impact on the quality and quantity of the adaptive response. ABPA is
correlated with polymorphisms in TLR9 [53]. The mechanism by which TLR9 predisposes to
ABPA in humans remains uncertain; however, pulmonary hypersensitivity induced by A.
fumigatus in TLR9 -/- mice is significantly reduced [54]. DCs of these mice have lower Dectin-1
levels and produce low amounts of interleukin (IL)-17, which was associated with pulmonary
infection of A. fumigatus. Multiple polymorphisms in other innate recognition systems including
TLR2 and TLR4 and humoral pattern recognition factors, such as mannose binding lectin and
surfactant protein A, have also been associated with ABPA and other different types of fungal
diseases [5559].
Collectively, it is clear that a complex multi-layered innate response to A. fumigatus has evolved to
prevent infection and subsequent invasive disease. Genetic variations in innate systems that impact
on pathogen recognition, fungal infection and induction of hypersensitivity responses have been
associated with fungal diseases including ABPA. The extent to which genetic variation within these
systems affects the development of ABPA in subgroups of CF or asthmatic patients requires
further attention and may have prognostic value for patient subgroups.
Adaptive immunity in ABPA

DCs are specialised cells that take up antigens at local inflammatory sites and then migrate to
draining lymph nodes or bronchus associated lymphoid tissue (BALT) where they activate nave
T-cells by presentation of antigenic peptides in the context of major histocompatibilty complex
(MHC) [50]. Upon activation of nave Th cells, these cells acquire distinct cytokine-secreting
properties that impact on the developing immune response. Multiple subsets of committed
antigen-experienced Th cells are recognised including Th1, Th2, Th17 and induced T-regulatory
(T-reg) cells [60]. In general, interferon-c producing Th1 and IL-17 producing Th17 subsets are
important inflammatory cells associated with cell-mediated immunity against viral infections and
intracellular bacteria, and are associated with multiple autoimmune diseases. IL-4 producing Th2
cells are typically associated with strong immune responses against large extracellular organisms
that cannot be cleared through phagocytosis, such as intestinal parasites, and are associated with
allergic diseases and ABPA in humans. Induced T-reg cells and natural T-reg cells are important to
dampen immunological responses by the production of IL-10 and transforming growth factor
(TGF)-b [61].
102
Th responses are skewed towards Th2 in ABPA as indicated by in vitro lymphocyte responses
against secreted proteins from A. fumigatus and animal models [26, 6266]. Th1 and Th17
responses against A. fumigatus appear protective against hypersensitivity and are associated with
clearance of Aspergillus [6769]. Why ABPA patients mount such a vigorous Th2-response is not
known and remains a key question. Activation of specific pattern recognition receptors and
cytokine receptors at the site of inflammation induces DCs to express surface molecules and
cytokines, which help to commit nave Th cells; however, T-cell intrinsic factors, such as T-cell
receptor (TCR) avidity for its antigen, also appear important.
Recently, epithelial products such as IL-25 and thymic stromal lymphopoietin (TSLP) have been
shown to alter DCs function and subsequent Th responses [7072]. TSLP stimulated DCs from
ABPA patients use ligand OX40 to potently induce Th2 responses [71]. Other ABPA-associated
polymorphisms in genes, e.g. TLR9, IL-4Ra subunit and the IL-10 promotor, may all affect DC
maturation and or induction of Th differentiation, but these proteins are expressed by many cells
and thus it remains difficult to pinpoint at which level these polymorphisms affect disease [73].
Th2 cells and their cytokines play a crucial role in B-cell class switching and the recruitment of
IgE-responding innate cells such as eosinophils, basophils and mast cells. Early studies indicate
that supernatants of lymphocytes incubated with A. fumigatus antigens regulate IgE production by
B-cells [74]. Cytokines, such as IL-4, IL-5 and IL-13, by Th2 cells facilitates B-cell class switching
to IgA and IgE in BALT, and induce the production and recruitment of eosinophils to the
inflammatory site [19]. IgE levels are quantitatively higher in ABPA compared with other atopic
conditions, though little is known about the width of the antibody response against A. fumigatus
and possible bystander antigens including self antigens. However, recent evidence indicates the
existence of a Th2-mediated immune response without the presence of IgE [75]. To place this
contradiction into perspective, data from a recent study indicated that out of 66 proteins present
in the cytosol of A. fumigatus, which were recognised by pooled serum of ABPA patients, 63 were
targeted by IgE and only three by IgG antibodies [76]. The prevalence of A. fumigatus-specific IgE
over IgG antibodies suggests BALT to be a primary site for development of high-specific
Aspergillus IgE and not the peripheral lymphoid system.
Upon comparison of atopic and ABPA patients, ABPA B-cells were found that expressed higher
levels of the low-affinity IgE receptor CD23 and the co-stimulatory molecule CD86 that is crucial
for positive reinforcement by Th cells, a phenotype associated with in vitro IL-4 responsiveness
[77]. Indeed, polymorphisms in IL-4Ra have been found to be enriched within ABPA patients in
comparison with non-ABPA patients. Furthermore, CF patients with ABPA are more sensitive to
IL-4 than CF patients without ABPA, a finding that was not observed for IL-13 [78, 79].
B. HILVERING ET AL.
TCRs that bind with low affinity to their cognate antigen may also confer Th2 properties in ABPA.
Variants of human MHC class II, such as HLA-DR2 and HLA-DR5 alleles, are associated with
ABPA and promote the expansion of T-cells with selective ab TCR chains. Although expression
of these MHC class II variants is not sufficient for ABPA disease, peptides of a dominant allergen
of A. fumigatus, termed Asp f1, are presented by these molecules and are recognised by lowaffinity, TCR-expressing Th2-skewed cells [74]. Other MHC class II alleles also appear to protect
against ABPA.
103
These antibodies trigger hypersensitivity responses by interacting with specialised innate immune
cells. IgA and IgE-responsive granulocytes, such as eosinophils, basophils, and mast cells are
activated by the Th2 response and recruited to the inflammatory site by a network of soluble
mediators and cell-surface molecules [80]. Ligation of IgE on mast cells releases histamine and
chemokines such as leukotriene B4 and platelet-activating factor, which induce smooth muscle
contraction, vascular permeability and attract eosinophils. RANTES (regulated on activation,
normal T-cell expressed and secreted), eotaxin and monocyte chemotactic protein (MCP)-3 are
other important chemoattractants for eosinophils. The receptor for eotaxin, chemokine receptor 3
(CCR3) is selectively expressed by Th2, eosinophils and basophils, and is upregulated by IL-4.
Th2-derived IL-5 is essential for increased eosinophil production from the bone marrow and their
activation but appears dispensible for A. fumigatus-induced hyperreactivity in mice [81].
Nevertheless, these cells are a prominent feature of ABPA and are highly present in bronchial
alveolar lavages suggesting their products to inflict tissue damage under chronic conditions [19].
Chemokines are implicated in various allergic conditions; however, their exact role in ABPA
requires further refinement as the blockade of these by therapeutics may control the inflammatory
cellular composition and local tissue destruction.
It has long been recognised that mucosal-associated immunity, especially in the gut, appears to be
regulated by T-lymphocytes expressing IL-10 and or TGF-b [82]. Recently, CF patients colonised
by A. fumigatus were shown to have increased levels of FoxP3-positive T-reg cells that expressed
higher levels of surface TGF-b upon A. fumigatus stimulation, and confer tolerance to oral
antigens in mice [61, 71]. The role of IL-10 producing T-reg cells (sometimes termed Tr1 cells) in
ABPA is not clear; however, IL-10 promotor polymorphisms have been associated with fungal
diseases and ABPA [73]. Adoptive transfer of T-reg cells is effective in lowering inflammatory
conditions in multiple animal models suggesting that modulation of the number and activation of
these cells in humans may control excessive inflammation in ABPA.
In conclusion, inflammatory mediators of Th2 cells including IL-4, IL5 and IL-13 play a dominant
role in the induction and maintenance of the hypersensitivity response in ABPA. These promote IgE and IgA isotype switching and attract typical innate effector cells associated with
hypersensitivity responses such as eosinophils, basophils and mast cells. Genetic variation in these
pathways predispose for ABPA; however, ranking these for their role in ABPA disease development
will prove difficult considering the impact of environmental variables and limited patient
numbers. Based on homology with other hypersensitivity disorders, the mechanisms that underlie
Th differentiation in ABPA can begin to be understood; however, the characterisation of Th
subsets and their role in ABPA development has only just started.
CFTR-related immunological disease mechanisms in ABPA

In general, the immune mechanisms in CF are normal; however, there is evidence to support that
ABPA, specifically, may also result from the abnormal function of CFTR in immune cells next to the
epithelial cells. The association between CF patients and allergic disease was reported in 1949 [83].
CF patients have mutations in CFTR that encodes an adenosine triphosphate (ATP)- and cyclic
adenosine monophosphate (cAMP)-regulated anion channel that regulates the composition of
excretions [84]. CFTR in the lung epithelium regulates the airsurface liquid layer that underlies the
mucus layer, which impacts the mucociliary clearance and functions of humoral components [85].
CFTR is expressed in multiple other tissues including the immune system, suggesting that the
hyperinflammatory status of CF patients that was previously believed to be secondary to infection
may result from a dysregulated immune response caused by a CFTR mutation [8689]. Genetic
studies in mice support a role for CFTR in macrophages, DCs and lymphocytes [90, 91]. In human
innate cells the impaired bacterial clearance by phagocytes has been observed; however, the
capacity of these cells to present antigens to T-cells has not been thoroughly assessed [92, 93].
MULLER et al. [91] reported that CFTR deficiency in mice provokes a stronger hypersensitivity
response to A. fumigatus, and a shift from a predominant cytokine profile of IL-5 to IL-4. Recently,
CD3 lymphocytes were implicated in the hypersensitivity response towards A. fumigatus by
adoptive transfer experiments [94]. Conditional knockouts that lack CFTR in lymphocytes have
enhanced basal and A. fumigatus-induced IgE levels, further supporting that CFTR is functional in
murine CD4+ lymphocytes by limiting Th2-skewing.
104
Asthmatic non-CF individuals with ABPA frequently carry a mutant CFTR allele [9598]. A recent
study, which involved the extensive CFTR sequencing of ABPA patients with normal sweat
chloride levels and pancreatic function, found that the CFTR mutation frequency in patients with
ABPA was approximately 48 higher compared with the general population [98]. Whether certain
CFTR mutations specifically cluster with ABPA remains to be seen, and as this is difficult to study
due to low patient numbers it remains undetermined. The strong correlation of ABPA with CFTR
heterozygocity is remarkable, as it has been generally accepted that approximately 20% residual
function is sufficient for epithelial functioning. This may point out that other tissues are more
strongly affected by CFTR deficiency, but cannot rule out epithelial involvement. The hypothesis
that CFTR mutant lymphocytes are intrinsically Th2-primed, as may be expected from mice
studies, requires further thorough investigation and should carefully address confounding factors,
such as genetic background, infectious status and therapeutic regimen.
Summary
To summarise, ABPA is mostly prevalent in CF patients compared with a small percentage of
asthma patients, and is a result of complex interactions between the invasive pathogen
A. fumigatus and the human immune system. Th2-skewing of Th cells followed by a strong
humoral IgE response and activation of IgE-responding effector cells are clear hallmarks of ABPA.
To date, genetic variation in CFTR itself appears to be the strongest genetic factor associated with
ABPA, also in asthmatics. A. fumigatus-driven hypersensitivity mouse models reflecting ABPA
strongly support a role for CFTR within the T-cell compartment [91, 94]. The strong relationship
between ABPA and CF may, therefore, not only result from impaired epithelial functioning but
may also result from lymphocyte defects that only become apparent upon strong Th2 stimuli
a) Infectious site
c) Infectious site
Mycelium
-glucans
Chitin
Galactomannan
Protruding
hyphae
Release of toxins,
proteases and other
secondary metabolites
Activation of pattern
recognition receptors
in lung epithelium and
innate immune cells
Non-inflammatory
clearance;
phagocytosis
CFTR-dependent
mucociliary system
Cellular damage;
release of
danger signals
TLR-4
TLR-2
Phagocytosis and
antigen processing
MHC
class II
NADPH
oxidase
Endosomal
proteases
Fungus-associated
inflammatory signalling
Inflammatory clearance
by resident cells and
attracted innate cells;
CFTR-dependent killing?
b) Lymphoid tissue
IL-25, TSLP, ATP
Fungus-associated
inflammatory signalling
B. HILVERING ET AL.
Exposure of cell wall

polysaccharides: -glucan,
chitin, galactomannan
Immune inhibitory
protein-rich outer shell:
RodA and melanin
Epithelium
Toll-like receptors
Dectin-1
Dendrtic cell
Mannose
receptor
DC-SIGN
C-type lectins
TLR-9
Germination
Conidium
Aspergillus fumigatus
Induction of Th
skewing conditions
Nucleus
d) Lymphoid tissue
Tissue-derived dendritic cells
Dendritic cell
Antigen presentation
MHC
class II
TCR
Nave T-cells
Nave B-cells
IL-25, IL-4
lgE+secreting
plasma cell
CD40
CD40L
T-helper cell
B-cell
MHC
class II
BCR
CFTR inhibits skewing
towards Th2 cells?
Co-stimulation
Th2 cells
Stimulation
of lgE-responsive
eosinophils
CD23
lgE class
switching
TCR
Th2 skewing
Eosinophil
CD40L
CD40 IL-4
IL-5
IL-13
Mast cell
Basophil
Figure 3. Immunopathogenesis of allergic bronchopulmonary aspergillosis. a) Aspergillus fumigatus asexual life
105
cycle and the interactions of innate epithelial and immune components with dormant conidia or germinating
conidia at the site of infection. b) Interactions between adaptive components of the immune system in the
lymphoid tissue showing proven or possible (&)
h involvement of cystic fibrosis transmembrane conductance
regulator (CFTR). Detailed schematic representation of molecular interactions between A. fumigatus and various
immune cell subsets at c) the infectious site or d) lymphoid tissue are shown. Local priming of dendritic cells
(DCs) by fungus and epithelial-derived products is important for T-helper (Th) cell skewing. DCs at the lymphoid
tissue stimulate nave Th cells by upregulation of major histocompatibilty complex (MHC) class II antigen
complexes in combination with specific co-stimulatory pathways that activate Th2 cells. These facilitate
immunoglobulin (Ig)E class switching of B-cells and the activation and recruitment of eosinophils, basophils and
mast cells. TLR: toll-like receptors; TSLP: thymic stromal lymphopoietin; IL: interleukin; ATP: adenosine
triphosphate; TCR: T-cell receptor; BCR: B-cell receptor.
associated with A. fumigatus. Therefore, it appears that next to environmental factors such as
nutritional status, co-infection and long-term immune suppression, genetic variations in the
systems underlying A. fumigatus recognition, clearance and Th2 skewing may also drive patientspecific ABPA susceptibility. The identification of ABPA-related disease mechanisms will be
crucial for future development of therapeutics that control immune-related tissue destruction
without impairment of fungal clearance. Figure 3 illustrates the immunopathogenecity of ABPA.
Clinical features and diagnostic approach
Patients with ABPA typically present with symptoms such as a low-grade fever, productive cough,
bronchial hyperreactivity, chest pain, wheezing, haemoptysis and expectoration of brownish
sputum plugs. Sometimes patients are asymptomatic and diagnosed during routine screening tests
in patients with asthma or CF. Physical examination can reveal wheezing or coarse crackles on
auscultation, clubbing of the fingers in 15% of patients and complications such as pulmonary
hypertension and/or respiratory failure [99, 100]. The diagnostic criteria for patients with asthma
are summarised in table 1. Because the primary disease symptoms in patients with CF can closely
resemble ABPA, adapted criteria for ABPA have been formulated within this patient category
(table 2). In CF, ABPA is diagnosed in the presence of the following: 1) acute or subacute clinical
deterioration not attributable to another aetiology; 2) total serum IgE concentration of
.500 IU?mL-1; 3) immediate cutaneous reactivity to A. fumigatus or in vitro demonstration
of IgE antibody to A. fumigatus; and 4) either precipitins to A. fumigatus or in vitro demonstration
of IgG antibody to A. fumigatus or new or recent abnormalities on radiological tests (CT scan or
chest radiograph).
Skin testing
In patients with bronchial asthma Aspergillus skin testing is recommended for screening purposes.
Intradermal injection is more sensitive in comparison to the skin-prick test [64, 102, 103].
A positive reaction to recombinant antigens of A. fumigatus termed rAsp f 4 and/or 6 reached a
sensitivity of 86.8% (95% CI 73.5100%) and a specificity of 92% (95% CI 83.9100%) in a study
with 50 CF patients [102]. Of those 50 patients, 12 suffered from ABPA, 21 were sensitised for
A. fumigatus and 17 were control patients. However, less promising results were obtained by
DE OLIVEIRA et al. [104] who subjected 65 patients with asthma and a positive skin-prick test to
Table 1. Criteria for the diagnostis of allergic bronchopulmonary aspergillosis (ABPA) in patients with asthma
Criteria
For ABPA central bronchiectasis
Asthma
Central bronchiectasis, inner two thirds of chest CT field
Immediate cutaneous reactivity to Aspergillus sp. or A. fumigatus
Total serum IgE concentration .417 kU?L-1/1000 ng?mL-1
Elevated serum IgE and or IgG to A. fumigatus
Chest roentgenographic infiltrates
Serum precipitating antibodies to A. fumigatus
For ABPA seropositive
Asthma
Immediate cutaneous reactivity to Aspergillus sp. or A. fumigatus
Total serum IgE concentration .417 kU?L-1/1000 ng?mL-1
Elevated serum IgE and or IgG to A. fumigatus
Chest roentgenographic infiltrates
Minimal essential
criteria
Yes
Yes
Yes
Yes
Yes
No
No
Yes
Yes
Yes
Yes
No
106
CT: computed tomography; A. fumigatus: Aspergillus fumigatus: Ig: immunoglobulin. Reproduced from [101]
with permission from the publisher.
Table 2. Diagnostic criteria for allergic bronchopulmonary aspergillosis (ABPA) in cystic fibrosis (CF) patients
as proposed during the 2003 CF Foundation Consensus Conference (Bethesda, MD, USA)
Classic case
1. Acute or subacute clinical deterioration (cough, wheeze, exercise intolerance, exercise-induced
asthma, decline in pulmonary function, increased sputum) not attributable to another aetiology.
2. Serum total IgE concentration of .1000 IU?mL-1 (2400 ng?mL-1), unless the patient is receiving
systemic corticosteroids (if so, retest when steroid treatment is discontinued).
3. Immediate cutaneous reactivity to Aspergillus (prick skin test wheal of 3 mm in diameter with
surrounding erythema while the patient is not being treated with systemic antihistamines) or
in vitro presence of serum IgE antibody to A. fumigatus.
4. Precipitating antibodies to A. fumigatus or serum IgG antibody to A. fumigatus by an in vitro test.
5. New or recent abnormalities on chest radiograph (infiltrates or mucus plugging) or chest CT
(bronchiectasis) that have not cleared with antibiotics and standard physiotherapy.
Minimal diagnostic criteria
1. Acute or subacute clinical deterioration (cough, wheeze, exercise intolerance, exercise-induced
asthma, change in pulmonary function, or increased sputum production) not attributable to
another aetiology.
2. Total serum IgE concentration of .500 IU?mL-1 (1200 ng?mL-1). If ABPA is suspected and the total
IgE level is 200500 IU?mL-1, repeat testing in 13 months is recommended. If the patient is taking
steroids, repeat when steroid treatment is discontinued.
3. Immediate cutaneous reactivity to Aspergillus (prick skin test wheal of 13 mm in diameter with
surrounding erythema, while the patient is not being treated with systemic antihistamines) or
in vitro demonstration of IgE antibody to A. fumigatus.
4. One of the following: precipitins to A. fumigatus or in vitro demonstration of IgG antibody to
A. fumigatus; or new or recent abnormalities on a chest radiograph (infiltrates or mucus plugging)
or chest CT (bronchiectasis) that have not cleared with antibiotics and standard physiotherapy.
recombinant antigen testing. 19 patients tested positive for at least one recombinant antigen;
however, only six of them met the classical criteria for ABPA.
Essential laboratory testing

Total serum IgE is the most important laboratory test for ABPA and is essential for the diagnosis
and monitoring of the disease. Normal levels of total serum IgE in patients that do not receive
glucocorticoid therapy exclude ABPA as a diagnosis. In patients with asthma the total IgE levels
should be .1,000 IU?mL-1, whereas in CF patients IgE levels of .1,500 IU?mL-1 can be detected.
IgE levels are also used to monitor treatment. A reduction of 3550% during treatment with
systemic steroids is considered as a remission [105].
B. HILVERING ET AL.
Ig: immunoglobulin; A. fumigatus: Aspergillus fumigatatis; CT: computed tomography. Reproduced from [19]
with permission from the publisher.
Increased levels of specific serum IgE antibodies to A. fumigatus distinguish ABPA from
A. fumigatus hypersensitivity (AH), which is defined as a positive skin test, and other allergic
conditions in asthmatics [106, 107]. The serum levels of Aspergillus-specific IgE are at least twice as
high in ABPA compared with AH [108]. In patients with CF, specific serum IgE antibodies Asp f 3
and Asp f 4 are specific for ABPA and not for Aspergillus hypersensitivity [109].
Supportive tests
107
The presence of serum precipitins, i.e. precipitating IgG antibodies, are supportive to the diagnosis
of ABPA [110, 111]. Peripheral eosinophilia is also regarded important in diagnosis; however, it
may have relatively low specificity or sensitivity [112]. A total of .1,000 cells?mL-1 has been set as a
cut-off value. The differential diagnosis of peripheral eosinophilia includes a range of other
disorders such as tuberculosis, sarcoidosis, drug-induced eosinophilia and ChurgStrauss
syndrome that should all be carefully ruled out. Sputum cultures are rarely used for diagnosing
ABPA as fungi can be prevalent in the lungs of many immunocompromised patients. Pulmonary
function testing is not suitable as a diagnostic test and is only useful as a rough indicator for the
severity of lung disease in general [113]. A promising serological test is for thymus and activationregulated chemokine (TARC). Diagnostic accuracy was proven to be greater for TARC (93%) than
for total IgE (74%), rAsp f 4 (75%) or rAsp f 6 (79%) in a small diagnostic study with 12 CF
patients with ABPA and 36 control patients [114]. The definition of the diagnostic accuracy was
the number of correctly positively categorised patients plus the correctly negatively categorised
patients as a percentage of the total.
Radiology
Radiological imaging in most patients with ABPA shows centrally located, cylindrical bronchiectasis,
while the presence of distal bronchiectasis is rare [115]. The radiological classification has
predominantly prognostic implications as it cannot distinguish between bronchiectasis caused by
ABPA or another factor [116]. HRCT scanning is regarded as the gold standard to identify
bronchiectasis as a morphological diagnosis and correlates with the functional lung capacity of
patients [117, 118]. Chest radiography lacks the sensitivity needed to rule out bronchiectasis and,
therefore, HRCT is required if no abnormalities appear and ABPA is suspected. In ABPA, HRCT can
be used to monitor disease progression and is directive for the therapeutic strategy.
Treatment
The treatment of ABPA depends upon two important factors: 1) glucocorticoids to dampen the
immunological activity, and 2) antifungal agents to suppress the antigenic load.
Although glucocorticoids are the mainstay in ABPA treatment, no well-designed studies have been
carried out. Neither the optimal dose regimen nor the optimal duration of therapy has ever been
determined [119]. In asthmatics the optimal dose and treatment scheme as regarded by expert
opinion is prednisone 0.51.0 mg?kg-1?day-1 for 2 weeks, followed by an alternate day regimen,
which is tapered to zero during a 36-month period. In CF patients the prolonged use of
glucocorticoids may induce severe side-effects such as glucose intolerance, growth suppression,
cataracts and osteoporosis [120122]. Therefore, the use of monthly pulses with methylprednisolone has been suggested as a treatment for ABPA in CF patients. Two small studies with 13 CF
patients showed clinical and laboratory improvement after 0.31 mg?kg-1?day-1 and 10
15 mg?kg-1?day-1, respectively [123, 124]. Figure 4 illustrates the effect of systemic steroids in a
CF patient with ABPA.
Inhaled glucocorticoids
108
Recently it was reported that inhaled glucocorticoids are significantly linked with the prevalence of
Aspergillus in lungs of CF patients [125], which might increase their risk of suffering from ABPA. The
efficacy of inhaled steroids in patients
with ABPA has never been docua)
b)
mented and hence this treatment is
not recommended in patients with
CF. Some small case series in patients
with asthma and ABPA indicate
some beneficial effects of inhaled
glucocorticoids [126, 127]. However, the single largest study with
inhaled beclomethasone shows no
beneficial effect at all [128]. Therefore, the use of inhaled glucocortiFigure 4. Chest radiograph of a 12-year-old cystic fibrosis patient
coids seems limited in CF patients
with allergic bronchopulmonary aspergillosis a) before and b) after a
and implicates limited value for
6-week course of systemic steroids.
patients with asthma.
Antifungal agents
It has been suggested that itraconazole modifies the immunological activation associated with
ABPA and can improve clinical outcome, at least over a 16-week period. The largest multicentre
randomised controlled trial found significantly lower need for steroids decreased serum IgE
concentrations and improved clinical findings in patients using itraconazole when compared with
those who did not [129].
The most recent Cochrane review (updated in 2010) on the efficacy of itraconazole in the
treatment of patients with CF concluded that evidence is limited and that further research is
required [13]. Itraconazole might be used as an adjuvant to glucocorticoid treatment, presumably
lowering the required dosage and thereby the side-effects of systemic steroids. The dosage of
itraconazole is generally accepted to be 200 mg twice a day with a start dosage of 200 mg three
times a day for 3 days. Liver function tests should be monitored monthly to prevent toxicity. A
potential concern in patients using both inhaled corticosteroids and itraconazole is adrenal
suppression due to an increase in steroid levels in serum [130].
With the progressing knowledge in the immunological mechanisms involved in patients with
ABPA, the possibility of developing a more cause-related therapy becomes ever more apparent. In
experimental settings some successes have been achieved. For example Asp f 1-derived peptide P1,
prophylactically and therapeutically administrated to BALB/c mice is effective in regulating an
allergic response to allergens/antigens of A. fumigatus [131]. The first results obtained by the
administration of allergen-derived peptides to shift an Aspergillus specific Th2 response to a
protective Th1 are promising.
An example of immunomodulative therapy in a clinical setting is the introduction of omalizumab
in children with CF and ABPA. Omalizumab is a humanised monoclonal antibody against IgE.
Currently, as documented in case reports, a total of seven children who were described as
irresponsive to glucocorticoid treatment were found to have improved lung function after using
300375 mg omalizumab subcutaneously every 2 weeks [132135]. However, in order to introduce
omalizumab in daily clinical routine, more clinical trials are warranted.
B. HILVERING ET AL.
Immunomodulatory therapy
Conclusion
The aim of this chapter was to provide an overview of the clinical features of ABPA, the diagnostic
criteria and the underlying pathophysiological immune mechanisms. ABPA consists of an A.
fumigatus-driven hypersensitivity reaction in predominantly asthmatic and CF patients.
Polymorphisms in genes that drive innate and adaptive immune mechanisms, as well as lossof-function mutations in CFTR, are associated with the development of a strong Th2 response and
ABPA. Continuous inhalation of A. fumigatus and resulting chronic infections, in combination
with genetic predisposition, fuel a chronic inflammatory hypersensitivity response that eventually
results in airway remodelling and functional impairment of the lung. The diagnostic process is
characterised by a combination of tests evaluating lung function, serum hypersensitivity parameters
(aspecific and specific for A. fumigatus), and radiological characteristics such as bronchiectasis.
Treatment consists of dampening the immune response by the use of glucocorticoids and
suppressing the fungal burden by antifungal agents.
109
Recent insights into the pathogenesis, diagnostic measures and treatment possibilities illustrate the
ongoing effort aimed at preventing ABPA from causing invalidating lung disease. Promising
examples are the establishment of CFTR mutations in ABPA pathogenesis, the superior test
characteristics of TARC regarding the diagnosis of ABPA in CF patients, and the beneficial role of
itraconazole to glucocorticoids in treatment.
None declared.
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Chapter 8
Nontuberculous
mycobacterial
infections
C.L. Daley
Summary
Keywords: Bronchiectasis, mycobacteria, Mycobacterium

avium complex, nontuberculous mycobacterial infections
Correspondence: C.L. Daley, Division

of Mycobacterial and Respiratory
Infections, National Jewish Health,
1400 Jackson Street, Denver, CO
80206, USA, Email
daleyc@njhealth.org
C.L. DALEY
Nontuberculous mycobacteria (NTM) represent a large group

of bacteria that have been isolated from environmental sources.
When NTM are inhaled by a susceptible individual, infection
can occur and lead to progressive lung disease. Epidemiological
studies have described increases in the prevalence of NTM
disease in multiple areas worldwide. Risk factors for disease
include chronic lung diseases, such as bronchiectasis and
chronic obstructive pulmonary disease, as well as various forms
of immune deficiency. Patients typically present with either
fibrocavitary or nodular bronchiectatic disease. Isolation of
NTM from respiratory specimens does not always indicate
disease so clinicians must evaluate clinical, radiographic and
microbiologic information in order to diagnosis NTM-related
lung disease. The American Thoracic Society has developed
diagnostic criteria that can aid clinicians but the criteria cannot
account for all clinical scenarios or for all NTM species given
the large spectrum of pathogenicity encountered. Treatment
usually consists of at least two antibiotics but the exact regimen
will vary depending on the species and there is some variation in
recommendations.
Eur Respir Mon 2011. 52, 115129.

Copyright ERS 2011.
ISSN: 1025-448x.
DOI: 10.1183/1025448x.10003810
115
ontuberculous mycobacteria (NTM) comprise ,140 species, many of which have been
reported to cause disease in humans. Based on their rate of growth in subculture, NTM have
traditionally been divided into slowly and rapidly growing species (table 1) [13]. Also referred to
as environmental mycobacteria, NTM have been isolated from natural and drinking water
supplies, as well as soil [47]. The presumed source of infection is exposure to these environmental
reservoirs because human-to-human transmission has not been documented. When inhaled by
susceptible individuals, such as those with chronic obstructive lung disease or bronchiectasis,
infection with NTM can lead to a chronic, progressive and sometimes fatal lung disease.
Table 1. Examples of slowly growing and rapidly growing nontuberculous mycobacteria that have been
reported to cause lung disease
Slowly growing mycobacteria
Mycobacterium
Mycobacterium
Mycobacterium
Mycobacterium
Mycobacterium
Mycobacterium
Mycobacterium
Mycobacterium
Mycobacterium
Mycobacterium
Mycobacterium
Mycobacterium
Mycobacterium
arupense
asiaticum
avium
branderi
celatum
chimaera
flavescens
florentinum
heckeshornense
intermedium
interjectum
intracellulare
kansasii
Mycobacterium
Mycobacterium
Mycobacterium
Mycobacterium
Mycobacterium
Mycobacterium
Mycobacterium
Mycobacterium
Mycobacterium
Mycobacterium
Mycobacterium
Mycobacterium
kubicae
lentiflavum
malmoense
palustre
saskatchewanse
scrofulaceum
shimodei
simiae
szulgai
triplex
terrae
xenopi
Rapidly growing mycobacteria
Mycobacterium abscessus
Mycobacterium alvei
Mycobacterium boenickei
Mycobacterium bollettii
Mycobacterium brumae
Mycobacterium chelonae
Mycobacterium confluentis
Mycobacteium elephantis
Mycobacterium goodii
Mycobacterium holsaticum
Mycobacterium fortuitum
Mycobacterium mageritense
Mycobacterium massiliense
Mycobacterium mucogenicum
Mycobacterium peregrinum
Mycobacterium phocaicum
Mycobacterium septicum
Mycobacterium smegmatis
Mycobaterium thermoresistible
NTM INFECTIONS
Despite their frequent isolation in the environment and human specimens, NTM were not
widely recognised as a cause of human disease until the late 1950s. Since that time, the number
of new species of NTM has grown dramatically [3] and the rate of disease related to NTM has
also increased, overtaking the rate of tuberculosis (TB) in some areas [8]. Diagnosis and
treatment of NTM lung disease remains challenging for clinicians and depending on the extent
of disease and species involved, a cure may be difficult to achieve. When considering treatment,
clinicians must weight the potential benefits of therapy against the cost and potential sideeffects of current regimens.
Epidemiology
Incidence and prevalence
The epidemiology of NTM disease has been difficult to determine because reporting is not
mandatory in most countries and differentiation between infection and disease is often difficult.
Although the incidence and prevalence of NTM infections have varied significantly across studies,
recent studies have reported high rates of NTM pulmonary disease, particularly in older
populations [912]. Among 933 patients with at least 1 NTM isolate in Oregon (USA), 527 (56%)
met the American Thoracic Society (ATS) microbiological definition for disease giving an
annualised prevalence of 5.6 cases per 100,000 for pulmonary disease [9]. The prevalence was
significantly higher in females (6.4 cases per 100,000) than males (4.7 cases per 100,000) and was
highest in persons aged .50 years (15.5 cases per 100,000). In another report from Oregon, the
overall 2-year prevalence of NTM pulmonary disease was 8.6 cases per 100,000 and increased to
20.4 cases per 100,000 in those aged o50 years [10]. The annualised prevalence of NTM lung
disease within four integrated healthcare delivery systems in the USA ranged from 1.4 to 6.6 per
100,000 [11]. Among persons aged o60 years, annual prevalence was 26.7 per 100,000.
116
Studies from Canada [8], Australia [12], Taiwan [13], the Netherlands [14] and the USA [11, 15]
have reported increases in the incidence or prevalence of NTM. MARRAS et al. [8] reported an
increase in the number of pulmonary NTM isolates in Ontario (Canada) from 9.1 per 100,000 in
1997 to 14.1 per 100,000 in 2003. Difficulty in eradicating NTM infections resulted in a prevalence
higher than that of tuberculosis [16]. More recently, two studies from the USA reported increases
in NTM pulmonary disease [11, 15]. In a study examining the prevalence of NTM lung disease in
four integrated healthcare delivery systems, there was a 2.6% and 2.9% increase per year in females
and males, respectively [11]. Pulmonary NTM hospitalisations increased significantly among both
males and females between 1998 and 2005 in a study involving 11 states in the USA [15]. Annual
prevalence increased among males and females in Florida (3.2% and 6.5%, respectively) and
among females in New York (4.6% per year) with no significant changes in California.
Earlier descriptions of pulmonary NTM disease described a male predilection for disease.
However, in three recent studies from the USA, a higher proportion of disease was observed in
females than males [911]. Over an 8-year period from 1998 to 2005, the overall prevalence rate of
hospitalisations for NTM pulmonary disease in the USA was highest in females aged o70 years
(9.4 per 100,000) compared with similarly age matched males (7.6 per 100,000) [11].
The reasons for the increase in incidence and prevalence have not been explained although
increased awareness of the disease and improved diagnostic techniques could be factors. A true
increase in incidence could be related to changes in the host such as an aging population, an
increased prevalence of chronic lung disease or an increase in the number of immunocompromised individuals. The observation of a decreased incidence of pulmonary TB and an increased
incidence of pulmonary NTM [8] could be explained by cross-immunity between mycobacterial
species. Finally, an increase in the prevalence or virulence of organisms in the environment or
changes in human behaviour that would lead to increased exposure to organisms could be
contributors. In support of the latter, the frequency of skin reactivity to purified protein
derivative-B, which used antigens from Mycobacterium intracellulare, increased from 11.2% in
19711972 to 16.6% in 19992000 [17].
Studies utilising delayed type hypersensitivity reaction to subcutaneously injected mycobacterial

antigens have estimated that 1133.5% of the population in the USA has been exposed to NTM
[1821]. A prospective study using skin testing data from Palm Beach, Florida reported that 32.9%
of 447 participants in a population-based random household survey had a positive reaction to
Mycobacterium avium sensitin [21]. Predictors of a positive reaction included Black race, birth
outside the USA and .6 years cumulative exposure to soil. Using data from the National Health and
Nutrition Examination Survey (NHANES), investigators reported similar findings with regards to
sensitisation to M. intracellulare [17]. Male sex, non-Hispanic Black race and birth outside the USA
were each independently associated with sensitisation. These two studies are interesting in that skin
test reactivity to either M. avium or M. intracellulare antigens was associated with factors probably
associated with soil exposure. However, at least in the USA, disease seems to be more common in
older Caucasian females. Thus, the risk factors for exposure and infection may be different from
those associated with disease.
C.L. DALEY
Risk factors for NTM infection and disease
Most NTM are significantly less pathogenic than Mycobacterium tuberculosis and probably require
some degree of host impairment to result in disease. Impairment can be caused by immune defects
or chronic lung disease of which the latter appears to be most common. NTM disease has been
described in association with cystic fibrosis (CF), chronic obstructive pulmonary disease including a1-antitrypsin deficiency, cavitary lung disease, pneumoconiosis, bronchiectasis, prior TB,
117
Historically male sex has been considered a risk factor for NTM lung disease and males continue
to make up the majority of patients in some areas [14]. However, studies from the USA and South
Korea have noted a female predominance. In Oregon, as noted previously, the rate of NTM
pulmonary diseases was higher in females than males and females made up 60% of cases. Why the
shift to a female predominance remains unclear. However, there is likely a genetic link because
many females who develop bronchiectasis and NTM infection share a similar body type
characterised by tall slender status with a higher frequency of pectus excavatum, kyphoscoliosis
and mitral valve prolapse than females who do not have NTM infection [2224]. This condition
was first described by PRINCE et al. [25] in 1989 and later referred to as the Lady Windermere
Syndrome after the character in Oscar Wildes play Lady Windermeres Fan, the reference
referring to fastidious behaviour in the character [26]. Recently, investigators reported that female
patients with pulmonary NTM disease were taller, thinner and weighed less than matched control
subjects [22]. To date, extensive evaluation of the immune system of these patients has been
unrevealing but mutations in the cystic fibrosis transmembrane conductance regulator gene are
common [22, 27].
pulmonary alveolar proteinosis and chronic lung injury due to aspiration from gastro-oesophageal
disorders [2834]. Bronchiectasis is an almost universal finding in females with NTM infection
and it is seen in many males with NTM infection. However, NTM infections have been reported to
occur in only 12% of bronchiectasis patients in two small series from the UK [35, 36]. In
contrast, studies have documented a high prevalence of NTM from sputum cultures in patients
with CF, with estimates ranging from 3% to 19.5% [37, 38].
Pulmonary disease due to NTM has been described in several other immunocompromised patient
populations including transplant recipients [3942], individuals taking tumour necrosis factor-a
inhibitors [4345], and patients with mutations in interferon (IFN)-c receptor 1, IFN-c receptor
2, interleukin (IL)-12 p40 and the IL-12 receptor [46, 47]. Most of these patients present with
disseminated disease. Scientists have hypothesised that in slender, older females, decreased leptin,
increased adiponectin and/or decreased oestrogens may account for the increased susceptibility to
NTM infections [48]. Additionally, anomalies of fibrillin that lead to the expression of the
immunosuppressive cytokine transforming growth factor-b may further increase susceptibility to
NTM lung disease [48].
NTM INFECTIONS
Diagnosis and management

Chronic pulmonary disease is the most common clinical presentation of NTM disease. In order to
diagnose pulmonary NTM infection clinicians must weigh clinical, bacteriologic and radiographic
information. Diagnostic criteria have been developed to aid the clinician in the diagnostic
evaluation of persons suspected of having pulmonary NTM disease (table 2) [3, 49]. Although the
diagnostic criteria provide a useful approach for the evaluation of patients with suspected NTM
disease, the approach has yet to be validated and it is impossible for a single set of diagnostic
criteria to be appropriate for all patients and species of NTM.
Unlike with TB, a single positive sputum culture for NTM is not diagnostic of pulmonary disease.
However, when two or more sputum cultures are positive the diagnosis of disease is more likely.
For example, 98% of patients with two or more positive sputum cultures for M. avium complex
(MAC) had evidence of progressive disease in a study from Japan [50]. Whether this microbiologic
criterion holds true for other NTM species is not known but given the wide range of pathogenicity
among the various NTM species it is unlikely. Patients who are suspected of having NTM lung
disease but do not meet the diagnostic criteria should be followed clinically until the diagnosis is
either firmly established or excluded.
Laboratory diagnosis
Ultimately, the diagnosis of NTM disease is based on isolation of these organisms from clinical
specimens. Both solid and broth media should be used for detection of mycobacteria and a semiquantitative reporting of colony counts is recommended [3]. Most NTM grow within 23 weeks
Table 2. Microbiological criteria for diagnosis of nontuberculous mycobacteria lung disease
Respiratory specimen
Sputum specimen
Bronchial wash/lavage
Tissue biopsy
Culture and histopathological results

ATS recommendations
BTS recommendations
At least two separate positive cultures
Positive cultures from specimens

obtained at least 7 days apart
Not described
Not described
One positive culture

Compatible histopathology
(granulomatous inflammation) and a
positive biopsy culture and/or a positive
sputum or bronchial wash/lavage culture
118
ATS: American Thoracic Society; BTS: British Thoracic Society. Data from [3, 49].
on subculture and rapidly growing mycobacteria usually grow within 7 days of subculture.
Identification of specific species can be based on phenotypic, chemotaxonomic and molecular
methods [3]. However, none of these procedures are sufficient to differentiate all NTM.
As noted previously, skin test reactions to mycobacterial antigens are common in people living in
endemic areas and, thus, are unable to distinguish NTM infection from disease. Tests that could
distinguish infection from disease would be very helpful for clinicians. Measurement of anti-A60
immunoglobulin (Ig)G was reported to have a sensitivtity of 87% and specificity of 97% for
detection of Mycobacterium abscessus disease in patients with CF [51]. In Japan, KITADA et al. [52]
evaluated the performance of an assay that detects serum IgA antibody to glycopeptidolipid core
antigen for the diagnosis of MAC lung disease. The sensitivity and specificity of the assay for
detecting MAC lung disease were 84% and 100%, respectively. Antibody levels were higher in
patients with nodular bronchiectatic disease compared with fibrocavitary disease and levels
correlated with extent of disease by chest computed tomography (CT) scans. In a follow-up study
of patients who underwent bronchoscopy, the sensitivity, specificity, positive predictive and
negative predictive values were 78.6%, 96.4%, 95.7% and 81.8%, respectively [53]. The sensitivity
and specificity of the test for MAC pulmonary disease in patients with rheumatoid arthritis was
43% and 100%, respectively [54]. Although these serologic assays are not widely available, they
may eventually find their way into diagnostic algorithms.
C.L. DALEY
The clinical usefulness of drug susceptibility testing in the management of patients with NTM
disease remains controversial because in vitro results do not correlate well with clinical outcomes
for some mycobacterial species. Unfortunately, there is no single susceptibility method that is
recommended for all species of slowly growing mycobacteria. For MAC, a broth-based culture
method with both microdilution and macrodilution methods are considered acceptable [3]. Initial
isolates, as well as those from patients who fail or relapse, should be tested to clarithromycin.
Isolates of Mycobacterium kansasii should be tested to rifampin as resistance to rifampin is
associated with treatment failure/relapse [3]. Broth microdilution minimum inhibitory concentration (MIC) determination for susceptibility testing is recommended for rapidly growing
mycobacteria.
Slowly growing mycobacteria

The slowly growing mycobacteria include organisms with wide ranging pathogenicity such as
M. kansasii and Mycobacterium szulgai, which are probably second only to M. tuberculosis in terms
of disease producing capability and Mycobacterium gordonae and Mycobacterium terrae, which
rarely cause lung disease (table 1). MAC is typically the most common NTM to cause pulmonary
disease but the frequency of M. avium versus M. intracellulare has varied between studies.
Recommendations for treatment vary between guidelines as highlighted in table 3 [3, 49, 55].
Mycobacterium avium complex

MAC includes the NTM species M. avium, of which there are several subspecies, M. intracellulare,
and some that are as yet poorly described species. The traditionally recognised presentation of
MAC lung disease has been as apical fibrocavitary lung disease similar to TB, usually in older males
who have a history of cigarette smoking and alcohol abuse (fig. 1). MAC lung disease also presents
with nodular and interstitial nodular infiltrates frequently involving the right middle lobe or
lingula, predominantly in post-menopausal, nonsmoking Caucasian females. This form of disease,
termed nodular/bronchiectatic disease, tends to have a much slower progression than cavitary
disease. Nodular/bronchiectatic MAC lung disease is radiographically characterised by chest highresolution CT (HRCT) findings that include multiple small centrilobular pulmonary nodules and
bronchiectasis (fig. 2).
119
Treatment of MAC pulmonary disease involves a two to three drug regimen, which includes
ethambutol, a rifamycin (rifampicin or rifabutin) and a macrolide (clarithromycin or azithromycin).
Mycobacterium
xenopi
Mycobacterium
malmoense
Mycobacterium
kansasii
ATS: American Thoracic Society; BTS: British Thoracic Society; MAC: Mycobacterium avium complex. #: treatment should continue for 12 months beyond the date of culture
conversion. Data from [3, 49, 55].
ATS: a fluoroquinolone could be substituted.

BTS: addition of clarithromycin may be best in terms of
efficacy but would be likely to increase risk of side-effects.
Rifampicin
Ethambutol
macrolide
12+
24
Rifampicin
Ethambutol
12+
24
Rifampicin
Ethambutol
12+
ATS: three times weekly therapy is recommended for those with

non-cavitary disease. In cavitary disease, an aminoglycoside
is recommended for the first 2 months of therapy.
BTS: in patients with compromised immune defences
continue treatment for 1524 months or until the sputum
has been negative for 12 months.
ATS: specific combinations of these drugs are not described.
24
Rifampicin
Ethambutol
12+
MAC
Rifampicin
Ethambutol
Macrolide
Rifampicin
Ethambutol
Isoniazid
Rifampicin
Ethambutol Isoniazid
fluoroquinolone or macrolide
Rifampicin
Ethambutol
Macrolide Isoniazidaminoglycoside
Drugs
Drugs
Duration
months#
Duration
months
Comments
BTS recommendations
ATS recommendations
Organism
Table 3. Recommendations for the treatment of select slowly growing nontuberculous mycobacteria
NTM INFECTIONS
120
Unfortunately, treatment outcomes have

varied significantly between studies [3, 56].
In a randomised controlled clinical trial
conducted by the British Thoracic Society
(BTS) comparing clarithromcyin versus
ciprofloxacin in combination with rifampicin and ethambutol for treatment of
pulmonary MAC, the clarithromycin-containing arm was associated with a higher
all-cause mortality (48% versus 30%) but
lower rates of failure and relapse (13% versus
23%) compared with the ciprofloxacincontaining arm [55]. In a previous BTS
study, rifampicin and ethambutol were associated with a failure and relapse rate of 41%
compared to 16% in the comparator arm,
which contained isoniazid. Because the
macrolides are the only antimicrobial agents
for which there is a correlation between in
vitro susceptibility and clinical response and
the high rate of poor outcomes reported
with rifampicin and ethambutol, the ATS
recommends inclusion of a macrolide in
all patients. [5762]. Therapy three times a
week is recommended for patients with noncavitary disease [3]: this recommendation is
based on a study that demonstrated poor
bacteriological responses in patients who
were treated three times a week and had
evidence of cavitary disease [63]. Intermittent therapy with ethambutol may
be associated with a lower rate of optic
neuritis [64].
In patients with extensive radiographic
disease, cavitary disease, marolide resistance
disease or treatment failure, an injectable
aminoglycoside (amikacin or streptomycin)
should be considered. A randomised trial
from Japan reported that patients who
received streptomycin three times a week
for the initial 3 months of therapy along
with three other drugs had a faster sputum
conversion rate compared with those that
were in the placebo arm [65]. However,
long-term relapse rates were not different
between arms.
Macrolide-resistant MAC lung disease is
associated with a poor prognosis [66]. The
two major risk factors for macrolideresistant MAC disease are macrolide monotherapy or treatment with macrolide and
inadequate companion medications. The
treatment strategy associated with

the most success for macrolideresistant MAC lung disease includes
the use of a multidrug regimen
including a parenteral aminoglycoside (streptomycin or amikacin) and
surgical resection (debulking) [66].
Clofazimine, in combination with
ethambutol and a macrolide, has
been used successfully to treat pulmonary MAC infections and, thus,
may be a possible alternative drug for
macrolide-resistant disease [67].
a)
Mycobacterium kansasii
According to the ATS, the recommended regimen for treating

M. kansasii pulmonary disease includes daily rifampicin (600 mg?
day-1), isoniazid (300 mg?day-1) and
ethfoambutol (15 mg?kg-1?day-1), all
administered for 12 months beyond
the date of culture conversion [3].
However, the BTS recommends rifampicin and ethambutol therapy for
a total of 9 months [49]. Substitution
of clarithromycin for isoniazid has
been associated with good short-term
treatment results with daily [69] and
intermittent therapy [70].
b)
C.L. DALEY
M. kansasii is one of the most common causes of NTM lung disease

in the USA, as well as some parts of
Europe and Asia. While most patients with M. kansasii lung disease
have upper lobe fibro-cavitary abnormalities similar to TB (fig. 3), essentially any pattern of radiographic
abnormality can occur, particularly
in HIV-infected patients [68].
Figure 1. A 59-year-old male smoker with cavitary Mycobacterium

avium complex lung disease. The patient, who presented with
cough, fatigue and weight loss, was found to have acid-fast bacilli
on smear microscopy. Previous treatment with rifampicin and
clarithromcyin resulted in macrolide resistance. a) Chest radiograph
showing cavitary consolidation in right upper lobe, volume loss,
pleural thickening and scattered nodular opacities. b) Computed
tomography slice showing large cavity in right upper lung with
adjacent consolidation and bilateral severe emphysema.
121
Patients whose M. kansasii isolates

have become resistant to rifampicin as a result of previous therapy
have been treated successfully with
a regimen that consists of highdose daily isoniazid (900 mg), highdose ethambutol (25 mg?kg-1?day-1) and sulfamethoxazole (1.0 g three times per day) combined
with several months of streptomycin or amikacin [71]. The excellent in vitro activity of
clarithromycin and moxifloxacin against M. kansasii suggests that multidrug regimens
containing these agents are likely to be even more effective for treatment of a patient with
rifampicin-resistant M. kansasii disease.
Mycobacterium malmoense
Mycobacterium malmoense is considered the second most serious
pathogen after MAC in northern
Europe, although the clinical relevance of M. malmoense isolates has
varied between studies. For example, in the Netherlands [72, 73],
7080% of isolates are reported to
be clinically relevant whereas in
the USA, M. malmoense is seldom
considered clinically significant. Patients with M. malmoense lung
disease frequently have pre-existing
obstructive lung disease and present
with radiograph findings similar to
other cavitary NTM lung disease
pathogens.
NTM INFECTIONS
Figure 2. A 65-year-old nonsmoking female with history of cough,

fatigue and sinopulmonary infections for several years. Her sputum
was culture positive for Mycobacterium avium complex. Chest
computed tomography slice showing right middle lobe and lingular
bronchiectasis with atelectasis and consolidation. Note the centrilobular nodules in the dependent areas of the lower lobes
bilaterally.
In a recent report, clarithromycin,

rifampicin and ethambutol were
compared with a regimen consisting of ciprofloxacin, rifampicin and
ethambutol [55]. Overall, a more
favourable response to therapy was
reported with the macrolide-containing regimen, although overall mortality was not different between the two regimens.
Although the optimal management of M. malmoense has yet to be determined [55, 73, 74] a two
to four drug regimen is recommended that would include, at a minimum, ethambutol and
rifampicin [73].
Mycobacterium xenopi
Figure 3. A 58-year-old female with Mycobacterium kansasii lung
122
disease. The patient presented with cough, fever and weight loss.
She was treated as a tuberculosis suspect initially but her sputum
specimen grew M. kansasii. Chest computed tomography slice
demonstrating a large right upper lobe cavity.
Mycobacterium xenopi is a common cause of NTM lung disease in

Canada, the UK, and some parts of
Europe [75]. Radiographic findings with M. xenopi pulmonary
disease are variable but most often
include upper lobe cavitary changes
compatible with TB. M. xenopi
isolates were reported to have favourable in vitro MICs to isoniazid,
rifampin and ethambutol in a study
from the Netherlands [75]; however, studies have failed to find a
correlation between in vitro drug
susceptibility results and treatment
outcomes [76].
To date, the optimal treatment
regimen has not yet been determined. In a multicentre, randomised trial comparing a regimen of
clarithromycin, rifampin and ethambutol with ciprofloxacin, rifampin and ethambutol [55],
there was no difference in the treatment success, failure or relapse rates between groups.
All-cause mortality was relatively high and somewhat higher in the ciprofloxacin arm, but
death directly related to M. xenopi was low. Even with variable treatment regimens,
antimicrobial treatment cured 58% of patients who met ATS criteria for M. xenopi lung disease
in a retrospective study from the Netherlands [75]. Currently, the BTS recommends
ethambutol and rifampicin for 24 months of therapy whereas the ATS recommends the
addition of a macrolide and isoniazid and possibly an aminoglycoside depending on the
severity of disease.
Rapidly growing mycobacteria

Because many rapidly growing mycobacteria are not pathogenic in humans it is important to
identify organisms within this group to the species level since this could affect both treatment and
prognosis (table 1).
M. abscessus is one of the most common NTM infections in the USA and accounts for 6580% of
lung infections due to rapidly growing mycobacteria [29, 77]. Recent studies have demonstrated
that M. abscessus consists of three species, M. abscessus (sensu stricto) Mycobacterium massiliense
and Mycobacterium bolettii [78, 79]. In the USA, most patients with pulmonary disease due to
M. abscessus complex are nonsmoking, Caucasian females with a median age of ,60 years
[29, 80]. Similarly, in South Korea the median age of patients with pulmonary disease is 55 years
and almost all of the patients are nonsmoking females [81]. However, in the Netherlands, over half
of the patients are male many of whom have predisposing lung disease [82].
The chest radiograph usually shows multi-lobar, reticulonodular or mixed reticulonodular-alveolar
opacities [29]. HRCT findings include the presence of cylindrical bronchiectasis with multiple small
nodules, similar to MAC lung disease (fig. 4) [29, 83, 84]. Cavitation has been reported in 1044% of
patients [29, 80, 81].
Figure 4. A 70-year-old nonsmoking female with several year history

of cough, fatigue and weight loss. The patient had a history of severe
gastro-oesophageal reflux and recurrent pneumonias. Her sputum
cultures were consistently positive for Mycobacterium abscessus.
Chest computed tomography slice showing diffuse bronchiectasis
with scattered centrilobular and subcentimeter nodules. There is an
area of airspace of opacity in the posterior left lower lobe.
123
Unfortunately, M. abscessus has

demonstrated in vitro activity to
only a few antimicrobial agents.
The ATS recommends therapy
with 24 months of intravenous
antibiotics such as imipenem or
cefoxitin plus amikacin given daily
or three times per week [3]. Oral
agents that have demonstrated in
vitro activity should be included in
the treatment regimen. Unfortunately, macrolides are the only oral
agents typically active in vitro
against M. abscessus. Studies have
demonstrated the presence of an
erythromycin ribosomal methylase
gene, erm(41), in M. abscessus,
which could result in the development of macrolide resistance and
possibly affect treatment responses
[77, 85]. Other drugs that sometimes demonstrate in vitro activity
C.L. DALEY
Mycobacterium abscessus complex
include linezolid and tigecycline, however, both drugs are associated with frequent adverse effects
[86, 87].
Because of the high levels of in vitro resistance, cure is difficult to achieve in patients with lung
disease due to M. abscessus. In South Korea, JEON et al. [81] reported the outcomes of 65 patients
with pulmonary disease who were treated with a standardised regimen. Patients were hospitalised
and treated with intravenous cefoxitin and twice daily amikacin plus oral clarithromycin,
ciprofloxacin and doxycycline. After 1 month the intravenous drugs were stopped and the oral
medications continued for a total of 24 months and at least12 months beyond the date of culture
conversion [81]. 83% of the patients reported improvement in symptoms and 74% had
radiographic improvement as documented by HRCT. Sputum conversion and maintenance of
negative sputum cultures for .12 months was achieved in 38 (53%) patients. However, drugrelated adverse events were common. Neutropenia and thrombocytopenia associated with
cefoxitin developed in 33 (51%) and four (6%) patients, respectively. Drug-induced hepatoxicity
occurred in 10 (15%) patients. Cefoxitin had to be stopped, and in some cases switched to
imipenem, in the majority of patients.
NTM INFECTIONS
In a recent report from Denver, CO, USA, the outcomes of 107 patients treated for pulmonary
M. abscessus disease were reported [80]. Treatment regimens varied but followed current ATS
recommendations. Cough, sputum production and fatigue remained stable, improved or resolved
in 80%, 69% and 59% of patients, respectively. Treatment outcomes were disappointing: 20 (29%)
out of 69 patients remained culture positive, 16 (23%) patients converted but relapsed, 33 (48%)
patients converted to negative and did not relapse and 17 patients (16%) died during the study
period.
As noted previously, speciation of the rapidly growing mycobacteria may be important because
outcomes may vary based on the species of NTM. KOH et al. [77] reported significant differences
in the clinical, radiographic and microbiologic outcomes in patients treated for M. abscessus versus
M. massiliense. Sputum conversion and maintenance of negative cultures occurred in 88% of
patients with M. massiliense compared with 25% of patients with M. abscessus, despite receiving a
similar treatment regimen. When isolates of M. abscessus were incubated with clarithromycin, all
became resistant within 7 days and the MIC continued to increase at day 14. In contrast, none of
the M. massiliense isolates acquired resistance upon exposure to clarithromycin. The erm(41) gene
was present in all of the M. abscessus isolates but was partially deleted in the M. massiliense isolates.
A combination of surgical resection and chemotherapy may increase the chance of cure in patients
who have focal lung disease and who can tolerate resection. Among 14 (22%) patients with
pulmonary M. abscessus infection in South Korea who underwent surgical resection, negative
sputum culture conversion was achieved within a median of 1.5 months and was maintained in
88% of those with pre-operative culture-positive sputum. Similarly, in a study from the USA,
patients who had surgical resection plus medical therapy were more likely to convert their cultures
to negative and not relapse compared with medical therapy alone (65% versus 39%; p50.041)
[80]. Moreover, significantly more patients who underwent surgery converted sputum cultures to
negative and remained negative for at least 1 year when compared with those who received
medical therapy alone (57% versus 28%; p50.022).
Mycobacterium chelonae and Mycobacterium fortuitum

Although Mycobacterium chelonae and Mycobacterium fortuitum are less likely to cause lung
disease than M. abscessus the clinical and radiographic presentations are similar [29, 88]. Of 26
patients in South Korea who grew M. fortuitum from two or more sputum specimens, 25 were not
treated and none showed evidence of progressive disease over a median of 12.5 months of followup [88].
124
Isolates of M. chelonae are usually susceptible to the macrolides, linezolid, tobramycin and
imipenem and uniformly resistant to cefoxitin [8991]. Other active drugs may include amikacin,
clofazimine, doxycycline and fluoroquinolones. The ATS recommends that treatment of

M. chelonae infections should consist of at least two drugs to which in vitro drug susceptibility
has been demonstrated. Unlike M. abscessus and M. fortuitum, M. chelonae does not appear to
possess a copy of erm(41) [85].
In contrast to M. abscessus and M. chelonae, M. fortuitum demonstrates broader in vitro susceptibility to both oral and intravenous antimicrobial drugs including the newer macrolides,
fluoroquinolones, tetracycline derivatives, sulfonamides and intravenous drugs imipenem and
cefoxitin [3]. Although most isolates of M. fortuitum are susceptible in vitro to the macrolides, they
should be used with caution because of the presence of erm(41) [92]. As with M. chelonae,
M. fortuitum lung disease should be treated with at least two drugs to which in vitro susceptibility
has been demonstrated [3].
Surgical therapy for NTM lung disease
The benefits must be weighed against the possible complications of surgery. In seven surgical
series reported during the macrolide era, the rate of complications varied from 0% to 44%
averaging approximately 25% [94100]. In the largest study to date in Colorado (USA),
MITCHELL et al. [99] reported the outcomes of 236 patients who underwent lung resection for
NTM pulmonary disease over a 23-year period. Minor complications were reported in 18.5% of
the patients with 31 (11.7%) suffering from serious complications. Bronchopleural fistula
occurred in 11 (4.2%) cases. No operative mortality was reported in six case series and postoperative mortality ranged from 0% to 11%. In the study from Colorado, seven (2.6%) patients
died as a result of the procedure; however, the mortality rate was only 0.6% for the last 162
patients that were operated on from 2001 to 2006. Many of these latter patients underwent
video-assisted thoracoscopic surgery. Because case volume may be associated with outcomes,
surgery should be performed by thoracic surgeons with extensive experience in performing this
type of surgery [99].
C.L. DALEY
Patients who have failed a standard therapeutic regimen, particularly those who harbour resistant
organisms, may benefit from surgical resection of the most affected areas. In 12 published series
involving a total of 602 patients (range 8236), the post-operative sputum culture conversion rate
ranged from 82% to 100% with a mean conversion rate of 94% [93]. Long-term relapse was not
reported in all studies but ranged from 0% to 13%.
Conclusion
NTM represent a broad array of organisms with varying prevalence and pathogenicity. Pulmonary
infections due to NTM appear to be increasing and the epidemiology is shifting toward a female
predominance in some areas. Clinicians must consider clinical, radiographic and bacteriologic
information when diagnosing NTM pulmonary infection. Although diagnostic criteria exist, these
have yet to be prospectively validated. Consideration of the species of NTM is an increasingly
important element of diagnosis and may impact the outcomes of therapy. Treatment regimens
vary by NTM species as do treatment outcomes. Future areas of research should focus on the
epidemiology of NTM infections, transmission of infection, risks for disease progression,
development of new diagnostics and ultimately development of new drugs and treatment
regimens. Until we have a better understanding of the transmission and pathogenesis of these
difficult to treat infections, it will be difficult to formulate a rationale plan for prevention of
infection.
125
None declared.
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Chapter 9
Ciliary dyskinesias:
primary ciliary
dyskinesia in adults
L.J. Lobo*, M.A. Zariwala# and P.G. Noone*
PCD IN ADULTS
Summary
Primary ciliary dyskinesia (PCD) is a genetic disorder of cilia
structure and function, chronic infections of the respiratory
tract, fertility problems and disorders of organ laterality.
Establishing a definitive diagnosis can be challenging, requiring
a compatible phenotype and detection of ciliary functional and
ultra-structural defects, along with newer screening tools such
as nasal nitric oxide and genetics testing. 10 known PCDcausing mutations within two genes are now available in a
clinical panel, and in the future, comprehensive genetic testing
may serve to identify young infants with PCD to improve the
long-term outlook for patients with the disease. Therapy
includes regular pulmonary function testing and monitoring
of sputum flora to allow a targeted approach to treatment.
Referral to an academic centre with expertise in bronchiectasis
and/or PCD is prudent to ensure access to the most recent
diagnostic testing and therapies. With increased understanding
of the disease it is likely that we will expand the definitions of
classic and non-classic PCD, as well as its relationship to less
common ciliopathies.
Keywords: Bronchiectasis, cilia, dynein, mucociliary clearance,
nitric oxide, primary ciliary dyskinesia
*Division of Pulmonary Diseases, and

#
Dept of Pathology and Laboratory
Medicine, University of North
Carolina, Chapel Hill, NC, USA.
Correspondence: P.G. Noone, CB
7020, Pulmonary Division, University
of North Carolina School of
Medicine, Chapel Hill NC 275997020, USA, Email
pnoone@med.unc.edu
Eur Respir Mon 2011. 52, 130149.

Copyright ERS 2011.
ISSN: 1025-448x.
DOI: 10.1183/1025448x.10003910
130
iliary dyskinesia refers to a syndrome of oto-sino-pulmonary disease with other

accompanying phenotypic features. It is often referred to as primary ciliary dyskinesia
(PCD) and sometimes referred to as immotile cilia syndrome (ICS) or Kartagener syndrome, or
occasionally the motile ciliopathies [13]. PCD is currently the preferred term [4]. Although
secondary ciliary dyskinesia may be seen in diseases associated with acute and chronic airway
inflammation and infection, this chapter will focus primarily on the genetically transmitted form
of the disease, that is PCD, rather than nongenetic, generally secondary forms of the syndrome [5].
Since the hallmarks of the disease are chronic lung disease with bronchiectasis, a brief discussion of
the major respiratory features (bronchiectasis) is included, as well as a brief review of airway host
defence. This will allow a better understanding of the role of cilia in health and disease. This
chapter will focus on disease in adults, as an excellent review of PCD in children was recently
published [6].
The major clinical characteristics of PCD are chronic ear, sinus and lower airways symptoms and
signs from birth because of the failure of one of the major airway defence mechanisms, that of
MCC. By adulthood, bronchiectasis is invariable and is characterised by an abnormal and
permanent dilation of bronchi. It is the consequence of inflammation and destruction of the
structural components of the bronchial walls, usually in the walls of the medium-sized airways,
often at the level of segmental and sub-segmental bronchi. Most experts accept that a vicious
cycle of infection and inflammation is created by the basic defect in airway host defence. This
generates airway damage and further impairment of airway clearance, eventually with chronic
colonisation/infection with a variety of microorganisms, leading to further infection and
inflammation and eventually destruction of conducting airways and even alveolar surfaces. In its
most severe form, bronchiectasis may lead to respiratory failure and death. For the clinician faced
with a patient with bronchiectasis, the diagnostic algorithm involves sifting through the various
causes of the disease, with a predominant cause often elusive; thus, it may be labelled either as
idiopathic or, with an appropriate history, as post-infectious bronchiectasis [9]. However, a
careful clinical history, together with focused tests, may find an underlying cause such as CF or
PCD, which is almost always helpful from genetic, prognostic, therapeutic and healthcare system
standpoints.
L.J. LOBO ET AL.
PCD is a rare, usually autosomal recessive disease characterised by oto-sino-pulmonary disease,

including bronchiectasis, organ laterality defects and male infertility. First described early in the 20th
century, its disease origins as a defect in ciliary structure and function were described in Sweden in
the 1970s [7, 8]. The last decade or so has seen resurgence in interest in PCD, specifically a new focus
has emerged from several groups worldwide on more precisely defining the major aspects of the
disease phenotype, including elucidating the molecular basis for the ciliary abnormalities. Such data
will help clinicians establish a diagnosis of PCD (which can be difficult in many circumstances),
which in turn, will hopefully allow more targeted therapeutic approaches. Cystic fibrosis (CF) has
long been recognised as a prototype genetic disease associated with severe pulmonary disease and
bronchiectasis, with intense research activity devoted to CF pathogenesis and treatment over the last
several decades. PCD offers a similar disease model to CF, albeit with a different basic aetiology,
offering complementary insights into significant human disease associated with dysregulation of the
mucociliary clearance (MCC) apparatus in the respiratory tract.
Thus, structural and functional abnormalities of motile cilia and human flagellated cells (sperm)
explain the complex PCD phenotype involving various organ systems. The motile cilia in the
respiratory tract are vital components of the mucociliary apparatus used in airway clearance and
the flagellated structures are important in the male and female reproductive systems. Leftright
asymmetric organ defects may also be part of the phenotype, for example, situs inversus totalis,
commonly known as Kartagener syndrome [10].
Normal cilia structure and function

In addition to humoral, cellular and innate immune systems, the respiratory tract has developed
complex local physical defences to protect the airways from the myriad of inhaled pathogens,
allergens and other inhaled noxious particles. One such mechanism is the mucociliary escalator,
which mechanically eliminates bacteria and particulates that deposit on the epithelial surface of the
respiratory tract.
131
Cilia are hair-like attachments found on the epithelial surfaces (,200 per cell) of various organs
and are anchored on by a basal body to the apical cytoplasm and extend from the cell surface into
the extracellular space. Each cilium is composed of approximately 250 proteins organised into
longitudinal microtubules, which make up the basic axonemal structure [11]. Based on the
arrangement of the microtubules,

cilia are classified into motile cilia,
Inner dynein arm primary cilia and nodal cilia [12].
Motile cilia are the cilia found in
the apical surfaces of the upper and
Microtubule A
lower respiratory tract, the ependymal cells lining the ventricles of
the central nervous system, the
Microtubule B
oviducts of the female reproductive
tract and the flagellum of the male
Radial spoke
sperm. Motile cilia are organised
into nine microtubule pair doubCentral complex lets, surrounding a central pair
creating a distinctive 9+2 arrangement (fig. 1) [3]. The central pair
is linked to the surrounding pair
Figure 1. Diagram of a cross-section of the basic ciliary structure.
doublet through an array of radial
spoke proteins and the surrounding pair doublets are linked to one another via nexin linked proteins. Through ATP-containing
dynein arms on the peripheral microtubules, the microtubules slide by one another to produce
ciliary motion [13]. The protein links between the microtubules limit the degree of sliding and
allow the cilium to bend. Dyneins can be sub-divided into axonemal and cytoplasmic dyneins.
Axonemal dyneins move cilia and flagella, as described previously, while cytoplasmic dyneins are
involved in the organisation of spindle poles during mitosis [14]. Axonemal dyneins form two
structures, the inner and outer arms, and are attached to the microtubules of the nine outer
doublets throughout the length of the axoneme, thus they are central to the process of the bending
of the cilium or sperm tail. Through coordinated and synchronised bending, wave like movements
occur at ,16 Hz, which function to propel mucus and adherent particles/bacteria on the surface
of the airway. Integral to the normal function of cilia is normal airway periciliary fluid layer
composition and function. One of the main pathogenetic mechanisms in CF is thought to be
dysregulation of this fluid layer, which bathes cilia with a thin mucus layer on top [15]. It can be
readily seen, therefore, that two discrete abnormalities of MCC, one involving the cilia themselves,
the other involving the fluid that bathes the cilia, may result in a broadly similar airway phenotype
(bronchiectasis).
PCD IN ADULTS
Outer dynein arm
Finally, nodal cilia occur during embryonic development. In contrast to the 9+2 structure of
motile cilia, they have a 9+0 configuration. They have a very interesting rotational movement,
resulting in leftward flow of extracellular fluid, which is important for cell signalling during the
development of normal human leftright asymmetry (situs solitus) [12]. Defects in the nodal cilia
may cause errors with leftright body orientation; for example, dextrocardia, situs inversus totalis
and situs ambiguous [1618]. This explains the association of organ laterality defects in PCD, as
well as other rare genetic diseases such as polycystic kidney disease, SeniorLoken syndrome,
Alstrom syndrome, BardetBiedl syndrome and retinitis pigmentosa [19].
Clinical manifestations
The clinical signs and symptoms of PCD are shown in table 1.
132
The clinical phenotype that occurs with defective ciliary structure and function is fairly
predictable. Cells lining the nasopharanx, middle ear, paranasal sinuses, the lower respiratory tract
and the reproductive tract contain cilia and are generally affected in PCD when the disease is fully
expressed. In contrast to CF, pancreatic function is preserved, and hepatobiliary disease is usually
not a feature. In general, the clinical course of the disease is milder, with absence of the systemic
problems associated with CF such as nutritional issues and diabetes. Although there are few data
By system affected
By age of presentation
Middle ear
Chronic otitis media with tube placement
Conductive hearing loss
Nose and paranasal sinuses
Neonatal rhinosinusitis
Chronic nasal congestion and mucopurlent rhinitis
Chronic pansinusitis
Nasal polyposis
Lung
Neonatal respiratory distress
Chronic cough (lifelong)
Recurrent pneumonia
Bronchiectasis
Genitourinary tract
Male and female fertility problem or history of
in vitro fertilisation
Laterality defects
Situs inversus totalis
Heterotaxy ( congenital cardiovascular
abnormalities)
Central nervous system
Hydrocephalus (rare)
Eye
Retinitis pigmentosa
Family history
Communities or ethnicities with consanguinity
Close (usually first degree) relatives with clinical
symptoms
Antenatal
Heterotaxy on prenatal ultrasound
Newborn period
Continuous rhinorrhoea
Respiratory distress or neonatal pneumonia
Childhood
Chronic productive cough
Atypical asthma unresponsive to therapy
Chronic rhinosinusitis
Recurrent otitis media with effusion
Adolescence and adult life
Same as for childhood
Subfertility and ectopic pregnancies in females
Infertility in males with immotile sperm
Sputum colonisation with smooth/mucoid
pseudomonas, other Gram-negative organisms,
or nontuberculous mycobacteria
on life expectancy in PCD, it is believed from clinical experience, and some cross-sectional and
longitudinal studies, that PCD carries a more favourable prognosis than CF [20, 21]. Nonetheless,
the disease may be quite severe and some patients develop respiratory failure requiring
consideration for lung transplant [21].
As with CF, a clue to the diagnosis is a family history of PCD, particularly in populations with high
levels of consanguinity [22]. For example, there is a reported 1 in 2,200 prevalence of PCD in the
Asian population of Britain [23]. The prevalence of PCD in the general population is unknown,
although estimates based on mass radiology studies in differing countries (Scandinavia and Japan)
suggest a range of ,1:16,000 to 1:40,000 depending on the techniques and calculations involved,
and taking into account the likelihood that its prevalence is almost certainly underestimated, even
in these focused studies [6].
L.J. LOBO ET AL.
Table 1. Clinical signs and symptoms of primary ciliary dyskinesia
Oto-sino-pulmonary disease
133
At birth, newborns with PCD often present with a clinical syndrome of neonatal respiratory
distress, indicating the importance of ciliary function in clearing the fetal lung [24, 25]. It is useful
to consider PCD with this clinical history, whether in later childhood or adulthood (although
adult recall of neonatal events may not be reliable). Early childhood atelectasis, pneumonia,
hypoxaemia or respiratory failure can be seen [4, 26]. Frequently, these problems may be
attributed to other aetiologies (for example wet lung, aspiration or pneumonia), and PCD maybe
overlooked for some time. This is borne out by data showing the mean age at diagnosis in children
with PCD was .4 years even when persistent pulmonary symptoms occurred, such as chronic
cough and persistent rhinitis [27]. Children with wheezing may also be labelled as having
atypical asthma that is unresponsive to appropriate therapy [28]. Frequently, infants and young
children have recurrent upper respiratory tract symptoms, including chronic rhinosinusitis and
chronic otitis media [27]. Nasal polyps and conductive hearing loss from the recurrent infections
and inflammation is common [29]. Most expert paediatricians discourage placement of drainage
tubes (grommets), as these frequently lead to otorrhoea, worsening of the tympanic scarring
and hearing loss over the long term [6, 25]. Although adult nutritional issues are generally not a
feature of PCD, infants with PCD may have significant issues with severe gastro-oesophageal
reflux, feeding and ability to obtain adequate nutrition and tend to be on the lower end of the
growth curve [30]. In later childhood and early adulthood, the impaired MCC in the lower
respiratory tract leads to recurrent episodes of bronchitis and pneumonias, which eventually leads
to bronchiectasis of the middle and lower lobes [31, 32]. In all age groups, chronic cough is a
predominant feature of the disease (often reported by family members), both in response to the
chronic inflammation and as a compensatory mechanism for defective ciliary function and MCC
[33]. Adults may develop clubbing as a marker of long standing pulmonary disease. By the time
patients present to adult clinics, many adults frequently have a history of lobectomy in early life,
prior to the diagnosis being established. Since this procedure cannot usually correct what is, after
all, a general problem in the lung, it can rarely be recommended [21]. Typically the disease
manifests itself as intermittent exacerbations of infectious symptoms, but always with a baseline
level of chronic symptoms (as is usual for most patients with bronchiectasis, whatever the cause)
[34]. At all stages of the disease the focus should be on minimising symptoms, improving quality
of life and slowing declines in lung function (see later). Another unusual, but recently reported
complication of chronic airway diseases in older patients with PCD is that of lithoptysis, that is,
expectoration of stone-like masses from the airways [35]. The hypothesis is that calcite stone
formation is a bio-mineralisation response to the chronic airway inflammation and retention of
infected airway secretions in some patients with PCD.
PCD IN ADULTS
Airway microbiology/imaging
It is not infrequent that adults present to bronchiectasis clinics having rarely had sputum cultures
[21]. However, monitoring of the flora of the airway is important, since older adults often harbour
problematic organisms that may require specific treatment [21]. Based on monitoring protocols
developed for CF and small studies in PCD, it is recommend that airway cultures be performed
every 3 to 6 months [20, 21]. Initially, cultures of airway secretions (sputum cultures) grow
Haemophilus influenzae, Streptococcus pneumoniae and Staphylococcus aureus. Once bronchiectasis
is evident on chest imaging (high-resolution computed tomography (HRCT)), smooth and
mucoid Pseudomonas aeruginosa and other opportunistic pathogens such as nontuberculous
mycobacteria (NTM) may be present. In cross-sectional studies series, all adults .30 years of age
had evidence of bronchiectasis, with an increasing prevalence of these organisms [21, 36].
Pulmonary function testing

Most patients demonstrate progressive obstructive defects with advancing age. Although there are
few longitudinal data, cross-sectional studies suggest that the disease is milder than CF in terms of
the progression of loss of lung function [21, 36]. Nonetheless, it is important in order to guide
treatment, to obtain baseline and serial measures of lung function and assess disease severity and
progression, as some patients will develop severe or end-stage lung disease [21]. Ongoing studies,
involving larger numbers of patients in multiple centres, will better define longitudinal markers
and the natural history of the disease.
Radiology
134
With more abundant and specialised imaging, bronchiectasis is being observed more frequently in
general. Thus, PCD may be considered in patients with HRCT-proven bronchiectasis. The
computed tomography scan characteristics of bronchiectatic airways are well described [37].
However, HRCT features alone do not usually allow a confident distinction between cases of
idiopathic versus post-infectious bronchiectasis versus known causes or associations of
bronchiectasis, although there are certain patterns of disease distribution that support a diagnosis
of PCD, for example, a predilection for the middle and lower lobes has been reported in patients
with PCD, in contrast to the upper lobe distribution of cylindrical bronchiectasis in patients with
CF [38]. Some authors suggest that absence of bronchiectasis on a HRCT scan may have a role in
excluding the diagnosis of PCD, at least in adults [31].
Reproductive tract abnormalities

Infertility in both males and females is also a prominent feature. 9899% of males with PCD have
impaired spermatozoa motility secondary to defective sperm flagella [39]. Data are scattered in
females, but a consistent feature is that of normal or delayed fertility in some, while other females
show impaired fertility with an increased risk of ectopic pregnancy, presumably because of
impaired ciliary function in the oviduct [40].
Organ laterality and other anatomic defects
Rare associations of PCD

PCD is occasionally seen with rare diseases linked to abnormalities in primary cilia or sensory cilia,
for example in the kidney, retina and embryonic node, which may lead to a wide spectrum of
clinical features. An example is PCD with retinitis pigmentosa. Mutations in the X-linked retinitis
pigmentosa GTPase regulator gene (RPGR) gene have been identified in a few cases of PCD cosegregating with retinitis pigmentosa [41, 42]. Ciliary dysfunction in both respiratory epithelium
and the photoreceptors of the retina seems to be the common factor [42]. Hydrocephalus may be
seen in mice with PCD, but its association in humans is less clear, the problem may be secondary
to the impaired cilia that line the ventricular ependymal cells of the central nervous system, which
helps cerebrospinal fluid flow through the sylvian aqueduct [4345].
L.J. LOBO ET AL.
During the embryonic period, thoraco-abdominal orientation is determined via the unidirectional, rotating beat of nodal cilia. With abnormal nodal ciliary structure and function, thoracoabdominal organ orientation is random. This leads to situs inversus with reversal of the thoracic
and abdominal organs in ,50% of patients with PCD [16, 21]. Occasionally, laterality defects are
not pure, that is, situs ambiguous/heterotaxy may be present. This is the phenomenon of left
right asymmetry within specific organ systems, leading to either sole or randomly combined
anatomical deformities of the heart, liver and spleen. A recent series found that at least 6% of
patients with PCD have heterotaxy, including complex congenital heart defects [17]. Defects in the
outer dynein arm (ODA) may be a more common cilia abnormality in patients with laterality
defects than that of the inner dynein arm (IDA) or central apparatus [17].
Diagnostic approaches
Overview
135
Since the first reports of abnormal ciliary structure as the cause of PCD, the diagnosis of PCD has
usually been established by obtaining nasal samples of airway cilia for examination under light and
electron microscopy. With appropriate techniques, ciliary motion (absent or dyskinetic in PCD) may
be defined and ciliary ultra-structure examined for abnormalities, the classic being absent or short/
stubby dynein arms. However, these tests are quite dependent on technical factors and local expertise,
and thus it can sometimes be a challenge to definitively diagnose PCD. Recently, however, the
diagnostic work-up for PCD has evolved to encompass other methodologies, for example, measures
of nasal nitric oxide (NO), more sophisticated analyses of ciliary structure and function and genetic
testing (see later). Often, the resources needed to make a definitive diagnosis are only available in
specialised centres. Nonetheless, a history yielding the symptomatic clues above should prompt
consideration of the diagnosis and, if necessary, referral to the growing number of centres with an
interest and expertise in the diagnosis and treatment of PCD and related diseases. An algorithm of
currently available tests is presented to help the clinician work through the process (fig. 2). It goes
without saying that prior to consideration of the diagnosis of PCD, and embarking on a detailed
Clinical suspicion of PCD
CT chest scan with bronchiectasis

(middle/lower lobe predominantly
and/or heterotaxy)
No
PCD unlikely#
Rule out cystic fibrosis with a sweat chloride
test and/or CFTR gene mutation analysis
Yes
Other aetiologies of bronchiectasis
ruled out
No
Rule out primary immunodeficiencies

with Ig levels (IgG, IgA and IgM) and serum
electrophoresis and consider vaccine response
Rule out connective tissue disorders with
RF, ANA and ANCA
Yes
Nasal NO level reduced (usually 5

20% of normal)
Consider ABPA, asthma, allergic rhinitis, gastrooesophageal reflux disease and 1-antitrypsin
deficiency
No
PCD unlikely#
PCD IN ADULTS
Yes
Cilia examination
via nasal biopsy
Yes
Ciliary beat frequency and pattern
Normal
PCD not ruled out
Abnormal
Electron microscopy with
ultra-structural defect in cilia
Normal
Normal beat frequency, pattern and

ultra-structure makes PCD unlikely,
but could be non-classic disease
Yes
PCD likely
Consider genetic testing for DNAI1 and

DNAH5 using clinical panel at select
institutions (accounts for ~40%) and there
are select genetic tests and gene analysis
available at specific academic centres
Figure 2. Diagnosis algorithm for primary ciliary dyskinesia (PCD) in adults. For clinical signs refer to table 1.
CT: computed tomography; NO: nitric oxide; CFTR: cystic fibrosis transmembrane conductance regulator;
Ig: immunoglobulin; RF: rheumatoid factor; ANA: antinuclear antibodies; ANCA: antineutrophil cytoplasmic
antibodies; ABPA: allergic bronchopulmonary aspergillosis. #: if clinical suspicion is still high for PCD other,
more specific tests may be undertaken; ": normal ciliary beat frequency and pattern does not completely rule
out PCD.
136
work-up, other diseases can be considered and ruled out as appropriate [9]. As there are wide
variations in PCD presentation and phenotype there may be overlap with CF, immunological
deficiencies, allergic bronchopulmonary aspergillosis (ABPA) and other causes of bronchiectasis.
Other chapters in this Monograph address these diseases in considerable detail.
Screening tests versus diagnostic tests

Tests of ciliary function can be divided into those that are indirect and may be used to screen
patients (e.g. the nasal saccharin test) and those that definitively assess function and structure
(ciliary beat frequency (CBF)/pattern tests and electron microscopy studies). Newer screening/
diagnostic tests currently undergoing study include nasal NO, which may reflect ciliary structure
function indirectly, immunofluorescent analysis of ciliary proteins, high-speed video-microscopy
to quantitate ciliary motion and clinically available panels of genetic tests known to be associated
with ciliary structural abnormalities.
MCC: the saccharin test

The saccharin test is cheap and can be readily performed in the clinical setting as a screening test.
However, it is subject to an array of technical factors that render it less reliable than other
methodologies. A 12 mm particle of saccharin is placed on the inferior nasal turbinate 1 cm from
the anterior end (if too far anterior cilia actually beat forwards from the nose). The difficult part is
that the patient must sit quietly with the head bent forward without sniffing, sneezing, coughing,
eating or drinking. The time it takes for the patient to taste the saccharin is a rough measure of
nasal MCC. Generally, tasting saccharin in ,30 minutes is normal. Patients with rhinosinusitis
commonly taste it within 60 minutes. If it is not tasted within 60 minutes, PCD can be considered.
The test is not suitable for small children who will not sit still for 60 minutes, patients with a poor
sense of taste and patients with a cold within the past 6 weeks [46].
NO is present in high concentrations in the upper respiratory tract and is produced by the
paranasal sinus epithelium [47]. NO is produced enzymatically from L-arginine by several
isoforms of NO synthase. NO appears to contribute to local host defence, modulate ciliary motility
and serve as an aerocrine mediator in helping to maintain adequate ventilationperfusion
matching in the lung [48]. Abnormal values of nasal NO have been reported in various sinus and
lung diseases; for example, acute and chronic sinusitis, CF and nasal polyposis [48]. Quite
fortuitously, low nasal NO levels were first reported in PCD in the early 1990s by a Scandinavian
group researching exhaled NO in a variety of normal and diseased states [49]. The observation has
been replicated on several occasions and, although not fully understood at a mechanistic level, it
seems to be a robust index of classic PCD [21, 50]. In individuals with PCD, levels of exhaled NO
are extremely low (,10% of normal values) even when compared with patients with CF and other
sinus disorders, where nasal NO may be low, although not usually in the PCD range [51, 52].
Interestingly, in one study, carriers (nonsmoking parents of patients with PCD) had intermediate
levels of nasal NO [21]. Confirmation of the diagnosis of PCD requires further diagnostic tests.
Nevertheless, the highly reproducible nature of low nasal NO levels make it a valuable screening
tool [53].
L.J. LOBO ET AL.
NO levels
Ciliary function
137
Transnasal brushings or nasal scrape samples may be obtained fairly readily via direct visualisation
of the inferior turbinate, without local anaesthesia or sedation [54]. Ciliary beat patterns and
frequency can be seen under direct visualisation using a microscope, and classed as qualitatively
normal, dyskinetic or immotile [21, 55]. For more quantitative measures, CBF can be measured
and the ciliary waveform can be analysed using high-speed digital video imaging to differentiate
between abnormal beating cilia and the normal beat patterns [56]. A cilium can be viewed in slow
motion or frame by frame, with 40 to 50 frames per ciliary beat cycle [57]. Normal cilia beat
forward and backwards within the same plane, with no sideways recovery sweep. Recent advances
in computer image processing software may help standardise measures of waveform and direction
of multiple cilia, as a measure of the effectiveness of ciliary transport [58, 59]. This software may
also efficiently compute ciliary activity with accuracy and reproducibility. CBF and beat pattern
abnormalities have been associated with specific ultra-structural defects such as isolated outer arm
defects, isolated inner arm or radial defects or transposition defects [58]. If patients have both a
normal CBF and a normal beat pattern, then classic PCD can reasonably be excluded. However, if
one or the other is abnormal, further studies are necessary. As with any studies of cilia structure
and function, it is critical to exclude ongoing inflammation as a cause of secondary ciliary
dysfunction leading to false positives [5].
PCD IN ADULTS
Ciliary structure
In patients with an appropriate phenotype, suspicion for PCD for other reasons (for example,
respiratory symptoms and a sibling with disease) or positive screening tests (saccharin test, nasal
NO or CBF abnormalities), the axonemal structure of the respiratory cilia should be studied using
transmission electron microscopy (TEM) [8]. Inflammatory influences can be avoided by
sampling the patient in a stable state, post-antibiotics or, if in vitro testing, by culturing the
epithelial cells in an inflammation-free environment. The yield may be higher in patients with
sino-pulmonary symptoms rather than isolated upper or lower respiratory tract symptoms [60].
There are a number of structural phenotypes associated with PCD [61]. Most cases of PCD are due
to a lack of ODA, or a combined lack of both IDA and ODA [21]. Less common defects include
IDA defects alone or defects in combination with radial spoke defects, or central microtubule pair
defects such as transposition or central microtubular agenesis [6264]. In a proportion of patients
with PCD, no structural defects were defined using existing TEM techniques [53, 60]. This, despite
a strong phenotype, defined ciliary functional abnormalities and demonstrated genetic defects,
underscoring the notion that the disease is almost certainly under-diagnosed, due to the hitherto
reliance on TEM as the gold standard for diagnosis of the disease. As seen later, advances in
molecular techniques will probably allow a broader definition of PCD (classic and non-classic
PCD, akin to the situation with CF), leading to more efficient diagnosis with subsequent beneficial
downstream effects for earlier diagnosis, treatment and improved long-term clinical outcomes.
Immunofluorescent stains
Immunofluorescent analysis using antibodies directed against the main axonemal components has
recently been used to facilitate identification of structural abnormalities of cilia, and is used in
diagnosis in some centres in Europe [65, 66]. PCD patients with ODA defects have absence of
DNAH5 staining from the entire axoneme and accumulation of DNAH5 at the microtubuleorganising centre as compared with normal individuals with normal DNAH5 staining along the
ciliary axoneme [66]. Recent work has also shown that antibody-based techniques can diagnose
not only ODA but also IDA abnormalities caused by KTU mutations in PCD [67]. In the future, it
may be possible to develop a panel of antibodies directed towards multiple ciliary proteins that
may enable the screening of respiratory epithelial samples.
Genetic testing
Overview
138
As the molecular underpinnings and the genetics of PCD become more defined, genetic testing
may overcome some of the drawbacks of the currently available diagnostic tests. Given the
complexity of ciliary structure and the genetic heterogeneity of PCD, finding gene mutations
causative for PCD has been challenging. Fortunately, non-human models have helped in the
process of discovery. Since the basic structure of cilia is highly conserved across species, an
example being a simple green alga, Chlamydomonas reinhardtii, extensive information has been
gleaned regarding the structure, function and genetics of human cilia, specifically identifying
candidate proteins and genes from mutant Chlamydomonas that are critical for normal ciliary function
(e.g. slow swimmers with ODA defects and mutant c-heavy chain dynein) [68]. Initial mutations
Table 2. Primary ciliary dyskinesia-causing genes in humans showing extensive locus heterogeneity
Human gene
DNAI1
DNAI2
DNAH5
DNAH11
TXNDC3
KTU/PF13
LRRC50
CCDC39
CCDC40
RSPH4A
RSPH9
Chromosomal
location
Axonemal
component
Ultra-structure of
patients with mutations
[Ref.]
9p13.3
7q25
5p15.2
7p21
7p15.2
14q21.3
16q24.1
3q26.33
17q25.3
6q22.1
6p21.1
ODA IC
ODA IC
ODA HC
ODA HC
ODA IC/LC
Cytoplasmic#
Cytoplasmic#
Ciliary Axoneme
Ciliary axoneme
RS
RS
ODA defects
ODA defects
ODA defects
Normal ultra-structure
ODA defects
ODA+IDA defects
ODA+IDA defects
Axonemal disorganisation
Axonemal disorganisation
Transposition defect
CP defects and normal
ultra-structure
[6973]
[74, 75]
[7678]
[7983]
[84]
[67]
[85, 86]
[87, 88]
[87, 89]
[90]
[90]
found using the candidate gene approach include mutations in DNAI1, homologous to the
Chlamydomomas genes IC78. This was discovered in PCD patients with ODA defects and
functional ciliary abnormalities [69, 70]. Since then, there have been several more PCD-causing
gene mutations published, using a variety of approaches (table 2). Homozygosity mapping in large
families that may or may not be consanguineous, but have multiple affected and unaffected siblings
can be successfully used to identify disease-causing genes. This method utilises the marker analysis
to look for the shared region of the genome from affected and unaffected individuals, to identify the
chromosomal locus/loci shared between the affected siblings. Genes within the shared locus/loci are
candidates, which can be further aided by the candidate gene approach to prioritise the genes to be
tested from the shared locus. OMRAN et al. [91] successfully used this method to localise the shared
locus in affected individuals from a large consanguineous family and identified mutations in the
DNAH5 gene. Genome-wide linkage analysis, another approach to find disease-causing mutations,
using 31 multiplex families with PCD failed to identify disease-causing genes [92]. The main
limitation of genome-wide linkage analysis is the extensive genetic and ultra-structural
heterogeneity in PCD that limits the comparison of data across the families to get meaningful
log of odds (LOD) genetic linkage scores that helps indicate the possible disease-causing loci. Other
methodologies include the comparative computational analysis approach, which identifies
candidate genes using the DNA information collected from various sequencing projects from
various distinct species. It assumes that higher-level organisms independently lost certain genetic
information during evolution once the information coding for the specific processes was obsolete.
Using subtraction analysis it is possible to find candidate genes necessary for cilia formation and
function by comparing the genome of a ciliated eukaryote with eukaryotes not dependent on cilia
[93, 94]. A comprehensive discussion of the molecular basis of PCD is beyond the scope of this
chapter; the reader is referred to KNOWLES et al. [4].
L.J. LOBO ET AL.
DNAI1: dynein, axonemal, intermediate chain 1 gene; DNAI2 : dynein, axonemal, intermediate chain 2 gene;
DNAH5: dynein, axonemal, heavy chain 5 gene; DNAH11: dynein, axonemal, heavy chain 11 gene; TXNDC3 :
thioredoxin domain containing 3 (spermatozoa) gene; KTU/PF13 : Kintoun; LRRC50 : leucine-rich repeat
containing 50; CCDC: coiled-coil domain containing; RSPH4A: radial spoke head 4 homologue A gene;
RSPH9 : radial spoke head 9 homologue; ODA: outer dynein arm; IC: intermediate chain; HC: heavy chain; LC:
light chain; RS: radial spokes; IDA: inner dynein arm; CP: central pair. #: cytoplasmic protein required for the
dynein arms assembly.
DNAI1 and DNAH5 are associated with ODA defects in PCD
139
Mutations in DNAI1 and DNAH5 [69, 70, 7173, 7678] that encode dynein axonemal
intermediate chain 1 and heavy chain 5, respectively, have been well documented in several studies
as causative for PCD. DNAI1 accounts for ,210% of patients with PCD, although if one
selected the phenotype to include patients with ODA defects alone, this increases to ,414%.
The commonest mutation (founder mutation) in DNAI1 is IVS+2_3insT, accounting for .50% of
mutations. DNAH5 is a heavy chain dynein and mutations in the gene were initially found in a
large inbred family of Arab descent. Subsequent studies show mutations in DNAH5 to be present
in ,1528% of patients with PCD. Together therefore, DNAI1 and DNAH5 account for ,2040%
of patients with classic disease with ODA defects. Despite extensive allelic heterogeneity, four
exons in DNAI1 and five exons in DNAH5 represent mutation clusters, which became the basis of
development of the clinical genetic testing for PCD.
PCD IN ADULTS
Miscellaneous other mutations associated with PCD

Mutations have been identified in other genes in patients with PCD, specifically, DNAH11, DNAI2,
KTU, RSPH9, RSPH4A, TXNDC3 and LRRC50, CCDC39 and CCDC40 (table 2) [26, 67, 74, 7981,
84, 85, 8890]. Some genotypephenotype associations have been defined amidst the plethora of
mutations found, primarily at the ultra-structural level (rather than at the clinical level). Mutations
in DNAH5, DNAI1 and DNAI2 are exclusively seen in patients with ODA defects, whereas
mutations in KTU and LRRC50 are exclusively seen in patients with combined ODA+IDA defects
[4]. The genetics of the DNAH11 (which encodes dynein axonemal heavy chain 11) mutation are
quite interesting as it was found in a patient with proven CF and situs inversus. It was not clear if this
patient had PCD/Kartagener syndrome, or isolated situs inversus, as there is an obvious phenotypic
overlap between the CF and PCD. However, the patient had abnormal ciliary beat pattern as seen in
PCD, normal ciliary ultra-structure, but with a mutation in the DNAH11 gene that was assumed to
be linked to the situs inversus [95, 96]. Subsequently, mutations in DNAH11 were unequivocally
shown to be PCD causing in a large German kindred and more recently two patients with PCD were
found to harbour mutations in DNAH11 [80, 81]. All of the patients with DNAH11 mutations
presented with normal dynein arms. This phenotype highlights the difficulty in diagnosis in those
patients with a strong clinical phenotype, but with normal cilia on TEM analysis. Mutations in
DNAI2 that encode for a dynein axonemal intermediate chain 2 have been identified in 4% of PCD
patients with ODA defects [79]. In contrast to the above proteins and genes, which encode for
dynein proteins, KTU is a cytoplasmic protein, required for the assembly of the dynein complex
[67]. First noted to be mutated in Mekada fish with laterality defects, and subsequently
Chlamydomonas, it was then found to be mutated in PCD patients with both IDA and ODA defects
(logical since it is required for normal ODA and IDA assembly and transportation). Mutations in
KTU are seen in ,12% of PCD patients with combined ODA and IDA defects. RSPH9, which
encodes for the radial spoke head protein 9, was identified as being a PCD-causing gene using
homozygosity mapping in two Arab Bedouin families. Subsequently, an identical homozygous 3-bp
inframe deletion mutation was identified in both families. Interestingly, the ultra-structure analysis
of patients from one family depicted 9+2 or 9+0 microtubular configuration, and from the other
family normal ciliary ultra-structure was seen [90]. Using homozygosity mapping in three inbred
Pakistani families, RSPH4A was identified as a PCD-causing gene that encode another radial spoke
head protein 4A. Ultra-structural analysis showed transposition defects with the absence of a central
pair and 9+0 or 8+1 configuration. TXNDC3 (encoding thioreduxin domain-containing protein 3)
is a component of the sperm flagella ODA, and a nonsense mutation on one allele and a splice
mutation on the other allele were found in one PCD patient [84]. Large genomic deletions, as well
as point mutations involving LRRC50 (leucine-rich repeat containing 50), are responsible for a
distinct PCD variant that is characterised by a combined defect involving assembly of the ODA and
IDA. Functional analyses shows that LRRC50 deficiency disrupts assembly of distally and
proximally DNAH5 and DNAI2 containing ODA complexes, as well as DNALI1-containing IDA
complexes, resulting in immotile cilia [85]. Multiple other candidate genes have been tested in
patients and families with PCD, and were found to be negative.
Other genetic associations
140
X-linked retinitis pigmentosa, sensory hearing deficits and PCD have been associated via
mutations in the RPGR, essential for photoreceptor maintenance and viability [41]. In addition, a
single family was reported with a novel syndrome that is caused by oral-facial-digital type 1 gene
(OFD1) mutations, and characterised by X-linked recessive mental retardation, macrocephaly and
PCD [45].
Animal models for PCD have been reported to occur in nature, although they have rarely been
studied in depth [97]. Similarly animals with a PCD phenotype have been constructed using
molecular techniques, mainly in mice [4]. Other than the Mdnah5 deficient mouse and the Dpcd/
poll knock out mouse, the causative gene in the other models are unknown. The Mdnah5 deficient
mice were created via transgenic insertional mutagenesis that leads to a frame shift mutation. The
mice have the classic PCD phenotype and the ultra-structural analysis reveals absent ODA [98,
99]. The Dpcd/poll knock out mice present a phenotype of sinusitis, situs inversus, hydrocephalus,
male infertility and ciliary IDA defects [43]. Recently, a murine mutation of the evolutionarily
conserved adenylate kinase 7 (Ak7) gene resulted in animals presenting with pathologic signs
characteristic of PCD, including ultra-structural ciliary defects and decreased CBF in respiratory
epithelium [100]. The mutation is associated with hydrocephalus, abnormal spermatogenesis,
mucus accumulation in paranasal passages and a dramatic respiratory pathology upon allergen
challenge. Ak7 appears to be a marker for cilia with 9+2 microtubular organisation. Mutations of
the human equivalent may underlie a subset of genetically uncharacterised PCD, although no
human mutations have been identified as yet. Finally, a novel method of developing a mouse
model with a PCD phenotype was recently published [101]. A transgenic mouse lacking an ODA
was developed by deleting Dnaic1, a mouse intermediate chain dynein. Importantly, the mice did
not develop many of the problems that usually result in an early death for the animals, such as
hydrocephalus or other severe developmental defects. Thus, the survival of the animals allowed the
investigators to show that the animals did experience problems consistent with defective MCC, at
least in the upper airway (severe rhinosinusitis). Objective measures of MCC were also consistent
with defective ciliary function in the nasal passage, though interestingly not in the lower airway,
possibly reflecting differing turnover of ciliated epithelium in various regions of the respiratory
tract (upper versus lower). This animal model may allow studies that attempt to dissect out the
relative importance of the various components of the MCC apparatus in different airway regions.
L.J. LOBO ET AL.
Future directions
Summary: an algorithm for testing

As there is no easy, single diagnostic test to diagnose PCD, it is recommended that the diagnosis be
based on multiple contributing pieces of data (fig. 2). A typical clinical presentation to suggest
additional testing for PCD includes recurrent respiratory tract infections (either upper or lower, or
both), neonatal respiratory distress, childhood ear infections, adult bronchiectasis in the absence
of a diagnosis and male/female fertility problems. Additional features to provoke further tests
include organ laterality defects, and complex congenital heart or other organ defects and retinitis
pigmentosa. Ciliary dyskinesia, sperm immotility or identification of specific defects of axonemal
structures on electron microscopy are also suggestive of the diagnosis. The reader should bear in
mind that patients with PCD with atypical histories may have no demonstrable ciliary ultrastructural defects on standard TEM. Nasal NO, if available, helps exclude the disease if normal or
very high and, if very low, strongly suggests the diagnosis. Recently, clinically available genetic
testing, a rapidly evolving field, may assist in an increasing number of patients with PCD.
Therapeutic approaches
Overview
141
The goal for the management of PCD is to prevent exacerbations and complications as much as
possible, and to slow the progression of disease. As the disease is generally not as severe as CF, and
PCD IN ADULTS
the diagnosis may be delayed, adults with the disease may not fully appreciate or understand the
nature and/or severity of the disease. Thus, education as to the diagnosis, prognosis and
therapeutic avenues need to be discussed thoroughly with the patients once the diagnosis is secure
(usually on several occasions). Although there are few literature-based studies in PCD, there are
enough studies in CF and non-CF bronchiectasis to allow significant extrapolation (although not
total, see later) into patients with PCD, to at least frame a plan of treatment depending on disease
severity, sputum microbiology and patient circumstances. Medical therapy has been shown to slow
the deterioration in lung function [20, 102]. ELLERMAN and BISGAARD [20] reported longitudinal
lung function in 24 patients diagnosed before and after the age of 18 years. They observed worse
lung function in patients diagnosed in adulthood, but did not find further deterioration in lung
function in either group once the diagnosis was established and routine care initiated. This
suggests that aggressive treatment could prevent further lung damage. It should be noted, however,
that other larger patient cohorts followed for a longer time period suggest that PCD may be a
serious threat to lung function as early as pre-school, with a high degree of variation in the loss of
lung function once diagnosed [103]. There was no link to either age or level of lung function at
diagnosis and early detection did not slow the rate of decline in lung function. These data support
the genetic and phenotypic heterogeneity of PCD. Despite this, regular clinical surveillance is
strongly recommended to establish trends of disease progression, and to detect exacerbations early
to attempt to prevent irreversible lung damage. This should include at least lung function testing,
sputum or throat cultures to assess airway microbiology and annual chest radiographs [104].
Pulmonary function in PCD patients appears to decline slower compared with patients with CF
and the majority of patients with PCD seem to have a normal to near normal life span [21].
However, there are patients that develop progressive bronchiectasis, leading to severe lung disease
and respiratory failure.
Specific therapies
There are no therapies to date that have been shown to correct ciliary dysfunction in PCD
patients. Some pilot or single case reports suggest benefit for some of the underlying
pathogenetic pathways in PCD, but none are yet available on a general basis, or proven in
randomised controlled studies (although patients will often inquire as to their availability)
[33, 105, 106]. Thus, therapies to enhance airway clearance, as well as to suppress or kill bacteria
are the cornerstones to PCD care.
Airway clearance
As with CF, routine airway clearance with cardiovascular exercise, percussion vests, chest physical
therapy and various valve/positive expiratory pressure devices should be performed on a daily
basis. The aims of respiratory physiotherapy include mobilising and aiding expectoration of
broncho-pulmonary secretions, improving efficiency of ventilation, maintaining or improving
exercise tolerance, improving knowledge and understanding and reducing breathlessness and chest
pain. There are no data in either CF or PCD to support any one method of airway clearance over
another, and in adults a good practice is to facilitate a consultation with a chest physiotherapist for
an education class, and to determine what modality of airway clearance and what devices the
patient prefers. As with any chronic lung disease, exercise is highly recommended for
cardiovascular fitness and specifically for airway clearance. Even though a chronic cough is a
major complaint, it should not be suppressed as it is a compensatory mechanism for mucus
clearance with dysfunctional cilia [33].
Antibiotics
142
Antibiotics are the mainstay of treatment for bacterial infections of the airways associated with
PCD. The microbiological flora of the airways is broadly similar to that of CF, although with a
delayed appearance of P. aeruginosa. Antibiotic therapy should be based on regular sampling of
Modulation of airway secretions

In the CF population, nebulised hypertonic saline (7% hypertonic saline) is beneficial by
modulating the liquid content of the periciliary fluid layer, thereby thinning thick secretions
and triggering a cough reflex [109, 110]. However, in PCD, its utility is less clear as it
stimulates cough to help clear secretions but its role in thinning secretions is not known [111].
A small study of 24 patients with non-CF bronchiectasis showed that hypertonic saline resulted
in greater expectorated sputum weight and a greater reduction in sputum viscosity compared
with the active cycle of breathing technique alone [112]. Thus, it may be considered in the
PCD population as it can augment mucus clearance with little to no risk, other than time.
Other aerosolised hypertonic agents such as dry powder mannitol are currently being
investigated and may be promising in the future [113]. Deoxyribonuclease (dornase alfa), an
enzyme that hydrolyses eukaryotic DNA released from decaying neutrophils to diminish
mucus viscosity and enhances clearance, is beneficial in CF patients, but its use by
extrapolation into PCD patients remains unproven and may even be detrimental to lung
function [114, 115].
L.J. LOBO ET AL.
airway secretions for Gram-positive, Gram-negative and acid fast pathogens to build a pattern of
the main pathogens in any given patients airways [21, 107]. In adults, sputum is usually easy to
acquire and bronchoscopy is not usually necessary to gather specimens. When PCD patients have
symptoms of a respiratory tract infection, they require treatment with antibiotics based on airway
cultures and sensitivities. H. influenzae, S. aureus, and S. pneumoniae are commonly isolated from
the airways of PCD patients. There are no randomised placebo-controlled studies evaluating the
efficacy of antibiotics in exacerbations in adults or children although numerous studies indicate
that antibiotics can improve symptoms and hasten recovery. Antibiotics are recommended for
exacerbations that present with an acute deterioration (usually over several days) with worsening
local symptoms (cough, increased sputum volume or change of viscosity, increased sputum
purulence with or without increased wheeze, breathlessness and haemoptysis) and/or a decrease in
lung function based on lung function testing. Expert consensus is that 2 weeks of therapy is
reasonable. The choice of antibiotics may be initially empirical, based on the likely microbial agent
or guided via previous sputum cultures in an individual (hence the recommendation to gather
serial samples). The recommended route of antibiotics needs further study to address the optimal
regimen, but most clinicians use oral antibiotics for milder exacerbations and combined antipseudomonal intravenous drugs for more significant deteriorations. Previous studies suggest that
the combination of intravenous and inhaled antibiotics might have greater efficacy than
intravenous therapy alone [34]. In patients chronically colonised with P. aeruginosa, the addition
of nebulised tobramycin to high-dose oral ciprofloxacin for 14 days led to a greater reduction in
microbial load at day 14 although there was no clinical benefit [108]. Attempts at early eradication
of newly acquired bacteria are recommended as in CF, although there are no data that show that
such an approach prevents the progression of lung disease. Long-term antibiotics or nebulised
antibiotics (tobramycin, colomycin or aztreonam) may be used in patients with chronic or
frequent exacerbations. Some patient do well on rotating cycles of oral antibiotics, although
there are no data to support such an approach and there is a general concern about inciting
microbial resistance.
Other airway treatments
143
Bronchodilators are not particularly effective in PCD or CF unless a coexisting asthmatic

component exists [116]. PCD patients may be initially misdiagnosed as asthmatics unresponsive to
conventional therapy, including b-agonists and inhaled corticosteroids. b-Adrenoceptor agonists
have been shown to augment CBF in functional cilia but there is little data in the dyskinetic cilia
seen in the PCD population [117]. Anti-inflammatory strategies such as alternate-day
prednisolone have not been shown to be effective in CF; there are no studies in PCD [118].
Inhaled steroids may or may not be of benefit in individual patients with PCD; a recent Cochrane
review concluded no benefit in non-CF bronchiectasis overall [119]. As with other inflammatory
diseases of the lung, the macrolide antibiotics may exert long-term benefits for the modulation of
airway inflammation and thus disease expression [106, 120].
Miscellaneous lung treatments
PCD IN ADULTS
L-Arginine
might hypothetically have a therapeutic role in PCD patients, in augmenting the

production of airway NO, theoretically enhancing CBF (although the exact role of NO in this
process is unknown). However, in the small studies performed, L-arginine did not normalise nasal
NO levels and no improvement in lung function was observed [121]. Uridine-5-triphosphate
(UTP), or its analogues, is also a potential therapy for CF and similar diseases [122]. UTP
stimulates chloride ion secretion and mucin release in goblet cells, therefore increasing airway fluid
hydration and enhancing cough clearance in healthy individuals. A small acute clinical trial of
nebulised UTP in PCD demonstrated enhanced airway clearance during cough, but no long-term
benefits in pulmonary function have been shown [33]. Localised surgery may be considered in
situations that resemble that of CF or idiopathic bronchiectasis, where occasionally very localised
lung disease is considered to be problematic in causing severe systemic symptoms, frequent
exacerbations and/or life threatening haemoptysis [123, 124]. Patients with such localised disease,
haemoptysis or refractory pulmonary infections, have undergone surgical resection of the
bronchiectatic lung but the long-term effects are unknown [124]. If PCD does progress to endstage lung disease, lung transplantation must be considered. PCD patients have undergone
successful heart-lung, double lung or living donor lobar lung transplant [125]. In patients with
situs inversus, the anatomic disorientation adds an extra challenge when considering the
anastomotic sites but is not a contraindication. The long-term survival appears similar to other
lung transplant recipients.
Treatment of extrapulmonary disease in adults

As PCD affects other aspects of the respiratory tract other than the lungs, treatment of those areas
must be considered. Chronic rhinitis and sinusitis may cause significant morbidity in patients with
PCD. As of now, no treatments have been shown to be unequivocally effective, although most
patients are treated with intranasal corticosteroids, sinus lavage procedures and antibiotics.
Antibiotics should be used sparingly for sinus symptoms as resistance occurs quickly and
antibiotics should be reserved for more pressing pulmonary symptoms. If sinus symptoms persist
despite aggressive medical management or are severe, endoscopic sinus surgery can be used to
promote drainage and better delivery of topical medications [126]. Male infertility due to sperm
immotility can be overcome by assisted fertilisation techniques such as intracytoplasmic sperm
injections [127]. Females, who are infertile secondary to fallopian tube dysfunction, can have
direct ovum harvesting from the ovaries and can get in vitro fertilisation.
P.G. Noone is principal investigator on an industry sponsored study (multicentre) looking at the
effects of inhaled mannitol in non-cystic fibrosis bronchiectasis (Pharmaxis). He is also principal
investigator on an industry sponsored study (multicentre) looking at the effects of inhaled
aztreonam in non-cystic fibrosis bronchiectasis (Gilead).
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912.
Chapter 10
Channelopathies in
bronchiectasis
I. Sermet-Gaudelus*,#,",+, A. Edelman*,# and I. Fajac*,+,1
CHANNELOPATHIES
Summary
Channelopathies are diseases caused by dysfunction of ion
channel subunits. They result in impaired mucociliary clearance
and may therefore lead to bronchiectasis.
The main channelopathy associated with bronchiectasis is
cystic fibrosis (CF), an autosomal recessive disease caused by
mutations in the CFTR gene, which encodes the chloride CFTR
channel.
Bronchiectasis can be associated to channelopathies in
following cases: 1) patients with already known typical CF; 2)
patients with bronchiectasis who, on investigation, are found
to have a single-organ manifestation of CF; 3) patients with
only one or none mutation of CFTR with abnormal sweat test
or nasal potential difference (PD) where CFTR mutations play
the role of a modifier deleterious gene; and 4) patients with
only one or no mutation of CFTR with normal sweat test or
nasal PD, who may still have an undefined channelopathy. In
these last two cases, it may be that, CFTR mutation combined
with another ion transport abnormality, in a situation of
transheterozygosity, creates the conditions for abnormal
airway surface liquid (ASL) hydration regulation and defective
mucociliary clearance.
Keywords: Airway surface liquid, bicarbonate, calciumdependent chloride channel, cystic fibrosis, cystic fibrosis
transmembrane conductance regulator, epithelial sodium
channel
*Universite Paris Descartes,

#
INSERM Unite 845,
"
Service de PneumoPediatrie, Hopital
Necker-Enfants Malades,
+
Assistance Publique Hopitaux de
Paris, and
1
Service de Physiologie-Explorations
Fonctionnelles, Hopital Cochin,
Paris, France.
Correspondence: I. Sermet-Gaudelus,
Service de PneumoPediatrie,
Universite Paris Descartes, Hopital
Necker-Enfants Malades, 149 rue de
Se`vres, 75015, Paris, France, Email
isabelle.sermet@nck.aphp.fr
Eur Respir Mon 2011. 52, 150162.

Copyright ERS 2011.
ISSN: 1025-448x.
DOI: 10.1183/1025448x.10004010
150
ronchiectasis is defined as an abnormal dilation of proximal medium-sized bronchi due to

weakening or destruction of the muscular and elastic components of the bronchial walls [1]. It
is caused by a vicious cycle of transmural infection and inflammation, resulting in retained
secretions that damage the airways and impair mucociliary clearance.
Bronchiectasis can appear as either a local obstructive process or a diffuse disease involving both
lungs. In the latter case, a systemic condition must be sought. These can include autoimmune
disease, a1-antitrypsin deficiency, connective tissue disorders, immunodeficiency states, allergic
bronchopulmonary aspergillosis and primary ciliary dyskinesia. Channelopathies, defined as

diseases caused by dysfunctioning ion channel subunits, are another possibility. Channels are
pore-forming proteins that provide pathways for the controlled movement of ions into or out of
cells, and are hence important in regulating mucociliary clearance [2]. The present chapter focuses
on the role of channelopathies as causative factors for the development of bronchiectasis.
The link between ion transport and mucus transport in

the airways
Two opposing transport systems tailored to controlling the volume of liquid on the
epithelial surface
When ASL volume is depleted, normal airway epithelium exerts dynamic regulation by switching its
status from net NaCl absorption to net secretion (fig. 2) [3, 4]. This requires the accumulation of Clwithin the cell through the action of the Na+/K+/2Cl- cotransporter located in the basolateral
membrane. Cl- then exits the cell
across the apical Cl- channels, at the Luminal
Basolateral
same time as apical Na+ absorption
Cl
slows and Na+ moves paracelluK+ Na+, K+-ATPase
larly to maintain electroneutrality.
Na+
+
Na
Adenosine triphosphate (ATP), reENaC
leased on to the airway surface, is
the main sensor for this regulation
K+
Cl[5]. Its actions are mediated by two
+
PKA
CFTR
purinergic receptor subtypes, the
Clpertussis-toxin-insensitive G-proCltein (Gq)-coupled ATP/uridine triphosphate (UTP)-sensing P2Y2
Figure 1. Cellular models of electrolyte secretion: absorption
P2Y receptor and the stimulatory
pathway. In airway epithelial cells, under resting conditions, Na+ is
G-protein (Gs)-coupled A2B adenotaken up by a luminal epithelial sodium channel (ENaC); Cl- is
sine receptor. Activation of the A2B
transported via the paracellular shunt and probably via cystic fibrosis
purinoreceptor raises cell cyclic adetransmembrane conductance regulator (CFTR) Cl- channels. Na+ is
pumped out of the cell by the basolateral sodiumpotassium
nosine monosphosphate (cAMP),
adenosine triphosphatase (Na+,K+-ATPase), whereas Cl- and K+
which, in turn, activates the CFTR
leave the cell via Cl- and K+ channels, respectively. PKA: protein
sufficiently to provide CFTR-depenkinase A. -: inhibition; +: stimulation.
dent Cl- secretion and negative ENaC
151
Under resting conditions, airway surface epithelia display net salt and fluid absorption (fig. 1),
driven by active apical Na+ absorption through the amiloride-sensitive epithelial sodium channel
(ENaC), passively accompanied by Cl-, in part, via a transcellular pathway, mainly the cystic
fibrosis transmembrane conductance regulator (CFTR), and, in larger part, via the paracellular
pathway [3]. This absorptive pattern occurs due to basolateral sodiumpotassium adenosine
triphosphatase (Na+,K+-ATPase), which generates an electrochemical gradient favourable for
apical Na+ absorption. ASL remains isotonic under basal conditions because of the airway
epitheliums permeability to water (due to the relative leakiness of the tight junctions) and the isoosmotic conditions of ion transport.
I. SERMET-GAUDELUS ET AL.
The thin film of liquid covering airway surfaces, called airway surface liquid (ASL), is partitioned
into two compartments, the mucus layer, which entraps particles and pathogens and has lubricant
activity, and the periciliary liquid (PCL) layer, which facilitates ciliary beating and separates the
mucus layer from the mucins tethered to the cell surface [3]. Normal airway surface epithelia can
regulate ASL volume by setting the height of the PCL to approximately the height of the extended
cilia (,7 mM) [3]. The coordination of sodium and chloride ion transport regulates ASL
homeostasis to provide efficient mucus transport.
Apical
Na H2O
ENaC
K+
Na+
-
regulation by the CFTR. Higher ATP

concentrations then activate the P2Y2
receptor, promoting, on the one
hand, the inhibition of Na+ absorp+ +
+ Na , K -ATPase
Na
tion and, on the other, Cl- secretion,
Na+/K+/2Cl- cotransporter mediated by another apical channel,
the calcium-activated chloride chanK+
nel (CaCC).
KV7.1
Basolateral
CFTR
Cl
HCO3Adenosine
ATP
UTP
CaCC
Cl-
PKA
cAMP
Ca2+
2ClK+
K+
KCa3.1
Na+ H2O
CHANNELOPATHIES
Figure 2. Cellular models of electrolyte secretion: secretory

pathway. In airway cells, under conditions triggering secretion, Clis taken up from the basolateral (blood) side by the Na+/K+/2Clcotransporter. K+ recycles through basolateral K+ channels. This
leads to basolateral membrane hyperpolarisation, which, in turn,
electrically drives Cl- to the luminal side of the epithelium and
stimulates Cl- secretion through the cystic fibrosis transmembrane
conductance regulator (CFTR) and/or calcium-activated chloride
channels (CaCCs). Activation of the A2B adenosine receptor results
in raised cell cyclic adenosine monosphosphate (cAMP) levels,
which, in turn, activate the CFTR sufficiently to provide CFTRdependent regulation of the epithelial sodium channel (ENaC) and
Cl- secretion, together with activation of the cAMP-dependent
potassium channel (KV7.1). Higher ATP concentrations activate the
P2Y2 P2Y receptor, inhibiting Na+ absorption and activating both
CFTR-dependent and CFTR-independent Cl- secretion, the latter
mediated by the release of cytoplasmic Ca2+, which, in turn,
activates the CaCC and the calcium-activated potassium channel
(KCa3.1). Na+ is pumped out of the cell by sodiumpotassium
adenosine triphosphatase (Na+,K+-ATPase). Na+ is secreted via the
paracellular shunt following the electrical driving force generated by
the negative transepithelial voltage in the lumen. ATP: adenosine
triphosphate; UTP: uridine triphosphate; PKA: protein kinase A.
q: increased; -: inhibition.
Finally, when ASL volumes are depleted, the epithelium rehydrates airway surfaces by: 1) inhibiting absorption (in the surface epithelium); and
2) activating secretion (in the submucosal glands).
Ion transporters involved in

mucociliary clearance
Consistent with these fundamental
observations, most of the channelopathies identified as possible
causes of the impaired clearance of
bronchial tree secretions appear to
involve Cl-, Na+ and bicarbonate
transport.
Cl- transporters
Cystic fibrosis transmembrane
conductance regulator
The CFTR is a member of the

ATP-binding cassette transporter
superfamily, principally expressed
in the apical membrane of epithelia. It plays a fundamental role in transepithelial fluid and
electrolyte transport because it functions as an anion channel and a regulator of ion transporters
in epithelial cells. The CFTR is a cAMP- and ATP-regulated Cl- channel that permits Cl- to be
released from the cell [6]. Recent data also suggest that the CFTR pore may switch dynamically
from a conformation permeable to Cl- to a conformation permeable to large anions, such as
glutathione and HCO3-, and may, therefore, be involved in pH regulation of the ASL and
mucus [7].
152
Apart from its secretory function, the CFTR has the regulatory function of other epithelial
channels. The CFTR inhibits ENaC activity and, therefore, conveys reduction in Na+
resorption [8]. The CFTR upregulates an outwardly rectifying chloride channel (ORCC)
following its activation by protein kinase A (PKA) [9]. The CFTR can also interact via its
extreme C-terminal amino acid sequence with PDZ-domain-containing proteins, which are
important organisers for receptors, ion transporters and regulatory elements present in airway epithelium [10]. For example, reciprocal activation between the CFTR and the solute
carrier (SLC) 26 transporter (SLC26T) family of HCO3-/Cl- exchangers has been shown to
depend upon PDZ domain interaction and binding of the sulfate transporter and anti-s
factor antagonist (STAS) domain of SLC26T family proteins to the CFTR regulatory (R)
domain [11].
Calcium-activated chloride channels

Airway epithelial cells display Ca2+-dependent Cl- secretion through CaCCs in response to
mucosal nucleosides. The mechanism relies on the stimulation by ATP or UTP of the Gq-coupled
P2Y2 purinergic receptors, which increases inositol 1,4,5-trisphosphate (IP3) production and
subsequently cytosolic Ca2+ release [12].
Transmembrane protein 16A (TMEM16A), which generates Ca2+-activated Cl- currents with
similar biophysical and pharmacological properties to those in native epithelial tissues, is a very
likely candidate for these CaCCs [13].
Chloride channel-2
Chloride channel (ClC)-2 is a member of the pH- and voltage-activated chloride channel family
and is present on the apical membranes of airway epithelial cells [14]. Activation of ClC-2 is
hypothesised to provide a parallel pathway for Cl- secretion [15].
Indirect activation of Cl- secretion by K+ channels
Na+ transporters
The ENaC is a heteromultimer composed of distinct but homologous a-, b- and c-subunits
known to be activated by selective endoproteolysis [17]. As pointed out above, it provides the
main pathway for apical Na+ absorption at the apical membrane [3, 4]. The ENaC and the CFTR
physically associate in mammalian cells [18], an interaction that may impede ENaC proteolytic
cleavage and inhibit stimulation of the channel open probability [19].
HCO3- transport
Activation of K+ channels at the basolateral side of the epithelium causes hyperpolarisation of the
basolateral membrane, which electrically drives Cl- to the luminal side of the epithelium and
stimulates Cl- secretion through the CFTR and/or CaCCs. At least two different populations of K+
channel are located on the basolateral side of airway epithelial cells that are activated by an increase
in either intracellular cAMP (cAMP-dependent potassium channel (KV7.1)) or Ca2+ (calciumactivated potassium channel (KCa3.1)) [16].
HCO3- plays a critical role in determining the viscosity of mucins and mucus by decondensing
mucin granules. Intracellularly, mucins are condensed in granules by high concentrations of Ca2+
and H+ that shield the repulsive forces of the anionic sites of mucin glycoproteins. As granules are
secreted, Ca2+ and H+ have to dissociate quickly from the mucin to unshield the negative sites, so
that Na+ can replace Ca2+ to allow mucin network hydration, swelling and dispersion. HCO3- is
critical for sequestration of Ca2+ and H+ and maintenance of a low concentration of these free
cations in solution, which, in turn, favour their disassociation from mucins [20, 21]. Moreover, a
normal pH is necessary for effective mucociliary clearance, as assessed by several observations. For
example, a reduction in extracellular pH of 0.5 reduces mucociliary beat frequency by 22% in
bronchi and 16% in bronchioles [22].
As stated above, the CFTR clearly plays a role in HCO3- transport. Cell membrane ion transporters
besides CFTR may also be involved in ASL and/or gland fluid pH regulation [23]. These include
the following.
The basolaterally located isoform sodium bicarbonate cotransporter (NBC) 1 permits the basal
influx of HCO3- followed by efflux through the apical CFTR [24].
153
Na+/HCO3- cotransporters
Cl-/HCO3- exchangers
Based on an analogy to SLC26A3 function in HCO3- secretion by the pancreatic duct epithelium,
WHEAT et al. [25] proposed a model for HCO3- transport in the airway epithelium: Cl-/HCO3exchange activity, governed by SLC26A3 in the apical membrane, might secrete HCO3- into the
ASL, with Cl- recycling through the CFTR. However, experiments in polarised airway epithelial
cells failed to confirm this hypothesis [26]. The role of Cl-/HCO3- exchangers in ASL pH
regulation at the apical membrane therefore remains speculative.
Investigation of ion transport in airway epithelium

Transepithelial potential difference (PDte) results from ion movements across both the basolateral
and apical membrane and leakiness of tight junctions. Its assessment has been applied in vivo to
both nasal and bronchial mucosa [27]. Nasal potential difference (PD)-based outcomes include
the stable maximum baseline (basal PD) and the successive net voltage changes after perfusion of
the mucosa with: 1) amiloride (an ENaC inhibitor), to assess Na+ transport (Damiloride); 2) lowchloride solution, to drive Cl- secretion (Dlow-chloride); and 3) isoproterenol in low-chloride
solution (Disoproterenol), to stimulate the cAMP-dependent Cl- conductance related to the CFTR
(fig. 3). The sum of Dlow-chloride and Disoproterenol serves as an index of CFTR function [28].
CHANNELOPATHIES
This PDte can also be measured in Ussing chambers, using either epithelial biopsy specimens or
airway epithelial cells in culture. This system measures transepithelial ion transport by evaluating
PDte in volts [29], by either applying a PD and measuring the resulting change in current
(technique of voltage clamping) or short-circuiting the tissue, i.e. clamping PDte at 0 V and
measuring the amount of current required.
Channelopathies: cystic fibrosis

Pathophysiology
Cystic fibrosis (CF) is one of the principal channelopathies resulting in abnormal mucus clearance.
It is an autosomal recessive disease caused by mutations in the CFTR gene (CFTR), which encodes
the CFTR Cl- channel [30].
In CF, defects in the mechanisms governing both Na+ absorption and Cl- secretion severely disrupt
ASL volume regulation on airway surfaces. Specifically, they accelerate the basal rate of net
epithelial Na+ absorption in CF airway epithelia, causing isotonic volume hyperabsorption that
reflects the absence of the tonic inhibitory effect of CFTR on ENaC activity [31, 32]. The
mechanism linking the missing CFTR and increased Na+ absorption in CF airway epithelia may be
the failure to protect ENaC from proteolytic cleavage and consequent activation [33].
CF airway epithelia also lack the capacity to enhance Cl- transport [34]. Therefore, whereas non-CF
epithelium can rehydrate when ASL volumes are depleted, by activating secretion and inhibiting
absorption, CF epithelium cannot switch from net absorption to net secretion [31]. This inability
may be due to its dependence on ATP signalling alone, in contrast to the dual signalling (ATP and
adenosine) systems that control ASL volume in normal epithelia [35]. In this model, ATP can inhibit
ENaC and activate CaCC, via the P2Y2 receptor, but the A2B pathway is blocked because the CFTR is
not functional. Under resting conditions, the P2Y2 pathway may be sufficient to produce an ASL
volume consistent with mucus transport. It may, however, be overwhelmed in a context of
respiratory infections, e.g. virus infections, which are frequent in early life. These infections and their
effect on this system might, therefore, be the initiating event of CF disease [31].
154
The resultant reduction in ASL volume is shared by the two layers: 1) the water content of the
mucus layer is reduced, producing a highly viscoelastic adhesive material; and 2) the water content
of the periciliary environment is depleted, causing the collapse of this layer and a loss of its
PD mV
-40
-30
Basal
PD
-20
amiloride
low
chloride
-10
isoproterenol
low-chlorideisoproterenol
-50
0
b)
-50
-40 Basal
PD
Ringer+amiloride
-30
amiloride
Low chloride
+amiloride
-20
Low chloride
+amiloride
+isoproterenol
-10 Ringer
0
Time seconds
Figure 3. Nasal potential difference (PD) trace showing the

response to perfusion of various solutions in a) a healthy control and
b) a cystic fibrosis (CF) patient. Baseline nasal PD (basal PD) is
measured after perfusion of nasal epithelium with saline solution.
Nasal PD changes (D) were recorded after perfusion with the
following solutions: 100 mM amiloride in saline solution (Damiloride),
100 mM amiloride in low-chloride solution (Dlow-chloride), and
100 mM amiloride plus 10 mM isoproterenol in low-chloride solution
(Disoproterenol). The sum of Dlow-chloride and Disoproterenol
(Dlow-chlorideDisoproterenol) serves as an index of transepithelial
cystic fibrosis transmembrane conductance regulator (CFTR)dependent Cl- transport because it reflects the cyclic adenosine
monosphosphate (cAMP) activation of nasal mucosal Cl- permeability. In CF patients: 1) basal PD is more negative than in healthy
controls because of increased Na+ transport (high depolarisation
following amiloride perfusion); and 2) there is no response following
low-chloride perfusion and isoproterenol administration, showing
the absence of Cl- permeability.
A recent hypothesis suggests that a

defect in HCO3- secretion plays a
critical role in the pathophysiology
of CF [39]. As pointed out above,
the level of monovalent cations in
ASL in CF patients is normal and
constant, whereas it is the concentration of HCO3- that is notably
subnormal, because of reduced
secretion due to the CFTR defect
[40]. Several studies have shown a
relatively acidic ASL [41] and an
intrinsic acidification defect in fluid
gland secretion in CF [42]. This
reduced HCO3- level is associated
with increased mucus viscosity due
to reduced Ca2+ chelation, necessary
for rapid mucin swelling and dispersion [21]. Importantly, the extent of these defects correlates with
the level of HCO3-, which suggests a
relationship between disease severity and the degree of impairment in
HCO3- secretion [43, 44].
a)
PD mV
lubricant activity. The combination

of the PCL and ASL defects causes
the mucus to adhere to the airway
[36]. Evidence of adhesion is available from early pathological studies
of CF airways, which reveal bronchiolar mucous plugs within 48 hours
of birth [37], and from radioparticle
deposition studies that show the
inability of the cough manoeuvre
to clear mucus adhering to airway
surfaces [38].
155
One consequence of mucus stasis

is the formation of thick mucous
plaques and plugs, in which microorganisms are embedded. Several
features of this thickened adherent
CF mucus promote persistent biofilm growth [45]. First, the increased
concentration of mucins limits bacterial motility, increases their binding to mucin epitopes and feeds
them. Thus bacteria deposited in CF mucus may proliferate densely in the area of droplet deposition.
Secondly, the concentrated mucin gel also limits the effectiveness of secondary defence mechanisms
that might normally resolve a bacterial infection, such as neutrophil migration or diffusion of
antimicrobial substances. Finally, cellular oxygen is consumed at high rates in CF airway epithelium
to fuel this increased Na+ transport, thereby creating hypoxic zones in adherent mucous plaques near
the cell surface that link the special CF low-oxygen environment and infection [46]. Pseudomonas
aeruginosa, specifically, adapts to the hypoxic zones by producing alginate and forming biofilm, thus
setting the stage for chronic infection. The persistence of chronic bacterial infection of the airway
lumen then stimulates airway defences and induces a chronic hyperinflammatory response, mainly
via the nuclear factor (NF)-kB-mediated pathway [47].
Taken together, these findings indicate that the combination of abnormal Na+ and Cl- transport in
CF leads to ASL volume regulation failure, mucus stasis, bacterial infection and inflammation.
These, in turn, result in inhibition of mucociliary and cough clearance, and, as a final consequence,
induction of bronchiectasis.
Clinical description
CHANNELOPATHIES
The diagnosis of CF is based on an abnormal sweat test result (sweat Cl- level of .60 mM) and the
finding of two CF-causing mutations in the CFTR and/or an abnormal PDte [30]. In the latter
case, the response to amiloride is increased because of lack of inhibition of Na+ resorption, and Clsecretion is absent in the presence of low-chloride solution and isoproterenol. CF clinical
presentation can be divided into two types: 1) classic disease, readily diagnosed based on clinical
and laboratory data; and 2) less-severe disease that manifests later in life and yields ambiguous
genetic testing results [48].
In the first case, CF is a life-limiting multisystemic disorder that affects the Cl- transport system in
exocrine tissues. The hallmark is a classic triad of symptoms, most often from infancy or
childhood: progressive obstructive lung disease with sputum infected by Staphylococcus aureus or
P. aeruginosa, exocrine pancreatic insufficiency, and a high sweat Cl- level. In males, this triad is
associated with congenital absence of the vas deferens, leading to sterility. Other specific clinical
phenotypes include CF-related liver disease, meconium ileus, CF-related diabetes, pansinusitis and
nasal polyposis. Mortality occurs mainly due to progression of lung disease and respiratory
insufficiency [49]. In children, bronchiectasis is a marker of respiratory disease severity, because it
is associated with increased morbidity and accelerated decline in pulmonary function [50]. It can
appear as early as 3 months in CF children [38]. In a cohort of 125 Australian children (from birth
to 6 years) diagnosed with CF after newborn screening, 22% showed evidence of bronchiectasis,
and the prevalence increased with age [51]. In the paediatric (but not adult) population, the
presence and severity of bronchiectasis is significantly related to respiratory infection with
P. aeruginosa [52], and, more specifically, mucoid P. aeruginosa [53].
In the second case, advances in basic CF science have broadened the clinical spectrum of CF and
highlighted less-severe, so-called CFTR-related, presentations. Most of these patients carry one
CF-causing mutation and one or two mutations retaining residual CFTR function [54]. It is not
clear whether CFTR-related bronchiectasis, in such cases, is a single-organ manifestation of CF or
a condition in which CFTR mutations play the role of a modifier deleterious gene, acting with an
environmental contribution.
156
Several studies [5566] have investigated the frequency of CFTR mutations in patients with
disseminated bronchiectasis (table 1). The prevalence of CFTR mutations in this population is
controversial. Four studies [5558] found no evidence of an increased prevalence of CFTR
abnormalities compared with the general population. Other series [5764] observed very few
patients finally diagnosed with CF on the basis of carriage of two CF-causing mutations and/or
elevated sweat Cl- levels (approximately 7% of all of the patients enrolled in those studies). Most
patients had at least one non-CF-causing mutation, including mutations classified as associated
with CFTR-related disorder [54]. Some of these mutations were associated with normal
or borderline sweat Cl- levels (substitution of aspartic acid 1152 with histidine (Asp1152His
or D1152H), cytosine to thymidine substitution 10 kb downstream of nucleotide 3849
(3849+10 kbC.T), 5T allele of polythymidine tract in intron 8 (IVS8-5T) and Arg117His). It
should be pointed out that many of the sequence variations identified are not recognised as CFTR
mutations, and still less as CF-disease-causing mutations, mainly because of the lack of established
or substantiated knowledge of their pathogenic potential. In these cases, CFTR functional
evaluation in epithelium might help in identifying patients with CFTR-related disease [28, 66]. A
cohort of patients with bronchiectasis and a sweat Cl- level of ,60 mM were investigated [66];
Table 1. Studies showing an increased prevalence of cystic fibrosis transmembrane conductance regulator
(CFTR) mutation in patients with bronchiectasis of unknown origin
First author [ref.]
Subjects n
P IGNATTI [60]
16
G IRODON [61]
B OMBIERI [62]
H UBERT [63]
C ASALS [64]
Z IEDALSKI [65]
B IENVENU [66]
32
23
601
55
50
122
Controls n
Healthy 66; COPD 33; nonobstructive RD 36; atopic 85

0
Healthy 33
0
Local historical cohort
0
Healthy 26; obligate heterozygotes 38;
typical CF 92
CFTR mutations
Two
One
4; IVS8-5T: 9
5
0
45
0
3
15
6
11
43
14; IVS8-5T: 4
18
22
COPD: chronic obstructive pulmonary disease; RD: respiratory disease; IVS8-5T: 5T allele of polythymidine
tract in intron 8; CF: cystic fibrosis.
Other channelopathies
The epithelial sodium channel
There are two principal, and rare, human clinical disorders that occur due to ENaC mutations
[67]. The first is Liddles syndrome, caused by gain-of-function mutations leading to enhanced
Na+ resorption in the renal tubule, and characterised by volume-expanded low-renin hypertension
and apparently no respiratory disease [68]. The other is pseudohypoaldosteronism (PHA) type I,
due to loss-of-function mutations [69]. In addition to kidney impairment, characterised by renal
salt wasting, hyperkalaemia and metabolic acidosis, such children also show defective Na+
transport in the sweat gland, which leads to elevated sweat Cl- and Na+ concentrations. Moreover,
children with PHA-I frequently exhibit respiratory tract diseases that involve increased
mucociliary clearance and decreased mucus viscosity [69].
15 patients carried two CFTR mutations and exhibited abnormal ion transport in the nasal
mucosa (i.e. increased Na+ transport and decreased Cl- secretion). They were finally diagnosed
with a CFTR-related disorder. In the same series, 22 patients carried only one mutation but
displayed abnormal ion transport in the nasal mucosa, intermediate between the normal and the
CF range. This led to the hypothesis that an as yet unidentified other factor, genetic or
environmental, may trigger the pathogenic role of a unique CFTR mutation. Among the
possibilities, abnormalities in ion tranporters other than CFTR should be considered.
157
Recently, ENaCs have been shown to play a critical role in the physiology of mouse airways.
Transgenic mice with airway-specific overexpression of the ENaC (b-subunit) develop CF-like lung
disease with mucous obstruction and poor bacterial clearance. The airway surfaces of these mice
absorb three times more Na+, causing ASL volume depletion, increased mucus concentration,
delayed mucus transport and increased mucus adhesion to airway surfaces [70]. These events cause
spontaneous and severe lung disease that shares features with CF, including mucous obstruction,
goblet cell metaplasia, neutrophilic inflammation and poor bacterial clearance. This outstanding
proof-of-concept study demonstrates that increasing airway Na+ absorption creates all of the
conditions for the onset of bronchiectasis and initiates a CF-like lung disease [71]. Further support
for this mechanism comes from the following two observations: 1) modulation of ENaC activity in
CF patients may potentiate disease severity, as suggested by studies showing an enhanced response to
amiloride solution in patients with poor respiratory function [72] or chronic P. aeruginosa
colonisation [66]; and 2) Na+ transport is significantly higher in bronchiectatic patients, even in
those with no or only one CFTR mutation, compared with control subjects [66].
The role of ENaCs in non-CFTR-related bronchiectasis has been investigated in a few studies.
SHERIDAN et al. [73] studied 20 patients with diffuse bronchiectasis and elevated sweat Clconcentrations but without two CFTR mutations and identified four patients with five missense
mutations and one splicing mutation in ENaC genes. Moreover, among 55 patients with idiopathic
bronchiectasis who did not have two mutations in the CFTR coding regions, 10 were identified with
an ENaC mutation [74, 75]. This was higher than the expected frequency, and, as these variants had
not been previously described, they are unlikely to be common polymorphisms. Moreover, six
patients showed evidence of abnormal ion transport, in either sweat glands or nasal epithelium.
Hence, although these variants were each found in a heterozygous state, they might be expected to
result in abnormal ENaC function. This hypothesis is further supported by recent evidence of ENaC
mutations leading to proved channel dysfunction and associated with atypical CF [76].
Other Cl- channels

The model of ASL homeostasis suggests that dysfunction of other Cl- channels may alter ASL
homeostasis. ClC-2 mutations have been identified in people with idiopathic generalised seizures, but
they are not associated with a history of lung disease [77]. Moreover, the ClC-2 knockout mouse
undergoes normal lung development, possibly because it has multiple alternative Cl- channel conductance pathways. A ClC-2 abnormality may, therefore, not be related to any human lung disease [15].
CHANNELOPATHIES
To date, no human disease has been linked to a defect in Ca2+-dependent Cl- channels. However,
mice that do not express TMEM16A, the best candidate for CaCCs, show greatly reduced
mucociliary clearance [13]. Therefore, the role of this channel in human bronchiectasis requires
further investigation.
Indirect inactivation of Cl- transport

A defect in basal K+ channels may affect the driving force necessary for Cl- to migrate to the apical
membrane, as shown by the strong reduction in Cl- transport in nasal, tracheal and bronchial cells
carrying mutations of KV7.1 and KCa3.1 [16, 78]. However, no lung disease has been reported
among patients with these channelopathies [16].
Alternatively, defective interaction between an ion transporter and a mutated protein modulating
its function may impair the channel function, as demonstrated for CFTR and SLC26A3. The
interaction between these two proteins leads to their reciprocal functional activation [11]. When
SLC26A3 displays a mutation identified in humans, i.e. responsible for congenital Cl- diarrhoea, its
interaction with the CFTR is altered, and CFTR activation suppressed [11, 79]. Therefore,
mutations in proteins that interact with the CFTR, and specifically other SLC26T members, may
affect the CFTR and induce a CF-like phenotype.
Bicarbonate
There is evidence that defective HCO3- secretion is associated with abnormal mucus hydration and
impaired mucociliary clearance [20]. The amount of mucus discharged is significantly reduced
when HCO3- secretion is impeded in the intestines [80] and uterine cervix [43]; a similar
mechanism might be anticipated in airways. Extracellular acidification also favours inflammation,
by inducing neutrophil activation [81] and delaying neutrophil apoptosis [82].
CF is clearly associated with a defect in ASL pH regulation. Defects in HCO3- transporters other
than the CFTR can be envisioned, but require further investigation.
Transheterozygosity
158
After extensive genetic screening, 3350% of patients with diffuse bronchiectasis are characterised
as heterozygous for the CFTR [66]. As the theoretical frequency of this heterozygosity in the
general population is 3.3%, this highly elevated frequency suggests that heterozygosity for the
CFTR may have pathogenic consequences. It may predispose to the development and severity of
bronchiectasis by potentiating other genetic factors affecting airway physiology or add to
deleterious environmental factors.
Further support for this hypothesis comes from evidence of an abnormal nasal electrophysiological phenotype in patients with bronchiectasis carrying one CFTR mutation, intermediate
between control subjects or patients with no CFTR mutations, on the one hand, and patients with
two CFTR mutations on the other [66]. However, the absence of any increased prevalence of
bronchiectasis in obligate heterozygotes [83], although they display abnormal Cl- transport [84],
suggests that carrying a single CFTR mutation is not solely responsible for development of the
disease.
A total of 55 patients with diffuse idiopathic bronchiectasis were studied and an unexpectedly high
proportion (5%) of heterozygosity was found for both CFTR and ENaC mutations [75]. As the
expected frequency of such transheterozygosity in the general population is 0.3%, the finding of so
high a prevalence of mutations of both ion transporters suggests that it is clinically relevant. Slight
defects in both channels, which separately would not be sufficient to alter ASL homeostasis, are
likely to combine their deleterious effects and lead to deficient ENaC/CFTR interaction. Along this
line, we speculate that transheterozygosity of a single CFTR mutation and a mutation in another
ion channel might create the conditions for abnormal ASL hydration regulation and defective
mucociliary clearance.
It is likely that the true incidence of cases of ion-transport-related bronchiectasis among all
bronchiectasis is underestimated, given the lack of specific symptoms. Although much is now
known about the CFTR, the study of other channelopathies is only just beginning. Except for
typical CF and CFTR-related syndrome, it is difficult to demonstrate a causal relationship between
bronchiectasis and ion transport defects. The continuum of ion transport dysfunction from
normal to disease phenotype makes it difficult to define a clear-cut level for the involvement of ion
transport defect in the physiopathology of bronchiectasis [85]. Therefore, in order to ascertain the
role of channelopathies in the genesis of bronchiectasis, mutations in a given channel and the
related ion transport function should be systematically investigated in bronchiectatic patients.
Such studies may point to interesting therapeutic pathways aimed at normalising the first cause of
the pathogenic cascade resulting in bronchiectasis.
Conclusion
None declared.
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Chapter 11
Bronchiectasis
associated with
inflammatory bowel
disease
Ph. Camus* and T.V. Colby#
The two major inflammatory bowel diseases (IBD), ulcerative

colitis and Crohns disease (CD), can involve the respiratory
system in several ways. The most typical pattern of involvement
is in the form of airway inflammation and narrowing, which
may involve specific areas of the tracheobronchial tree from the
trachea to the bronchioles or which can be diffuse. Marked
inflammation, which can be granulomatous in CD, causes, at
times, marked airway obstruction. This pattern of involvement
is amenable to different forms of inhaled and oral corticosteroid
therapy. Drugs used to treat IBD are though to have no
responsibility in causing the syndrome. This is in contrast to
parenchymal lung disease in IBD. Colectomy may trigger the
onset of airway involvement and will not improve or cure
established airway inflammation in IBD.
Keywords: Airway inflammation, bronchiectasis, bronchiolitis
obliterans-organising pneumonia, granulomatous inflammation,
inflammatory bowel disease
*Dept of Pulmonary Disease and

Intensive Care, University Medical
Center Le Bocage and Medical
School, Universite de Bourgogne,
Dijon, France.
#
Dept of Pathology, Mayo Clinic,
Scottsdale, AZ, USA.
Correspondence: Ph. Camus, Dept of
Pulmonary Disease and Intensive
Care, University Medical Center Le
Bocage and Medical School,
Universite de Bourgogne, POB
77908- F-21079, Dijon, France, Email
ph.camus@chu-dijon.fr
Ph. CAMUS AND T.V. COLBY
Summary
Eur Respir Mon 2011. 52, 163177.

Copyright ERS 2011.
ISSN: 1025-448x.
DOI: 10.1183/1025448x.10004110
163
atients with either of the two major inflammatory bowel diseases (IBD), ulcerative colitis
(UC) and Crohns disease (CD), may develop a host of unusual, well-defined thoracic
manifestations (table 1) [16]. Among these manifestations, a distinctive pattern of airway
inflammation and scarring involving the major and minor airways (depending on the patient) has
emerged clinically, endoscopically and pathologically as a consistent and increasingly recognised
form of respiratory involvement in IBD. The severity ranges from the asymptomatic state to
copious and disabling bronchorrhea or acute asphyxia. In addition, IBD is also associated with
interstitial lung disease (ILD) with a variegated pattern on high-resolution computed tomography
(HRCT), sterile necrobiotic neutrophilic nodules and pleuropericardial involvement. It is
important to appreciate that therapy with several IBD-modifying drugs can also produce diffuse ILD,
164
UC,CD
UC,CD
UC,CD
CD..UC
UC.CD
UC..CD
+
++
Uncommon
Does not apply
+++
++
++
++
++
++
++
+
Does not apply
Does not apply
+
Moderate
Weak
Unknown
UC.CD
CD..UC
+++
+++
Very rare
Moderate
Weak
Low
Weak
No
Strong
Strong
+
++
UC,CD
No
NSIP
Pulmonary infiltrates with
eosinophilia
BOOP
ILD with granulomas
Desquamative interstitial
pneumonia
Localised mass or masses and
nodules
Granulomatous inflammation
Localised BOOP
Necrobiotic nodules"
Therapy-related lung disease
Drug-induced pneumonitis
Opportunistic infections
Pleural surface
Serositis
Effusion
Pericardial surface
Pericarditis
Pericardial effusion or tamponade
Unknown
UC.CD
Drugs
Moderate
Moderate
Strong with CD
Moderate
Moderate
Strong
Strong with CD
Unknown
Moderate
Low
Strong
IBD
Evidence base for

association with
+++
++
++
++
+++
+++
UC
versus CD
Main bronchi
Small/peripheral airways#
Infiltrative lung disease
Diffuse ILD
Trachea
Airway inflammation/
deformity/scarring
Glottis, larynx, subglottic region
Onset
post-colectomy
Frequency/
incidence
Table 1. Airway involvement in inflammatory bowel disease
INFLAMMATORY BOWEL DISEASE
Malignancy, infection, autoimmune
Malignancy, infection, autoimmune
Bacterial infection
TB, sarcoidosis
Malignancy
BOOP of other causes

TB, sarcoidosis, HSP
ILD due to drugs/other causes,

metastatic lymphangitic spread
ILD due to drugs/other causes
PIE due to drugs/other causes
ANCA related (granulomatosis with

polyangiitis (Wegeners)), TB, sarcoidosis
Herpes virus, polychondritis, TB,
maligancy, papilloma
Classic chronic bronchitis/smoking bronchiectasis
Other causes of acute/chronic bronchiolitis
Main competing diagnosis
The evidence that IBD is causally associated with

airway inflammation is based on: 1) the steady flow
of consistent clinical descriptions of an association
worldwide since the 1960s; 2) the common embryologic ancestry of the bronchi and bowel suggests coinvolvement in the same disease process; 3) the
frequent reports of airway involvement occurring
post-colectomy in individuals with UC with no
history of lung disease [1, 7]; 4) the impressive
response of airway inflammation to inhaled or oral
corticosteroid therapy at least in patients with mild
or moderate disease [1, 811]; and 5) epidemiologic
studies showing greater prevalence of bronchitis in
IBD patients overall [12]. Taken together, these
findings suggest a true causal association of IBD
with airway inflammation [12, 13].
In approximately 75% of IBD patients who develop
airway involvement, the onset of respiratory symptoms is weeks to years after the development of
clinically confirmed IBD. Post-colectomy patients
are not immune to the development of airway
involvement (which may be very severe) and
colectomy may even be a risk factor for onset and
progression of severe airway involvement in UC
[1, 7]. Less often, IBD-related airway involvement
pre-dates the onset of the IBD (raising difficult
diagnostic issues), develops concomitantly with the
inaugural flare of the IBD, or parallels flare ups of the
IBD [1, 6]. Contrasting with ILD (the other major
pattern of respiratory involvement in IBD), many
IBD patients who develop airway involvement do so
at a time when they are no longer exposed to IBDmodifying drugs, either because the IBD is quiescent
or because of their post-colectomy status.
This chapter will focus on airway inflammation in

IBD which can occur in both UC and CD, with
greater incidence in the former. Although some
overlap exists, the inflammation associated with each
condition has distinct clinical and pathologic features.
Notably, granulomatous inflammation is observed in
the airways and/or lung parenchyma in CD, while
non-granulomatous inflammation is seen in UC.
Airway involvement in IBD is generally inflammatory in nature and therefore typically amenable to
therapy with inhaled or oral corticosteroids, may
165
+
Very rare at present
UC,CD
+
++
Other thoracic manifestations

Venous/pulmonary
thromboembolism
Fistulas1
Low serum albumin and
pulmonary oedema
Onset
post-colectomy
Frequency/
incidence
UC: ulcerative colitis; CD: Crohns disease; IBD: inflammatory bowel disease; BOOP: bronchiolitis obliterans-organising pneumonia; ILD: interstitial lung disease; NSIP:
nonspecific interstitial pneumonia; ANCA: antineutrophil cytoplasmic antibody; TB: tuberculosis; PIE: pulmonary infiltrates and eosinophilia; HSP: hypersensitivity pneumonitis.
: no/never; +: unusual; ++: occasional; +++: common among IBD-related respiratory manifestations (overall incidence is low with 177 instances in 155 patients in 2007 [6];
.: greater, ..: far greater; ,: lower; ,: equal to. #: .7th generation; ": also named pulmonary Pyoderma gangrenosum; 1: colobronchial or oesotracheal.
No
Drugs
IBD
Strong; odds
ratio,3
Strong
Main competing diagnosis

Evidence base for
association with
UC
versus CD
Table 1. Continued.
involvement of the pleural space or cardiac hypersensitivity reactions. Several drugs used to treat IBD,
such as anti-tumour necrosis factor (TNF)-a therapy,
put patients at risk of developing opportunistic
pulmonary infections, including pulmonary tuberculosis and should be considered in the list of differential diagnoses.
localise from the glottis to the smallest airways depending on patient and stage of the disease, may
be localised or diffuse in the airways, or may lead to a reduction in airway patency which, when
involving the upper airway (in particular larynx, vocal cords or glottis), carries the risk of rapidly
progressive life-threatening airway obstruction [1, 14, 15].
The diagnosis of any respiratory manifestation in IBD is one of exclusion and the main competing
diagnoses are listed in table 1. Differential diagnoses include other systemic conditions capable of
involving the central airways, such as sarcoidosis, relapsing polychondritis, tracheal amyloidosis or
papillomatosis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (granulomatosis
with polyangiitis (Wegeners)), idiopathic subglottic stenosis, chronic bronchitis, bronchiectasis or
suppurative airway disease of other causes [16, 17]. One must also consider drug-induced disease,
since the IBD-modifying drugs sulfasalazine and mesalazine can produce adverse reactions in the
lung or heart [18]. Similarly, therapy with corticosteroid drugs and anti-TNF-antibody therapy
increases the risk of developing opportunistic pulmonary infections including tuberculosis.
Therefore, IBD patients who present with ILD, purulent necrobiotic nodules, acute bronchiolitis and
granulomatous airway inflammation need to be carefully investigated to exclude infection and drug
induced changes [3, 19, 20].
Literature milestones
The first report on airways disease in UC by LOPEZ BOTET and ROSALEM ARCHER [21] described the
essentials of a unique disease, subsequently identified in many patients in several studies. The
authors reported the occurrence of aggressive ulcerous bronchitis and bronchiectasis (confirmed
on contrast bronchography), associated with profuse bronchorrhoea and haempotysis, in a 38year-old female 10 years after colectomy for UC. Prednisolone treatment improved her symptoms
temporarily before she developed refractory airways disease, amyloidosis and eventually died. The
authors suggested that the two manifestations reflected one single disease, and that the
inflammatory process may have shifted to the airways.
In 1976, KRAFT et al. [22] drew attention to the potential association of IBD and disabling airway
disease. In their seminal paper they described six adult IBD patients; five UC and one with regional
enteritis (CD). All of the patients were nonsmokers who developed chronic, otherwise unexplained,
bronchorrhea 313 years after the onset of their IBD. In two patients, the airway disease developed
following total proctocolectomy. There was a correlation of bowel and respiratory symptoms in four
patients. Five patients had an obstructive pattern of pulmonary dysfunction. Bronchiectasis was
evidenced using contrast bronchography in four patients. Oral corticosteroid therapy used to treat
the underlying IBD was not reported to notably influence the course of airway involvement.
HIGENBOTTAM et al. [8] described 10 nonsmoking patients with UC who presented with a chronic
productive cough, which was not felt to be due to sulfasalazine treatment. Bronchial epithelial
biopsies from four patients revealed basal reserve cell hyperplasia, basement membrane thickening
and submucosal inflammation. Treatment with inhaled corticosteroid (beclomethasone diproprionate) relieved the cough in seven patients. These investigators highlighted the possibility that airway
involvement in UC might be explained by the common embryologic ancestry of the bronchial and
intestinal epithelium, representing a new extra-intestinal manifestation (EIM) of the disease.
166
These observations were expanded in a study by CAMUS et al. [1] of 33 IBD patients (UC n527,
CD n56) of whom 20 presented with airway involvement. Three out of these 20 patients
presented with severe upper airway inflammation narrowing and tortuosity, 15 with central airway
inflammation or suppurative airways disease (trachea or major bronchi), of whom six had
documented bronchiectasis, and two with small airway involvement or bronchiolitis. In the three
patients with central airway involvement and upper airway obstruction, airway endoscopy showed
friable, velvety airway inflammation with cobble stoning and haemorrhage. Airway patency was
reduced to 20% of normal in one case and appearance of the mucosa in the airway was
reminiscent of that in the colon. In the 15 patients who presented with large airway inflammation,
airway endoscopy also showed severe inflammation with glittering erythema and oedema severely
narrowing the airway lumen with effacement of bronchial cartilaginous rings. The bronchoalveolar
lavage (BAL) showed increased neutrophil counts, which diminished in responders once
corticosteroid therapy was administered in parallel with the resolution of the airways symptoms of
cough and sputum. Pulmonary function (notably forced expiratory volume in 1 second) also
improved dramatically by o50%, even in patients with bronchiectasis. Six further patients
presented with febrile pulmonary infiltrates corresponding pathologically to bronchiolitis
obliterans-organising pneumonia (BOOP), a disease of the transitional zone of the lung that is
traditionally considered an ILD. However in IBD, BOOP was notable for prominent ulcerative or
suppurative involvement of the distal bronchioles, raising the question of the dominant site of
involvement in IBD-related BOOP. Inhaled corticosteroids were effective in controlling the
symptoms of cough, sputum and airway pathology in those patients with chronic bronchitis (in
,60%), but were less efficacious in doing so in patients with bronchial suppuration,
bronchiectasis or chronic bronchiolitis (,30%) in whom oral corticosteroid were effective. A
literature review indicated that upper airway involvement accounted for 11.1% of the reported
cases, large and small airway involvement 83.3% and 5.6%, respectively, and that about half the
cases of IBD-associated airway involvement had developed post-coletomy.
CASEY et al. [24] reviewed their experience with 11 lung biopsies from CD patients who presented
with diffuse or localised pulmonary opacities. Workup for an infection was negative in all 11 cases.
The major pathologic features in four patients were chronic bronchiolitis with non-necrotising,
non-coalescent granulomatous bronchocentric inflammation. Two further patients had acute
bronchiolitis associated with a neutrophil-rich bronchopneumonia with suppuration and vague
granulomatous features resembling that seen in UC. The remaining five patents were diagnosed
with ILD or organising pneumonia.
In 2007, BLACK et al. [6] reviewed the literature on 171 instances of respiratory pathology (99 with
airway involvement) in 155 IBD patients. Large airway involvement was found to be the most
common pattern of involvement, accounting for 67% of the cases overall, with bronchiectasis
being the most frequently reported pattern. Involvement of the upper airway (glottis and larynx)
and small airway accounted for 15% and 17% of the cases, respectively.
GARG et al. [23] described the HRCT features of airway inflammation in seven patients with UC
(five post-colectomy) who presented with cough and recurrent respiratory infections. Fibreoptic
bronchoscopy in six patients showed diffuse mucosal erythema and oedema that were most severe
in the proximal airways. Sinus imaging showed mucosal thickening in six patients, a feature that
has not been described previously. HRCT features included bronchiectasis in six patients,
peripheral airway involvement in four patients and a rigid and stenotic trachea in three patients.
Several other notable papers have consistently described similar, if not identical, cases and/or
reviewed earlier literature. Taken together, these studies further confirm a true association of IBD
and large or small airway involvement, and the beneficial effect of corticosteroid therapy in many
cases [3, 9, 11, 20, 2530].
Epidemiology: risk factors

Clinically apparent airway involvement is uncommon in IBD. KRAFT et al. [22] calculated a
prevalence rate of 0.21% in their IBD clinic. In a recent study of 165 patients with bronchiectasis
detected on computed tomography scans, an underlying cause was identified in 122 (74%)
patients; five patients had a history of IBD (up to 10 years earlier in one case), two were postcolectomy and in one patient the diagnosis was made during a flare up of IBD [17].
167
Figures for prevalence may be higher if subclinical airway involvement is defined by subnormal
pulmonary physiology (a common occurrence in IBD, particularly during flare ups) [3134],
increased exhaled nitric oxide [35], minimal changes of uncertain significance on imaging [36] or
changes in induced sputum cytology [35, 37, 38]. However, although subclinical changes in BAL
cell profile have been found in IBD [35, 39], there is no current evidence to suggest a link between
these subtle changes and the likelihood of developing overt airway or parenchymal lung
involvement at a later time. Females outnumber males with an approximate ratio of 1.82.1 [1, 6].
Colectomy has been suspected to be a risk factor for the development of IBD (mainly UC)-related
airway involvement [1, 8, 22]. Recently, KELLY et al. [7] confirmed this in 10 patients with IBD
(CD n55) and bronchiectasis. Eight of these patients had developed respiratory symptoms from
within a few weeks to decades after colectomy. One may question whether IBD-associated airway
involvement is linked to colectomy per se, or occurs as a result of IBD-modifying drug withdrawal
post-colectomy. However, the long time delay of several decades in some patients tends to support
the notion that airway involvement in IBD is an EIM of the disease, rather than a complication of
drugs or a result of drug withdrawal. Furthermore, colectomy in patients with IBD and airway
involvement may lead to deterioration of the respiratory condition and should not be proposed in
an attempt to cure the airway involvement [1]. A high rate (52%) of EIM other than in the lung
was noted in IBD patients with airway involvement. Smoking is unlikely to play a causal role as
most patients with the association are nonsmokers or reformed smokers [1, 40].
Clinical presentations
Upper airway obstruction: glottic and subglottic

This presentation is unusual and it is the most worrisome pattern of involvement in IBD as this may
cause rapidly progressive, severe airway compromise and acute asphyxia. IBD-related upper airway
obstruction has been described in both UC and CD, often in association with active IBD, having a
similar clinical presentation in both conditions (figs. 1 and 2). Early onset of symptoms of sore
throat and hoarseness can be mistaken as upper respiratory tract infection [1, 6, 14, 15]. These
annunciating symptoms may not receive appropriate attention. Following this a continuous
resonant deep-toned barking cough may develop, sometimes with hoarseness due to vocal cord
oedema or dysmotility, stridor and blood-tinged sputum [1, 14, 41, 42]. The overall amount of
sputum is usually insignificant, except if patients have associated tracheal or large airway
involvement, which is frequent. In a few patients, flow reduction [43] is noted on the inspiratory and
expiratory limb of the flowvolume loop [26], indicating fixed as opposed to variable airway
obstruction. Inexplicably, upper airway inflammation can accelerate and progress rapidly, producing
severe airway compromise within a few hours or days [1, 6, 14, 15, 28], at times requiring mechanical
ventilation [15]. Unequivocal airway stenosis can be visualised on computed tomography [44, 45].
On endoscopy, there is marked erythema of the vocal cords, glottis or subglottic region with oedema,
a velvety friable oedematous mucosal swelling, whitish or reddish nodules, distorted anatomy and
pus. In some cases, the 5-mm fibreoptic bronchoscope could not be passed through and beyond the
stenotic area without causing further compromise [1, 14], or progression of the scope in the trachea
required repeat bending to reach the more distal trachea [1]. Macroscopically, appearance of the
airway walls is reminiscent of that in the colon in UC [25, 40]. Beyond the stenotic area, there is
marked inflammation and bulging of tracheal walls. The extent of involvement varies depending on
the patient, being limited to the upper trachea in some and in others extending upstream beyond the
tracheal bifurcation to involve the main stem bronchi, also in the form of diffuse inflammation or
erythematous or haemorrhagic nodular deformity, distorting and reducing airway patency [25].
Imaging studies using HRCT planar reconstruction or magnetic resonance imaging demonstrate
marked thickening of the airway wall and a correlative reduction in airway calibre [1, 43, 45, 46].
Pathologically, bulging of the airway wall corresponds to dense lymphoplasmacytic and oedematous
mucosal infiltrate with, sometimes, lymphocytes, neutrophils or rare eosinophils permeating the
mucosa up to the epithelium which is also infiltrated (fig. 2a and b). The overlying airway mucosa
may show squamous metaplasia or may be ulcerated [1, 47]. When present, noncaseating
granulomas suggest a diagnosis of CD as opposed to UC.
168
The pattern of upper airway obstruction in UC requires expeditious and emergent management to
restore airway patency via interventional endoscopy using debridement, laser, argon plasma
a)
g)
e)
c)
f)
h)
Figure 1. Chest and endocopic imaging in inflammatory bowel disease-related airway involvement. Upper
airway inflammation and stenosis is best evidenced using a) computed tomography (CT) reconstruction or
magnetic resonance imaging and b) fibreoptic bronchoscopy. Inflammation may localise in the glottic or
subglottic area, often involving the trachea (b) and proximal airways which show b) cobble stoning and c)
inflammation and pus. d) Radiographically, minimal changes are present in early disease in the form of bibasilar
bronchial tramlines. On CT examination there is a combination of e) airway wall thickening, f) glove-finger
shadows reflecting airway filling by inspissated secretions or g) a tree-in-bud appearance reflecting small airway
inflammation. h) Late changes are in the form of bronchiectasis. Often changes on endoscopy and imaging will
improve with inhaled alone or inhaled and oral corticosteroid therapy.
d)
b)
coagulation, electrocautery, dilation, stent placement (if the lesion does not occupy the glottic and
subglottic space and does not involve the vocal cords) and topical injections of corticosteroids and/
or mitomycin C [28, 45, 46]. Inhaled, nebulised and parenteral corticosteroids and infliximab have
also been used and this has met with success in a few cases [45]. Breathing a heliumoxygen mixture
(heliox) is indicated during the acute phase of the disease. Prudent dilatation of the airway using
calibrated bougies can be considered to restore airway patency. However, this was complicated by
mediastinitis in one case [43]. Overall, the response to combined treatment is encouraging.
Central airway involvement: trachea and main stem bronchi
169
This is the most common and most disabling pattern of airway involvement in IBD with 67 cases
reported overall (figs. 1 and 2) [1, 6, 22, 23, 40, 4752]. Age at onset of the airway disorder is, on
average, 43 years. Two-thirds of the patients were females [6]. Three main patterns were described:
1) chronic bronchitis with cough and moderate sputum, 2) suppurative airway disease with
abundant bronchorrhea, and 3) chronic bronchiectasis [1, 6]. It is unclear whether there is a
a)
b)
c)
d)
e)
f)
g)
Figure 2. Airway pathology in inflammatory bowel disease (IBD)-related airway involvement. a, b)

Tracheobronchial inflammation is in the form of a dense and florid mixed submucosal lymphoplasmacytic
infiltrate within the airway wall, sometimes markedly reducing airway patency. The mucosa can be ulcerated (a)
and the inflammatory infiltrate (including neutrophils and a few eosinophils) can be seen permeating and homing
toward the airway mucosa (b). Bronchial glands may be damaged or destroyed (not shown). Inflammation may
also involve c) the more distal airways or bronchioles (diameter of the airway lumen ,1.8 x 1 mm) down to d) the
smallest airways (showing at least six bronchioles involved) in the form of acute and chronic exquisitely bronchoor bronchiolocentric inflammation, while the vasculature is spared and uninvolved. Occasionally, there is e)
purulent bronchiolitis (can also be seen in IBD-associated bronchiolitis obliterans-organising pneumonia) and/or
f) purulent bronchiolar and tissue necrosis. g) In a few cases constrictive bronchiolitis and chronic obstruction to
airflow develop as a late manifestation.
continuum from chronic bronchitis to suppurative airways disease or bronchiectasis in a given

patient. However, the clinical impression is that some patients do progress from simple chronic
bronchitis to bronchiectasis in the absence of, and sometimes in spite of, corticosteroid therapy for
a few months or years. Cough and sputum are typically unexplained other than by the background
history of IBD. The condition essentially occurs in adulthood in nonsmoking IBD individuals with
no history of lung of airway disease. Typically, IBD-related large airway disease manifests with the
insidious or rapid development of cough productive of variable amounts of clear, purulent or
blood-stained sputum. Copious bronchorrhea (.100 mL and o500 mL) has been reported in a
few cases [1, 53]. Some patients experienced parallel flare ups of bowel and bronchial symptoms,
further reinforcing the notion of a true association [1, 8, 49]. In several instances abundant
bronchorrhea and severe airway involvement developed a few days to a few weeks after total
colectomy as though aggressive inflammation had shifted away from the bowel to the airways
[7, 48, 51]; although inexplicably, airway involvement can occur much later [1, 7, 21].
170
Pulmonary function testing usually reveals a moderate-to-severe obstructive or mixed obstructive

and restrictive spirometric profile [1]. There is little change in airflow upon inhalation of a
bronchodilator drug. Bronchial responsiveness to methacholine is usually normal [1], and this
contrasts with the background of pronounced inflammation noted on pathology. The figures often
improve dramatically following inhaled and/or oral corticosteroid therapy [1, 11].
171
Findings on endoscopy may be near normal in patients with early or mild symptoms such as
cough, or may show diffuse erythema. Bronchial biopsy specimens at this stage may evidence
submucosal inflammation [1, 3]. Neutrophils are increased in the BAL [1] and on follow-up these
cells diminish in number and percentage in patients who respond to inhaled corticosteroids in
terms of improvement in cough and sputum [1]. In general, in patients with IBD-related airway
involvement, changes are evident endoscopically [1, 9, 23] in the form of erythema, oedema,
velvety bulging of the tracheal or bronchial walls and whitish or reddish cobble stoning [46, 47].
The changes may be predominant in the trachea or they may extend in the form of sparkling
oedema in main stem bronchi and more distally. At times, reduced airway patency prevents full
inspection of the bronchial tree [1, 60]. Pathologically, the underlying IBD seems to repeat the
abnormalities found in the bowel [1, 3]. A dense submucosal collection of plasma cells and
lymphocytes deeply infiltrates the airway wall [1, 3, 11]. The epithelium undergoes squamous
metaplasia and/or is ulcerated. Neutrophils and rare eosinophils may be interspersed in the
cellular infiltrate and epithelium. Subepithelial airway glands beneath the mucosa may be
destroyed by the infiltrate and inflammatory cells may extend around the ducts of the bronchial
glands and into the glands themselves
[1]. IBD-related bronchiectasis differs
Table 2. Airway involvement in inflammatory bowel disease
clinically and pathologically from typical
Site of involvement
bronchiectasis. The former is positively
Larynx/glottis/subglottic area
2 (2.2)
influenced by corticosteroid therapy and,
Trachealsubglottic inflammation/stenosis
15 (16.6)
pathologically, the latter shows a less
Bronchiectasis
44 (48.9)
dense and conspicuous cellular infiltrate
Chronic bronchitis
13 (14.4)
and with more germinal centres (follicuSuppurative airways disease
5 (5.6)
lar bronchiectasis). The inflammatory
Bronchiolitis/granulomatous bronchiolitis
10 (11.1)
Diffuse panbronchiolitis
1 (1.1)
infiltrate in IBD-related airway involvePure constrictive bronchiolitis
2 (2.2)
ment may extend to more distal airways
ILD with a bronchiolitis component
21
which, if available for examination, for
such as BOOP
example on a lung resection specimen [1, 3],
Data are presented as n (%) or n. ILD: interstitial lung
show a similar pattern of inflammation
disease; BOOP: bronchiolitis obliterans-organising pneuand stenosis down to the bronchioles
monia. Data from [6].
(fig. 2c) [1, 57]. There is histological
Although the extent of abnormalities on imaging is generally in proportion to the severity of

clinical symptoms, abnormalities on the chest radiograph can be surprisingly small and discreet,
being simply in the form of linear basilar opacities or the dirty lung, despite disabling cough and
abundant sputum. Radiographically, early or mild cases show minimal or no changes. More
advanced or progressive cases show bibasilar tramlines indicating bronchial wall thickening,
especially in cases with suppurative airway disease. Tubular or cystic bronchiectases are seen in yet
more advanced cases [52]. On HRCT examination, early cases may evidence non-uniform lung
emptying on full expiration thought to reflect peripheral airway obstruction [36, 52]. In more
advanced cases, thin-cut sections of airway on HRCT [54] show airway wall thickening [11] and
an increased external diameter of the airway compared to the adjoining vessel. In more severe
cases, extensive bronchial wall thickening and basilar or widespread dense-tubulated or
dichotomously-branched opacities, which are also known as glove-finger shadows, are seen
[1, 53]. The latter changes are reminiscent, if not similar to, those in allergic bronchopulmonary
aspergillosis and may represent impaction of inspissated mucoid or purulent secretions filling the
airway lumen. However, more advanced cases show basilar or more widespread cystic
bronchiectasis in addition to the aforementioned changes [1, 53, 5558]. Subtle changes can be
present in distal regions of the lung in the form of small irregular dichotomously branched
shadows, the so-called tree-in-bud appearance, more often than not [58] subpleurally in the
bibasilar lung [53]. These changes are thought to represent peribronchiolar cellular cuffing and
may correlate pathologically with acute, subacute and/or chronic bronchiolitis [3, 20, 59]. HRCT
imaging of maxillary and ethmoid sinuses may demonstrate mucosal thickening in up to 60% of
patients with UC-related large airway involvement [23].
Table 3. Airway involvement in inflammatory bowel disease (IBD): evidence of relationship

High prevalence of co-existing extra-intestinal manifestations including sclerosing cholangitis
Absence of a history of airway or lung disease in childhood or adulthood
Low incidence of smoking
No other cause identified at the origin of the airway inflammation or bronchiectasis, no immune deficiency
Onset of airway involvement following the onset of the IBD
Parallel flares of airway and bowel manifestations (rare)
Onset of airway involvement after (sometimes very shortly or up to several years) proctocolectomy
Colectomy tends to aggravate symptoms and extent of involvement in the airways
Distinctive pathologic features or airway (trachea to the smallest airways) involvement
Similar macroscopic appearance and microscopic features of airway and interstinal inflammation
Marked improvement with corticosteroid therapy, unlike classic airways diseases except asthma
Relapse of airway symptoms and inflammation with corticosteroid withdrawal
Similar embryologic ancestry of airways and bowel
similarity between the airways and colonic mucosa in UC-related large airway involvement,
particularly with regards neutrophilic infiltration, mucosal ulceration and dense underlying
chronic inflammation with plasma cells [3].
There is little correlation between the degree of airway inflammation seen on endoscopy and the
amount of expectorated sputum. Stains and cultures yield inconsistent results, being sterile or
showing normal flora, with rare Pseudomonas colonisation. Symptoms inconsistently improve
following a course of antibiotics except if used in conjunction with inhaled or oral corticosteroids
(see later section). In patients who respond to corticosteroid therapy, the airway appearances can
return to normal [30]. In a few patients, however, late changes will develop in the form of tracheal
stricture or deformity, cicatricial obliteration of one or more bronchial orifices or localised weblike strictures.
Small airway involvement: bronchiolitis

There is some confusion surrounding the term bronchiolitis, according to whether the condition is
suspected clinically using HRCT, pulmonary function testing or BAL, or is diagnosed pathologically
using transbronchial sampling or surgical biopsies (the latter is rarely indicated). Bronchiolitis is best
defined pathologically by inflammatory events centred on small noncartilagenous airways generally
measuring ,2 mm (approximately the 7th generation). These airways are situated in the central
portion of the secondary pulmonary lobule and, when inflamed, result in centrilobular nodules
visible on HRCT. Bronchiolitis may be the predominant finding on a lung biopsy specimen
(although it may simply reflect or accompany inflammatory changes in proximal bronchi in
bronchiectasis) and/or may extend and transition into more distal alveolar lung in the form of
BOOP. Evaluation of bronchiolitis requires careful exclusion of an infectious aetiology.
Small airway involvement in IBD has been reported in 17 patients overall [6]. The condition
occurs at a younger age (29 years on average) and in both sexes equally, compared to large airway
involvement [6]. In approximately a third of the patients, bronchiolits pre-dated the onset of the
IBD [6]. Cough and sputum are not always present and the condition may manifest with cough,
dyspnoea, or wheeze accompanied by obstructive or restrictive lung function abnormalities [1, 43, 61].
Radiographically, the chest film can be normal or demonstrate small diffuse irregular or nodular
opacities [24, 62, 63].
172
Although bronchiolitis can be the predominant histopathologic finding in both UC and CD [1, 3,
6, 19, 24, 43, 6265], the pathological features differ between these conditions. In CD, there is
associated non-caseating, non-coalescent bronchiolocentric granulomatous inflammation [24, 66]
while in UC, there is dense bronchiolocentric neutrophilic inflammation of the airway wall or
suppurative bronchiolitis with neutrophils filling the lumen. Although inflammation has a
predilection to involve the bronchioles, inflammation of the neighbouring lung can be present,
producing some parenchymal shadowing or consolidation on imaging [62], or focal suppuration
resembling Pyoderma gangrenoum in the skin [19]. Some cases show florid organising pneumonia
(BOOP) in addition to acute bronchiolitis [1, 67]. A few cases exhibited a pattern identical to diffuse
panbronchiolitis [1], as originally described in Japanese individuals [68], with interstitial foam cells
in addition to acute and chronic bronchiolitis [1, 3]. Scarring may follow acute and chronic
bronchiolitis in the form of constrictive bronchiolitis characterised by severe obstruction to airflow
(fig. 2g) [43]. In such patients, lung transplantation may be an option. The link between UC or CD
and small airways involvement is more than tenuous and acute or chronic bronchiolitis should be
considered as part of the spectrum of UC-related airway involvement. Some investigators have
compared bronchiolitis, as it occurs in UC, to sclerosing cholangitis, another UC-associated EIM.
Management
There is sparse and limited evidence to indicate classic IBD-modifying drugs specifically in
patients with IBD-related airway involvement as these agents are largely ineffective. Although
anecdotal reports described improvement of airway pathology after infliximab [45], IBDmodifying drugs are not recommended as a first-line treatment in this condition. Similarly, no
response has followed therapy with azathioprine or cyclophosphamide.
Corticosteroid drugs are the mainstay of treatment of IBD-related airway involvement. The route
of administration, dosage, titration and duration of treatment with corticosteroid varies with the
patient and is largely empirical.
In patients with airway involvement of moderate severity, such as mild chronic bronchitis, inhaled
corticosteroids are the treatment of choice. It is customary to start with a high dosage (2,000
2,500 mg?day-1) [1, 60]. Adjunctive oral corticosteroid therapy may be used but does not seem to
be an absolute requirement in early/mild disease. Inhaled corticosteroid therapy often provides
convincing improvement and excellent clinical control of the airway disease at this stage.
Improvements in pulmonary function (if decreased prior to onset of treatment), imaging,
endoscopy and BAL neutrophilia accompany the clinical improvement [1, 11, 30, 46]. Once a
satisfactory response to treatment is obtained, inhaled corticosteroids can be slowly tapered every
month or so to lower dosages similar to those used to treat asthma (1,2001,600 mg?day-1). Patient
education will permit any recrudescence in symptoms to be self managed by an increased dose of
inhaled corticosteroids. The addition of oral corticosteroids (e.g. 2560 mg oral prednisolone or
equivalent depending on sex, weight and severity) is normally indicated when there has been no or
very slow clinical improvement after a few weeks of inhaled corticosteroid therapy. Oral steroids
are more readily efficacious [40] enabling quicker control of symptoms and are indicated in
patients with moderate or severe airway involvement. It seems important to reach the normal
clinical state as quickly as possible to ensure the best possible quality of remission. Oral
corticosteroids are tapered in a few weeks to the minimal effective dosage and withdrawn if
possible. Short (26 weeks) bursts of oral corticosteroid may be indicated during relapses, should
inhaled corticosteroids not suffice in controlling the disease.
Colectomy has not shown to be of benefit in the management of IBD-associated airways disease,
and bowel surgery should be critically discussed in such patients. Furthermore, a number of
instances have described the sudden onset, or clear deterioration, of IBD-associated airway
involvement shortly after colectomy.
173
Importantly, patients with more advanced or aggressive IBD-related large airway involvement, with
or without bronchiectasis, may also benefit from long-term inhaled corticosteroid therapy. Imaging
or pathology cannot readily identify which patient will respond to corticosteroid therapy [1], and
clinical response may be associated with no change on imaging and little change in physiology
[5556, 69]. Cases with copious bronchorrhea are less likely to improve on inhaled corticosteroids,
possibly due to altered pharmacokinetics of ICS in the diseased bronchial tree [1]. In such patients a
nebulised corticosteroid is indicated (e.g. 1 mg budesonide b.i.d. to q.i.d.), in addition to more
classic oral and inhaled corticosteroids until improvement in symptoms occurs [1].
Dosage and duration of treatment with oral and inhaled steroids are guided by clinical response,
pulmonary function, bronchoscopy and follow-up HRCT (weighing up the risk of increased
radiation exposure particularly in young people). Although there is no evidence favouring this, we
advise patients to: 1) take their drugs accurately, avoiding any drug holiday even though they may
feel better; 2) exercise regularly with the hope that inspissated secretions dislodge, enabling inhaled
corticosteroids to reach deeper, more distal airways and with the hope of minimising the
musculoskeletal adverse effects of corticosteroids regardless of the route of administration; and
3) receive regular chest physiotherapy unless they reach the asymptomatic state. Fine-tuning of all
aspects of steroid treatment in IBD-related airways disease is best carried out in close co-operation
with the patient, who is often a very astute observer of his/her own illness. It is interesting that
paying attention to such small details such as careful explanation of how treatment works, and
punctuality in terms of inhalation and exercise often meet with improved compliance and
significant clinical improvement, while the nominal dosage of corticosteroids was left unaltered.
Additional treatment options include courses of antibiotics since bouts of infection may repeatedly
complicate the course of the airways disease, and expectorate actively by positional and voluntary
coughing to clear the airways. There is no published or presented experience with azithromycin in
IBD-associated airway involvement. Given the benefit of this drug in other forms of inflammatory
airways disease, an empirical therapy may be worth trying in selected patients [70].
Two issues are currently unresolved. 1) Although corticosteroid therapy is indicated, the specific
effect of inhaled, nebulised, systemic or topical corticosteroids in IBD-related upper airway
involvement is unclear and difficult to evaluate separately. 2) Management of patients who present
with aggressive airway inflammation and stenosis immediately or later during the course of their
disease are a real concern. Corticosteroids may have transient or not perceptible effects and few
options are left available, in as much as patients may suffer adverse effects of prolonged
corticosteroid therapy. We attempted to deliver higher steroid dosages topically via bronchial
instillations of methylprednisolone in saline via the fibrescope three times per week. A typical
4080 mg dose in normal saline is instilled alternatively in the right and left bronchial tree every
23 days. Responders show a decrease in symptoms and some bleaching in the airways consistent
with reduced inflammation. The time interval between two instillations can be expanded to
56 days in those who respond. Still, some patients illness is refractory to any form of therapy,
with bronchial inflammation progressing to uncontrollable destruction of the entire tracheobronchial tree, pulmonary function deteriorating and adverse effects of corticosteroid therapy
tragically increasing with time. Lung transplantation and novel techniques of airway management
need to be discussed in such desperate cases [71, 72].
None declared.
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Chapter 12
Immunodeficiencies
associated with
bronchiectasis
J.S. Brown*, H. Baxendale#," and R.A. Floto",+
IMMUNODEFICIENCY
Summary
Bacterial infection of the lung is a cause of bronchiectasis and
also the main clinical problem in patients with bronchiectasis.
As a consequence, inherited or acquired immunodeficiencies
that allow repetitive lung infection with respiratory pathogens (such as Streptococcus pneumoniae and Haemophilus
influenzae) can drive the development and progression of bronchiectasis. The immune defects most strongly associated with
bronchiectasis are those resulting in hypogammaglobulinaemia.
These include the primary immunodeficiencies, common
variable immunodeficiency and X-linked agammaglobulinaemia
and the secondary immunodeficiences caused by lymphoproliferative malignancy, allogeneic bone marrow transplantation
and chemo/immunotherapy. Identifying hypogammaglobulinaemia is important and allows patients to be given immunoglobulin replacement, reducing exacerbation frequency and
probably progression of bronchiectasis. Conditions resulting
in T-cell dysfunction (such as chronic HIV infection or
immunosuppression), reduced bacterial opsonisation (such as
complement deficiencies), failure of phagocyte migration
(leukocyte adhesion deficiency) and impaired intracellular
killing of bacteria (chronic granulomatous disease) may also
predispose to bronchiectasis. In this chapter we describe the
main immunodeficiencies associated with bronchiectasis and
suggest a staged approach to immunological investigations.
Keywords: Antibody, bronchiectasis, haematopoietic stem cell
transplant, HIV, immunodeficiency, T-helper cell type 17
*Centre for Respiratory Research,

Dept of Medicine, Rayne Institute,
Royal Free and University College
Medical School,
#
Division of Infection and Immunity,
Dept of Immunology, Royal Free and
University College Medical School,
London,
"
Cambridge Centre for Lung
Infection, Papworth Hospital, and
+
Cambridge Institute for Medical
Research, University of Cambridge,
Cambridge, UK.
Correspondence: J.S. Brown, Centre
for Respiratory Research, Dept of
Medicine, Rayne Institute, Royal Free
and University College Medical
School, 5 University Street, London
WC1E 6JF, UK, Email
jeremy.brown@ucl.ac.uk
Eur Respir Mon 2011. 52, 178191.

Copyright ERS 2011.
ISSN: 1025-448x.
DOI: 10.1183/1025448x.10004210
178
ronchiectasis is characterised by damage and dilatation of the bronchi allowing chronic

colonisation with significant numbers of bacterial pathogens. The initial damage to the bronchi
can be caused by infection. It is therefore not surprising that a range of immunodeficiences
predisposing to recurrent respiratory tract infections can lead to the development of bronchiectasis.
Immunodeficiencies are defined as primary immunodeficiencies (PIDs), resulting from deleterious

genetic mutations, or secondary immunodeficiencies (SIDs), where acquired insults have compromised immune function. The pathogens usually associated with milder bronchiectasis include
Streptococcus pneumoniae and Haemophilus influenzae. Both are common nasopharyngeal commensals in adults and children that also cause acute bronchitis and pneumonia. It is probable that
impaired host immunity to these pathogens initiates the development of bronchiectasis, which then
further compromises mucosal defences permitting infection and sometimes colonisation with
environmental bacteria, such as Pseudomonas aeruginosa.
Existing data on the causes of bronchiectasis is derived from relatively low numbers of patients,
usually from specialist centres, who have been immunologically investigated to a variable extent as
discussed by BILTON and JONES [1] in the first chapter of this Monograph. As a consequence, the true
proportion of bronchiectasis patients with a definable immunodefiency is unclear (and will certainly
increase with modern molecular diagnostic approaches). From published reports, up to 7% of adults
and up to a third of children presenting with bronchiectasis will have a PID [26]. Reported rates of
SID are lower but are likely to increase in line with more frequent use of immunotherapy, solid organ
and bone marrow transplantation and improved survival from HIV. In this chapter we will discuss
each of the major PIDs and SIDs that have been associated with bronchiectasis (table 1), before
drawing some more general conclusions about mucosal immunity to bacterial infection.
Primary immunodeficiencies
In most case series the commonest immune disorders associated with bronchiectasis are antibody
deficiencies [27]. Antibody deficiency can be inherited or acquired and can be caused by a range
of specific defects in antibody production, leading to several distinct immunological phenotypes
the most important of which are discussed below. S. pneumoniae and H. influenzae are both
surrounded by an antigenic polysaccharide capsule which is a major virulence determinant for
invasive infection. The close association of antibody deficiencies as causes of bronchiectasis
perhaps indicates that antibody-mediated immunity is a non-redundant mechanism for airways
immunity to these pathogens. Since antibody deficiency syndromes are responsible for significant
numbers of patients with bronchiectasis [3, 5, 6] and require specific management strategies
including antibody replacement, it is important that patients presenting with bronchiectasis
should be appropriately investigated for these conditions by measuring total serum antibody
levels, specific antibody titres and antibody responses to vaccination.
J.S. BROWN ET AL.
Antibody deficiency syndromes
Failure of any of the steps involved in antibody production can potentially lead to defective humoral immunity. Gene mutations affecting early pre-B-cell development (such as
recombination-activating gene) will usually also impair T-cell production and lead to severe
combined immunodeficiencies which almost always present in childhood. In contrast, adults may
present de novo (although with a long history) with a block in pre-B-cell to immature B-cell
development giving rise to: X-linked agammaglobulinaemia (XLA) (usually caused by mutations
in Brutons tyrosine kinase (Btk)); defects in class switch recombination and/or somatic
hypermutation (which are necessary to generate high-affinity immunoglobulin (Ig)G, IgA and
IgE) resulting in hyper IgM syndromes; and defects (which are currently only partially
characterised) in generating functional antibody responses leading to common variable
immunodeficiency (CVID), IgA or IgM deficiency, IgG subclass deficiency and isolated specific
antibody deficiency. The most common of these conditions are discussed below.
Common variable immunodeficiency
179
CVID is the most common adult primary immunodeficiency, with an estimated prevalence of 1 in
25,000 in Caucasians [8]. Although many patients with CVID develop bronchiectasis, CVID is
Table 1. Primary and secondary immunodeficiencies associated with bronchiectasis

Type of
immunodeficiency
Mechanism of
immune defect(s)
Patients with
bronchiectasis
Bronchiectasis attributable
to this immunodeficiency
Primary
X-linked
agammaglobulinaemia#
CVID#
Mutation in Brutons tyrosine

kinase
85% unknown
f32%
,3% children,
very rare in adults
210% children,
0.72.4% adults
1015% mutations in TACI,

CD28, ICOS
Unknown
Unknown
Unknown
Unknown
Specific antibody
deficiency"
Hyper IgE syndrome
Poor antibody response to

polysaccharide antigens
Mutations STAT3
Unknown
Unknown
Phagocyte defects
Varied
Unusual
TAP deficiency
TAP1 or TAP2 mutations
Most patients
Antibody deficiency
Antibody deficiency
Unknown
Unknown
Unknown
Unknown
Rare
Rare
Rare
Associated with bronchiolitis

obliterans
42% of
bronchiolitis
obliterans
patients
Rare
Unknown
Rare
Rare?
Rare
616%
Unknown - depends on
incidence of HIV
f50%
severe COPD
Potentially common
IgG subclass
deficiency"
IgA deficiency"
Secondary
CLL"
Multiple myeloma"
Other haematological
malignancy
HSCT"
IMMUNODEFICIENCY
37%
Antibody deficiency
Post-infective?
Immuosuppressive therapy?
Lung transplant
Associated with bronchiolitis
obliterans
Post-infective?
Other solid organ transplant
Post-infective?
HIV infection
Recurrent pneumonia
COPD
Associated with LIP

Low CD4 count
Post-tuberculosis?
Impaired mucosal immunity?
Children unknown,
448% adults
Children unknown,
2% adults
Children unknown,
411% adults?
,2.5% children,
very rare adults
,110% children,
,1% adults
Rare in children,
very rare in adults
CVID: common variable immunodeficiency; Ig: immunoglobulin; TAP: transporter antigen peptide; CLL: chronic
lymphocytic leukaemia; HSCT: haematopoietic stem cell transplantation; COPD: chronic obstructive pulmonary
disease; TACI: transmembrane regulator, calcium modulator and cyclophilin ligand interactor; ICOS: inducible
T-cell surface expressed CD28 co-stimulatory molecule; STAT3: signal transducer and activator of transcription
3; LIP: lymphocytic interstitial pneumonitis. #: treated with intravenous Ig (IVIG) ": consider treatment with IVIG.
relatively rarely identified as the cause of bronchiectasis in most published data for adult patients,
varying from 0.7% to 2.4% of cases [3, 4, 6], and in 210% of childhood cases [2, 5].
180
CVID is characterised by reduced circulating Ig concentrations of one or more isotypes, with IgG
levels two standard deviations below normal [9] and poor responses to immunisation. The mean
age at diagnosis has two peaks of around 30 years and in younger children [10, 11]. Adult patients
with CVID have often had symptoms for many years before diagnosis [11]. Familial CVID
CVID is characterised by reduced serum IgG concentrations, so finding levels of serum IgG below
the normal range will identify nearly all potential cases. Patients with low IgG levels (even if just
above the bottom of the normal range) should be further evaluated initially by measuring:
1) serum IgA, IgM and IgE; 2) IgG subclasses; and 3) levels of specific antibodies (against for
example, tetanus toxin, pneumococcal serotype-specific capsular polysaccharide and H. influenzae
capsular polysaccharide B) before and following vaccination if appropriate. More detailed
investigations, usually conducted by clinical immunologists, include B-cell and T-cell immunophenotyping and T-cell proliferative responses to common mitogens (to subclassify CVID and
exclude T-cell immunodeficiency). Patients will most likely require lifelong Ig replacement
therapy. The main complications of therapy are fever, headache and chills, which are managed
through pre-medication with anti-histamines and hydrocortisone. Anaphylactic reactions are rare.
Ig replacement may be given by intravenous infusion (i.v. Ig (IVIG), 400 mg?kg-1 every 34 weeks)
or by subcutaneous injection (100 mg?kg-1 weekly). Although there are few data on the long-term
consequences of IVIG treatment, IVIG reduces the incidence of respiratory tract infections
[1820] and computed tomography (CT) scores of inflammation associated with bronchiectasis
[21], so is likely to prevent or slow the progression of bronchiectasis. Early identification of CVID
cases is therefore important, and measuring serum IgG levels in all cases of bronchiectasis is
recommended in the recent British Thoracic Society guidelines [22]. CVID patients are often given
prophylaxis with continuous low-dose oral antibiotics as well as IVIG therapy. The long-term
prognosis of bronchiectasis in CVID patients is not known, but chronic lung disease is a
prominent cause of death for CVID patients [23]. Historically, the dose of replacement IVIG given
is based on a trough IgG level with the objective of keeping this within the normal range (7
15 g?L-1). Generally, this results in most patients running a trough IgG at the lower end of the
normal range, but recent data suggests that for some patients this is inadequate to keep them free
of infection. Individualised Ig therapy using a dose that prevents infection has therefore been
advocated to minimise the risk of progressive lung disease [24].
J.S. BROWN ET AL.
accounts for 1020% of cases, generally with an autosomal dominant inheritance pattern (often
with partial penetrance); although many of the more recently identified genetic defects associated
with CVID have an autosomal recessive inheritance pattern. For the majority of patients the
molecular defects causing CVID are not known, but in 1015% mutations affecting Ig production
have been described. These include mutations of the inducible T-cell surface expressed CD28 costimulatory molecule (,1% CVID); the B-cell activating factor receptor (,1% CVID); the CD19
component of the co-receptor for the B-cell antigen receptor (,1% CVID); the transmembrane
regulator, calcium modulator and cyclophilin ligand interactor (1015% CVID); and a B-cell
surface receptor involved in B-cell proliferation [8, 12]. These mutations affect quite different
parts of the immunological response required for antibody production, suggesting that the
molecular causes of CVID are heterogeneous and perhaps explaining why there is a large range of
clinical associations with CVID that only affect a proportion of patients [13]. For example, up to
25% of patients with CVID also develop autoimmune and lymphoproliferative complications
including granulomatous disease, lymphocytic infiltrations of the lungs or lymphoma [7, 10,
11, 14]. Although these complications have been particularly associated with known genetic
polymorphisms, variations in gene dosage and penetrance has frustrated attempts to generate
robust clinical phenotypegenotype classifications [1517]. Most patients seem to be susceptible
to respiratory and gastrointestinal infections, although selection bias and small numbers means
that the precise incidence of respiratory tract complications in CVID varies between publications. In a large French series encompassing the national experience of patients with CVID,
pneumonia occurred in 58% (31% due to S. pneumoniae and 12% due to H. influenzae),
bronchitis in 69% and sinusitis in 63% of patients [11]. In total, 37% of patients were diagnosed
with bronchiectasis. The pattern of bronchiectasis in CVID tends to be diffuse lower and middle
lobe disease associated with chronic upper respiratory tract symptoms, similar to idiopathic
181
Long-term management of patients with CVID should also include: 1) optimised treatment of
their bronchiectasis focusing on appropriated oral and/or nebulised antibiotic prophylaxis
(as discussed by HAWORTH [25]), anti-inflammatory therapy (described by SMITH et al. [26]) and
airway clearance strategies (described by BYE et al. [27]); 2) vigilance for the development of
lymphoma, lymphoproliferative lung infiltration and granulomatous disease (although there is no
consensus on the type or frequency of screening [28]); 3) a low threshold for investigation of
gastrointestinal symptoms or B12/folate deficiency to pick up CVID-associated inflammatory
enteropathy and Giardia infection; and 4) specialist management of associated idiopathic
thrombocytopenic purpura and other autoimmune disease if present.
X-linked agammaglobulinaemia
IMMUNODEFICIENCY
XLA is a rare disorder of B-cell development characterised by absent serum antibodies and no
circulating B-lymphocytes. It is usually caused by inherited mutations in the Btk gene, although
clinically similar autosomal recessive diseases have been described due to other mutations affecting
B-cells [7]. Patients present with recurrent bacterial and viral infections in early childhood. Similar
to CVID, patients with XLA are particularly susceptible to infections caused by encapsulated
bacteria such as S. pneumoniae and H. influenzae. As a consequence of recurrent lung infection,
lung disease can develop bronchiectasis; in one survey 32% of adult patients with XLA had chronic
lung disease, mainly bronchiectasis [29]. The relative risk of developing structural lung damage is,
however, reported to be less with XLA compared with CVID [20]. XLA has been associated with
up to 3% of cases of childhood bronchiectasis [5] but is only a rare cause in adults. No specific
pattern of bronchiectasis in patients with XLA has clearly been described. The long-term prognosis
has improved with aggressive treatment with IVIG and antibiotic therapy, although there are few
data on the rate of progression of bronchiectasis and chronic lung disease remains a significant
cause of death [29].
IgA, IgM and IgG subclass deficiencies

In case series of paediatric and adult patients with bronchiectasis, small numbers of patients have
selective IgM (,1%), IgA (2%) [3] or IgG subclass deficiency [3032]. However, the clinical
significance of deficiency of IgM or IgA with normal IgG remains unclear. The incidence of
isolated IgM deficiency in the normal population is not known and whether IgM can mediate
immunity at the mucosal surface has not been clarified. IgA is present at mucosal surfaces
including the airway lining fluid [33] and is thought of as an important component of mucosal
immunity. IgA deficiency is relatively common [3, 9], with a prevalence of 1 in 600 of the
population, but may be more likely to lead to lung damage if combined with IgG subclass
deficiencies or specific antibody responses to carbohydrate antigens (see later) [34]. IgG subclass
deficiency, especially IgG2, has been associated with bronchiectasis, particularly in children.
However, the incidence of IgG subclass deficiency varies widely in patients with bronchiectasis,
from 4% to 48% [3, 6, 30, 35, 36] and the significance of subclass deficiency has been questioned
as it is relatively common in a normal population [37]. IgG2 deficiency may be associated with
reduced natural or vaccine-induced specific antibody to S. pneumoniae or H. influenzae as
discussed later. As such, IgG2 deficiency may reflect poor antibody responses to the bacteria that
are associated with bronchiectasis and thus represent a risk factor for disease [38]. Overall, at
present there is no clear consensus that identification of isolated IgA, IgM or IgG subclass
deficiency in a patient with bronchiectasis is necessarily clinically relevant [6].
Specific antibody deficiency
182
The high incidence of bronchiectasis in patients with hypogammaglobulinaemia is probably related

to lack of antibody-mediated immunity to the encapsulated respiratory pathogens S. pneumoniae
and H. influenzae. Antibody responses to S. pneumoniae and H. influenzae that recognise capsular
polysaccharides are protective, and hence a number of groups have explored whether selective
deficiencies in antibody responses to polysaccharide antigens could also cause bronchiectasis.
Antibody responses to polysaccharide antigens are described as being T-independent and generated
through mechanisms that are different from T-dependent antigens [39]. Distinct B-cell subpopulations respond to polysaccharide antigens and patients who have poor responses to capsular
polysaccharide vaccines or who lack particular B-cell subpopulations are particularly susceptible to
S. pneumoniae pneumonia [40] and perhaps the development of bronchiectasis [41]. Antibody
responses to polysaccharide antigens can be tested by evaluating capsule-antigen specific responses
after vaccination against S. pneumoniae or H. influenzae, and can be compared with antibody
responses to a protein antigen vaccine, such as diptheria or tetanus [42]. Specific antibody deficiency
has been identified in 58% of patients with idiopathic bronchiectasis [38], but this was a small study
in which the immunological criteria used for specific antibody deficiency has been queried [43].
Other larger series of adult patients with bronchiectasis suggest specific antibody deficiency has an
incidence varying from 4% to 11% [3, 41]. In some cases, an impaired specific antibody response was
associated with selected IgG subclass deficiencies [36]. However, antibody responses to vaccination
with polysaccharide antigens are variable and affected by age. Up to 10% of the normal population
may be nonresponders [44, 45]. Hence it is difficult to evaluate the significance of specific antibody
deficiency as a cause of bronchiectasis without further studies involving large numbers of
bronchiectasis patients and matched controls. Furthermore, naturally acquired immunity to at least
S. pneumoniae may actually be partially dependent on antibody responses to protein rather than
capsular antigens [46], undermining the reasoning why a specific defect in carbohydrate responses
could cause bronchiectasis.
There are many other immunodeficiencies reported to lead to recurrent lung infection, many of
which have been associated with bronchectasis. Although often very rare, these diseases are of
importance as they indicate which components of the immune response are necessary for
preventing recurrent bacterial infections of the lung.
Transporter antigen peptide deficiency syndrome

Transporter antigen peptide (TAP) proteins are required for the transfer of peptide antigens from
the cytosol into the endoplasmic reticulum where they associate with human leukocyte antigen
(HLA)-1 for presentation on cell surfaces. Autosomal recessive mutations in the TAP1 or TAP2
genes result in reduced HLA-1 expression and CD8 lymphocyte numbers, but with an increase in
natural killer (NK) and cd T-cells [47, 48]. The majority of subjects with TAP deficiency have
recurrent sino-pulmonary infections with common respiratory tract bacterial pathogens and
develop bronchiectasis [47, 48]. Only a handful of families with TAP deficiency have been
described, and this genetic defect will be responsible for a vanishingly small proportion of cases of
bronchiectasis. However, the association of TAP deficiency and other very rare familial T-cell
disorders [49, 50] with bronchiectasis demonstrates that there are previously unsuspected
mechanisms of immunity to extracellular bacterial pathogens involving CD8 lymphocytes that
requires further investigation. In addition, it has been suggested that an excess of NK and cd Tcells might promote bronchiectasis due to a dysregulated inflammatory response in reply to
infection with bacterial pathogens [48].
J.S. BROWN ET AL.
Other PIDs and bronchiectasis
Disorders of macrophage or neutrophil function
183
There are a wide range of inherited disorders affecting neutrophil function such as chronic
granulomatous disease (CGD), leukocyte adhesion deficiency and ChediakHigashi syndrome
[51]. Although these disorders are extremely rare, making it difficult to accurately evaluate their
clinical associations, neutrophil disorders classically lead to recurrent pneumonia and abscesses
but are not necessarily closely associated with bronchiectasis. In relatively large series of adult
patients with bronchiectasis, tests of neutrophil function only occasionally identify patients with
abnormal responses and even in these patients the relationship of the defect to bronchiectasis is
not clear [2, 3, 5]. CGD has been associated with cases of bronchiectasis in some paediatric case
reports or case series but these reports are likely to have been affected by selection bias as they
originate from specialist centres [2, 5, 52]. The seemingly weak association of neutrophil defects
with bronchiectasis may also reflect the range of pathogens these patients are most susceptible to,
which include Staphylococcus aureus, Nocardia, Aspergillus and Candida species but excludes
S. pneumoniae and H. influenzae, the pathogens most closely associated with development of
bronchiectasis in Ig deficiencies [51]. Primary defects of macrophage function generally affect
intracellular killing and lead to increased incidences of infection with intracellular pathogens such
as mycobacteria, Histoplasma, Listeria and Salmonella species [51] but again are generally not
directly associated with the development of bronchiectasis. What is unclear is the extent to which
functional polymorphisms of phagocytic receptors (such as Fc gamma RIIA H/R 131) or pattern
recognition receptors (such as Toll-like receptors) may predispose to bronchiectasis through
impaired phagocytosis of opsonised/non-opsonised bacteria or aberrant inflammatory responses.
IMMUNODEFICIENCY
Hyper IgE syndrome

Hyper IgE syndrome is a rare autosomal dominant inherited syndrome that causes susceptibility to a
range of infections as well as bone, dental, vascular and joint abnormalities [53]. Most patients have
the classical clinical triad of massively raised IgE levels, recurrent pneumonia and soft tissue abscesses
(hence the condition is also called Jobs syndrome). The majority of cases are caused by mutations
affecting the signal transducer and activator of transcription 3, an intracellular signalling protein
important for regulating cellular responses to cytokines [53, 54]. Patients have both an exaggerated
and reduced cytokine response to infection. In particular, patients with hyper IgE syndrome have an
impaired T-helper cell type 17 (Th17) CD4 response [55], which seems to be important for mucosal
immunity to some respiratory pathogens such as Klebsiella pneumoniae and S. pneumoniae [56, 57],
as well as S. aureus [58] and Candida species [59]. Th17 CD4 immune responses assist neutrophil
recruitment to sites of infection as well as local mucosal immunity [56, 57]. Pneumonia in patients
with hyper IgE syndrome is often complicated by pneumatoceles, but can also lead to
bronchiectasis in a significant proportion of patients [53]. Although hyper IgE syndrome is a rare
disease that is only occasionally found in cases series of patients with bronchiectasis [2, 5], the
identification that the underlying genetic defect of a Th17 response demonstrates the importance
of this pathway for immunity to common bacterial pathogens of the lung.
Other PIDs associated with bronchiectasis

Patients with inherited disorders of DNA repair such as ataxia telangiectasia are more susceptible to
infections as the development of adaptive immunity is impaired. Many of these patients are antibody
deficient and have bronchiectasis [60]. Similarly WiskottAldrich syndrome, an X-linked
immunodeficiency caused by mutations in the WASP gene leading to low levels of T- and Blymphocytes, NK cells and serum IgM, develop infections with encapsulated organisms and
therefore are at risk of bronchiectasis [61]. Both these disorders are rare causes of bronchiectasis in
paediatric case series [2, 5]. A major component of immunity to extracellular bacterial pathogens is
the complement system, and inherited complement deficiencies such as C2 or mannose-binding
lectin (MBL) deficiency are associated with recurrent respiratory infections [62, 63]. However,
although MBL deficiency is a relatively common condition affecting up to 25% of the normal
population [62] there are only occasional reports linking isolated MBL deficiency with
bronchiectasis [5]. MBL deficiency may increase the likelihood of bronchiectasis in patients with
CVID [6466] and is associated with more severe disease in patients with cystic fibrosis (CF) [67],
suggesting MBL may help control disease progression in other immunodeficiencies associated with
bronchiectasis. Lower levels of L-ficolin, another MBL pathway opsonin, has also been found in
patients with bronchiectasis compared with controls [68], although these data need to be replicated.
Other complement deficiencies are very rare and there are no data linking them to bronchiectasis.
184
The majority of patients with CF and ciliary dyskinesias will develop bronchiectasis and clearly
have impaired physical immune defences of the lung through the effects of the gene defects on
mucociliary clearance. Neither are usually characterised as immunodeficiencies. However, recent

data suggest mutations of the CF transmembrane conductance regulator in CF also cause a variety
of defects in mucosal innate immunity. These include impaired phagocyte function, reduced
efficacy of antibacterial peptides, and failure of bacterial internalisation by epithelial cells, as well as
an exaggerated inflammatory response to infection [69, 70]. This constellation of multiple defects
in innate immunity could make a significant contribution to the development of bronchiectasis in
patients with CF, but this will be difficult to establish conclusively.
Secondary immunodeficiencies
Good clinical data on the associations of different secondary immune deficiencies with
bronchiectasis are more limited than the available data for PIDs. In general an accurate
assessment using the published data of the importance of SIDs as causes of bronchiectasis is not
possible. However, recognised causes of SIDs are probably relatively rare causes of bronchiectasis,
with the potential exception of children in areas with a high incidence of HIV infection.
Many haematological malignancies result in B-cell and/or T-cell dysfunction and predispose to
recurrent lung infection and subsequent development of bronchiectasis. In addition, profound
immunodeficiency may occur as a result of treatment for these conditions. Case reports or case
series have described bronchiectasis complicating chemotherapy, acute and chronic leukaemias,
myeloma and lymphomas [5, 7173]. In particular, due to the combination of prolonged survival
and the high frequency of secondary hypogammaglobulinaemia, multiple myeloma and chronic
lymphocytic leukaemia (CLL) seem to be relatively commonly associated with bronchiectasis,
although the exact incidence has not been reported [72]. CLL and myeloma patients with proven
bronchiectasis and hypogammaglobulinaemia should be assessed for IVIG therapy. Bronchiectasis
has also been reported to develop in association with more acute haematological malignancies,
perhaps as a consequence of severe lung infections and/or due to the affects of leukaemia or
chemotherapy on host immunity [71]. However, there are no precise data on the incidence and
rate of progression of bronchiectasis in patients with haematological malignancies.
J.S. BROWN ET AL.
Haematological malignancies
Post-transplantation
Haematopoietic stem cell transplantation (HSCT) is associated with an increased incidence of
respiratory infections and potentially prolonged defects in cellular and humoral immunity in
survivors [74]. These factors could predispose to bronchiectasis [75] and, in the authors
experience, serial CT scans after allograft HSCT can demonstrate rapidly developing bronchiectasis
over a period of weeks to months. In addition, up to 10% of HSCT allograft recipients will develop
bronchiolitis obliterans (the main pulmonary manifestation of graft versus host disease) which
precedes the appearance of diffuse bronchiectasis in ,40% of cases [76, 77]. Hence, although there
are no precise prevalence data on bronchiectasis post-HSCT, it is probably a relatively common
complication, especially in allograft recipients. Similarly, patients who develop bronchiolitis
obliterans after lung transplantion may also have CT evidence of bronchiectasis [78], and there are
case reports of bronchiectasis developing after transplantation of other solid organs [79],
presumably because of damage caused by intercurrent pneumonias and/or impaired pulmonary
immunity due to prolonged immunosuppressive therapy.
HIV
185
HIV infection in most patients leads to a progressive T-cell defect characterised by a fall in CD4 Thelper cells. HIV-infected subjects suffer recurrent infections with conventional and opportunistic
pulmonary pathogens, including mycobacteria species and S. pneumoniae. With the increasing
duration of long-term survival after HIV infection it is therefore perhaps not surprising that up to
16% of HIV-infected children develop bronchiectasis [80, 81]. The incidence of bronchiectasis in
HIV-infected adults may also be significant [82, 83]. The aetiology of HIV-related bronchiectasis is
not well understood but may include direct effects of HIV infection on T-cell-dependent
immunity and local macrophage- and monocyte-dependent pulmonary immunity, secondary
effects on humoral responses, as well as direct effects of bronchial wall damage due to intercurrent
pneumonia or tuberculosis, and possibly the association of HIV in adults with chronic obstructive
pulmonary disease (COPD) [84]. The limited available publications suggest that in children
bronchiectasis is more likely in subjects with CD4 counts ,100 mm3, or who have had recurrent
pneumonia [80]. Interestingly, there is also a specific association with lymphocytic interstitial
pneumonitis (LIP), with up to 40% of HIV-infected children with LIP developing bronchiectasis
[80, 85]. Whether this reflects accelerated bronchial wall damage due to the lymphocytic infiltrate
or reduced mucosal immunity in LIP is not clear. There are no comparative data on the pattern
and progression of bronchiectasis in HIV-positive patients compared with patients with
bronchiectasis due to other causes. More studies are required on the prevalence and associations
of HIV infection with both adult and paediatric bronchiectasis to allow specific risk groups to be
defined and managed aggressively to prevent progressive bronchiectasis. In addition, in areas with
significant levels of HIV infection whether patients diagnosed with bronchiectasis warrant a HIV
test as part of the diagnostic work-up needs consideration.
IMMUNODEFICIENCY
COPD and asthma

There is a high incidence of bronchiectasis in patients with severe asthma and COPD according to
CT criteria [86, 87], although the exact incidence is not known and is confounded by both asthma
and irreversible airways obstruction being complications of bronchiectasis. Bronchiectasis could
be associated with asthma and COPD due to the cycles of recurrent infection and localised
bronchial wall inflammation associated with both conditions. The clinical importance of
bronchiectasis in patients with airways disease is not clear at present, but as bacterial infections
frequently drive exacerbations of COPD, significant bronchiectasis could be clinically highly
relevant. Patients with asthma and COPD may have altered mucosal immune responses to
microbial pathogens and impaired macrophage function that, along with the marked airway
inflammation that characterises both diseases, might contribute towards the development of
bronchiectasis [88, 89]. The effects of asthma and COPD on pulmonary immunity need further
investigation. Due to the rising incidence of COPD and more extensive use of CT scanning, severe
COPD is likely to become an increasingly common association in series of adult patients with
bronchiectasis.
Biological therapies
Therapies that inhibit tumour necrosis factor-a (such as infliximab) or deplete B-cells (rituximab)
are increasingly used to treat rheumatological and other autoimmune conditions. Both therapies are
associated with increased risks of infection [90, 91]. These therapies may make management of
existing bronchiectasis more challenging and, in our experience, usually require an escalation of
antibiotic prophylaxis. Furthermore, they could potentially trigger the development of bronchiectasis by increasing the frequency and/or severity of respiratory infections. Repeated administration of rituximab is often associated with the development of hypogammaglobulinaemia, which in
the context of recurrent infection, should be managed by immunoglobulin replacement [92]. The
effects of biological therapies are discussed in detail in the chapter by DHASMANA and WILSON [93].
What information do PIDs and SIDs provide about immunity to

airways infection?
186
The identification of patients with bronchiectasis due to PIDs provides clear evidence for which
aspects of the immune system are required for protection against bacterial infections of the lung.
The close association of bronchiectasis with CF, primary ciliary dyskinesia and antibody deficiency
syndromes such as CVID and XLA demonstrate that physical defences and IgG (and perhaps IgA,
specific IgG subclasses or anti-polysaccharide antibody responses) are required for the prevention of
chronic bacterial infection of the lungs, as discussed in the chapter by LAMBRECHT et al. [94].
Although the mechanisms remain poorly defined, the clinical manifestations of TAP deficiency and
hyper IgE syndrome with bronchiectasis suggest there is also an important and previously
unsuspected role for CD8 and Th17 CD4 lymphocytes for the prevention of bacterial lung infection.
Conversely, despite the prominence of neutrophil and macrophage infiltration in pneumonia and
bacterial bronchitis, defects of phagocyte and complement function are only loosely associated with
bronchiectasis. Humoral immunity therefore seems to be more important for bacterial clearance
from the bronchial tree than phagocytes. This is perhaps a surprising observation as the main
mechanism by which antibody assists pulmonary immunity to bacterial infection would have been
predicted to be through promoting bacterial phagocytosis. Despite these clues provided by PIDs and
SIDs, large gaps remain in our knowledge on the immune mechanisms required to prevent bacterial
infections of the lung. Specific important areas of future research include the mechanisms by which
antibody promotes clearance of bacteria from the lung, the bacterial target antigens for these
antibody responses, and the role of different T-cell subsets for lung immunity.
We recommend a sequential approach to investigation of immune function in patients with

bronchiectasis or recurrent infection summarised in table 2. First-line investigations involve
measurement of total serum Ig, IgG subclasses and specific antibody levels before and after
vaccination (to detect CVID, XLA, IgA/IgM and IgG subclass deficiency) and, where appropriate,
test for HIV infection. Further testing can then be initiated (following discussion with a clinical
immunologist). Second-line tests include T- and B-cell immunophenotyping (to examine for
defects in lymphocyte differentiation), neutrophil superoxide measurements (to look for CGD)
and complement (to check for deficiency). A number of third-line tests involving gene sequencing
and functional assays (examples shown in table 2) may also be indicated. One important clue to
the type of immunodeficiency is the type of infections affecting the patient which can direct
J.S. BROWN ET AL.
A strategy for immunological investigation of patients with

bronchiectasis
Table 2. Suggested staged immunological investigations of patients with bronchiectasis

First-line tests
Second-line tests
Third-line tests
Serum IgG, IgA, IgM, IgE
Immunophenotyping
(including B-cell subsets)
Specific gene sequencing

(e.g. ICOS, TACI, STAT)
IgG subclasses
Targetted genotyping
(MBL, FccRIIa)
TCR Vb usage
Levels of specific antibodies against:

Neutrophil superoxide
pneumococcal serotype specific
capsular polysaccharide, tetanus toxin
If low, assess vaccination response
TCR spectratyping
Autoantibody screen
Functional assays
(e.g. chemotaxis, cytokine
release assays,
phagocytosis and bacterial
opsonisation assays)
Complement levels
White cell differential count

HIV test
187
Ig: immunoglobulin; MBL: mannose-binding lectin; ICOS: inducible T-cell surface expressed CD28 costimulatory molecule; TACI: transmembrane regulator, calcium modulator and cyclophilin ligand interactor;
STAT: signal transducer and activator of transcription 3; TCR: T-cell receptor.
laboratory investigations: encapsulated bacteria in B-cell immunodeficiencies; fungi, viruses and

mycobacteria in T-cell immunodeficiencies and catalase-positive organisms (e.g. Staphylococcus,
Aspergillus) in neutrophil disorders.
IMMUNODEFICIENCY
Future directions
2653% of patients with bronchiectasis have no defined cause [3, 4]. Many of these patients also
have upper respiratory tract disease such as sinusitis, suggesting they may have a global defect in
preventing chronic bacterial infection of the respiratory tract. Recently, there has been increasing
evidence that unsuspected immune defects may underpin many childhood infectious diseases [95]
and intensive screening of children with idiopathic bronchiectasis may identify additional PIDs.
For example, as untreated patients with primary ciliary dyskinesia and CF almost always develop
significant bronchiectasis, other more minor defects in physical defences could be important
causes of idiopathic bronchiectasis in adults and children. However, redundancy may limit the
role of immunological defects as causes of bronchiectasis. For example, even with significant IgG
deficiency the clinical phenotype of bronchiectasis has only partial penetrance and a significant
proportion of subjects do not develop chronic lung infection. Hence, in adults, bronchiectasis
could be a multifactorial disorder requiring two or more immune defects or a combination of an
immune defect with a specific environmental insult in order to develop. The role of many aspects
of lung immunity such as mucosal anti-bacterial peptides and proteins have yet to be investigated,
and the complexity of the respiratory immune system could make identifying novel immune
defects associated with bronchiectasis difficult. Despite this, polymorphisms affecting NK cell
function or TAP and HLA associations with bronchiectasis have been described [9698]. Further
genetic studies of large numbers of patients with bronchiectasis are likely to identify additional
polymorphisms or mutations affecting different aspects of immune function which could be
related to the development of bronchiectasis.
Conclusions
Characterisation of patients with bronchiectasis has demonstrated close associations with a wide
range of PIDs and SIDs, confirming that effective pulmonary immunity is necessary to prevent
chronic bronchial damage due to bacterial infection. PIDs associated with bronchiectasis provide
clear evidence for the vital role of physical defences for preventing lung infection, with important
supportive roles from antibody and T-cell. SIDs causing bronchiectasis are less well characterised,
but the effects of long-term HIV infection, the new biological therapies and perhaps chronic
airways disease on pulmonary immunity are likely to be increasingly associated with the
development of bronchiectasis. Patient with SID should be monitored for the development of
recurrent lung infections and, where appropriate, the development of hypogammaglobulinaemia.
Despite intense investigation for all the known causes of bronchiectasis, a large proportion of
patients will still have idiopathic disease. An even more detailed immunological assessment of
patients with idiopathic bronchiectasis combined with investigations for novel gene defects and
polymorphisms will probably reveal a range of minor defects that affect immune function in a
significant proportion of these patients. Although the challenge will then be to confirm that these
minor immune defects actually contribute to the development of bronchiectasis, we would predict
that increasing numbers of immunodeficiencies associated with bronchiectasis will be identified in
the future.
188
H. Baxendale has received research grant funding from Biotest and GlaxoSmithKline PLC to
explore natural and vaccine related immunity to Streptococcus pneumoniae. Travel to ESI 2010
biannual meeting was funded by Grifols UK, Ltd.
189
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Chapter 13
Bronchiectasis and
autoimmune disease
D.J. Dhasmana and R. Wilson
BRONCHIECTASIS AUTOIMMUNITY
Summary
The association between bronchiectasis and autoimmune
disease is well recognised, and best described with rheumatoid
arthritis. The prevalence of bronchiectasis in rheumatoid
arthritis varies considerably in studies, with obliterative
bronchiolitis a common feature. The prognosis of rheumatoid
arthritis with bronchiectasis seems to be worse than either
condition alone. The advent of high-resolution computed
tomography has increased the sensitivity of detecting bronchiectasis, but this should be assessed for clinical significance.
Traction bronchiectasis results from interstitial fibrosis pulling
the airway wider, rather than damage weakening the bronchial
wall, and is less likely to lead to bronchial suppuration.
Bronchial wall damage in bronchiectasis is caused by inflammation, but it is difficult to differentiate damage caused by
severe or recurrent infections, predisposed to by immunosuppression related to the autoimmune disease itself or its
treatment, from damage caused by the autoimmune process.
Increased use of new immunomodulatory or immunosuppressive agents has proved successful in modifying autoimmune
disease processes, but has also led to emergence of infective
complications that can cause bronchiectasis or exacerbate preexisting disease.
Keywords: Autoimmune, bronchiectasis, immunosuppression,
rheumatoid arthritis, Sjogrens syndrome, vasculitis
Host Defence Unit, Royal Brompton

Hospital, London, UK.
Correspondence: R. Wilson, Royal
Brompton Hospital, Fulham Road,
London, SW3 6NP, UK, Email
r.wilson@rbht.nhs.uk
Eur Respir Mon 2011. 52, 192210.

Copyright ERS 2011.
ISSN: 1025-448x.
DOI: 10.1183/1025448x.10004310
192
n association between bronchiectasis and autoimmune disease has long been recognised. The
main autoimmune diseases in which bronchiectasis has been described are discussed in this
chapter with emphasis on rheumatoid arthritis, for which there is best evidence of a true
association. When information is available we discuss estimated prevalence, pathogenesis, clinical
features and management where this differs from that in usual bronchiectasis and prognosis. In
addition, we have discussed screening and risk stratification in the context of immunosuppression
following the use of biological agents such as anti-tumour necrosis factor (TNF) in autoimmune
disease.
193
Mixed selected and unselected

Various, including large
prospective and cross-sectional
Various selected
Primary bronchiectasis
not described
,1046%
,221%
723%
f59%
f50%
12%
Rare
Sjorgens
SLE
Largest body of data, variable conclusions but largest

evidence base of autoimmune diseases
Most data based on incidental findings on HRCT,
patients often asymptomatic
Frequent finding of bronchiectasis on HRCT but poor correlation
with symptoms; complications of infection and thrombosis are signficant
and may dominate over clinically meaningful bronchiectasis
Traction bronchiectasis common, but usually asymptomatic;
morbidity usually through non-respiratory complications
NSIP, pulmonary hypertension and traction bronchiectasis common;
primary bronchiectasis less so and perhaps more in diffuse disease
Several old studies pre-1986 and pre-HRCT so likely gross overestimate
Where present, traction bronchiectasis more likely than primary
bronchiectasis, again usually asymptomatic
NSIP and organising pneumonia common, traction bronchiectasis
rarely reported and primary bronchiectasis rare
Granulomatosis with polyangiitis (Wegeners) and MPA most common of
primary vasculitides; BPI-ANCA linked to Pseudomonas
Comments
[4149]
[3840]
[3034]
[3537]
[2529]
[17, 2024]
[1719]
[1316]
[112]
[Ref.]
RA: rheumatoid arthritis; SLE: systemic lupus erythematosus; AS: ankylosing spondylitis; RP: relapsing polychondritis; MCTD: mixed connective tissue disease; PM/DM:
polymoyositis/dermatomyositis; HRCT: high-resolution computed tomography; NSIP: nonspecific interstitial pneumonia; MPA: microscopic polyangiitis; BPI-ANCA: bactericidal/
permeability-increasing protein-antineutrophil cytoplasmic antibodies.
Vasculitis
PM/DM
RP
MCTD
Scleroderma
AS
Various according to type
250%
RA
Patient selection
and study type
Approximate prevalence in
main studies
Disease
Table 1. Summary of the features of bronchiectasis in different autoimmune diseases
D.J. DHASMANA AND R. WILSON
There are several recurring

themes that are worth noting:
1) high-resolution computed
tomography (HRCT) scanning, which has significantly increased the sensitivity of
imaging of bronchiectasis, was
not available when older studies were performed and so
the diagnosis of bronchiectasis may be less certain; 2)
presence of radiological bronchiectasis versus symptomatic
disease; and 3) the use of
retrospective data in analyses
of complex often heterogeneous populations. Another
theme is traction bronchiectasis that may be present in
patients with lung fibrosis due
to involvement of the lung
parenchyma by autoimmune
disease-causing fibrosis. The
scarring pulls the airways
apart as it contracts. The airway mucosa is normal with
intact mucociliary clearance
and possibly for this reason
patients are not usually prone
to bacterial infections. However, in some cases with traction bronchiectasis there will
also be bronchiectasis in parts
of the lung without fibrosis,
suggesting that an inflammatory process has involved
the airways and damaged the
structure of the bronchial wall.
These patients may be more
prone to the clinical syndrome
of bronchiectasis. A summary
of the features of the main
studies carried out are shown
in table 1.
Autoantibodies should not be

routinely tested for during the
investigation of a patient with
bronchiectasis; they should
only be tested for if there
are particular clinical features
raising autoimmunity as a
possible association [50]. In
addition, rheumatoid factor is
nonspecific but high levels do characterise a group of patients with prominent small airways
disease in whom immunosuppression should be considered. Anti-cyclic citrullinated peptide
which is more specific for rheumatoid arthritis has not as yet been investigated in relation to
bronchiectasis.
Rheumatoid arthritis
The association of rheumatoid arthritis and bronchiectasis is well described [1, 51] and it is the
major autoimmune condition associated with bronchiectasis. One important question which
remains unanswered is how the two conditions are related and how one develops in the context of
the other. One hypothesis is that the initial event is recurrent antigen stimulation from recurrent
lower respiratory tract infections, and the immunopathological sequence of events that follows
leads to the development of a multi-system inflammatory disorder with a predilection for
arthropathy. An alternative hypothesis is that bronchiectasis arises from the immunosuppression
associated with rheumatoid arthritis itself and/or its treatments.
Prevalence
The reported prevalence of rheumatoid arthritis with bronchiectasis varies considerably largely
due to patient selection and study type. Reports describe between approximately 2% and 50%
prevalence of bronchiectasis in the largest studies of rheumatoid arthritis published between 1967
and 2006 [112]. A major issue is whether radiological evidence of bronchiectasis, either by chest
radiography or by HRCT scanning, represents disease that is clinically significant. Studies that
have tried to explore this demonstrate poor correlation with radiology [3, 8, 9, 52]. In most
studies, the prevalence is calculated on the HRCT findings rather than on clinical evidence of
bronchiectasis and patients may be entirely asymptomatic with incidental HRCT findings.
Most reports of prevalence have used heterogeneous populations and so carry several potential
confounding characteristics including duration of illness, age (mean age of 4564 yrs across
studies), cigarette smoking history and drug-treatment schedules, which might include corticosteroids and immunosuppressants, such as methotrexate, which could influence susceptibility
to infection. Moreover, the data is typically retrospective bringing with it recall and reporter bias.
DESPAUX et al. [8] report prospective data on 46 unselected patients with rheumatoid arthritis
(34 females, 12 males; mean age 60.1 yrs) collected over an 18-month period. In this study in
which all patients had a HRCT, they found 23 (50%) patients with radiological evidence of
bronchiectasis, 18 of whom were previously undiagnosed. 13 (57%) of these 18 patients were
asymptomatic, thus giving a total of 22% (10 out of 46 patients) with clinically significant
bronchiectasis. In two other prospective studies of 75 consecutive patients [10] and 63
consecutive patients [12] with rheumatoid arthritis, 19% and 29% of patients, respectively, were
found to have bronchiectasis on HRCT, although it is not clear what proportion of these were
symptomatic. A retrospective uncontrolled study of 20 life-long nonsmokers showed a high
proportion of bronchiectasis with five (25%) out of 20 demonstrating basal bronchiectatic
changes, but whilst three of these five gave a past history of pleurisy or pneumonia none had
ongoing symptoms [3]. In other more heterogeneous studies, sub-group analysis has not been
able to demonstrate a relationship between smoking and bronchiectasis in rheumatoid arthritis
[8, 9, 52]. We are not aware of any study that has attempted to correlate the severity of
bronchiectasis using one of the accepted scoring systems with severity of arthritis, either in terms
of joint damage or immunological measures.
194
The immunological diagnosis of rheumatoid arthritis may also complicate prevalence data. In
particular, there may be other autoimmune diseases present within the population studied, such as
Sjogrens syndrome [53, 54]. With modern day biochemical and immunological markers, there is
a more robust system to better differentiate autoimmune diseases from one another, which will
allow better definition of disease in the future.
Finally, the patients ethnic status may have an additional impact on the development of
bronchiectasis with rheumatoid arthritis. This is rarely mentioned within studies. The largest
cohorts are described in France close to the Alps [8] and close to the North Atlantic [4], North
Africa [9], New England in the USA [2] and in central and northern England, UK [3]. The
antigenic stimulation by community pathogens is likely to vary markedly in these different
settings.
Pathogenesis
Whilst the association of bronchiectasis and rheumatoid arthritis has long been recognised
[1, 8, 51], the mechanisms of how one condition develops in the context of the other remains
unclear. While the co-existence of the two separate conditions is possible, the frequency of
bronchiectasis in rheumatoid arthritis is well above that found in the non-rheumatoid arthritis
population and suggests that these are not chance findings [4, 7, 8]. Three mechanisms have been
considered: 1) bronchiectasis gives rise to the development of rheumatoid arthritis; 2) bronchiectasis and rheumatoid arthritis are caused by similar immunological processes, or because of
immunosuppression due to rheumatoid arthritis or its treatments; and 3) other diagnoses and/or
comorbid conditions drive the development of rheumatoid arthritis or bronchiectasis. These will
be discussed in turn, although in reality there may well be several mechanisms interacting in a
particular case.
The nature of the complex immunological mechanisms present in the bronchiectatic airways has
been studied. The neutrophil plays a central role in what has been called the vicious circle
hypothesis, but in addition abnormal mucus clearance and cellular immune responses are
important [5558]. In this context, one proposed mechanism is that persistent immunological
pressure stimulated by chronic bacterial infection drives a sequence of events that leads to the
formation of autoantibodies to self components and ultimately the development of a systemic
inflammatory disorder. For this mechanism to operate lung disease would need to precede
rheumatoid arthritis. Most reports suggest that this is the case. DESPAUX et al. [7] described from
an extensive literature review that 90% of 289 reports published since 1928 document respiratory
symptoms prior to articular symptoms. While this study combines old reports with variable
diagnostic criteria for both rheumatoid arthritis as well as bronchiectasis, in an era before
computed tomography (CT) imaging, the temporal sequence is in fact corroborated in several
individual and more recent studies [4, 5, 54]. Even in newly diagnosed rheumatoid arthritis
present for ,1 year, with normal chest radiographs and normal respiratory function tests, 58% of
patients were found to have HRCT evidence of bronchiectasis. This study demonstrates
established bronchiectasis, albeit subclinical, by the time of a formal diagnosis of rheumatoid
arthritis [59]. However, since the bronchiectasis was subclinical, sufficient antigenic stimulation by
bacterial infection seems unlikely.
Bronchiectasis gives rise to the development of rheumatoid arthritis
Bronchiectasis is caused by similar immunological processes or by

immunosuppression due to rheumatoid arthritis or its treatments
HRCT has made it clear that airway disease is common in rheumatoid arthritis (fig. 1). Follicular
bronchiolitis is due to lymphoid aggregates, with or without germinal centres, which lie in the wall
of bronchioles and sometimes compress their lumens. This appears as centrilolobular nodules,
peribronchial nodules and patches of ground-glass shadowing [60]. Airway wall thickening
(indicating bronchitis without dilatation) and bronchiectasis (fig. 1a and b) are both more
common in patients than matched controls [61].
195
There is a recognised association of rheumatoid arthritis and obliterative bronchiolitis, also known as
constrictive bronchiolitis, in which bronchioles are destroyed and replaced by scar tissue (fig. 1c).
a)
b)
c)
Figure 1. High-resolution computed tomography.

a) Mild tubular bronchiectasis in both lower lobes,
together with mosaic perfusion, in a patient with
rheumatoid arthritis. b) Tree-in-bud exudative
bronchiolitis is widespread in both lower lobes of a
patient with rheumatoid arthritis. Small airways having
thickened walls and plugged with mucus are seen as
multiple white dots. c) Severe bilateral lower lobe
bronchiectasis in a patient with poor lung perfusion
due to a constrictive obliterative bronchiolitis.
Several associations have been observed with obliterative bronchiolitis outside of the well-known
association with tissue rejection in heart and lung transplantation. Drug treatment, especially with
gold and penicillamine, has been implicated in the development of obliterative bronchiolitis [62, 63]
but it also occurs in patients who have had neither drug. Obliterative bronchiolitis is welldocumented post-infection and although more recognised in children, has been documented with
adenovirus, measles, influenza and Mycoplasma [6469]. Not only could such an outcome easily go
unnoticed until later in life, but this could represent a plausible mechanism for the later development
of formal bronchiectasis or rheumatoid arthritis. Early toxin exposure might also account for
obliterative bronchiolitis and later bronchiectasis or rheumatoid arthritis in a similar step-wise
mechanism [70]. Certain human leukocyte antigens (HLA) have been associated with obliterative
bronchiolitis, including the presence of HLA-DR1 in obliterative bronchiolitis with rheumatoid
arthritis, while a large population fail to have an identifiable cause [7173]. Bacterial infection may
complicate the picture by itself provoking inflammation in the lung and causing damage to the airway
wall, as well as exciting rheumatoid arthritis-driven inflammatory processes. Mosaic perfusion and
gas trapping are present on HRCT. In the context of the above, patients complain of progressive
breathlessness, develop irreversible airflow obstruction and subsequently carry a poor prognosis with
death due to respiratory failure [74, 75].
196
It is interesting to speculate whether these different manifestations of airway disease in rheumatoid

arthritis are a single inflammatory process affecting different parts of the bronchial tree, or whether
they are discrete inflammatory conditions. In favour of the former suggestion, all manifestations
described previously can be seen in the HRCT scan of some patients. However, it is usually necessary
to postulate that constrictive obliterative bronchiolitis has been preceded by exudative bronchiolitis,
rather than being able to demonstrate this by sequential radiology. However, bronchiectasis could
develop in the context of additional local structural damage caused by bacterial infection as a
consequence of functional immunosuppression. DEVOUASSOUX et al. [75] report a study of 25
patients with rheumatoid arthritis and obliterative bronchiolitis and demonstrate HRCT evidence of
bronchiectasis in 44% of the cohort. All patients were breathless and bronchorrhoea was present in
44%. They go on to report that in a follow-up of approximately 4 years, treatment was poorly
effective, chronic respiratory failure occurred in 40% and death in four patients.
Methotrexate forms part of many rheumatoid arthritis treatment regimens and despite early
clinical impressions, probably does not significantly increase the infection risk in patients with
poorly controlled rheumatoid arthritis [7981]. This may be because the immunosuppressive
nature of unchecked inflammation in rheumatoid arthritis in the absence of methotrexate
is greater than that conferred by methotrexate itself. However, long-term corticosteroids,
cyclophosphamide and azathioprine certainly do lower the threshold for opportunistic infection
and with the emergence of biological agents such as anti-TNF, the complication of serious
infection and ensuing bronchiectasis becomes more likely [82]. In patients with recurrent
infections on rheumatoid arthritis-treatments it is difficult to define the nature of any immune
paresis, and where specific functional defects are demonstrated it is difficult to ascribe them to the
disease or the therapy that has been prescribed. Gold has been associated with functional antibody
defects, but in a study of rheumatoid arthritis patients with and without bronchiectasis, evidence
of antibody deficiency was apparent in those with bronchiectasis as well as those without, and
independent of any co-incident gold therapy [83]. Other reports of late bronchiectasis may have
case-specific explanations, where resistant pathogens, abnormal airways and/or impaired clearance
lead to unchecked infection and inflammation and usually localised bronchiectasis [84].
Other diagnoses or comorbid conditions that drive the development of

rheumatoid arthritis and bronchiectasis
Rheumatoid arthritis itself is associated with increased morbidity and specifically an increased risk
of infection when compared with the general population [7678]. In a predisposed individual,
regular infection with poor immunological clearance of microbes could subsequently lead to
formation of bronchiectasis. In contrast to the reports described previously, SHADICK et al. [2]
describes 23 patients with rheumatoid arthritis and bronchiectasis, in whom 18 (78%) patients
had rheumatoid arthritis symptoms prior to the diagnosis of bronchiectasis. These patients had a
mean duration of arthritic symptoms of 25 years prior to bronchiectasis, 17 out of 18 patients had
used corticosteroids and respiratory symptoms were present for an average of 4.3 years prior to
the formal diagnosis of bronchiectasis. When compared with the five patients who described
bronchiectasis before rheumatoid arthritis, those with late bronchiectasis used more diseasemodifying agents, had more severe joint disease, were more likely to have rheumatoid nodules and
carried a greater morbidity. This would support the idea that advanced rheumatoid arthritis
disease and increasingly immunosuppressive medications might contribute to the development of
secondary bronchiectasis as a late complication of rheumatoid arthritis.
In most cases today, a clear diagnosis of rheumatoid arthritis and bronchiectasis can be made that
is based upon the history, clinical features and immunology profile. However, in older studies it is
worth noting that either the diagnosis of rheumatoid arthritis may be incorrect, or there may be
significant comorbid conditions that drive the disease phenotype. For example, the finding of
greater numbers of abnormal Schirmers tests (test of tear production) by MCMAHON et al. [54] in
a case-controlled study of 32 patients with rheumatoid arthritis and bronchiectasis when
compared with rheumatoid arthritis without bronchiectasis did increase the possibility that
Sjogrens syndrome was involved in the pathogenesis of one or both conditions, possibly by
affecting mucociliary clearance in the lung. However, this finding was not reproduced by
MCDONAGH et al. [52], and KELLY and GARDINER et al. [53] who found no significant difference in
abnormal tear production in their rheumatoid arthritis patients with bronchiectasis (six out of 10
patients) compared with those without bronchiectasis (18 out of 30 patients).
197
The cystic fibrosis transmembrane conducatance regulator (CFTR) mutation DF508 present in
cystic fibrosis (CF) has been implicated through a study of a French cohort that has demonstrated
its increased presence in rheumatoid arthritis with bronchiectasis [85]. In this study, four (15.4%)
out of 26 Caucasians with a median age of 59 years with rheumatoid arthritis and bronchiectasis
carried the heterozygote genotype compared with none from 29 consecutive rheumatoid arthritis
patients without bronchiectasis, and none from 29 patients with diffuse bronchiectasis. This is a
striking difference when noted in the context of a 2.8% allelic frequency in the general Caucasian
European population. In addition, those with the mutation demonstrated more frequent sinusitis,
lower nasal potential differences and a trend towards more severe lower respiratory tract disease,
while there was no relationship to the severity of articular features.
HLA associations are well characterised for rheumatoid arthritis and the HLA-DRB1 gene locus
from the DR4 family is perhaps the most closely associated susceptibility locus implicated in
rheumatoid arthritis [86]. In a large case-controlled study of patients HLA associations in a UK
cohort, HILLARBY et al. [87] demonstrated the predicted DR4 association in 79% of rheumatoid
arthritis alone patients but no pattern of DR4 subtypes in those with rheumatoid arthritis and
additional respiratory features, including pulmonary fibrosis and bronchiectasis. However, there
was a significant association of rheumatoid arthritis and bronchiectasis with DQB1*0601,
DQB1*0301, DQB1*0201 and DQA1*0501 when compared with rheumatoid arthritis alone. The
group of patients with bronchiectasis in a separate prospective HRCT study of 68 consecutive
rheumatoid arthritis patients showed a low prevalence of DQA1*0501 when compared with the
rheumatoid arthritis group without bronchiectasis [6].
Immune dysregulation is seen in both bronchiectasis and rheumatoid arthritis, and a shared defect
in both rheumatoid arthritis and bronchiectasis may impact upon the shape of the final disease
phenotype. Common variable immunodeficiency (CVID) is the most common primary
immunodeficiency and is frequently associated with both respiratory tract infections and
autoimmune conditions including rheumatoid arthritis [88]. Defective antibody production has
been recognised in rheumatoid arthritis and with rheumatoid arthritis treatments. A UK study of
80 patients was carried out and comprised of 20 patients with rheumatoid arthritis and
bronchiectasis, 20 patients with each disease separately and 20 healthy matched controls. Three
out of 20 from the rheumatoid arthritis-bronchiectasis group demonstrated an impaired antibody
response post-immunisation, two out of 20 rheumatoid arthritis alone patients showed a poor
response (both groups of patients contained individuals on gold therapy) and the control group
demonstrated neither. Immunological defects, when investigated, are likely to be more common
than is currently believed and may play important roles as co-factors in the developing
Yellow nail syndrome (YNS) is a heterogeneous disorder that includes bronchiectasis and has been
associated with rheumatoid arthritis-drug therapy, particularly penicillamine. YNS does occur in
rheumatoid arthritis and other autoimmune diseases independent of drug therapy and its
aetiology remains unclear [90, 91]. Abnormal T-cell responses that are thought to drive disease in
YNS may similarly drive a specific phenotype in the presence of rheumatoid arthritis and act as a
co-factor in development of bronchiectasis.
Management of bronchiectasis in the presence of rheumatoid arthritis
198
There are no specific features in the management of bronchiectasis associated with rheumatoid
arthritis. We have not identified any patients requiring antibody replacement in our own group of
rheumatoid arthritis-bronchiectasis patients, but it would be reasonable to measure total antibody
levels and specific antibody responses to polysaccharide (pneumococcal and Haemophilus
influenzae type b and protein (tetanus)). Some patients have progressive obliterative small airways
disease. Our own experience is that there is a poor response in these patients to increasing
immunosuppression, and this approach to treatment creates more problems by making infections
worse. Once the patient is established by the rheumatologist on a regimen that may include
methotrexate, we have adopted the strategy of trying to reduce the level of bronchial infection by
using antibiotic prophylaxis, including the ketolide antibiotic azithromycin as a putative
immunomodulator [92], and treating exacerbations aggressively. We hypothesise that avoiding the
antigenic stimulation of bacterial infections may reduce the inflammatory processes causing
obliterative bronchiolitis.
The presence of bronchiectasis with rheumatoid arthritis appears to carry a significantly worse
prognosis, although only one report examines mortality and morbidity in this specific context.
SWINSON et al. [93] studied a UK cohort of 32 rheumatoid arthritis patients with bronchiectasis
alongside matched controls with either rheumatoid arthritis alone or bronchiectasis alone. They
found the mortality in the group with both diseases to be considerably higher, with a standardised
mortality ratio five times and 2.4 times greater than that of the rheumatoid arthritis alone and
bronchiectasis alone groups, respectively. The groups shared similar scores of physical activity and
of radiological destruction (Larsen score). While several parameters carried high relative risks of
mortality including grip strength and presence of rheumatoid nodules, the finding of a raised
white cell count and the presence of circulating immune complexes carried the highest relative
risks, the latter being the only one which demonstrated confidence intervals outside parity (relative
risk 4.5, 95% CI 1.413.9). The 5-year survival rate in the combined rheumatoid arthritisbronchiectasis group can be calculated at 69%. Finally, it is interesting to note that those in the
combined disease group did have a lower baseline forced expiratory volume in 1 s (FEV1), as well
as lower forced vital capacity (FVC) and fewer patients with signs of reversibility. Airflow
obstruction in the presence of lung restriction has been identified in one large bronchiectasis study
as a risk factor for mortality. In this study, carried out over 13 years, 29.7% of patients with
bronchiectasis of many different aetiologies died [94]. In contrast, MCMAHON et al. [54] reported
no significant effect of bronchiectasis on the activity and outcome measures of arthritis when
compared with those with rheumatoid arthritis alone.
Sjogrens syndrome
The study of the association of Sjogrens syndrome and bronchiectasis has been made more
difficult by: the presence of primary, secondary and mixed syndromes; serological overlap with
systemic lupus erythematosus (SLE; in particular, Sjogren syndrome-related antigen A) and also
systemic sclerosis; and the inconsistencies in the literature about how the diagnosis of
bronchiectasis was made. The diagnosis of Sjogrens syndrome includes the presence of dry eyes
and dry mouth for 3 months, a positive Schirmers test, anti-Ro and anti-La autoantibodies and a
minor salivary gland biopsy demonstrating a focus score .1. While the use of this definition was
not clear across all studies, an international consensus was obtained to rectify the differences [95].
Clinically significant bronchiectasis is uncommon and so most information on the prevalence of
bronchiectasis in Sjogrens syndrome necessarily comes from imaging studies of patients with
respiratory symptoms or from studies in those who are asymptomatic. Bronchiectasis is variably
reported in such studies ranging from ,10% to 46% [1316]. In a study of 24 German patients
with primary Sjogrens syndrome (excluding smokers and those with other autoimmune disease or
other unrelated bronchopulmonary disorders), 19 were found to have HRCT abnormalities and 11
of these bronchiectatic changes (46% of all patients) [14]. These changes were more central,
predominantly lower lobe, bilateral in eight cases and unilateral in three cases. The precise
symptoms of these patients are not given but the cohort comprised of patients referred for
investigation over a 10-year period to a tertiary referral centre.
Prognosis
199
The aetiology of Sjogrens syndrome is unknown but viral infection is implicated, including EpsteinBarr virus (EBV), cytomegalovirus and retroviruses such as HIV and human
T-lymphocyte virus, with good evidence from animal studies [96]. Both B- and T-cells are
recognised to infiltrate exocrine glands but the pathogenesis is likely to involve a complex interplay
of glandular epithelial and endothelial cells, dendritic cells and B- and T-cells in the context of an
environmental insult in a predisposed individual [97]. Hydration of the airways may be impaired
together with inspissations of secretions as a result of atrophied respiratory tract mucus glands.
Bronchiectasis is proposed to develop subsequently due to recurrent bacterial infections which are
predisposed to by impaired mucociliary clearance. Neutrophilic inflammation provoked by
infection leads to thickened dilated lower airways and eventually bronchial wall destruction.
Amyloid has been recognised in Sjogrens syndrome and may be implicated in the development of
bronchiectasis with its presence confirmed in peribronchial walls, as well as the interstitium [98].
Management of bronchiectasis associated with Sjogrens syndrome

There are no clinical studies reported in the literature. In our own practice we have attempted to
improve mucus clearance by nebulising normal saline regularly several times per day and
emphasising to patients the importance of physiotherapy. Recently we have begun to nebulise 7%
hypertonic saline which has an osmotic effect, with success in individual cases. Optimal antibiotic
management of lower respiratory tract infections may shorten the length of infective exacerbations
and so reduce airway wall damage.
Systemic lupus erythematosus

The first reports of bronchiectasis in SLE emerged in the early 1960s with the use of bronchograms
and pulmonary function tests [99101]. With the advent of CT imaging, there has been a greater
understanding of the radiological abnormalities in SLE. However, there remains some uncertainty
about the significance of the reported abnormalities and the prevalence of clinically significant
bronchiectasis. FENLON et al. [17] prospectively studied 34 patients with SLE with HRCT data
alongside various clinical and lung function data. Of note, they found seven (21%) patients with
bronchiectasis on HRCT, second only to interstitial lung disease (ILD) (11 patients), mediastinal
or axillary lymphadenopathy (six patients) and pleuropericardial abnormalities (five patients).
However, while the presence of HRCT abnormalities was high they found no correlation with
symptoms or disease activity, and none of the patients had recurrent respiratory infections. In a
separate cross-sectional study of 60 Norwegian adults of childhood-onset SLE, any HRCT
abnormality was found in only five patients and in just one (,2%) was there radiological evidence
of bronchiectasis; none had clinical evidence of bronchiectasis [18]. These patients had a median
duration of 11 years of disease by the time of cross-sectional imaging. In contrast, BANKIER et al.
[19] reported a much higher frequency of CT abnormalities with 17 out of 48 patients with SLE
showing abnormalities (45 of whom had normal chest radiographs). They went on to show
correlation of extent of disease radiologically with duration of clinical history (r50.93), gas
transfer (r50.8) and ratio of FEV1/FVC (r50.77). However, once again there was poor correlation
of bronchiectasis on CT scans and clinical symptoms of the disease. Lung fibrosis may cause
traction bronchiectasis and it is not clear in reports whether bronchiectasis is present in parts of
the lung not affected by fibrosis.
As with other systemic diseases, it has been suggested that confounding factors might explain the
association of bronchiectasis with SLE, including the increased risk of infection associated with a
multi-system disease and use of immunosuppressive treatments to control the disease. Mannosebinding lectins (MBL) have been suggested to play a role in SLE in a report of two patients with
SLE who went on to develop CVID [102]. The infrequent MBL haplotype 4Q-57Glu was present
in both, while the haplotype 4P-57Glu in the second case was associated with recurrent respiratory
infections, bronchiectasis and low circulating levels of MBL. This report raises the possibility of
MBL polymorphisms in the development of autoimmune disease and significant infections which
cause bronchiectasis.
200
The clinical features of bronchiectasis in SLE are not described in the literature. However, it is
apparent that the most common pulmonary complications are infection and vascular events [103].
While the reported frequency of clinical bronchiectasis is low, as described previously, there may
be under-diagnosis of post-infective bronchiectasis in patients who have not had HRCT examination.
Respiratory function tests frequently demonstrate reduced spirometry (typically subclinical), reduced
gas diffusion and, depending on severity of disease, decreased lung capacity. These changes appear to
be independent of cigarette smoking [103105].
HRCT features reported in SLE include pleuritis with or without pleural effusion, acute interstitial
pneumonia and acute pulmonary haemorrhage and thrombosis [17, 106]. Morbidity and
mortality in SLE are associated with infection and vascular complications [107, 108]. There is
greater mortality in the first 5 years, partly linked to the use of immunosuppressive therapy in
aggressive SLE disease and the subsequent complications of infection surrounding this.
There are several pulmonary manifestations of ankylosing spondylitis which include apical
fibrobullous disease, secondary infection, chest wall restriction, obstructive sleep apnoea,
spontaneous pneumothorax and bronchiectasis [109]. A typical course is the development of
chronic bi-apical fibrobullous areas with nodules that eventually coalesce to form cysts, cavities
and bronchiectasis, and later superadded infection with Aspergillus and environmental Mycobacteria species may occur. Abnormalities evident on HRCT in those either asymptomatic or with
early disease are well documented with frequencies of all abnormalities in the region of 40% to
80% [2022, 110]. However, little is published regarding bronchiectasis specifically. HRCT
evidence of bronchiectasis has been found in 723% of ankylosing spondylitis patients in the
largest cohort studies performed to date [17, 20, 2124]; in most studies, patients do not report
symptoms of bronchiectasis. Traction bronchiectasis is the most likely explanation in this context
caused by pleuropulmonary fibrosis. FENLON et al. [111] reported a total of six (23%) cases of
bronchiectasis from their prospective cohort study of 26 patients with ankylosing spondylitis from
an out-patient setting in Ireland, of which four were primary bronchiectasis and two had traction
bronchiectasis. The four with primary bronchiectasis consisted of three patients with significant
smoking histories, two each with disease in the upper and lower lobes and only one with
symptoms of cough and breathlessness. The latter patient with bronchiectasis had ankylosing
spondylitis for significantly longer duration of 28 years, and had an abnormal plain chest
radiograph (demonstrating upper lobe bronchiectasis) with restrictive respiratory function tests.
Three out of four patients with bronchiectasis in a separate study from Brazil were also current
smokers, although this population with several radiological abnormalities may have had other
infective causes [23].
Tracheobronchomegaly or MounierKuhn syndrome, which is due to a congenital cartilage
abnormality, has also been reported with ankylosing spondylitis and this mechanism may
influence the development of bronchiectasis in some cases [112]. HLA-B27 does not appear to
correlate with general HRCT abnormalities where this has been assessed, and while it is possible
that ankylosing spondylitis disease severity correlates indirectly with respiratory abnormalities in
general, there are too few cases with bronchiectasis to assess any relationship with this specifically
[23, 113, 114]. There is insufficient data to comment on the timing of bronchiectasis compared
with the development of ankylosing spondylitis, although it appears that the majority of those
found to have bronchiectasis are asymptomatic with incidental findings on imaging only [2024,
110, 115]. Ankylosing spondylitis mortality is usually caused by non-respiratory illnesses such as
cardiovascular disease, renal failure and amyloid and through complications of treatment, and
only occasionally through respiratory disease [116118].
Ankylosing spondylitis
Scleroderma/systemic sclerosis
201
Lung involvement in scleroderma or systemic sclerosis is very common. HRCT has played an
important role in better characterising and following up abnormalities, and disease has also been
well documented by post mortem examination with the identification of pulmonary disease in
systemic sclerosis in 80% of one cohort [2527]. The findings of an ILD, typically a nonspecific
interstitial pneumonia (NSIP) pattern and pulmonary hypertension, are quite common on HRCT.
Any honeycombing is usually mild and localised and the more typical pattern is the near-confluent
ground-glass opacification, fine reticular markings and associated traction bronchiectasis. Primary
bronchiectasis is uncommon [28, 29], as are reports of clinically significant disease.
In one of the larger studies of systemic sclerosis patients alone, ANDONOPOULOS et al. [29]
investigated 22 patients with a full history, respiratory function tests, blood tests and HRCT
imaging. Cylindrical bronchiectasis was evident in 13 (59%) out of 22 patients and was more
common in diffuse rather than limited systemic sclerosis disease, although this finding fell short
of statistical significance and did not correlate with gas transfer, ground-glass opacification or
with the patients duration of illness. In another single case report of clinically significant
bronchiectasis, there were other potential causes including Sicca syndrome and immunosuppressant treatment [119].
Relapsing polychondritis
The tracheobronchial tree is affected and typically leads to thickened and sometimes narrowed
airways, impaired clearance and the development of airway infection and inflammation. Lower
respiratory tract symptoms and significant disease developed after the initial diagnosis of relapsing
polychondritis in an early and one of the largest prospective studies of 23 patients with relapsing
polychondritis [30]. However, this was not the case in the only other smaller prospective series
20 years later where in six out of nine patients the respiratory symptoms were the presenting
symptoms of relapsing polychondritis [31]. Cohort studies since 1966 report a prevalence of
respiratory symptoms in up to 50% of those with relapsing polychondritis, although given the
nature and time of these studies, accurate prevalence of bronchiectasis is not possible to estimate.
A small number of cohort studies have analysed the natural history, morbidity and mortality of
patients with relapsing polychondritis. Respiratory infection appears to play a significant part.
Bronchiectasis is not defined by todays standards of HRCT imaging given that these studies were
carried out between 1966 and 1986. However, it can be implied that together with vasculitis and
valvular heart disease, respiratory infection carries a worse prognosis [30, 32, 33]. MICHET et al.
[32] describe their single-centre experience of 112 patients in the US in which they identified
respiratory infection as one of the leading causes of death alongside vasculitis and cancer. Of
further interest is that only 10% of deaths were directly attributed to airway involvement of the
disease, that anaemia was a significant poor prognostic marker and that the use of corticosteroids
did not impact on survival.
BEHAR et al. [34] analysed past records of a cohort of 160 patients collected over 10 years from two
referral centres and scrutinised records from 15 patients who had undergone any thoracic CT
imaging. They identified increased attenuation in the tracheal walls of all 15 patients (with
narrowing in one third of these patients), and also in the bronchial walls of 11 patients (73% of
those scanned). Of the 11 patients who had complete lung view imaging, three were found to have
bronchiectasis (two upper lobe, one diffuse), two demonstrated no significant airway stenoses and
one showed widespread tracheal and bronchial stenoses. 12 (83%) out of 15 patients demonstrated
thickened airway walls.
Mixed connective tissue disease
202
Mixed connective tissue disease (MCTD) is a distinct clinicopathological entity with unique
positive antibodies against ribonucleoprotein that shares several clinical and radiological features
with SLE, systemic sclerosis and polymyositis/dermatomyositis (PM/DM). The frequency of
respiratory manifestations in MCTD is reported to be between 20% and 80%, more commonly the
higher end of this range, although the reports are typically based upon radiological findings rather
than clinical significance [35, 120, 121]. The prevalence of bronchiectasis is not available in these
older studies, once again because of the absence of HRCT. MCTD is not usually associated with
primary bronchiectasis, rather with traction bronchiectasis associated with architectural distortions and the interstitial pneumonia patterns more commonly seen in this disorder [36, 37].
KOZUKA et al. [37] analysed the abnormal HRCT imaging of 41 patients with confirmed MCTD
and characterised the radiological abnormalities that were observed. They identified 18 patients
with traction bronchiectasis. Primary bronchiectasis was observed in five (12%) out of 41 patients,
although no clinical features were reported in this study to assess the significance of this.
Polymyositis/dermatomyositis
PM/DM is typically associated with ILD with a strong correlation with anti-Jo1 antibodies, most
commonly an NSIP pattern and also an organising pneumonia [38, 39]. Primary bronchiectasis is
not reported and traction bronchiectasis is rarely reported, especially given that honeycombing is
an infrequent finding in contrast to ground-glass opacification and patchy consolidation [3840].
Bronchiectasis and vasculitis
The vasculitic process may be localised or involve many systems with increasing severity. The
extent of disease may be such as to require aggressive immunosuppressive therapy with
corticosteroids and cyclophosphamide to control the vasculitis, alongside continued antimicrobial
treatment for concomitant bacterial infection [126]. Evidence of immune-mediated injury and
vasculitis has been demonstrated in the context of H. influenzae and Staphylococcus aureus, as well
as Pseudomonas aeruginosa [2, 42, 125].
Antineutrophil cytoplasmic antibodies (ANCA) form an important component of vasculitides of
which classical ANCA (c-ANCA) against the antigen proteinase-3 and perinuclear ANCA
(p-ANCA) against myeloperoxidase make up the major pathogenic types [43]. Of the primary
vaculitides, granulomatosis with polyangiitis (Wegeners) with associated c-ANCA antibodies and
microscopic polyangiitis (MPA) with myeloperoxidase antibodies have been most linked with
bronchiectasis. A chronic pulmonary illness typically predates the development of ANCAassociated disease in various reports and although other ANCA may exist their roles may be more
specific [41, 4446]. In a retrospective cohort study of 26 patients with MPA in Japan, nine (35%)
were diagnosed with bronchiectasis, four of whom had bronchiectatic symptoms prior to the
diagnosis of MPA [45]. The precise role and timing of the development of autoantibodies to selfcomponents remains unclear. FORDE et al. [47] analysed sera from a large number of patients with
a wide variety of inflammatory and infective disorders in order to investigate any association of
autoantibodies with acute and chronic infection. They concluded that antibodies to neutrophilic
cytoplasmic components were predominantly associated with chronic bacterial infection, while
antibodies to monocyte cytoplasmic components were predominantly associated with chronic
granulomatous disorders such as sarcoidosis. The implication was that persistent stimulation of
phagocytic cell components by bacterial infection drives the formation of autoantibodies to those
components and a pathological humoral response.
It has long been recognised that immune complexes and autoantibodies can accompany bronchial
infection [41, 122125]. ABRAMOWSKY and SWINEHART [123] demonstrated renal failure associated
with immune complexes in patients with CF and immune complex-mediated injury was proposed
in CF patients who presented with purpuric lesions late in their disease course [124]. Immune
complexes adhere to the endothelium through binding with the C1q component of complement
causing vasculitis and/or the complexes interfere with the intended complement-mediated
clearance of pathogens.
203
More recently, studies have begun to confirm the temporal relationship of immune-complex
activity with infection. MAHADEVA et al. [48] identified and characterised a new antigen
bactericidal/permeability-increasing protein (BPI)-ANCA in the context of Pseudomonas infection.
They went on to identify this in several patient groups including those with CF and non-CF
bronchiectasis, inflammatory bowel disease and renal failure [49]. Other groups explored its
behaviour in the context of Pseudomonas and proposed that high levels of BPI-ANCA correlated
with chronic Pseudomonas infection and poorer prognosis [46, 127, 128]. Of note, BPI binds with
high affinity to lipopolysaccharide (LPS) on Gram-negative bacteria, and the presence of high
levels of circulating antibodies to BPI may interfere with clearance of LPS bacteria giving rise to
concomitant severe infection.
There are several other rare primary immunodeficiencies that are associated with bronchiectasis
and vasculitis about which little is known. For example, an X-linked lymphoproliferative disorder
linked to a specific T-cell defect in EBV immunity that is associated with multi-system vasculitis,
bronchiectasis, respiratory failure and death [129] and an, as yet, poorly defined syndrome
consisting of childhood dermatitis, profoundly elevated immunoglobulin E, severe pneumonia
(and subsequent bronchiectasis) and multiple central neurological abnormalities [130].
The use of immunosuppressive agents and bronchiectasis
There is an increasing use of immunomodulatory or immunosuppressive therapy that is proving

successful in modifying autoimmune disease processes [82]. However, their availability has raised
fresh concerns, mainly surrounding opportunistic infection and cancer [131135]. In the
autoimmune diseases discussed herein, those drugs used frequently include steroid-sparing agents
such as azathioprine and methotrexate, alternative potent immunosuppressive drugs such as
leflunomide and cyclophosphamide, biological agents that include anti-TNF agents (etanercept,
infliximab and adalimumab), anti-CD20 molecules (rituximab), interleukin (IL)-6 receptor
antagonists (tocizilimab) and co-stimulatory inhibitor molecule (abatacept).
Reactivation of tuberculosis (TB) is a recognised risk of the use of anti-TNF therapy and the
British Thoracic Society and others have issued guidelines for their use in those at risk of TB
reactivation [136, 137]. TB and nontuberculous Mycobacteria [138] are pathogens that can both
cause bronchiectasis and infect patients with existing bronchiectasis. Care must be taken to stratify
the risk of reactivation following immunosuppressive therapies, and one should be aware that
traditionally non-pathogenic strains can emerge as fatal infections [139]. Evidence for latent TB
infection should be sought with the use of a detailed history, chest radiograph or CT, tuberculin
skin testing and interferon-c release assays (IGRA). IGRAs are now well established and should be
used to risk-stratify in the context of anti-TNF therapy. While in theory latent viruses including
herpes zoster and EBV, fungus, opportunistic bacteria and parasites are all more likely to reemerge with immunosuppressive therapy, this has not been a consistent finding [140145].
There may be a gradation of risks within this group of agents. Anti-CD20 therapy in the form of
rituximab may generally be considered less aggressive. CD20 is expressed by haematopoietic
progenitor cells and newly differentiated plasma cells, and while reactivation of latent virus is well
documented, infection with other bacteria or parasites or TB is infrequently reported [146, 147].
Safety and long-term data are still emerging with tocilizumab, an IL-6 receptor antagonist found
to be effective in rheumatoid arthritis and still being investigated for SLE [147150]. To date, no
surprising opportunistic infection data has emerged and meta-analyses have placed a figure of
approximately six additional infections per 100 patient-years; those infections are mostly termed
pneumonia [149, 151]. Abatacept, a newer co-stimulatory modulator that interferes with T-cell
activation may not share the same documented risks of TB reactivation and may prove to be better
tolerated than anti-TNF therapies, although longer term safety data on this drug is still emerging
[152155].
204
In general, physicians using these agents must be diligent and counsel patients about the risks of
infections, particularly if patients already have susceptibility to infection due to concomitant
bronchiectasis. In this case the patient should be co-managed with a respiratory physician, sputum
should be screened for Mycobacteria sp. and other opportunistic pathogens, the patient should
have an antibiotic management plan if infective exacerbations develop, and antibiotic prophylaxis
should be considered if infective exacerbations become frequent. These agents often provide
marked improvement in the patients control of their autoimmune disease, which means that
when the agents are used in bronchiectasis patients with associated autoimmune disease, treatment
of chronic bronchial infection and infective exacerbations of bronchiectasis should be intensified
to allow the agent to be continued when this is deemed to be safe. Good communication between
the rheumatologist and pulmonologist is essential.
None declared.
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Chapter 14
Antibiotic treatment
strategies in adults
with bronchiectasis
C.S. Haworth
Summary
Keywords: Antibiotics, bronchiectasis, exacerbation,

intravenous, nebulised, prophylaxis
Correspondence: C.S. Haworth,

Cambridge Centre for Lung Infection,
Papworth Hospital, Cambridge, CB23
3RE, UK, Email
charles.haworth@papworth.nhs.uk
C.S. HAWORTH
Antibiotics play a crucial role in the management of patients

with bronchiectasis by disrupting the vicious circle of infection,
inflammation and airway damage central to the pathophysiology of the condition. Antibiotic use in patients with bronchiectasis can be divided into exacerbation treatment, chronic
suppressive treatment and eradication treatment.
Antibiotics administered during exacerbations are known
to reduce serum C-reactive protein concentrations, sputum
volume and bacterial density, as well as ameliorate symptoms.
Clinical experience suggests that better outcomes are seen
with higher dose/longer duration regimens.
The prescription of long-term oral antibiotics should be
considered in patients requiring exacerbation treatment at least
three times per year. As patients chronically infected with
Pseudomonas aeruginosa tend to have a faster rate of lung
function decline, more admissions to hospital and a worse
quality of life compared with bronchiectasis patients with other
microorganisms, nebulised antipseudomonal antibiotics are
commonly prescribed.
Eradication antibiotics should be considered following
identification of new growths of P. aeruginosa due to the
increased morbidity associated with chronic infection.
Eur Respir Mon 2011. 52, 211222.

Copyright ERS 2011.
ISSN: 1025-448x.
DOI: 10.1183/1025448x.10004410
211
ronchiectasis is a condition characterised by irreversible dilatation of the bronchi [1] resulting

from changes in the elastic and muscular components of the bronchial wall. COLE [2]
proposed the vicious circle hypothesis in the 1980s to explain the pathogenesis of bronchiectasis.
He suggested that an initial insult to the airway leads to bronchial wall inflammation and damage,
disordered mucociliary clearance, a predisposition to chronic or recurrent infection and as a
result, further airway damage. Antibiotic use in patients with bronchiectasis can be divided into
exacerbation treatment, chronic suppressive treatment and eradication treatment. Treatment of

pulmonary diseases related to nontuberculous mycobacteria and fungi will be covered by other
chapters in this issue.
Antibiotic treatment in exacerbations of bronchiectasis

Patients with bronchiectasis may expectorate significant volumes of mucopurulent sputum when
well. It is therefore important to document stable state symptoms so that exacerbations can be
accurately identified. Failure to do this can result in inappropriate antibiotic treatment.
Acute exacerbations of bronchiectasis are characterised by an increase in cough frequency, sputum
volume, sputum purulence and viscosity. Patients may also complain of chest tightness, wheeze
and breathlessness. Other common features include streaky haemoptysis, chest discomfort and
temperatures. Symptoms usually progress over days, but patients can experience a more insidious
decline over weeks or months.
ANTIBIOTIC TREATMENT STRATEGY
There are no randomised placebo-controlled trials evaluating the effect of antibiotic treatment
during exacerbations of bronchiectasis. However, antibiotics are known to reduce serum
C-reactive protein, sputum inflammatory indices, sputum volume, sputum purulence and
bacterial density, as well as ameliorate symptoms [38].
The published literature evaluating antibiotic treatment during exacerbations of bronchiectasis is
heterogeneous in terms of the class of antibiotic studied, the route of administration and the
sputum microbiology of the participants. However, important management principals emerge:
high doses of an antibiotic are often more effective than lower doses of the same antibiotic [3];
patients with purulent sputum after antibiotic treatment have a shorter time to next exacerbation
compared with patients with mucoid sputum [3]; sputum culture sensitivity results do not
necessarily predict clinical response to antibiotic treatment [9]; short courses of oral antibiotics
prescribed during acute exacerbations reduce airway inflammatory indices to pre-exacerbation
levels, but chronic low-grade inflammation persists [4]; and clinical improvement may not be
associated with significant increases in spirometry [7, 8, 10].
Initial treatment usually involves a course of oral antibiotics unless the patient is sufficiently
unwell to require intravenous treatment. The optimal dose and duration of antibiotic treatment to
manage bronchiectasis exacerbations is currently undefined. Clinical experience suggests that
better outcomes are seen with higher dose/longer duration regimens, which presumably reflects
the difficulty of achieving adequate antibiotic concentrations within the lumen of bronchiectatic
airways, particularly in the context of chronic infection where bacteria are often resistant and
protected by biofilms. Expert consensus is that bronchiectasis exacerbations should be treated with
14 days of antibiotics [11]. A sputum sample should be sent for culture before starting empirical
antibiotic treatment and the results can influence changes in treatment if the patient is not
responding.
Oral antibiotic treatment for exacerbations of bronchiectasis
212
Oral antibiotic choices should be guided, where possible, by previous sputum microbiology and
suggestions for treatment are outlined in table 1. Empirical treatment may be with amoxicillin
500 mg t.i.d. or co-amoxiclav 625 mg t.i.d. in patients in whom b-lactamase-producing
organisms are suspected. Doxycycline 100 mg b.i.d. is an alternative choice in the context of
penicillin allergy and ciprofloxacin 750 mg b.i.d. should be prescribed if Pseudomonas aeruginosa
infection is thought to be likely. Patients with a history of methicillin-resistant Staphylococcus
aureus (MRSA) infection may be treated with rifampicin 600 mg q.d. and fucidin 500 mg t.i.d.
The potential for antibiotic related complications such as Clostridium difficile infection need
to be considered when choosing oral or i.v. antibiotic regimens to treat exacerbations of
bronchiectasis.
Table 1. Oral antibiotic regimens commonly used to treat acute exacerbations of bronchiectasis in adults#
First line
Second line
"
Streptococcus pneumoniae
Amoxicillin 5001000 mg t.i.d.
Amoxicillin 5001000 mg t.i.d."
Co-amoxiclav 625 mg t.i.d.
Flucloxacillin 5001000 mg q.i.d."
MRSA
Rifampicin 400600 mg q.d.+ and

fucidin 500 mg t.i.d.
Coliforms
Stenotrophomonas maltophilia
Achromobacter xylosoxidans
Ciprofloxacin 750 mg b.i.d.

Cotrimoxazole 960 mg b.i.d.
Minocycline 100 mg b.i.d.
Clarithromycin 500 mg b.i.d.

Doxycycline 100 mg b.i.d.
Moxifloxacin 400 mg q.d.
Trimethoprim 200 mg b.i.d.
Moxifloxacin 400 mg q.d.
Linezolid 600 mg b.i.d.
q.d.: once daily; b.i.d.: twice daily; t.i.d.: three times daily; q.i.d.: four times daily; MRSA: methicillin-resistant
Staphylococcus aureus. #: recommended treatment duration 1014 days; ": dose according to severity;
+
: dose according to weight.
Intravenous antibiotic treatment for exacerbations of bronchiectasis

Patients with severe exacerbations or exacerbations that fail to resolve with oral antibiotic
treatment may require treatment with i.v. antibiotics. This usually involves admission to hospital,
but some centres run community-based i.v. antibiotic programmes, which allow patients to have
all, or a proportion, of their treatment at home. This is particularly helpful for younger patients
who have educational commitments or for those that do not want to take time out from work.
Patients must demonstrate that they are competent at i.v. drug administration before discharge
and the home environment needs to be appropriate. Most centres recommend that the first dose is
administered in hospital to ensure patients can infuse the antibiotic correctly and to ensure there
are no adverse events. Robust systems need to be in place to monitor drug levels in patients
prescribed aminoglycosides and careful monitoring of renal function is essential in patients
receiving nephrotoxic medicines.
C.S. HAWORTH
Organism
Antibiotic i.v. administration during bronchiectasis exacerbations can be achieved through use of
peripheral cannulas, long lines, peripherally inserted central catheters (PICC) and totally
implantable venous access devices (TIVAD) (fig. 1). PICCs and TIVADs are particularly useful in
patients with difficult peripheral access who require frequent courses of i.v. treatment. However,
these devices require regular flushing and potential complications include thrombosis and
infection, particularly in higher risk groups such as the elderly and those with a primary or
secondary immunodeficiency.
213
Antibiotic i.v. choices should be based on previous sputum microbiology results and suggested
regimens are outlined in table 2. Empirical antibiotic treatment may include cefuroxime or
ceftriaxone, unless patients are thought to be infected with P. aeruginosa. As the efficacy of
b-lactam antibiotics is related to the time above the mean inhibitory concentration, once daily
antibiotics may be less effective than antibiotics taken three times a day due to the potential
problem of maintaining an adequate intraluminal antibiotic concentration in the context of

structural lung damage and biofilm
formation.
Antibiotic i.v. treatment in

patients infected with
P. aeruginosa
Empirical antibiotic treatment in
patients with P. aeruginosa may
include a b-lactam, such as ceftazidime. Monotherapy may suffice
in patients infected with fully
sensitive P. aeruginosa, but in the
context of a resistant organism or
chronic infection where patients
Figure 1. Chest radiograph of a male patient with primary ciliary
are likely to require repeated treatdyskinesia, dextrocardia, severe bilateral bronchiectasis and chronic
ment courses in the future, many
Pseudomonas aeruginosa infection who self-administers i.v. anticlinicians advocate dual therapy
biotics via a totally implantable venous access device at home.
with an aminoglycoside to reduce
the risk of antibiotic resistance, as
well as harnessing the synergistic effects between aminoglycoside and b-lactam antibiotics [1214].
In a study evaluating the effect of i.v. azlocillin + placebo versus i.v. azlocillin + tobramycin in
patients with cystic fibrosis (CF), initial clinical outcomes were comparable, but P. aeruginosa
density decreased more and time to next hospitalisation was significantly longer in the group
receiving dual therapy [15]. These data suggest that dual antibiotic therapy is preferable in the
context of chronic P. aeruginosa infection and the absence of significant comorbidity (such as renal
dysfunction).
Table 2. Antibiotic i.v. regimens commonly used to treat acute exacerbations of bronchiectasis in adults#
Organism
MRSA
Coliforms
First line
Second line
Benzylpenicillin 1.2 g q.i.d.
Cefuroxime 1.5 g t.i.d. or

Ceftriaxone 2 g q.d.
Piperacillin with
Tazobactam 4.5 g t.i.d.
Piperacillin with
tazobactam 4.5 g t.i.d.
Teicoplanin"
Linezolid 600 mg b.i.d.
Tigecycline 50 mg b.i.d.
Fosfomycin 5 g t.i.d.
Aztreonam 2 g t.i.d.+
Piperacillin with
tazobactam 4.5 g t.i.d.+
Meropenem 1 g t.i.d.+
Piperacillin with
tazobactam 4.5 g t.i.d.
Tigecycline 50 mg b.i.d.
Meropenem 1 g t.i.d.

ceftriaxone 2 g q.d.
Vancomycin"
Ceftazidime 2 g t.i.d.+

Cotrimoxazole 1.44 g b.i.d.
Piperacillin with tazobactam 4.5 g t.i.d.
214
q.d.: once daily; b.i.d.: twice daily; t.i.d.: three times daily; q.i.d.: four times daily; MRSA: methicillin-resistant
Staphylococcus aureus. #: recommended treatment duration 1014 days; ": dose according to weight and
drug levels; +: dual therapy with gentamicin or tobramycin may be required.
The role of antibiotic sensitivity testing in patients with bronchiectasis and chronic P. aeruginosa
infection is contentious due to hypermutation and the poor correlation between in vitro antibiotic
sensitivity test results and clinical outcomes [19, 20]. FOWERAKER et al. [19] studied sputum
samples from patients with CF and found an average of four P. aeruginosa morphotypes per
sputum sample and three distinct antibiotic sensitivity profiles per morphotype. 48 colonies with
varying antibiotic sensitivity profiles were cultured from one sputum sample and it was noted that
susceptibility profiles of single P. aeruginosa isolates correlated poorly with pooled cultures (the
pooled cultures underestimated levels of antibiotic resistance). FOWERAKER et al. [19] also showed
that sensitivity results from one sputum sample tested in duplicate by eight biomedical scientists
within one laboratory and by biomedical scientists in seven other laboratories did not correlate
well. These data are supported by the findings of SMITH et al. [21], who showed no correlation
between the susceptibility of P. aeruginosa to ceftazidime or tobramycin and clinical response to
these antibiotics in 77 chronically infected patients with CF. Furthermore, a randomised
controlled trial evaluating clinical outcomes, using multiple combination bactericidal testing
versus clinician preference, to guide i.v. antibiotic choices to manage CF pulmonary exacerbations
showed no advantage in using the more sophisticated microbiological tests [22]. Based on the
above evidence, a pragmatic approach is required when choosing antibiotic combinations for
patients with bronchiectasis and chronic P. aeruginosa infection. It is common practice to choose
two antipseudomonal antibiotics (usually a b-lactam in combination with tobramycin) to which
the majority of morphotypes are sensitive. An alternative approach involves basing antibiotic
choices predominantly on what has worked well for the patient in the past.
Nebulised antibiotic treatment for exacerbations of bronchiectasis

The nebulised route enables delivery of high concentrations of antibiotic to the airways and
reduces the likelihood of gastrointestinal adverse events. However, airway inflammation may lead
to bronchoconstriction and drug deposition may be limited by sputum plugging.
C.S. HAWORTH
The most appropriate choice of aminoglycoside remains a matter for debate, but recent reports
suggest that the risk of renal impairment, ototoxicity and vestibular damage is greater with
gentamicin than tobramycin [16, 17]. While, once daily versus three times daily tobramycin dosing
in children with CF appears to offer equivalent clinical outcomes and reduced renal toxicity [18],
the most appropriate dosing regimen has not been established in adults with bronchiectasis.
BILTON et al. [6] tested the effect of adding inhaled tobramycin solution to oral ciprofloxacin for
treatment of bronchiectasis exacerbations in the context of P. aeruginosa infection. The study involved
53 adults recruited from 17 study centres in the UK and USA. There was evidence of superior
microbiological efficacy in patients receiving inhaled tobramycin and ciprofloxacin compared with
those receiving ciprofloxacin alone, but superior clinical efficacy was not demonstrated. Patients
treated with inhaled tobramycin and ciprofloxacin were more likely to experience respiratory adverse
events, in particular wheeze (50% in the inhaled tobramycin group compared with 15% in the
placebo group). Although treatment emergent wheeze was not a significant cause for withdrawal from
the study, it is probable that it influenced the clinical efficacy outcome data. It is also notable that
patients with ciprofloxacin resistant strains of P. aeruginosa were excluded from the study and it is
possible that the inclusion of such patients, as would occur in routine clinical practice, may have
resulted in more favourable outcomes in the inhaled tobramycin-treated patients.
Antibiotic prophylaxis in adults with bronchiectasis
215
Antibiotics are commonly prescribed on a long-term basis in patients with bronchiectasis with a
view to improving symptoms, decreasing exacerbation rates and optimising quality of life. The
most likely mechanism by which antibiotics achieve these aims is by reducing bacterial load and
airway inflammation. The immunomodulatory benefits of long-term macrolide antibiotics are
discussed in a later chapter by SMITH et al. [23].
Antibiotics used on a long-term basis are usually administered orally or through a nebuliser.
However, within the CF population, some centres advocate 3-monthly elective courses of i.v.
antibiotics for patients chronically infected with P. aeruginosa [24]. This approach has not been
taken up widely due to concerns about toxicity (particularly renal, vestibular and auditory),
psychosocial well-being (disruption to family life, work and education), healthcare costs and those
concerns relevant to all forms of antibiotic prophylaxis: increasing bacterial resistance and the
creation of a niche for new organisms (both bacteria and fungi) [25, 26].
Oral antibiotic prophylaxis in adults with bronchiectasis

The evidence base for oral antibiotic prophylaxis in bronchiectasis dates back to the early 1950s
when a number of unrandomised studies were performed [27, 28]. However, these were soon
superseded by the Medical Research Council study which involved 122 subjects randomised to
receive penicillin, oxytetracycline or placebo [29]. The drugs were provided as indistinguishable
0.25 g capsules and patients were asked to take two capsules four times a day on two days each
week for 1 year. Outcome measures included 24-h sputum volume and the severity of cough,
dyspnoea, haemoptysis and disability. Unfortunately no formal statistical analysis was performed.
After 1 year, oxytetracycline treatment was associated with a reduction in sputum volume to 64%
of pre-treatment levels and the purulent fraction was reduced by 50%. Treatment with
oxytetracycline was also associated with fewer days off work and fewer days confined to bed. Less
marked changes were evident in patients allocated to the penicillin and placebo groups.
Gastrointestinal symptoms were reported by a minority of patients (five on oxytetracycline, three
on penicillin and two on placebo) and one patient in the oxytetracycline and penicillin groups
discontinued treatment due to antibiotic intolerance. Unfortunately, sputum microbiology data
were not reported and so it is not possible to make an assessment of whether sensitivity profiles
affected outcomes. Subsequent studies in the 1950s and 1960s provided further support for the use
of long-term tetracycline/penicillin based antibiotic regimens in patients with bronchiectasis
[30, 31]. However, the latter study also reported an increase in the isolation of Pseudomonas and
Proteus species, suggesting that microbial flora of sputum may be altered by long-term antibiotic
treatment.
CURRIE et al. [32] performed a randomised placebo-controlled trial evaluating the effect of highdose amoxicillin in patients with bronchiectasis. 38 subjects were randomised to receive
amoxicillin 3 g b.i.d. or placebo for 32 weeks. Assessment of overall response based on diary card
data showed that a higher proportion of patients improved in the amoxicillin group (11 out of 17)
compared with the placebo group (four out of 19). Patients in the amoxicillin group also spent
significantly less time confined to bed and away from work compared with the placebo group. The
frequency of exacerbation was similar in the two groups, but the exacerbations were less severe in
the amoxicillin group than before the study was started. There was also a greater reduction in
purulent sputum volume in the amoxicillin group (20% of pre-treatment volume) compared with
the placebo group (88% of pre-treatment volume). One patient in the amoxicillin group withdrew
from the study due to the development of rash and one patient from each group withdrew due to
diarrhoea. There was a trend towards greater antibiotic resistance in patients treated with
amoxicillin. No patients developed C. difficile-related diarrhoea.
In a 16-week open-label study of oral and nebulised amoxicillin involving 10 patients with
bronchiectasis and variable sputum microbiology (predominantly Haemophilus influenzae),
treatment was associated with reduced sputum purulence and volume, reduced sputum
inflammatory indices, improvements in lung function and improved patient well-being [33].
After cessation of treatment, sputum purulence returned after a median of 2.5 months.
216
RAYNOR et al. [34] performed a retrospective case note review of 10 patients with bronchiectasis
prescribed .90 days of continuous oral ciprofloxacin. Pre-treatment sputum microbiology results
from nine patients showed a variety of organisms including P. aeruginosa (n55), H. influenzae
(n53) and Streptococcus pneumoniae (n51). At the end of treatment six patients had sterile sputum
cultures, of which two had previously grown P. aeruginosa, three H. influenzae and one had no
pathogen. In one patient P. aeruginosa was replaced by S. pneumoniae, two patients continued to
culture P. aeruginosa (which had become resistant to ciprofloxacin) and S. pneumoniae persisted in
one patient. While exacerbation frequency and hospital admissions reduced with treatment, the
development of ciprofloxacin-resistant strains of P. aeruginosa is of concern, particularly as this
finding coincided with a relapse in symptoms requiring admission to hospital for i.v. antibiotics.
In practice, the prescription of long-term oral antibiotics is considered in patients requiring
exacerbation treatment at least three times per year (or in patients with fewer exacerbations but
greater associated morbidity) [11]. There may also be a lower threshold to prescribe long-term
antibiotics in patients with a primary or secondary immunodeficiency. Common long-term oral
antibiotic regimens are outlined in table 3. Where possible, antibiotic choices should be based on
sputum microbiology data. While there is no evidence currently in favour of antibiotic rotation
over single agent prophylaxis in terms of the development of antibiotic resistance and efficacy, it is
important to record exacerbation rates before and after starting long-term oral antibiotics and to
perform regular sputum surveillance to monitor antibiotic resistance patterns and to identify
treatment emergent bacteria and fungi.
Nebulised antibiotic prophylaxis in patients with bronchiectasis
Antipseudomonal nebulised antibiotic regimens evaluated to date include nebulised gentamicin,

nebulised tobramycin, nebulised tobramycin in combination with nebulised ceftazidime and
nebulised colistin. The largest published study was performed by BARKER et al. [36] and evaluated
the microbiological efficacy and safety of inhaled tobramycin in patients with bronchiectasis
infected with P. aeruginosa. Patients were randomly assigned to receive either tobramycin solution
for inhalation (n537) or placebo (n537) twice daily for 4 weeks. At week 4, the tobramycin
solution for inhalation group had a mean decrease in P. aeruginosa density of 4.5 log10 colony
forming units per gram (CFU?g-1) of sputum compared with no change in the placebo group
(p,0.01). Logistic regression analysis showed that decreases in CFU?g-1 of sputum were significant
predictors of improved well-being. 2 weeks after cessation of the trial, P. aeruginosa was eradicated
in 35% of the tobramycin-treated group, but was detected in all placebo patients. 62% of
C.S. HAWORTH
There have been a number of studies conducted using nebulised antibiotics in patients with
bronchiectasis. The majority involve antipseudomonal agents, although earlier studies evaluated
the use of nebulised amoxicillin in patients predominantly infected with H. influenzae [3, 33, 35].
While the results of the nebulised amoxicillin trials are largely positive, in practice this
intervention is rarely used as high-dose oral regimens are easier and cheaper to administer.
Table 3. Oral antibiotic prophylaxis for adult patients with bronchiectasis based on sputum microbiology
Organism
First line
Second line
Amoxicillin 500 mg b.i.d.

Doxycycline 100 mg q.d.
MRSA
Flucloxacillin 500 mg1 g b.i.d.

Cotrimoxazole 960 mg b.i.d.
217
q.d.: once daily; b.i.d.: twice daily; MRSA: methicillin-resistant Staphylococcus aureus.
tobramycin-treated patients showed improvement in their medical condition compared with 38%
of the placebo patients (OR 2.7, 95% CI 1.16.9), but there was no significant change in lung
function between the treatment groups. Tobramycin-resistant P. aeruginosa strains developed in
four (11%) out of 36 of tobramycin-treated patients and one (3%) out of 32 of placebo-treated
patients. Three of the four patients in the tobramycin-treated group who developed resistant
P. aeruginosa strains showed no microbiological response and all four failed to improve clinically.
More tobramycin-treated patients than placebo patients reported increased cough, breathlessness,
wheezing and non-cardiac type chest pain, but the symptoms did not appear to limit therapy.
A second trial evaluating tobramycin solution for inhalation involved 41 bronchiectasis patients
infected with P. aeruginosa and employed an open-label design consisting of three treatment cycles
(14 days of drug therapy and 14 days off) [37]. During the 12-week treatment period significant
improvements occurred in the pulmonary symptoms severity score and in quality of life
measurements. However, tobramycin-resistant strains of P. aeruginosa developed in two subjects
and 10 patients dropped out due to adverse events, the most common being cough, wheeze and
breathlessness. Five subjects died during the study period due to the underlying disease, one
during the 12-week treatment period and four during the 40-week follow-up period. None of the
deaths were considered to be related to the drug treatment.
DROBNIC et al. [38] evaluated an alternative formulation of tobramycin in a double-blind placebocontrolled cross-over trial involving 30 patients. Patients received aerosolised tobramycin 300 mg
or placebo twice daily for 6 months, with a 1-month wash out period between interventions. 20
patients completed the protocol as three patients withdrew from the study due to bronchospasm,
five patients died from respiratory failure and two others dropped out (one failed to adhere to the
study protocol and one relocated). The number of admissions and in-patient days reduced during
the tobramycin period. There was also a decrease in P. aeruginosa density which persisted up until
3 months after nebulised tobramycin treatment had been stopped and there was no difference in
the emergence of bacterial resistance between the two study periods. However, there was no
significant difference in the number of exacerbations, antibiotic use, lung function or quality of life
between the tobramycin and placebo periods.
ORRIOLS et al. [39] performed a 12-month study in which patients with bronchiectasis were
randomised to receive nebulised ceftazidime 1 g b.i.d. + tobramycin 100 mg b.i.d. or symptomatic
treatment. One out of eight patients in the nebulised antibiotic group withdrew having developed
bronchospasm and one out of nine patients in the control group died. While there were
significantly less admissions and in-patient days in the nebulised antibiotic group, these findings
need to be interpreted with care owing to the open-label design of the study. Interestingly, there
was no difference in the use of oral antibiotics or change in lung function between the two
treatment groups. There was also no difference in the emergence of antibiotic resistant bacteria
between the two treatment groups.
LIN et al. [40] performed a randomised controlled trial assessing the effect of aerosolised
gentamicin 40 mg (n516) versus 0.45% saline (n515) administered twice daily for 3 days in
patients with bronchiectasis. Gentamicin-treated patients showed significant reductions in sputum
volume and sputum inflammatory indices (there was a significant correlation between the change
in sputum volume and sputum myeloperoxidase) in conjunction with significant improvements in
peak expiratory flow rate and 6-min walk distances.
218
MURRAY et al. [41] performed a longer term study evaluating the effect of nebulised gentamicin in
patients with bronchiectasis. 65 patients were randomised to receive gentamicin 80 mg or 0.9%
saline twice daily through a nebuliser for 12 months. Inclusion criteria included a history of
chronic sputum colonisation with potentially pathogenic organisms when clinically stable. After
12 months, use of nebulised Gentamicin was associated with significant reductions in bacterial
density with a 30.8% eradication rate in patients infected with P. aeruginosa and a 92.8%
eradication rate in patients infected with other pathogens. There was reduced sputum purulence (8.7%
versus 38.5%, p,0.001), greater exercise capacity (median (interquartile range) 510 (350690) m
versus 415 (267530) m, p50.03), fewer exacerbations (median (interquartile range) 0 (01)
versus 1.5 (12), p,0.001), increased time to first exacerbation (median (interquartile range) 120
(87161) days versus 61 (20122) days, p50.02) and greater improvements in quality of life in
patients treated with gentamicin. There were no differences between groups in 24-h sputum
volume, forced expiratory volume in 1 second, forced vital capacity (FVC) or forced expiratory
flow at 2575% of FVC. There was no development of gentamicin-resistant isolates of
P. aeruginosa.
Small retrospective studies have evaluated the effect of nebulised colistin in patients with
bronchiectasis and P. aeruginosa infection [42, 43]. Owing to the retrospective nature of the
studies the results need to be interpreted with care, but the data suggest that nebulised colistin has
beneficial effects in this patient population in terms of exacerbation frequency, admission rates,
sputum volume and lung function. An international multicentre randomised placebo controlled
trial evaluating the effect of nebulised colistin (promixin) on time to next exacerbation in patients
with bronchiectasis and chronic P. aeruginosa infection is underway and will report in the next
2 years.
Eradicating new growths of specific organisms in patients with

bronchiectasis
There are no trials to date evaluating antibiotic eradication regimens in patients with
bronchiectasis. However, in clinical practice, eradication regimens are often prescribed following
identification of new growths of P. aeruginosa due to the increased morbidity associated with
chronic infection [4448]. Some of the oral and nebulised antibiotic studies in patients with
bronchiectasis report variable success rates in eradicating P. aeruginosa, but these studies were not
designed to address this specific issue and largely involved patients with chronic P. aeruginosa
infection [34, 3639, 41]. In the absence of conclusive trial data, many clinicians follow treatment
protocols used in patients with CF, where early eradication therapy and the subsequent reduction
in prevalence of chronic P. aeruginosa infection is thought to have had a major impact on survival
[49]. Experience suggests that eradication of P. aeruginosa is less likely once the organism has
converted to the mucoid form, which reinforces the need for early intervention [14]. In patients
C.S. HAWORTH
Patients with bronchiectasis and P. aeruginosa chronic infection tend to have more severe lung
disease based on physiological and computed tomography parameters, a faster rate of lung
function decline, more admissions to hospital and a worse quality of life compared with patients
with other microorganisms [4448]. Thus, nebulised antibiotics are frequently prescribed for
patients with bronchiectasis and chronic P. aeruginosa infection in order to improve well-being
and prevent disease progression, consistent with CF management principals [14, 25]. Common
nebulised antibiotic regimens are outlined in table 4. It is important to record exacerbation rates
before and after starting long-term nebulised antibiotics and to perform regular sputum
surveillance to monitor antibiotic resistance patterns and treatment emergent bacteria and fungi.
Table 4. Nebulised antibiotic prophylaxis for adult patients with bronchiectasis chronically infected with
Drug and formulation#
Colistin (Colomycin)
Colistin (Promixin)
Gentamicin 40 mg?mL-1
Tobramycin (Tobi)
Tobramycin (Bramitob)
Aztreonam lysine (Cayston)
Ceftazidime
Dose
Diluent
2 MU b.i.d.
1 MU b.i.d.
80 mg b.i.d.
300 mg b.i.d.
300 mg b.i.d.
75 mg t.i.d.
1 g b.i.d.
4 mL 0.9% sodium chloride

1 mL water for injection

3 mL water for injection
219
MU: million units; b.i.d.: twice daily; t.i.d.: three times daily. #: unlicensed indication.
with CF and a new growth of P. aeruginosa, the prescription of ciprofloxacin + nebulised colistin
resulted in 16% of treated patients developing chronic P. aeruginosa infection compared with 72%
of untreated historical controls (p,0.005) after 3.5 years follow-up [50]. More recent data showed
that .90% of patients with CF and early P. aeruginosa infection had negative cultures 1 month
after completing a 4-week course of nebulised tobramycin (tobi 300 mg q.i.d.) [51]. In practice,
many clinicians prescribe a 3-month course of nebulised colistin in combination with oral
ciprofloxacin for patients with bronchiectasis and a new growth of P. aeruginosa [11, 14, 52], and
offer i.v. therapy if this intervention fails.
Eradication regimens are also commonly instituted in patients who culture MRSA in their sputum
for the first time, due to the fact that it is a resistant organism and has significant infection control
implications. Oral rifampicin and fucidin with or without nebulised vancomycin is used in some
centres, but treatment regimens should be based around local policies.
Future antibiotic treatment strategies
It is likely that antibiotic treatment options for patients with bronchiectasis will change
significantly over the next decade. New nebulised (amikacin, aztreonam, colistin and fosfomycin
in combination with tobramycin) and dry powder (ciprofloxacin, colistin and tobramycin)
antibiotic formulations have been developed and may be beneficial in patients with bronchiectasis.
New ways of using old antibiotics may also lead to improved outcomes. For example, due to the
time-dependent antibacterial activity of b-lactam antibiotics, continuous infusions may offer
superior efficacy compared with intermittent infusions [53], particularly in the context of severe
structural lung damage and biofilm formation.
Conclusion
Antibiotics play a crucial role in the management of patients with bronchiectasis by disrupting the
infection component of the vicious circle of infection, inflammation and airway damage central to
the pathophysiology of bronchiectasis. Antibiotics can be used for treatment of exacerbations, for
chronic bacterial suppression and for eradication. Antibiotic choices should be based on sputum
microbiological results. Careful monitoring is required regarding microbial resistance patterns and
treatment emergent bacteria/fungi, gastrointestinal adverse events (C. difficile infection) and
antibiotic related toxicity (particularly with aminoglycosides). In the future, antibiotic options are
likely to increase through the development of new nebulised and dry powder formulations.
C.S. Haworth has received educational grants, speaker fees or performed consultancy work for
Chiesi, Gilead, Novartis and Forest.
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of Aspergillus colonization in adult cystic fibrosis patients. Respir Med 1999; 93: 835838.
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450454.
28. McVay LV, Sprunt DH. Antibiotic prophylaxis in chronic respiratory disease. Ann Intern Med 1953; 92: 883886.
29. Medical Research Council. Prolonged antibiotic treatment of severe bronchiectasis; a report by a subcommittee of
the Antibiotics Clinical Trials (non-tuberculous) Committee of the Medical Research Council. BMJ 1957; 2: 255259.
30. Cherniack NS, Vosti KL, Dowling HF, et al. Long-term treatment of bronchiectasis and chronic bronchitis. Arch
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38. Drobnic ME, Sune P, Montoro JB, et al. Inhaled tobramycin in non-cystic fibrosis patients with bronchiectasis and
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chronic bronchial infection by Pseudomonas aeruginosa. Respir Med 1999; 93: 476480.
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in bronchiectasis. Am J Respir Crit Care Med 1997; 155: 20242029.
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42. Steinfort DP, Steinfort C. Effect of long-term nebulized colistin on lung function and quality of life in patients
with chronic bronchial sepsis. Int Med J 2007; 37: 495498.
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bronchiectasis colonised with Pseudomonas aeruginosa. Thorax 2010; 65: 553.
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45. Wilson CB, Jones PW, OLeary CJ, et al. Effect of sputum bacteriology on the quality of life of patients with
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Chapter 15
Anti-inflammatory
therapies in
bronchiectasis
D.J. Smith*,#, A.B. Chang",+,1 and S.C. Bell*,#,+
Although the use of anti-inflammatory therapies in bronchiectasis remains an attractive proposition, there is currently
insufficient evidence to support the use of inhaled and oral
corticosteroids, non-steroidal anti-inflammatory drugs and
macrolides. Individual patient trials may be warranted for
inhaled corticosteroids and macrolides. It is hoped that recently
completed and ongoing randomised control trials of macrolides
will better define the use and safety in bronchiectasis. There
remains an urgent need to perform adequately powered
multicentre trials of other potentially useful therapies.
It is anticipated that specialised bronchiectasis clinics will
provide greater opportunities to study disease epidemiology
and pathogenesis and allow better definition of study population for inclusion within future trials. There is a need for a more
defined study population and a widely accepted definition of a
pulmonary exacerbation in bronchiectasis which may be
applied uniformly across studies to allow direct comparison of
study outcomes. Finally, care should be taken to ensure
adequate follow-up to detect potential adverse effects of new
therapies, particularly on microbial resistance patterns.
Keywords: Anti-inflammatory therapy, bronchiectasis,
inflammation, inhaled corticosteroids, macrolides
*Dept of Thoracic Medicine,

#
School of Medicine, University of
Queensland, The Prince Charles
Hospital, Chermside,
"
Queensland Childrens Respiratory
Centre,
+
Queensland Childrens Medical
Research Institute, Herston,
Queensland, and
1
Menzies School of Health Research,
Charles Darwin University, Darwin,
Northern Territory, Australia.
Correspondence: S.C. Bell, Dept of
Thoracic Medicine, The Prince
Charles Hospital, Rode Road,
Chermside, Brisbane, QLD, 4032,
Australia, Email
scott_bell@health.qld.gov.au
D.J. SMITH ET AL.
Summary
Eur Respir Mon 2011. 52, 223238.

Copyright ERS 2011.
ISSN: 1025-448x.
DOI: 10.1183/1025448x.100004510
223
ronchiectasis is an under-recognised condition characterised by pathological dilatation of

bronchi, persistent neutrophilic airway inflammation and, in many, chronic bacterial
infection. Bronchiectasis develops in the susceptible host through a vicious cycle of airway
infection and inflammation [1]. The causes of non-cystic fibrosis (CF) bronchiectasis are diverse,
the cohort populations are heterogeneous and the evidence to support therapies limited [2].
Factors which may have contributed to the limited evidence for treatment are likely to include
population and disease severity heterogeneity, limited funding sources for clinical trials and the
diverse manner that patients with bronchiectasis are managed. This appears to be changing with
the advent of specialised bronchiectasis clinics which are providing an opportunity to develop
focused research programmes. There are a limited number of high-quality randomised controlled
trials (RCTs) cited in recently published management guidelines for bronchiectasis [35].
Airway biology in bronchiectasis

Cohort studies of patients with bronchiectasis reveal Haemophilus influenzae and Pseudomonas
aeruginosa to be the most frequently isolated organisms from airway secretions. Streptococcus
pneumoniae, Moraxella species and nontuberculous mycobacteria (NTM) are reported less
commonly [68]. Although infection triggers inflammation, ongoing neutrophilic infiltration of
the airways is apparent even in the absence of persistent infection, suggesting dysregulation of
immune responses [9]. Neutrophils are the predominant inflammatory cell found in sputum and
bronchoalveolar lavage fluid (BALF) in patients with bronchiectasis [9, 10]. It is hypothesised that
neutrophil apoptosis and clearance may be defective in bronchiectasis [11]. Non-apoptosed cells
die by necrosis leading to exudation of toxic products (e.g. exoenzymes, oxygen free radicals,
myeloperoxidase, etc.) which cause both localised tissue damage and provide an ongoing stimulus
for the inflammatory response. Macrophages, lymphocytes and eosinophils are similarly present in
increased number in the bronchiectatic airway, however, their role is poorly defined [12].
ANTI-INFLAMMATORY THERAPY
Acute respiratory exacerbations in patients with bronchiectasis are poorly understood but are
thought to be related, in part, to increased load of existing airway bacteria and/or infection with a
new bacterial pathogen. These changes provide rationale for the use of targeted antibiotics in
patients with bronchiectasis during respiratory exacerbations which are discussed in detail in the
chapter by FOWERAKER and WAT [13].
Targeting inflammation in bronchiectasis

An alternative approach to targeting infection with antimicrobial agents is to attempt to modify
the immune response to infection. In this chapter we focus on the use of anti-inflammatory agents
and examine the evidence for the use and potential pitfalls of these therapies. We also explore
future treatment options and studies that are in progress.
Anti-inflammatory therapies will be discussed in one of three broad categories: 1) general antiinflammatory therapies which have broad immunosuppressive effects on inflammatory pathways
(e.g. corticosteroids or nonsteroidal anti-inflammatory drugs (NSAIDS)); 2) novel antiinflammatory therapies which have immunomodulatory properties in addition to the cellular
effects for which they are conventionally utilised (e.g. macrolides and hydroxy-methyl-glutarylcoenzymeA (HMGCoA) reductase inhibitors); and 3) targeted anti-inflammatory therapies which
block a specific mediator of the immune response (e.g. anti-immunoglobulin E or anti-tumour
necrosis factor (TNF)-a).
General anti-inflammatory agents

Corticosteroids
224
Corticosteroids have broad anti-inflammatory effects through inhibition of inflammatory

mediator synthesis and release and impairment of inflammatory cell migration [14].
Corticosteroids stimulate eosinophil apoptosis but paradoxically inhibit neutrophil apoptosis
which, in part, possibly explains their variable anti-inflammatory effectiveness in different clinical
settings [15]. Inhaled corticosteroids improve asthma control [16, 17] and are associated with
reduction in exacerbation frequency in chronic obstructive pulmonary disease (COPD) [18], yet
their withdrawal in patients with CF has minimal impact on symptoms, lung function or
exacerbations [19]. Short courses of oral steroids have an established role in the treatment of
exacerbations of asthma and COPD [20, 21]; however, their role in CF is more controversial [22].
Inhaled corticosteroids
Recently, KAPUR et al. [23] identified six RCTs of inhaled steroids in non-CF bronchiectasis
(table 1). The meta-analysis of these studies failed to provide conclusive evidence that inhaled
corticosteroids result in a clinically significant improvement in lung function, affect exacerbation
rates or improve quality of life in patients with bronchiectasis (fig. 1).
Two larger and longer trials studying fluticasone diproprionate (500 mg b.i.d.) in adults with
bronchiectasis, demonstrated a reduction in sputum quantity [28, 29]. In a post hoc analysis TSANG
et al. [28] observed that this effect was most pronounced in those patients with chronic P. aeruginosa
infection. However, each of these studies had significant limitations including no placebo arm in the
former and variable baseline sputum production in the treatment arms in the latter, precluding their
data from being included in the assessment of this outcome measure in the Cochrane Review.
Although therapy was generally well tolerated for the duration of the trials, long-term safety is
uncertain in dosage regimens which would currently be considered to be high. In addition, one shortterm study [25], the data on density of total bacteria, commensal bacteria and P. aeruginosa in sputum
showed an increasing trend after 4 weeks of therapy with inhaled steroids.
Based on the available evidence from these published studies, KAPUR et al. [23] concluded that there is
currently insufficient evidence of both benefit and safety to recommend routine use of inhaled
corticosteroids in patients with bronchiectasis, however, it may be appropriate to consider a trial in
severely symptomatic patients on a case by case basis, with close monitoring for adverse effects.
D.J. SMITH ET AL.
The earliest study, published in 1992 by ELBORN et al. [24], enrolled 20 patients in a 12-week
crossover trial of high-dose beclomethasone diproprionate/placebo (6 weeks drug, 6 weeks
placebo). Despite five patients dropping out of the study, the authors reported an 18% reduction
in volume of sputum and reduced bronchoprovocation during histamine challenge testing. A
subsequent study demonstrated inhaled fluticasone diproprionate reduced sputum levels of proinflammatory mediators (interleukin (IL)-8, leukotriene B4 (LTB4) and IL-1b) and sputum
leukocyte density in bronchiectasis [25]. Combined with the consistent finding that inhaled steroids
have no effect on sputum bacterial load [25], this suggests that any beneficial effect they may exert is
most likely explained by anti-inflammatory as opposed to antimicrobial activity. Studies by TSANG
et al. [26] and JOSHI and SUNDARAM [27] reported no change in exhaled nitric oxide and no change in
lung function, respectively.
Oral corticosteroids
There is currently no evidence supporting the use of oral corticosteroids. A Cochrane Review by
LASSERSON et al. [30] failed to identify any RCTs in non-CF bronchiectasis either for short-term
(during an exacerbation) or long-term use. The only evidence of potential benefit is from the
paediatric CF literature in which prednisolone at a dose of 1 mg?kg-1 on alternate days was
associated with reduced rate of lung function decline [22]. The long-term adverse effects including
effects on growth and cataract resulted in the early termination of the trial.
NSAIDS
225
NSAIDS non-selectively block the activation of the cyclo-oxygenase pathway of pro-inflammatory

prostaglandins. A landmark placebo controlled RCT examined the effects of ibuprofen in people
with CF [31]. The study included 85 patients (age range 539 years) and demonstrated that those
treated with high-dose ibuprofen (dose range 16.231.6 mg?kg-1) experienced a slower rate of
decline in forced expiratory volume in 1 second (FEV1), as well as improved maintenance of
weight when compared with control subjects over the 4-year study period. Post hoc analysis
revealed these effects to be most pronounced in those participants ,13 years of age at study
commencement. Ibuprofen therapy was well tolerated with only one patient withdrawing due to
side-effects clearly attributable to ibuprofen (conjunctivitis and epistaxis).
226
RCT
(parallel)
China
(Hong
Kong)
India
China
(Hong
Kong)
T SANG
[26]
T SANG
[28]
Drug
Fluticasone
proprionate
(500 mg b.i.d. or
250 mg b.i.d.)
4 weeks
52 weeks
8 weeks
(4 weeks
each arm,
2 week
washout)
52 weeks
36 weeks
Yes
Yes
Yes
Yes
Yes
12 weeks
(6 weeks
each arm,
no washout)
Yes
93
86
20
60
24
20
Placebo Duration Subjects

n
Findings
No change in
lung function
No change in eNO
None
None reported
but trend
towards
increased
sputum
density
of commensal
flora and
P. aeruginosa
Not reported
Oral
candidiasis
(n51)
Adverse
events
Sputum volume
Reduced sputum
Sore throat
and purulence, volume, no change in
(n57)
exacerbation rates, exacerbation rates,
lung function
sputum purulence,
lung function
HRQoL
Improved dyspnoea, Dry mouth (n58),
reduced sputum
local irritation
volume, reduced
(n54), dysphonia
b-agonist use
(n54), oral
(high-dose group)
candidiasis
(n52), aphthous
ulcer (n51)
Lung function
eNO
Lung function,
Improved FEV1,
PD20 metacholine, improved morning
sputum producPEFR, improved
tion, pulmonary
cough, reduced
symptoms
sputum volume
24 h sputum
Reduced sputum
(volume/leukocyte
leukocyte density,
counts/microbial
reduced IL-1b,
concentrations/
IL-8 and LTB4,
IL-1/IL-8/TNF-a/ no change in sputum
volume, no change in
LTB4),
lung function
lung function
Outcome
measures
DBRCT: double-blind (DB) randomised controlled trial (RCT); b.i.d.: twice daily; FEV1: forced expiratory volume in 1 second; PD20: provocative dose causing a 20% fall in FEV1;
PEFR: peak expiratory flow rate; IL: interleukin; TNF-a: tumour necrosis factor-a; LTB4: leukotriene B4; P. aeruginosa: Pseudomonas aeruginosa; eNO: exhaled nitric oxide;
HRQoL: health-related quality of life. #: the only blinded component of this study was for the dose of inhaled corticosteroids.
Bronchiectasis
Adults
Bronchiectasis,
Fluticasone
(mean age
nonsmokers
proprionate
56 yrs)
(500 mg b.i.d.)
DBRCT
Adults/
Bronchiectasis, Beclomethasone
(crossover)
children 12% improvement diproprionate
(1560 yrs)
post(400 mg b.i.d.)
bronchodilator
FEV1
DBRCT
Adults
Bronchiectasis, no Fluticasone
(parallel)
(mean age
oral/inhaled
proprionate
58 yrs)
corticosteroids
(500 mg b.i.d.)
Fluticasone
proprionate
(500 mg b.i.d.)
Bronchiectasis, Beclomethasone
no prior
diproprionate
oral/inhaled
(750 mg b.i.d.)
corticosteroids
Inclusion
criteria
Adults
Bronchiectasis
(mean age .10 mL sputum
55 yrs)
per 24 h
RCT-non
Adults
MARTINEZ- Spain
DB# (parallel) (mean age
GARCIA
[29]
69 yrs)
J OSHI
[27]
DBRCT
(parallel)
China
(Hong
Kong)
T SANG
[25]
Population
DBRCT Adults (30

(crossover)
65 yrs)
UK
E LBORN
[24]
Design
Country
Study
Table 1. Randomised controlled trials of inhaled corticosteroids in bronchiectasis
ICS
MeanSD
Total
Placebo Total Weight

%
MeanSD
FEV1 L#
0.0110.11
-0.0450.14
JOSHI [27]
10
0.0640.154
MARTINEZ [29]
29 0.0380.107
0.20.87
00.739
TSANG [25]
12
Subtotal (95% Cl)
51
Heterogeneity: 2 = 0.59, df = 2 (p = 0.74); I2 = 0%
Test for overall effect: Z = 3.04 (p = 0.002)
FVC L#
JOSHI [27]
10
0.0380.16
-0.0670.16
MARTINEZ [29]
29 -0.0620.181
0.0250.104
TSANG [25]
12
0.11
01
Subtotal (95% Cl)
51
Peak flow L.min-1#
JOSHI [27]
10
1727.36
-7.847.82
12
TSANG [25]
35111
-2122.58
Subtotal (95% Cl)
22
Diffusion capacity % pred
84.210
29
86.910
MARTINEZ [29]
71.828.63
12
7021.86
TSANG [25]
Subtotal (95% Cl)
41
RV % pred
10810
29
10629.2
MARTINEZ [29]
10948.11
12 135.859.46
TSANG [25]
Subtotal (95% Cl)
41
TLC % pred
MARTINEZ [29]
89.610
86.410
29
TSANG [25]
83.819.32
87.520.83
12
Subtotal (95% Cl)
41
Mean difference
IV, fixed, 95% Cl
10 27.7
28 71.5
12 0.8
50 100
0.06 (-0.05_0.17)
0.10 (0.03_0.17)
0.20 (-0.45_0.85)
0.09 (0.03_0.15)
10 23.0
28 76.3
12 0.7
50 100
0.11 (-0.04_0.25)
0.09 (0.01_0.16)
0.10 (-0.70_0.90)
0.09 (0.02_0.16)
10 88.2 24.80 (-9.35_58.95)

12 11.8 37.00 (-56.56_130.56)
22 100 26.23 (-5.84_58.31)
28 93.9
12 6.1
40 100
2.70 (-2.49_7.89)
1.80 (-18.58_22.18)
2.65 (-2.39_7.68)
10 84.6 2.00 (-16.46_20.46)

12 15.4 -26.80 (-70.08_16.48)
22 100 -2.43 (-19.41_14.55)
28
12
40
3.20 (-1.99_8.39)
90.5
9.5 -3.70 (-19.77_12.37)
2.55 (-2.39_7.49)
100
Mean difference
IV, fixed, 95% Cl
D.J. SMITH ET AL.
Study or subgroup
-50 -25
0
25 50
Favours placebo Favours ICS
Figure 1. Forest plot of lung function indices comparing adults with bronchiectasis (in stable state) on inhaled
corticosteroids (ICS) versus controls. FEV1: forced expiratory volume in 1 second; FVC: forced vital capacity; %
pred: % predicted; RV: residual volume; TLC: total lung capacity. #: end study minus baseline values; ": end of
study values. Reproduced from [23] with permission from the publisher.
227
A Cochrane Review by LANDS and STANOJEVIC [32] of NSAIDs in CF, including four RCTs,
concluded that high-dose ibuprofen is capable of slowing disease progression; whilst NSAIDs are
an attractive potential therapy in patients with bronchiectasis the benefits of treatment
demonstrated in patients with CF cannot necessarily be extrapolated. This has been demonstrated
with the use of human recombinant DNase, which when trialled in non-CF bronchiectasis resulted
in increased pulmonary exacerbations and greater decline in lung function [33].
Two recent Cochrane Reviews of oral and inhaled NSAID therapy in non-CF bronchiectasis were
able to identify only one study suitable for inclusion [34, 35]. In this study 25 adults with chronic
lung disease (eight bronchiectasis, 12 chronic bronchitis and five diffuse panbronchiolitis) received
inhaled indomethacin or placebo for 14 days. In the treatment group (inhaled indomethacin)
compared with placebo, there was a significant reduction in sputum production over 14 days
(difference -75 g?day-1; 95% CI -134.61 -15.39) and significant improvement in dyspnoea score
(difference -1.90; 95% CI -3.15 -0.65). There was no significant difference between groups in
lung function or blood indices [36].
Novel immunomodulatory agents

Macrolides
Macrolides have been in clinical use as antimicrobial agents for .50 years. There are three classes
of macrolides based on the central ring structure: 14-membered ring macrolides (e.g.
erythromycin, roxithromycin and clarithromycin); 15-membered ring macrolides (also known
as azolides, e.g. azithromycin); and 16-membered ring macrolides (e.g. spiramycin and
josamycin) (fig. 2). The variation in structure of each class influence pharmacokinetic and
pharmacodynamic properties [38]. Importantly, compared with other classes, the 15-membered
ring structure azolides have less drug interaction, improved gastrointestinal tolerance and
enhanced ability to concentrate within the neutrophil [39].
Antimicrobial properties
Macrolides exert their antimicrobial action against Gram-positive, Gram-negative and intracellular
organisms by binding to ribosomal subunits required for protein replication. Of particular relevance
to their use in bronchiectasis is their antimicrobial activity against H. influenzae, Moraxella
catarrhalis and S. pneumoniae. Similarly their activity against atypical respiratory pathogens
(including Legionella pneumophila, Chlamydia spp. and Mycoplasma pneumoniae) has led to their
widespread usage in the treatment of community-acquired pneumonia [40, 41].
At least two compounds (clarithromycin and azithromycin) have demonstrated activity in NTM
infection and are important components of multi-drug regimes for treatment of Mycobacterium
avium complex [42]. If adherence to treatment regimens is poor or if macrolide monotherapy is
administered, NTM species may develop resistance. This may result in poorer clinical outcome [43].
This is a major concern when macrolides are prescribed in disease processes where mycobacterial
infections can co-exist. The recently published Australia and New Zealand bronchiectasis guidelines
recommend screening for NTM prior to initiation of macrolide therapy and regular sputum
surveillance during treatment [5].
Anti-pseudomonal properties
228
The reported prevalence of P. aeruginosa infection in bronchiectasis varies from 12% to 33% [8]
and is associated with radiological disease severity [44], increased lung function decline [45] and
mortality [46]. Mucoid transformation of P. aeruginosa allows alginate secretion and biofilm
production which provides a physical barrier from the immune system and contributes to
persistent airway infection and inflammation [47]. P. aeruginosa within biofilms can communicate
through quorum sensing systems (las and rhl) which are important in coordination of the
expression of virulence factors and biofilm maturation [48]. Azithromycin has been shown to
suppress both lasI and rhlI in vitro [49].
Macrolides have also been shown to suppress

various P. aeruginosa virulence factors including
protease, elastase, leucocidin, pyocyanin, phospholipase C and exotoxin A [5153]. Suppression
of P. aeruginosa virulence varied depending on P.
aeruginosa strains studied and the specific macrolide used. In general, azithromycin has been
shown to be more effective than other macrolides
[51, 52]. Azithromycin has also been shown to
inhibit P. aeruginosa antibiotic efflux pumps
thereby potentially contributing to synergy and
increasing the efficacy of other classes of antimicrobials [54]. Although these studies suggest
macrolides are capable of impairing P. aeruginosa
virulence, it is important to highlight that most of
these studies were performed with laboratory
strains of P. aeruginosa using in vitro systems.
a)
O
CH3 HO
H3C
OH
CH3
O
HO
N
O
CH3
HO
H3C
O
CH3
CH3
O CH3
O
CH3
OH
CH3 O
CH3
H3C
b)
CH3
H3C
OH
CH3
O
HO
CH3
N
HO
N
H3C
CH3
HO
H3C
CH3
O
CH3
CH3
CH3
CH3
OH
O
CH3
CH3
c)
N
O
Anti-inflammatory properties
Anti-inflammatory properties of macrolides were
first considered in the 1970s when observational
studies noted that steroid-dependent asthmatics
were able to reduce their dose of oral corticosteroid dose while prescribed erythromycin and
triacetyloleandomycin [55]. The steroid sparing
effect was later confirmed in prospective studies in
patients with severe corticosteroid dependent
asthma [56]. Furthermore, a reduction in bronchial hyperreactivity in asthmatic subjects was
seen in patients receiving erythromycin, clarithromycin or roxithromycin [5759].
CH3
H3C
CH3
D.J. SMITH ET AL.
P. aeruginosa is considered to be inherently

resistant to macrolides as the in vitro minimal
inhibitory concentration (MIC) is significantly
higher than the concentration achievable in vivo
[50]. However sub-MIC concentrations of macrolides may inhibit P. aeruginosa virulence. Type IV
pili on the surface membrane of P. aeruginosa
increase the organisms motility and are believed
to be critical in adhesion of P. aeruginosa to
epithelial cells and colony expansion, and in
facilitating biofilm formation. Sub-MIC concentrations of clarithromycin inhibit adherence of P.
aeruginosa to cell surface pili and retard biofilm
maturation in vitro [50].
CH3
CH3
CH3
OH
CH3
CH3 CH3
OH
N
O
H3C
OH
O
OH CH3
OH
CH3
CH3
Figure 2. Structure of macrolides (representative

examples). a) 14-membered ring (erythromycin);
b) 15-membered ring (azithromycin); and c) 16membered ring (spiramycin I). Reproduced from
[37] with permission from the publisher.
229
However, it was in the 1980s when use of

macrolides revolutionised the treatment of diffuse
panbronchiolitis (DPB) that their immunomodulatory properties came under closer scrutiny.
DPB is an idiopathic inflammatory airway condition found almost exclusively within the South
East Asian populations (especially in Japan), which histologically is characterised by intense
neutrophilic inflammation of the bronchioles [60]. Its typical onset is in the second to fifth decade
of life which, when untreated, progresses to severe bronchiectasis, chronic airway infection and
ultimately respiratory failure. Prior to the introduction of macrolides in the mid 1980s, 10-year
survival rates were low (,33%) [61], and even lower in those patients with chronic P. aeruginosa
infection [62]. Since the introduction of erythromycin and subsequently other macrolides, survival
has improved dramatically achieving 10-year survival rates .90% [61].
Immunomodulatory properties
Herin we briefly review the supportive evidence with more comprehensive reviews in the literature
[63, 64]. While anti-inflammatory actions of macrolides are well established, the differences seen
in some studies are probably attributable to variance in methodology, model system used and the
macrolide agent studied.
Endotoxins produced by invading bacteria stimulate human epithelial cells both directly and
through toll-like receptors, triggering an inflammatory cascade leading to the activation of nuclear
factor (NF)-kb [65]. NF-kb is central in regulating transcription of genes which encode proinflammatory mediators, including IL-6, IL-8, TNF-a (cytokines) and the intercellular adhesion
molecule-1 (ICAM-1). In vitro studies have demonstrated both erythromycin and clarithromycin
to be capable of inhibiting NF-kb activation [66, 67] and complimentary studies have
independently demonstrated release of lower levels of IL-1, IL-6, IL-8 and ICAM-1 from
activated bronchial epithelial cells when exposed to macrolides [6870].
Neutrophils recruited to the site of inflammation become activated allowing phagocytosis
of microorganisms and production of proteases (including neutrophil elastase and matrixmetalloproteinases (MMP)-9), and reactive oxygen species (ROS) responsible for the oxidative
burst believed to be fundamental to killing the phagacytosed microorganism [71, 72]. In the
setting of infection, spillage of these proteases and ROS from necrotic neutrophils contributes
towards localised tissue damage and provides ongoing stimulus to the inflammatory process.
Macrolides are able to modulate neutrophil function by several mechanisms. In an animal model
of bronchiectasis, macrolides inhibit ICAM-1 expression which may reduce neutrophil migration
to the site of inflammation [64]. Various 14-membered macrolides have been shown to inhibit the
oxidative burst [72] and similarly erythromycin and flurythromycin inhibit the release of
neutrophil elastase [73].
Interestingly, macrolides are associated with increased neutrophil degranulation [63]. A shortterm study of the effect of azithromycin (3 days) in healthy volunteers demonstrated an
immediate increase in neutrophil degranulation and circulating ROS, but decreased IL-8. This was
followed by a delayed inhibitory effect on oxidative burst, myeloperoxidase, IL-6 and increased
neutrophil apoptosis [74]. These in vitro studies provide impetus for studying the potential impact
of macrolides on neutrophil dominated airway diseases such as bronchiectasis.
Macrolides and mucus hypersecretion

Mucus hypersecretion is a hallmark of bronchiectasis, which in combination with impaired
mucociliary clearance produces a local environment conducive to chronic infection. Mucins
(macromolecular glycoproteins) are major constituents of mucus and are encoded by a number of
genes. One such gene, MUC5AC is specifically expressed by bronchial epithelial goblet cells [75] and
in vitro studies demonstrate erythromycin and clarithromycin attenuate lipopolysaccharide-induced
increased MUC5AC gene expression [64]. Azithromycin demonstrates similar effects on the
MUC5AC gene in P. aeruginosa quorum sensing mediator stimulated human epithelial cells [76].
These effects are supported by in vivo responses to macrolides in varied animal models [77, 78].
230
In summary, the potential benefits of macrolide therapy in patients with bronchiectasis may result
from antimicrobial properties and effects on biofilm development in patients with P. aeruginosa
infection, by down-regulating acute and chronic inflammatory responses and limiting mucus
hypersecretion.
Clinical trials of macrolides

To date there have been limited studies examining the effectiveness of macrolides for treatment of
non-CF bronchiectasis. Those published studies have been performed in small patient populations
and have varied considerably in study design including duration, dose and specific macrolide,
outcome measures and whether a control group was used as a comparator (table 2).
The first double-blind, placebo-controlled RCT of macrolides in non-CF bronchiectasis compared
the effect of roxithromycin (4 mg?kg-1 b.i.d.)/placebo for 12 weeks in children with a clinical
diagnosis of bronchiectasis and evidence of airway hyperreactivity [79]. There was a significant
reduction in sputum purulence, leukocyte concentration and a reduction in airway reactivity
(provocative dose causing a 20% fall in FEV1 to metacholine). However, there was no change in
lung function when compared with placebo.
A double-blind RCT of erythromycin in adults with non-CF bronchiectasis compared 8 weeks

of erythromycin (500 mg b.i.d., n514) with placebo (10 patients) during a period of clinical
stability [81]. Three patients, each receiving erythromycin withdrew (adverse effect n51, poor
adherence n52). A per protocol analysis based on those who completed the trial demonstrated an improvement in lung function (mean increase in FEV1 and forced vital capacity of
140 mL and 120 mL, respectively) and decreased sputum production in those receiving
erythromycin. There were no differences in levels of inflammatory cytokines (IL-8, TNF-a or
LTB4) in sputum.
Several uncontrolled studies have also been reported. An open label, randomised, crossover study
of 6 months of azithromycin 500 mg twice weekly and standard treatment in 12 patients (11
included in analysis) demonstrated a reduction in the number of exacerbations requiring
antibiotics (five versus 16, p,0.019) and sputum volume during azithromycin therapy and no
change in lung function [82]. Notably, the investigators aimed to recruit 30 subjects for the study
based on pre-study power estimates.
D.J. SMITH ET AL.
In a second macrolide trial also in children with stable non-CF bronchiectasis, YALCIN et al. [80]
compared the impact of clarithromycin with conventional treatment administered for 3 months
on immune mediators within BALF. The study demonstrated greater reduction in sputum volume
and BALF total cell counts, neutrophil ratios and IL-8 levels in the clarithromycin group.
Interestingly, there was no significant change in sputum microbiology. This study had the major
limitation of the lack of a placebo.
A prospective cohort study of azithromycin in adult patients with frequent pulmonary

exacerbations (.4 in the year prior to enrolment), employed a treatment protocol of azithromycin
500 mg?day-1 for 6 days, then 250 mg?day-1 for 6 days, followed by maintenance treatment of
250 mg three times per week [83]. Six (15%) of the 39 patients recruited withdrew due to adverse
effects. Analysis based on those who tolerated therapy demonstrated a reduction in exacerbation
rate (from 0.71 to 0.13 per month, p,0.001), reduction in number of courses of antibiotics (0.08
to 0.003 per month, p,0.001) and a trend to improvement in lung function parameters.
Respiratory symptoms improved in those treated with azithromycin over a mean follow-up period
of 20 months (in-house symptom questionnaire).
Finally a cohort study of 56 adult patients treated with azithromycin 250 mg three times per week,
of which 50 patients completed a minimum of 3 months (mean duration 9.1 months),
demonstrated a reduction in exacerbation rate and sputum production (compared with the
6 months prior to treatment) and an improvement in FEV1 (only 29 patients assessable) [84].
231
In summary, these small studies have demonstrated that macrolide therapy is generally well
tolerated and reduces sputum volume, however, effect on pulmonary function is unclear. Several
studies have reported significant participant dropout due to gastrointestinal adverse events.
Routine use of macrolides cannot be supported based on current evidence and there is an urgent
need for large randomised placebo controlled trials to assess tolerability, clinical impact, which
232
DBRCT Adult (mean Bronchiectasis Erythromycin

(parallel) age 55 yrs)
.10 mL
(500 mg b.i.d.)
sputum per
24 h
Open label
Adult
Bronchiectasis Azithromycin
(crossover) (mean age
(500 mg b.i.d.)
71 yrs)
Cohort
Cohort
China
(Hong
Kong)
USA
UK
UK
T SANG
[81]
C YMBALA
[82]
D AVIES
[83]
A NWAR
[84]
No
No
No
Yes
No
Yes
204 weeks
52 weeks
(26 weeks
each arm,
4 weeks
washout)
Mean
80 weeks
8 weeks
12 weeks
12 weeks
56
39
12
24
34
25
Placebo Duration Subjects

n
Findings
Diarrhoea (n53)
Withdrew due to
rash (n51)
None
None
Adverse
events
Withdrew (n56);
abnormal liver
function (n52),
diarrhoea (n52),
rash (n51),
tinnitus (n51)
Exacerbation rates,
Reduced sputum
Withdrew
lung function,
volume, reduced
(n56)"; diarrhoea
(n53), abdominal
sputum volume/
exacerbation rates,
microbiology
reduced positive sputum cramps (n52),
skin rash (n52)
microbial cultures
Exacerbation
Reduced exacerbation
rates, antibiotic
rate, reduced antibiotic
usage, lung function
usage, improved
DL,CO, no change
in FEV1, FVC
Reduced sputum
Sputum
purulence/leukocyte
purulence/WCC,
counts, reduced airway
FEV1, PD20
metacholine
reactivity, fall in FEV1
Sputum volume,
Reduced sputum
lung function,
volume, reduced BALF
BALF (leukocyte
neutrophil ratio, IL-8,
counts, microbial increased FEF2575, No
change in FEV1
cultures, IL-8,
IL-10, TNF-a)
24 h sputum
Reduced sputum
(volume/WCC/
volume, improved FEV1
and FVC, no change in
microbial
concentrations/ microbial concentration,
immune mediators#), no change in immune
lung function
mediators
Sputum volume,
Reduced sputum
exacerbation
volume, reduced
rates, lung function
exacerbations, no
change in lung function
Outcome
measures
DBRCT: double-blind randomised controlled trial (RCT); b.i.d.: twice daily; WCC: white cell count; FEV1: forced expiratory volume in 1 second; PD20: provocative dose causing a 20% fall in
FEV1; BALF: bronchoalveolar lavage fluid; IL: interleukin; TNF: tumour necrosis factor; FVC: forced vital capacity; FEF2575%: forced expiratory flow at 2575% FVC; q.d.: once daily; DL,CO:
diffusing capacity of the lung for carbon monoxide; MWF: Monday, Wednesday, Friday. #: immune mediators: IL-1a, TNF-a and leukotriene B4; ": seven adverse events in six patients.
Adult
Bronchiectasis, Azithromycin
(1877 yrs)
.4
(500 mg q.d.
6 days,
exacerbations
prior 52 weeks 250 mg q.d.
6 days,
250 mg MWF)
Adult
Bronchiectasis, Azithromycin
(mean age
o3
(250 mg MWF)
63 yrs)
exacerbations
prior 26 weeks
Children Bronchiectasis, Clarithromycin

(718 yrs) no antibiotics in (15 mg?kg-1
b.i.d.)
prior 16 weeks
RCT
(parallel)
Turkey
Drug
Children Bronchiectasis, Roxithromycin

(mean age
airway
(4 mg?kg-1 b.i.d.)
13 yrs)
hyperreactivity
Inclusion
criteria
Y ALCIN
[80]
DBRCT
(parallel)
Population
South
Korea
Country Design
K OH
[79]
Study
Table 2. Clinical trials of macrolide therapy in bronchiectasis
macrolide is most beneficial and to assess the risk of macrolide resistant infections. This latter
point is important given the emerging evidence of macrolide resistance in Europe [8587] and in the
CF population [8890]. Several studies have either recently been completed, are actively recruiting or
about to commence, which will hopefully address some of these important issues (table 3).
HMGcoA reductase inhibitors

HMGcoA reductase inhibitors (statins) have established clinical utility as lipid lowering agents
in patients with hyperlipidaemia. They also have widely recognised anti-inflammatory and
immunomodulatory properties. In vitro studies of HMGCoA reductase inhibitors have
demonstrated inhibition of neutrophil migration and epithelial cell production of chemoattractants and proteases and potentiation of macrophage efferocytosis [72].
There are currently no studies of the use of HMGCoA reductase inhibitors for bronchiectasis, however,
the findings of the studies in other airway diseases suggest that future studies are worthwhile.
Targeted agents
There are currently no phase III trials of targeted therapies in inflammatory airway diseases, however, a
number of potential candidate agents specifically targeting neutrophilic inflammation are under
investigation.
D.J. SMITH ET AL.
In animal models of COPD, simvastatin has been shown to inhibit airway remodelling, lower
TNF-a and MMP-9 levels and reduce peribronchial and perivascular inflammation [91, 92]. A
recent systematic review identified nine studies using HMGCoA reductase inhibitors in patients
with COPD [93], however, only one of these was a prospective RCT. Collectively, these studies
demonstrated beneficial effects on pulmonary function, exacerbation rates and mortality and
provide the foundation for further study. Large, prospective RCTs are currently underway. Studies
in asthmatic subjects have yielded more variable results. Reduction in airway hyperreactivity has
been seen in one study [94], no benefit in another [95] and one retrospective review even
suggested HMGCoA reductase inhibitor use was associated with poorer clinical outcomes [96]. A
recent placebo-controlled, double-blind RCT of simvastatin 40 mg?day-1 in patients with steroid
responsive (eosinophilic) asthma failed to demonstrate any clinically significant steroid sparing
effect from the addition of simvastatin [97].
The CXC chemokines and their associated receptors (CXCR1/CXCR2) are believed to have a key
role in neutrophilic inflammation in pulmonary disease and recently a number of agents which
inhibit this pathway have been developed [98]. A phase II study of an anti-CXCL8 monoclonal
antibody in COPD has demonstrated safety and improvement in dyspnoea scores over 3 months
[99]. In a complimentary in vitro study ELR-CXC antagonists inhibited neutrophil chemotactic
factors in the sputum of bronchiectatic patients [100]. These studies suggest that further
investigation of these agents may be valuable.
Anti-TNF-a agents have an established role in treatment of systemic inflammatory diseases,
including rheumatoid arthritis [101] and Crohns disease [102]. In short-term trials of anti-TNF-a
agents in inflammatory lung diseases variable efficacy has been reported. While improvement in
exacerbation rates in asthma have been demonstrated [103], no effect was seen in patients with
COPD [104]. The major concerns associated with the use of these agents in patients with
pulmonary disease are the potential for the emergence of opportunistic infections, in particular the
re-activation of mycobacterial disease [105] and their possible association with acute deterioration
of fibrotic lung disease [106].
233
With the emerging array of anti-inflammatory monoclonal antibodies and targeted receptor
blocker drugs, new therapeutic options will potentially become available. Carefully conducted
trials will be required to support the use and examine adverse consequences. Although
manipulation of the immune response is an attractive prospect for treatment of a range of
234
DBRCT
(parallel)
DBRCT
(factorial
design),
stratified
by P.
aeruginosa
status
Australia
DBRCT
(parallel),
stratified by
P. aeruginosa
status
DBRCT
(parallel)
DBRCT
(parallel)
Design
New
Zealand
The
Netherlands
Australia
International
multicentre
study
(Australia,
New Zealand)
Country
Confirmed
bronchiectasis (HRCT)
Confirmed
bronchiectasis (HRCT),
o2 exacerbations in
prior 52 weeks, daily
productive cough,
clinically stable (4 weeks)
o1 pulmonary
exacerbation prior
52 weeks, confirmed
bronchiectasis or
chronic SLD
Inclusion criteria
Azithromycin
(250 mg q.d.)
140
130
26 weeks
72
26 weeks
52 weeks
118
Erthromycin
(400 mg b.i.d.)
48 weeks
Subjects
n
88
Duration
104 weeks
Azithromycin
(30 mg?kg-1?week-1)
Drug
Confirmed
Azithromycin
bronchiectasis (HRCT),
(500 mg MWF)
clinically stable, o1
exacerbations in prior
52 weeks
Adults (18 Bronchiectasis (HRCT +
Azithromycin
80 yrs
clinical), clinically
(250 mg q.d.) or
including
stable, o2 weeks hypertonic saline 7%
or both
indigenous
since antibiotics for
adults)
exacerbation
Adults (18
80 yrs)
Adults
(.18 yrs)
Adults
(1880
yrs)
Indigenous
children
(18 yrs)
Population
Completed
Study
completed,
yet to report
Ongoing
Exacerbations
Study completed,
(time to first/rate/severity),
yet to report
change in lung function,
HRQoL, change
in sputum cell count
HRQoL, exacerbation rate,
Recruitment to
change in lung function,
commence
change in symptoms score,
early 2011
change in airway
microbiology, sputum
inflammatory markers,
adverse events
Exacerbation rate, change in

lung function, change in
symptom scores, change in
airway microbiology, sputum
inflammatory markers,
HRQoL, adverse events
Exacerbation rate, antibiotic

usage, HRQoL, sputum
volume/inflammatory markers
Exacerbations (time to first/ Recruitment until

rate/severity), safety/adverse
Dec 2010
events, antimicrobial
resistance
Outcome
measures
BIS: bronchiectasis intervention study; BLESS: bronchiectasis and low-dose erythromycin study; BAT: bronchiectasis and long-term azithromycin treatment; EMBRACE:
effectiveness of macrolides in patients with bronchiectasis using azithromycin to control exacerbations; DBRCT: double-blind randomised controlled trial; SLD: suppurative lung
disease; HRCT: high-resolution computed tomography; b.i.d.: twice daily; HRQoL: health-related quality of life; q.d.: once daily; P. aeruginosa: Pseudomonas aeruginosa; MWF:
Monday, Wednesday, Friday.
EMBRACE
BAT
BLESS
BIS
Study
acronym
Table 3. Registered trials of macrolide therapy in bronchiectasis
inflammatory medical conditions, history advocates caution. In March 2006, six healthy
volunteers enrolled in a phase I trial were administered a first-in-man anti-CD28 humanised
monoclonal antibody (TG1412) designed to modulate regulatory T-cells. Within hours of
administration each volunteer experienced a severe cytokine storm resulting in multi-organ failure
[107]. Although all six survived, the most severely affected subject required intensive care support
for 3 weeks. Similarly, in a recent study in children and adults with CF the use of an LTB4
antagonist (BIIL284) resulted in increased respiratory exacerbations resulting in the study being
prematurely terminated after interim data analysis [108].
These studies highlight that in conditions characterised by infection associated with inflammation,
anti-inflammatory therapies may be associated with adverse consequences and require very careful
and detailed analysis.
Conclusion
Evidence for the use of anti-inflammatory therapies in bronchiectasis is limited and more
adequately powered studies are required [109, 110]. There is currently insufficient evidence to
support the use of inhaled and oral corticosteroids, NSAIDs and macrolides. Individual patient
trials may be warranted for inhaled corticosteroids and macrolides and other therapies remain
unproven with no evidence to support use as anti-inflammatory therapy in bronchiectasis.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
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18.
19.
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Chapter 16
Pharmacological
airway clearance
strategies in
bronchiectasis
P.T. Bye*,#,", E.M.T. Lau*,#," and M.R. Elkins*,"
Impaired mucociliary clearance and mucus retention contribute to the chronic cycle of airway inflammation, infection
and damage in bronchiectasis. There is a strong rationale for
the use of pharmacological strategies to aid airway clearance,
often in combination with chest physiotherapy. Despite the
availability of many candidate mucoactive agents, the evidence
base for recommending these agents is currently limited.
Recent research and trials have focused particularly on osmotic
agents (hypertonic saline and mannitol), which increase airway
hydration, and early studies appear promising for both of these
agents. Dornase alfa is not effective in non-cystic fibrosis (CF)
bronchiectasis, which underscores the importance of conducting high quality and adequately powered trials that specifically
address the therapeutic options for non-CF bronchiectasis.
Keywords: Bronchiectasis, mucoactive, mucociliary clearance,
mucus
*Dept of Respiratory and Sleep

Medicine, Royal Prince Alfred
Hospital,
#
Sydney Medical School, University
of Sydney, Camperdown, and
"
Woolcock Institute of Medical
Research, Glebe, Australia.
Correspondence: P.T. Bye, Dept of
Respiratory and Sleep Medicine,
Royal Prince Alfred Hospital,
Missenden Road, Camperdown,
NSW 2050, Australia, Email
peterb@med.usyd.edu.au
P.T. BYE ET AL.
Summary
Eur Respir Mon 2011. 52, 239247.

Copyright ERS 2011.
ISSN: 1025-448x.
DOI: 10.1183/1025448x.10004610
239
on-cystic fibrosis (CF) bronchiectasis is a heterogeneous disorder defined by irreversible

dilatation of the airways [1]. Although a wide variety of underlying pathological processes
can initiate the development of bronchiectasis, the final common pathophysiological pathway is
one characterised by the vicious cycle of chronic infection and inflammation leading to progressive
airway damage [2]. Impaired mucociliary clearance is a feature of the abnormal bronchiectactic
airway [3, 4], and may represent the primary abnormality in conditions such as primary ciliary
dyskinesia. Mucus retention, the result of defective mucociliary clearance, not only produces the
classic symptom of chronic productive cough but also causes airflow obstruction and ventilation/
perfusion mismatch and forms a nidus for ongoing infection. Therefore, interventions aimed at
promoting clearance of excess mucus may be beneficial in patients with non-CF bronchiectasis.
The normal mucociliary escalator forms an essential element of the innate host defence
mechanism against inhaled pathogens. The complex physiology of mucociliary clearance in health
and disease has been reviewed in detail elsewhere [57]. Briefly, this process is dependent upon
normal ciliary function, optimal rheological properties of the airway mucus and an adequate
volume of airway surface liquid (ASL). The lung has the additional mechanism of cough for airway
mucus clearance, although the effectiveness of cough clearance itself is also dependent upon the
viscoelastic properties of mucus [8].
Agents that are intended to facilitate airway mucus clearance are termed mucoactive drugs. A
classification of mucoactive agents, based on their mechanism of action, is summarised in table 1.
Despite these agents having been available for many years, limited high-quality clinical trials have
been undertaken exploring the efficacy of mucoactive agents in non-CF bronchiectasis. Indeed, since
the mid-2000s, multiple authors have called for a coordinated approach in order to establish
multicentre clinical trials and for funding bodies to consider support for this disease, highlighting the
huge unmet needs in non-CF bronchiectatic therapy [911]. The present chapter reviews the current
pharmacological strategies available for enhancing airway clearance in non-CF bronchiectasis.
Hypertonic saline
PHARMACOLOGICAL AIRWAY CLEARANCE
Hypertonic saline is a sterile salt solution with a higher concentration of salt (typically 37%) than
plasma (0.9%), and is delivered by inhalation via a nebuliser. Hypertonic saline accelerates
mucociliary clearance in both healthy subjects and patients with cystic fibrosis (CF), as
demonstrated in radioaerosal studies [1215]. It is thought to enhance airway clearance by altering
the viscoelastic properties of mucus, increasing hydration of the ASL and also directly stimulating
cough [1518].
The hydrating effect of hypertonic saline on mucociliary function has been best characterised in
the CF airway. In health, ASL is present as a bilayer, with a superficial mucus layer and a layer of
periciliary liquid (PCL) interposed between the mucus and the epithelium. The PCL layer
approximates the height of the cilia and provides a low-viscosity fluid in which the cilia beat [5].
A critical depth of PCL is crucial for ciliary function and mucociliary transport [6]. CF
transmembrane conductance regulator dysfunction leads to airway dehydration and depletion of
the PCL layer of the ASL [19]. The addition of hypertonic saline to the CF epithelium rapidly
restores the depth of the ASL by creating an osmotic gradient and drawing water across the
Table 1. Common mucoactive drugs and their mechanisms of action
Agent
Expectorants
Hypertonic saline
Mannitol
Mucolytics
N-Acetylcysteine
Nacystelyn
Dornase alfa
Mucoregulators
Carbocisteine
Glucocorticoids
Macrolide antibiotics
Anticholinergics
Mucokinetics
b2-Agonists
Surfactant
240
Modified from [8].
Predominant mechanism
Increases airway hydration; stimulates cough
Interrupts disulfide bonds linking mucin polymers; anti-inflammatory and

antioxidant effects
Interrupts disulfide bonds; increases chloride secretion
Cleaves DNA polymers
Modulates mucus content; anti-inflammatory and antioxidant effects
Reduces airway inflammation and mucin secretion
Reduces airway inflammation and mucin secretion
Decreases volume of secretions
Increases cilia beat frequency; improves cough clearance by increasing
expiratory flows
Decreases mucus adherence to epithelium
respiratory epithelium [15]. Restoration of the depth of ASL not only optimises ciliary function
but also causes excess water entering the airway to be stored in the mucus layer, making its
rheological properties more favourable for clearance [18].
The efficacy of long-term inhalation (48 weeks) of hypertonic saline has previously been
demonstrated in a randomised placebo-controlled trial for patients with CF [20]. Regular
hypertonic saline inhalation significantly improved lung function and reduced pulmonary
exacerbations. These changes were accompanied by prescription of fewer courses of antibiotics,
reduction in absenteeism from school and work, and improved quality of life. A recent Cochrane
review, which included 12 trials (442 participants aged 646 years), indicated that hypertonic
saline is a safe, low-cost and effective therapy in CF [21].
More recently, NICOLSON et al. [23] reported, in abstract form, the results of a randomised controlled
trial on the effect of long-term hypertonic saline inhalation. A total of 40 patients were randomised
to hypertonic saline (6%) or isotonic saline (0.9%) though an Aeroneb1 Go nebuliser (Aerogen,
Galway, Ireland) twice daily for 12 months while performing the ACBT. The mean forced expiratory
volume in 1 second (FEV1) of the study group was 83% of the predicted value. No differences in
lung function, number of exacerbations or quality of life were observed at 3, 6 and 12 months
between the hypertonic and isotonic saline groups. Both the hypertonic saline and isotonic saline
groups demonstrated clinically significant improvement in health-related quality of life compared to
baseline. However, this study was substantially underpowered to examine the effect of hypertonic
saline relative to isotonic saline. As clinically worthwhile benefits were not excluded by the
confidence intervals (CIs), further investigation of this promising agent is warranted.
P.T. BYE ET AL.
Preliminary evidence suggests that hypertonic saline may be clinically effective in non-CF
bronchiectasis. In a randomised crossover trial, KELLETT et al. [22] evaluated the effect of
hypertonic saline as an adjunct to physiotherapy in 24 stable bronchiectatic patients. Subjects were
allocated to receive four different single-session treatments in random order: 1) active cycle of
breathing technique (ACBT) alone, 2) nebulised terbutaline followed by ACBT, 3) nebulised
terbutaline followed by isotonic saline (0.9%) and then ACBT, and 4) nebulised terbutaline
followed by hypertonic saline (7%) and then ACBT. Each single-treatment session was followed by
a 1-week washout period. When hypertonic saline was used, physiotherapy yielded greater sputum
weight, increased the ease of sputum expectoration and reduced sputum viscosity. Although
encouraging, this study has clear limitations. The study only included patients who were minimal
sputum producers (,10 g?day-1), a phenotype which is clearly distinct from high sputum
producers. Patient blinding was incomplete (taste masking not performed), and the results only
represented the effect of a single treatment dose.
Hypertonic saline appears to be well tolerated by patients with bronchiectasis. In 50

administrations of hypertonic saline to patients with acute exacerbations, no major bronchoconstriction (fall in FEV1 of .20%) or oxygen desaturation occurred [24]. Routine premedication
with a bronchodilator is recommended (typically 200400 mg salbutamol delivered via a spacer
device). We generally recommend that spirometry is performed and oxyhaemoglobin saturation
measured before and after delivery of the first dose.
Mannitol
241
Mannitol is a six-carbon monosaccharide (sugar alcohol), and is commercially available in an

encapsulated stable dry powder formulation for inhalation. Similar to hypertonic saline, creation of
an osmotic gradient causing influx of water into the airway and increasing the ASL layer is
considered to be its primary mechanism of action [25]. In addition, mannitol may cause the release
of mediators that may stimulate ciliary beat frequency [26, 27], although direct evidence that
mannitol stimulates the cilia has not been established. Mannitol may also alter the viscoelastic
properties of mucus by breaking the hydrogen bonds between mucins [28]. Mannitol (160480 mg)
increases mucociliary clearance in a dose-dependent manner in radioaerosal studies [2931].
In a phase-3 randomised double-blind placebo-controlled trial in CF, inhalation of mannitol (400 mg

b.i.d.) for 6 months resulted in an early and sustained improvement in FEV1 compared to placebo
(118 mL change from baseline to week 26; p,0.001) [32]. The benefit in FEV1 was seen irrespective
of the concurrent use of dornase alfa. The study was not sufficiently powered to show a reduction in
the secondary end-point of exacerbations. Results from the 12-month open-label phase of the study
have also been reported. The improvement in lung function with mannitol appeared to be maintained
for up to 18 months of treatment [33]. The full results of this study are yet to be published.
There is emerging evidence that mannitol is an effective treatment in non-CF bronchiectasis. In an
open-label pilot study, DAVISKAS et al. [34] treated nine patients with bronchiectasis with 400 mg
mannitol daily for 12 days. Lung function was unchanged by treatment apart from an
improvement in forced expiratory flow (FEF). However, health-related quality of life had
improved at the end of the treatment period and was maintained for 1 week thereafter. Mannitol
reduced the surface tension, increased the wettability and reduced the cohesiveness and solids
content of sputum. Cough transportability, measured by an in vitro simulated cough machine, also
increased. All subjects tolerated treatment well, without report of any adverse events.
A phase-3 multicentre randomised controlled trial has recently been completed and its data presented
in abstract form [35]. Subjects with bronchiectasis and mild-to-moderate lung function impairment
(FEV1 of .50% pred and o1 L) were randomised to 320 mg inhaled mannitol (n5185) or placebo
(n595), given twice daily for 3 months. Subjects treated with mannitol exhibited a significant
reduction in the St Georges Respiratory Questionnaire total score of 3.9 units compared to 2.0 units
in the placebo group. In the mannitol group, the time to first antibiotic use was longer and total
antibiotic use was less than for placebo. The full report of this study is awaited with interest.
Dornase alfa
Dornase alfa is a proteolytic enzyme that cleaves DNA polymers [8]. DNA is released into the
airway mucus in large amounts by degenerating neutrophils, and neutrophilic inflammation is a
feature of both CF and non-CF bronchiectasis. Purulent airway secretions, particularly in CF,
show an abundance of highly polymerised DNA, which contributes to mucus hyperviscosity and
adhesiveness [36].
Daily inhalation of dornase alfa is a well-established therapy in CF bronchiectasis, resulting in
improvement in lung function and reduction in exacerbations, in both mild and severe disease
[3740]. In contrast, clinical studies in non-CF bronchiectasis have shown that dornase alfa is of
no benefit, and may even be harmful. In a short-term study of WILLS et al. [41], dornase alfa was
not associated with any improvement in lung function and quality-of-life measures in patients
with non-CF bronchiectasis. Indeed in vitro sputum transportability fell following the addition of
dornase alfa to non-CF bronchiectatic sputum. A subsequent international multicentre study
randomised 349 patients with stable non-CF bronchiectasis to either dornase alfa or placebo over a
24-week period (and remains the largest therapeutic trial in non-CF bronchiectasis to date) [42].
Pulmonary exacerbations were more frequent, and FEV1 decline was greater in patients who
received dornase alfa.
The reasons for this difference in response between patients with CF and non-CF bronchiectasis
remain unclear. The biological rationale for the use of dornase alfa in non-CF bronchiectasis was
strong, but the unexpected detrimental finding highlights the importance of performing welldesigned studies that address the therapeutic options for non-CF bronchiectasis, rather than
merely extrapolating the results of trials involving patients with CF.
N-Acetylcysteine, carbocisteine and other thiol derivatives

242
N-Acetylcysteine (NAC) is the classic mucolytic agent, and disrupts the disulfide bonds in mucus
when delivered via the aerosolised route [8]. In addition to reducing sputum viscosity, NAC
demonstrates antioxidant, anti-inflammatory and potentially antibacterial properties [4345].

NAC exhibits extremely low bioavailability, and is not readily detectable in bronchoalveolar lavage
fluid following oral administration [46]. Thus the mechanism of action of oral NAC is unlikely to
be mediated via its mucolytic properties. Carbocisteine, although commonly regarded as a
mucolytic, has a mechanism of action that differs from that of the classical mucolytics. Mucus
produced under the action of carbocisteine shows an increase in sialomucin content. Sialomucins,
which are structural components of mucus, influence the viscoelastic properties of mucus [47].
Similar to NAC, carbocisteine also exerts anti-inflammatory actions, and, in pre-clinical studies, it
has been shown to decrease levels of the cytokines interleukin (IL)-6 and IL-8 and reduce
neutrophil influx into the airway lumen [48, 49].
The evidence supporting the use of NAC and thiol derivative in bronchiectasis is even more
limited. There are several studies of oral and inhaled NAC in CF, but most studies have only
evaluated changes in the rheologicaal properties of CF sputum [52]. The few controlled clinical
studies in CF performed to date have consistently shown no clinical benefit [5355].
There are currently no well-designed studies of NAC and thiol derivatives in non-CF
bronchiectasis. This is supported by a Cochrane review, which concluded that there is insufficient
evidence to evaluate the routine use of these agents in non-CF bronchiectasis [56].
P.T. BYE ET AL.
The majority of clinical studies of NAC and thiol derivatives have been performed in chronic
obstructive pulmonary disease (COPD), with conflicting results. The Bronchitis Randomized on
NAC CostUtility Study (BRONCUS), which randomised 523 patients (Global Initiative for Chronic
Obstructive Lung Disease (GOLD) stage 2 and 3) to 600 mg oral NAC daily or placebo, showed that
NAC was ineffective at reducing pulmonary exacerbations and decline in lung function over a 3-year
period [50]. This is in contrast to the large Chinese Preventive Effects on Acute Exacerbations of
COPD with Carbocisteine (PEACE) study, which randomised 709 patients (GOLD stage 2, 3 and 4)
to receive carbocisteine or placebo for 1 year [51]. The primary end-point of exacerbation rate over
the 1-year period was met, with carbocisteine demonstrating a significant reduction in exacerbations
(risk ratio 0.74; 95% CI 0.610.89). The discrepant findings between these two large randomised
controlled trials may have been explained by the different rates of inhaled corticosteroid usage (less in
the PEACE study) and phenotypic differences in COPD across ethnicities.
Bronchodilators
b2-Agonists are commonly prescribed to treat airflow obstruction and bronchial hyperreactivity,
and as an adjunct to physiotherapy in patients with bronchiectasis. Between 20 and 46% of
patients with bronchiectasis display bronchodilator reversibility [57, 58]. b2-Agonists may
facilitate airway clearance by increasing ciliary beat frequency via stimulation of b2-receptors and
downstream increase in cyclic adenosine monophosphate (cAMP) signalling [59]. cAMP is a
regulator of ciliary beat frequency in human airway epithelia [60, 61]. The bronchodilatory effect
of b2-agonists may serve to increase expiratory flow rates and thus enhance cough clearance.
Two small studies have demonstrated that nebulised terbutaline, given immediately prior to
physiotherapy, yields greater sputum production [22, 62], and also improved mucociliary clearance
in a radioaerosal study [62]. Although it seems reasonable and logical that b2-agonists be used to
treat airflow limitation (particularly if objective bronchodilator reversibility is demonstrated), and as
an adjunct to chest physiotherapy in non-CF bronchiectasis, this is currently not supported by the
evidence. The relevant Cochrane reviews found no randomised controlled trials of the use of shortacting or long-acting b2-agonists in non-CF bronchiectasis [63, 64].
Surfactant
243
A thin layer of airway surfactant phospholipid separates the PCL layer and the mucus gel layer,
and effectively functions as a lubricant to facilitate mucus transport [8]. Furthermore, depletion of
the PCL layer leads to entanglement and adhesion of mucus to the underlying epithelial surface.
Surfactant is a potential therapeutic candidate for enhancing mucociliary clearance by reducing
the molecular interactions that bind mucus to the airway. Patients with CF display alterations in
the composition of the pulmonary surfactant system, with a reduction in the surface-active
fractions, such as phosphatidylcholine and phosphatidylglycerol [65, 66]. This suggests that
surfactant dysfunction may contribute to impaired mucociliary function in CF.
Preliminary clinical studies of exogenous surfactant therapy have only been performed in COPD and
CF populations. A single randomised controlled trial of 66 patients with COPD and symptoms of
chronic bronchitis showed that aerosolised surfactant for 2 weeks increased in vitro sputum
transportability, improved FEV1 and forced vital capacity (FVC) by .10%, and reduced gas-trapping
[67]. The result of a phase-2 study of pulmonary surfactant in CF was recently reported in abstract
form. In this placebo-controlled crossover trial, 16 subjects (aged .14 years and with an FEV1 of
.40% pred) were assigned to five doses of nebulised surfactant or five doses of nebulised saline
(0.9%) over a 24-hour period, with a washout period of 2 weeks. Aerosolised surfactant was well
tolerated and not associated with any serious adverse events. No difference in mucociliary clearance
(quantified by radioaerosal labelling) was observed between surfactant and saline (0.9%) treatment.
Humidification
Humidification is commonly used to relieve sputum retention. CONWAY et al. [68] performed a
small crossover study evaluating the role of humidification as an adjunct to chest physiotherapy in
seven subjects with moderate-to-severe bronchiectasis. Humidification with cold water via a jet
nebuliser for 30 minutes prior to chest physiotherapy was compared to chest physiotherapy alone.
Radioaerosal clearance and sputum weight both increased when humidification was performed
prior to chest physiotherapy.
In a recent study of REA et al. [69], long-term domiciliary humidification was evaluated in a
randomised placebo-controlled trial. A total of 108 subjects with COPD (n563) or bronchiectasis
(n545) were randomly assigned to humidification or usual care for 12 months. Fully saturated
humidified air at 37uC was delivered via nasal cannulae at a flow rate of 2025 L?min-1 via a
humidifier and flow source. Patients were encouraged to use humidification for o2 hours?day-1.
The primary end-point of the study, exacerbation frequency during the study period, was
nonsignificant but showed a trend favouring the humidification group (3.36 versus 2.97; p50.067).
However, patients on long-term humidification therapy showed significantly fewer exacerbation
days and increased time to first exacerbation compared to usual care. Quality-of-life scores and lung
function had also improved significantly with humidification therapy at 3 and 12 months. The
authors hypothesised that improvement in mucociliary clearance with humidification was one of the
main mechanisms accounting for the observed benefit. The limitations of this study include the
absence of a placebo, which resulted in subjects and investigators being unblinded to the
intervention assignment. The study population included both COPD and bronchiectasis, which are
clearly two very distinct disorders. Compliance with therapy was poor (mean 1.6 hours?day-1), but,
despite this, the secondary outcomes of the study were still significantly in favour of humidification
therapy. The high flow rate of the humidification system was equivalent to the delivery of 1
3 cmH2O of positive end-expiratory pressure (PEEP). PEEP, even at this low pressure, may by
physiologically relevant in reducing the work of breathing by offsetting intrinsic PEEP, recruiting
alveolar units to improve ventilation/perfusion matching and providing partial stabilisation of the
upper airway if used during sleep. Thus the mechanisms via which long-term high flow
humidification might be beneficial in obstructive airways disease remain uncertain.
Conclusion
244
Bronchiectasis is increasingly recognised as a major cause of respiratory morbidity. Research projects

are required in order to establish therapies for this under-investigated, under-recognised and
undertreated disease. Such trials should focus on the experimental agents effects on quality of life,
use of healthcare resources and participation. Hypertonic saline, NAC and carbocisteine are
promising candidates for such trials. There is proof of concept for the use of bronchodilators in
combination with physiotherapy, but trials with clinically important outcome measures are needed.
Mannitol appears effective, but clinicians must await publication of the full results of the most recent
trials and commercial availability of the dry powder formulation. Humidification also appears
effective. Dornase alfa has detrimental effects and should not be used in non-CF bronchiectasis.
M.R. Elkins has received financial assistance for travel to the European Cystic Fibrosis Conference
from Praxis Pharmaceuticals.
245

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Chapter 17
Surgery for
bronchiectasis
D.C. Mauchley* and J.D. Mitchell*,#
SURGICAL MANAGEMENT
Summary
Surgical resection for bronchiectasis should be reserved for
patients with localised disease who have failed medical
management and have persistent symptoms that negatively
affect their quality of life. Patients with unilateral segmental
disease have the best outcomes. The key to successful surgical
intervention includes: 1) complete resection of all affected areas;
2) relatively early intervention to prevent development of
resistant organisms and spread to adjacent lung segments; 3)
pre-operative targeted antimicrobial therapy based on in vitro
sensitivities; 4) continuation of antimicrobial therapy postoperatively; 5) pre-operative nutritional supplementation when
indicated; and 6) anticipation of potential complications that
may alter the surgical approach. Surgical resection can be
accomplished with minimal morbidity and mortality and it
can usually be completed with a video-assisted thoracoscopic
approach. The only surgical option for diffuse bronchiectasis is
bilateral lung transplantation and is mainly employed when
treating patients with cystic fibrosis.
Keywords: Bronchiectasis, lobectomy, lung transplantation,
pulmonary infections, segmentectomy, video-assisted thoracic
surgery
*Dept of Surgery, Division of

Cardiothoracic Surgery, Section of
General Thoracic Surgery and Center
for the Surgical Treatment of Lung
Infections, University of Colorado
Denver, Aurora, and
#
National Jewish Health, Denver, CO,
USA.
Correspondence: J.D. Mitchell,
Section of Thoracic Surgery, Division
of Cardiothoracic Surgery, C-310,
University of Colorado, Denver
School of Medicine, 12631 E. 17th
Avenue, C310, Aurora, CO 80045,
USA, Email
john.mitchell@ucdenver.edu
Eur Respir Mon 2011. 52, 248257.

Copyright ERS 2011.
ISSN: 1025-448x.
DOI: 10.1183/1025448x.10004710
ince its first description by LAENNEC [1] in 1819, bronchiectasis continues to be recognised as a
cause of considerable respiratory illness. This disease is characterised by abnormal dilation of
bronchi and is usually the result of recurrent pulmonary infections. Patients suffer from chronic
cough, excessive sputum production, a progressive decline in respiratory function and haemoptysis that can be life threatening. The majority of patients can be treated medically, but those
that fail or become intolerant of medical treatment may be eligible for surgical management.
248
Initial attempts at surgical treatment of bronchiectasis were fraught with complications. Postoperative bronchopleural fistula (BPF) and empyema occurred in f50% of cases [2, 3].
Perioperative mortality was as high as 46% [3]. By 1950, the introduction of effective antibiotics in
addition to improvements in surgical technique led to a dramatic decline in perioperative morbidity
and mortality. Currently, surgical intervention is mainly reserved for patients with focal disease that
remain symptomatic despite optimal medical management. Diffuse bronchiectasis may be treated
with bilateral lung transplantation and is mainly limited to patients with cystic fibrosis (CF).
General principles
Once thought to be in decline, the incidence of non-CF related bronchiectasis is now felt to be on
the rise in North America and throughout the world [4]. Patients present with recurrent
pulmonary infections accompanied by copious sputum production and occasional bouts of
haemoptysis. Traditional treatment paradigms have consisted of rotating schedules of targeted
antibiotic therapy along with manoeuvres to promote secretion clearance. Surgical resection for
bronchiectasis is reserved for patients who demonstrate disease progression despite optimal
medical treatment, or become intolerant of medical therapy. Failure of such treatment represents
the most common reported indication for surgical resection [513].
The basic concept behind surgical resection for bronchiectasis is to remove permanently damaged
areas of lung parenchyma that antibiotics penetrate poorly, and thus serve as a reservoir for
microbes leading to recurrent infection. Resection of diseased segments will alter the pattern of
repeated bouts of infection, and provide significant symptom relief regarding cough and excess
sputum production. Patients with concomitant cavitary lung disease or recurrent bouts of
haemoptysis may also benefit from surgery.
Medical therapy should always be attempted prior to entertaining the idea of surgery as the vast
majority of patients will improve. There have not been any prospective randomised trials
comparing the short- or long-term efficacy of medical treatment and surgery [15]. However,
retrospective studies comparing patients requiring hospitalisation treated either medically or
surgically found that those in the surgical group were more likely to be symptom-free at the time
of follow-up. They also had fewer yearly hospital days and an overall trend toward decreased
mortality [16, 17].
Pre-operative assessment
Patients with bronchiectasis most commonly present with recurrent pulmonary infections.
Symptoms associated with these infections include productive cough, foul-smelling sputum,
haemoptysis, fever and dyspnoea on exertion. The presence of a nonproductive cough is
suggestive of upper lobe involvement. Adequate pulmonary reserve is determined through
standard pre-operative pulmonary function testing and occasionally split function perfusion
testing when appropriate.
D.C. MAUCHLEY AND J.D. MITCHELL
The ideal candidate for surgical therapy should have truly localised disease that is amenable to
anatomic lung resection. Non-anatomic (wedge) resections should be avoided if possible as this
strategy frequently results in incomplete removal of the affected area. Incomplete resection has
overwhelmingly been found to be the greatest predictor of symptomatic failure in these patients
[5, 7, 8, 10, 1214]. The diseased areas of lung tend to contribute little to the patients overall lung
function, thus supporting an aggressive surgical approach.
249
The diagnosis and location of bronchiectasis is made using standard radiographic techniques.
Chest radiographs are often abnormal demonstrating focal areas of consolidation, atelectasis
and occasional evidence of thickened bronchi. High-resolution computed tomography
(HRCT) scanning has replaced contrast bronchography as the gold standard for radiologic
diagnosis of bronchiectasis. This imaging modality can detect the distribution of bronchiectatic
alterations with only 2% false-negative and 1% false-positive rates [18]. Findings suggestive of
the disease include bronchial dilation such that the internal diameter of the affected bronchus
is greater than the accompanying bronchial artery, and a lack of bronchial tapering on
sequential slices [4]. The extent of disease seen on HRCT scans has been correlated to quality
of life and subsequent functional decline [19, 20]. The left lung is more commonly affected
than the right and the dependent lower lobes tend to harbour more disease than the upper
lobes (fig. 1). Middle lobe and lingular disease is often associated with nontuberculous
a)
mycobacterial disease (fig. 2). Upper

lobe involvement is suggestive of
CF or allergic bronchopulmonary
aspergillosis.
Bronchoscopy is performed preoperatively, primarily to identify
the offending organisms and to rule
out concomitant endobronchial pathology. When patients present with
active haemoptysis, bronchoscopy
can be utilised to localise the source
within the bronchial tree to the
segmental or even subsegmental
level. Sputum and bronchoalveolar
lavage specimens are collected to
allow identification of the microbial
pathogens involved. Culture results
should include in vitro susceptibility
testing appropriate for the cultured
organism to assist in pre-operative
antimicrobial therapy.
SURGICAL MANAGEMENT
b)
Many patients who have been

suffering with chronic lung infections will have lost weight and
can be significantly malnourished
at presentation. If this is the case,
an aggressive pre-operative regimen of nutritional supplementation is recommended. This may
require the placement of a nasojejeunal feeding tube or a percutaneous gastrostomy. We have found
that this is typically not necessary
for those with limited, focal parenchymal disease.
250
At our institution (National Jewish

Health, Denver, CO, USA), we have
employed a multimodality treatment approach where patients appropriate for surgical therapy are
discussed at a weekly multidisciplinary conference attended by
surgeons, pulmonologists and infectious disease physicians with speFigure 1. a) Axial and b) coronal high-resolution computed
cialisation in respiratory infectious
tomography images of a patient with severe left lower lobe
disease. This approach ensures that
bronchiectasis.
the patients receive the appropriate
antimicrobial therapy and assists in
optimal timing of surgical intervention. In fact, the timing of resection should be dependent on the
pre-operative antimicrobial regimen, allowing enough time to produce a bacterial nadir at the time
of surgery. We feel this is critical to minimise the risk profile in the perioperative period.
Surgical technique
A standard anaesthetic technique
utilised for thoracic surgical procedures is employed. Single-lung
ventilation is accomplished with
the use of a double-lumen endotracheal tube, or rarely a single
lumen endotracheal tube with the
use of a bronchial blocker. Early
lung isolation may also limit dispersion of purulent secretions of
uninvolved areas of the lungs. A
thoracic epidural may be placed for
post-operative analgesia when a
thoracotomy is planned. This is
usually not necessary in the event
Figure 2. Axial high-resolution computed tomography image of a
of a thoracoscopic approach, where
patient with right middle lobe and lingular bronchiectasis in the
post-operative analgesia is provided
setting of nontuberculous mycobacterial disease termed Lady
Windermere syndrome.
by intercostal administration of
0.25% bupivicaine at multiple levels
placed at the end of the procedure by the operative team. An arterial line and urinary catheter are
placed and intra-operative fluid administration is limited as with other forms of extensive lung
resection. Extubation at the end of the procedure is planned.
Surgical approach
Bronchoscopy is routinely performed prior to initiation of the surgical procedure, clearing the
airway of secretions to optimise ventilation during the operation. It is important to rule out
bronchial obstruction secondary to a tumour or aspirated foreign body prior to attempting
resection. If severe airway inflammation is found at the time of bronchoscopy, surgical therapy
may be delayed until infection control is optimised. Finally, there is always the possibility that the
patient may have normal variations in bronchial anatomy which would be helpful to know prior
to attempting anatomic resection.
Surgical resection for bronchiectasis is classically approached via lateral thoracotomy, tailored for
the targeted segment or lobe. In the setting of significant disease, a full posterolateral thoracotomy
may be employed. The mobilisation of muscle flaps should be accomplished at the onset of the
thoracotomy, for transposition into the hemithorax later in the case after completion of the
resection. An extrapleural dissection plane, if needed, may be initiated prior to placement of the
rib spreader.
Anaesthesia
251
Several important differences exist between anatomic resection for infectious lung disease and
resection for malignancy. Pleural adhesions are frequently present, and in some cases can be
extensive and vascular in nature. They are typically localised to the involved segment(s) of lung,
but can be scattered throughout the hemithorax. In upper lobe predominant disease, the
adhesions to the overlying parietal pleura can be significant. The presence of dense adhesions can
be predicted on the pre-operative HRCT, but the amount of pleural symphysis is often
underestimated. Pleural adhesions can usually be divided safely with a thoracoscopic approach,
often with improved visibility compared with open thoracotomy. During division of dense
adhesions, care must be taken to avoid adjacent vital structures such as the phrenic nerve or great
vessels.
The bronchial circulation is frequently hypertrophied in cases of longstanding bronchiectasis, and

particular care must be taken to assure haemostasis. Bronchial arteries should be ligated with clips
if enlarged. Significant lymphadenopathy is also usually present, and in the setting of chronic
granulomatous disease can make dissection at the pulmonary hilum and around vessels hazardous.
When dividing pulmonary fissures with stapling devices, we advocate a line of division just on the
side of the uninvolved lobe. This will assure complete resection and will avoid a staple line in
infected, devitalised tissue.
SURGICAL MANAGEMENT
The pulmonary vessels and bronchus are divided and sealed using standard stapling devices. Once
the resection is completed, the diseased segment or lobe should be placed in a bag for removal,
unless the thoracotomy is generous enough to avoid contamination with the specimen. In the
setting of routine cases of anatomic resection for bronchiectasis, we typically do not buttress the
bronchial closure with autologous tissue. The intrathoracic space is irrigated and then drained
with one or two 28 French thoracostomy tubes. Portions of the specimen are sent for culture, and
the remainder for pathologic analysis.
Despite the fact that the majority of published series [510, 12, 16] of surgery for bronchiectasis
describe resection using an open (thoracotomy) approach, a video-assisted thoracoscopic (VATS)
approach has been successfully employed in some studies, and is the preferred approach at our
institution [21, 22]. A standard VATS technique uses two 10-mm ports and a 4-cm utility incision
centred over the anterior hilum. No rib spreading is used with this technique. The two 10-mm
ports are placed first with one in the seventh intercostal space in the anterior axillary line, and the
other just posterior to the scapular tip. Once the feasibility and safety of a VATS approach are
confirmed, the utility incision is then made. We employ a wound protector for the utility incision
to avoid contamination and retract the soft tissues of the chest wall. Modifications can be made to
this technique to better serve the specifics of the planned resection. Adhesions are well visualised,
and are typically easier to lyse thoracoscopically, although the presence of dense adhesions or
complete pleural symphysis may suggest conversion to thoracotomy. The planned resection is then
completed in a manner analogous to an open approach.
Use of tissue flaps

Although not routinely performed, tissue transposition should be considered in any patient who is
at increased risk for breakdown of the bronchial stump. Indications for autologous tissue coverage
of the bronchial stump would include poorly controlled infection prior to surgery, resection in the
setting of significant drug resistance or in the rare case of pneumonectomy for bronchiectasis [23].
We favour use of either a latissimus dorsi or intercostal muscle flap for coverage of a bronchial
stump and omentum for use after a right pneumonectomy [24]. We avoid the use of a serratus
muscle flap as there tend to be problems with wound healing in these characteristically thin
patients related to the winged scapula following serratus transposition. Mobilisation of the
latissimus is performed at the initiation of the procedure, and the muscle is transposed through
the second or third intercostal space. When using an omental flap, the omentum is mobilised via a
midline laparotomy prior to thoracotomy and tacked to the undersurface of the right
hemidiaphragm for retrieval later during lung resection. Occasionally, significant intrathoracic
space issues may result after resection, and may be at least partially addressed with latissimus
transposition.
Post-operative management
252
Management of patients after surgery for bronchiectasis is similar to that of any patient who has
undergone anatomic lung resection. Emphasis is placed on early mobilisation, aggressive
pulmonary toilet, chest physiotherapy and nutritional supplementation. Chest tube management
is routine. Appropriate antimicrobial therapy is maintained in the post-operative period and is
often continued for several months, depending on the isolated organism. In patients who present
with bilateral disease and consequently are left with unilateral disease post-operatively, bronchoscopy may be necessary to help with mobilisation and clearance of secretions. Those who are
treated with a thoracoscopic approach can leave the hospital as early as second or third postoperative day, while those who undergo thoracotomy often stay for up to a week.
Complications
Although it is rare, the development of BPF is a source of significant morbidity, particularly

after pneumonectomy. It occurs more commonly on the right side, after completion
pneumonectomy, and in the setting of patients who have persistently positive sputum cultures
for organisms such as multidrug-resistant Mycobacterium tuberculosis [22, 24]. When presented
with a patient at high risk of development of BPF, prevention is paramount. Appropriate
antimicrobial coverage should be given before surgery; a tension-free technique used to close
the bronchus and muscle or omentum used to buttress the closure. Typical findings of a BPF
after pneumonectomy include fever, cough productive of serous followed by purulent sputum,
contralateral lung infiltrates and a dropping airfluid level on chest radiograph. Management
begins with prompt drainage of the infected space to prevent further damage to the remaining
lung. If the BPF is diagnosed very early after resection, primary repair of the bronchial stump
with rebuttressing may be attempted. When diagnosis is delayed management usually requires
rib resection and creation of an Eloesser flap followed by BPF closure and subsequent Clagett
procedure.
As mentioned previously, intrathoracic space problems are somewhat more common after surgery
for bronchiectasis, mainly due to the fact that the remaining lung is often unable to fully expand.
This leaves residual space that is usually not a problem, but can lead to development of empyema
in cases that involve significant pleural soilage or parenchymal injury. Again, prevention is key and
patients with these potential problems should be anticipated. Liberal use of muscle flaps to
minimise the space can help prevent complications.
The complications that accompany lung resection for bronchiectasis mirror those that follow lung
resection for other indications with a few exceptions. Overall morbidity following resection ranges
from 9% to 25% depending on the series. The most common complications after surgery for
bronchiectasis include atelectasis requiring therapeutic bronchoscopy, prolonged air leak, space
problems, empyema, BPF and wound infection (table 1) [5, 713, 22]. Absence of pre-operative
bronchoscopy, forced expiratory volume in 1 second of ,60% of the predicted value and
incomplete resection have all been associated with the development of post-operative
complications [25].
Table 1. Summary of morbidity after surgical resection for bronchiectasis

First author
[ref.]
D OGAN [9]
AGASTHIAN [5]
FUJIMOTO [10]
P RIETO [13]
K UTLAY [12]
B ALKANLI [8]
G URSOY [11]
B AGHERI [7]
Z HANG [22]
Prolonged air Atelectasis Empyema/

leak/space
BPF
issues
0
4.5
5.6
5.9
1.7
2.5
9.8
3.2
2.7
1.4
6.7
6.7
0
2.3
2.9
3.2
3.6
2
1.8
4.5
6.7
0
1.2
1.7
0
3.2
1
Wound Bleeding Arrhythmia Overall

infection
morbidity
7.4
0
0
0
0
0
3.3
5.7
0
0
3
1.1
3.4
1.7
1.7
0
0
1.1
0
2.2
0
3.4
0
0
0
0
4
10.6
24.6
19.6
12.6
11.4
8.8
16.3
15.8
16.2
253
Data are presented as % of all patients in each reference. BPF: bronchopleural fistula.
Table 2. Summary of patient characteristics and operative mortality after surgical management of
bronchiectasis
First author
[ref.]
D OGAN [9]
A GASTHIAN [5]
F UJIMOTO [10]
P RIETO [13]
K UTLAY [12]
B ALKANLI [8]
G URSOY [11]
B AGHERI [7]
Z HANG [22]
Study period
Patients n
19761988
19761993
19901997
19881999
19902000
19922001
20022007
19852008
19892008
487
134
90
119
166
238
92
277
790
Age years
25.5
48
44.7
42.2
34.1
23.7
38.7
34.7
41.6
(256)
(489)
(975)
(1177)
(770)
(1548)
(1067)
(865)
(679)
Males
Left-sided
disease
Complete
resection
Operative
mortality
57
41
49
40
45
86
41
72
59
64
Not stated
59
Not stated
59
Not stated
74
70
Not stated
Not stated
80.6
83.3
90.8
88.5
64.7
90.2
82.7
89
3.5
2.2
0
0
1.7
0
1.1
0.7
1.1
Data are presented as mean (range) or %, unless otherwise stated.
SURGICAL MANAGEMENT
Results
Perioperative mortality after resection for bronchiectasis is very low with contemporary rates
ranging from 0% to 3.5% (table 2). Completion pneumonectomy remains a highly morbid
procedure and leads to many of the deaths related to surgical treatment of this disease [5, 24].
Renal failure and advanced age (.70 years) are associated with post-operative mortality in this
group of patients [22]. Mean age at the time of surgery ranges from 25.5 to 48 years and more
female patients seem to be affected than male patients. Female predominance is not as consistent
in reports from developing countries [79, 22]. The most common indication for surgical
intervention is failure of medical therapy. Left-sided disease predominates and complete resection
of disease is usually possible 8090% of the time. The most commonly performed procedure is
lobectomy, followed by segmentectomy, lobectomy with segmentectomy, and pneumonectomy.
Very few patients undergo bilobectomy for bronchiectasis (table 3). The most common reported
reason for incomplete resection is bilateral disease, although the majority of these patients should
be candidates for contralateral resection at a later date. The vast majority of patients are either
asymptomatic or are symptomatically improved at follow-up (table 4). Lack of symptomatic
improvement is most commonly associated with incomplete resection [5, 7, 8, 10, 12, 13, 22, 25],
but has also been associated with saccular bronchiectasis, history of sinusitis and tuberculous
infection [10, 22].
The results of VATS lung resection for bronchiectasis have been examined in two studies in the last
decade. WEBER et al. [26] described thoracoscopic lobectomy using five trocars with subsequent
mini-thoracotomy in 76 patients with benign lung disease. 49 of the patients had bronchiectasis or
Table 3. Summary of operative procedures performed for the surgical management of bronchiectasis
First author
[ref.]
D OGAN [9]
A GASTHIAN [5]
A SHOUR [6]
F UJIMOTO [10]
P RIETO [13]
K UTLAY [12]
B ALKANLI [8]
G URSOY [11]
B AGHERI [7]
Z HANG [22]
Lobectomy
Pnemonectomy
Segementectomy/
wedge
41.5
64.2
64.7
54.3
62
63.4
79.4
39.1
42.2
62.9
39
15.7
16.5
6.5
8
7.5
5.5
10.9
7.9
11.3
0
13.4
18.8
33.7
13
12.2
2.1
Not stated
6.5
4.7
254
Data are presented as % of total resections for each reference.
Lobectomy + Bilobectomy
segment
14.8
6.7
0
0
14
10.5
13
34.8
23.5
14
4.7
0
0
5.4
3
6.4
0
Not stated
19.9
7.1
Table 4. Summary of pulmonary symptoms after surgical resection for bronchiectasis

First author
[ref.]
D OGAN [9]
A GASTHIAN [5]
A SHOUR [6]
F UJIMOTO [10]
P RIETO [13]
K UTLAY [12]
B ALKANLI [8]
G URSOY [11]
B AGHERI [7]
Z HANG [22]
Mean follow-up
time years
% Follow-up
Asymptomatic
Symptomatic
improvement
No change in
symptoms/worse
4.6
6
3.8
6.1
4.5
4.2
0.75
1.3
4.5
4.2
Not stated
76.9
100
87.8
90.8
89.2
96.2
81.5
100
89.4
71
45.5
74.1
40
61.3
66.9
79.4
68.5
68.5
60.5
Not stated
22.4
22.4
33.3
26.1
18.7
12.2
8.7
23.8
14.1
Not stated
9
3.5
14.5
3.4
3.6
4.6
4.3
7.5
14.8
chronic lung infection. The mortality rate was 0%, morbidity rate was 18.7% and 12 (15.3%) cases
were converted to open procedure. Reasons for conversion to open procedure included dense
adhesive disease as well as upper lobe-predominant disease. Compared with those who underwent
open thoracotomy during the same time period, patients undergoing VATS resection suffered
fewer post-operative complications, had less blood loss and a shorter hospital stay. More recently,
ZHANG et al. [27] reported 52 patients who underwent VATS lobectomy using two 12-mm trocars
and a 45-cm incision. Overall, they had similar findings with no mortality, a morbidity rate of
15.4% and conversion to thoracotomy in 13.5% of patients. Furthermore, those who were treated
with a VATS approach had less morbidity and a shorter hospital stay compared with a cohort of
patients who underwent open thoracotomy for resection during the same time period. Pain scores
based on an 11 point pain scale were also lower in the VATS group. The conclusions of both
reports were that benign lung disease, including bronchiectasis, could feasibly be resected using a
VATS approach with negligible mortality and lower morbidity than with thoracotomy.
Lung transplantation
Lung transplantation in patients with bronchiectasis is only indicated for those with diffuse disease
that is not amenable to segmental surgical resection and declining lung function despite maximal
medical therapy. The vast majority of transplants for bronchiectasis are performed on patients with
CF. Bronchiectasis develops in nearly all cases of CF and leads to chronic cough, expectoration of
abnormal mucus, progressive airflow obstruction and persistent respiratory tract infections. Those
with advanced bronchiectasis have poor quality of life and are at increased risk of death secondary to
declining lung function. Lung transplantation has been shown to both improve quality of life and
prolong survival in appropriately selected patients with advanced bronchiectasis [28, 29].
Data are presented as % of all patients (including those lost to follow-up) from each reference, unless otherwise
stated.
CF is the third most common indication for which lung transplantation is performed [30]. The
current recommendation is for bilateral lung transplant in those with suppurative lung disease
secondary to CF, even in those with heterogeneous disease. Single lung transplantation would risk
contamination of the new graft by the old lung in an immunocompromised patient. Some centres
will perform a single lung transplant in conjunction with contralateral pneumonectomy to avoid
this risk.
255
The guidelines for referral of patients with CF and bronchiectasis for transplantation are listed in
table 5 [30]. Additionally, patients should be considered for transplantation if there is a ,50%
likelihood of survival over 2 years without transplant, if quality of life is likely to be improved as a
result of transplant, there are no contraindications to transplant, and they are informed of the risks
and benefits of the operation and committed to proceeding with evaluation and listing. Young
females with CF are considered for early referral if they suffer rapid deterioration in pulmonary
Table 5. Guidelines for lung transplantation in diffuse bronchiectasis (both cystic fibrosis and non-cystic
fibrosis)
Guidelines for referral to
a transplant centre
Guidelines for transplantation
FEV1 ,30% predicted or a rapid decline in FEV1, particularly

in young female patients
Exacerbation of pulmonary disease requiring ICU stay
Increasing frequency of exacerbations requiring antibiotic therapy
Refractory and/or recurrent pneumothorax
Recurrent haemoptysis not controlled by embolisation
Progressive decline in lung function
Oxygen-dependent respiratory failure
Hypercapnia
Pulmonary hypertension
FEV1: forced expiratory volume in 1 second; ICU: intensive care unit.
SURGICAL MANAGEMENT
status as they have a particularly poor prognosis [30]. Finally, several studies in the 1990s
described infection with Burkholderia cepacia in prospective CF transplant candidates to be
associated with significant post-transplantation infectious complications and poor outcomes
[31, 32]. This has led to the presence of B. cepacia infection to be a relative contraindication
to lung transplantation in the CF population, although some centres continue to offer
transplantation therapy in this setting. More recent evidence suggests that some, but not all
subspecies within the B. cepacia complex confer an increased risk [33].
A number of complications may occur after lung transplantation for CF and bronchiectasis,
including haemorrhage, pulmonary oedema, primary graft dysfunction, anastomotic dehiscence and
various infectious complications. Bacterial infections are common after transplant for bronchiectasis
as numerous pathogens chronically dwell in respiratory tract secretions of these patients. Antibacterial regimens guided by pre- and perioperative cultures are used post-operatively in addition to
standard prophylactic medications given for viral and fungal pathogens [34].
Patients with CF and bronchiectasis can expect a dramatic improvement in pulmonary function
after lung transplant as well as the ability to perform activities of daily living without limitations.
Long-term survival has been demonstrated in a review of 123 patients with CF who underwent
either bilateral lung transplantation or bilateral lower lobe transplant from living donors [35].
Survival rates were 81% at 1 year, 59% at 5 years and 38% at 10 years. A sustained improvement
in quality of life after transplantation can be expected for at least 13 years [34].
Transplantation for non-CF bronchiectasis is rare and specific referral guidelines have not been
developed. For this reason, the guidelines used for those with CF bronchiectasis are generally used [30].
None declared.
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20. Sheehan RE, Wells AU, Copley SJ, et al. A comparison of serial computed tomography and functional change in
21. Mitchell JD, Bishop A, Cafaro A, et al. Anatomic lung resection for nontuberculous mycobacterial disease. Ann
Thorac Surg 2008; 85: 18871892.
22. Zhang P, Jiang G, Ding J, et al. Surgical treatment of bronchiectasis: a retrospective analysis of 790 patients. Ann
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23. Shiraishi Y, Nakajima Y, Katsuragi N, et al. Pneumonectomy for nontuberculous mycobacterial infections. Ann Thorac
Surg 2004; 78: 399403.
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Cardiovasc Surg 2005; 129: 12581265.
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bronchiectasis. J Thorac Cardiovasc Surg 2007; 134: 392398.
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cases. Eur J Cardiothorac Surg 2001; 20: 443448.
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Chapter 18
Conclusions and
future developments
R.A. Floto
Correspondence: R.A. Floto, Cambridge Institute for Medical Research, University of Cambridge, Addenbrookes Hospital, Hills Road, Cambridge, CB2
0XY, UK, Email: arf27@cam.ac.uk
FUTURE DEVELOPMENTS
his Monograph represents a state-of-the-art review of non-cystic fibrosis (CF)

bronchiectasis and highlights many recent advances in our understanding of this condition
and how best to manage it. However, it is clear, that many important unanswered questions
remain about the patho-physiology, investigation and treatment of bronchiectasis. The management of these patients remains hampered by a paucity of clinical trial evidence which, through
necessity, requires us to draw on potentially misleading data from CF or chronic obstructive
pulmonary disease studies. Furthermore, inadequate education and training of physicians remain
barriers to optimal delivery of care to patients with non-CF bronchiectasis, something which this
Monograph may hopefully begin to address.
There are a number of potential future developments, discussed below, which may significantly
contribute to our understanding of why non-CF bronchiectasis develops in particular individuals, how to best investigate possible aetiological factors and how to optimally manage these
patients.
Why does bronchiectasis develop?

As described in the chapter by BILTON and JONES [1], a large number of conditions leading to
impaired host immunity and/or defective muco-ciliary clearance have been implicated in the
development of non-CF bronchiectasis. However, using established investigative approaches,
outlined by DRAIN and ELBORN [2], we are currently unable to define an obvious triggering cause in
a large percentage of adults with bronchiectasis.
Immunity and inflammation

Developments in our understanding of the mechanisms controlling lung inflammatory and
immune responses [3] and their resultant effects on lung tissue [4] may allow researchers to focus
on specific critical host responses that may qualitatively or quantitatively vary within a population
predisposing particular individuals to bronchiectatic lung damage. Future developments in
immunological testing [2, 5] may focus on identifying aberrant responses in patients immune
cells to inflammatory or infective stimuli. Furthermore, more detailed analysis of patients with
bronchiectasis associated with inflammatory bowel disease [6] and systemic autoimmunity [7]
may provide important insights into how aberrant immunological responses might lead to
bronchiectasis.
258
Eur Respir Mon 2011. 52, 258261. Printed in UK all rights reserved, Copyright ERS 2011. European Respiratory
Monograph; ISSN: 1025-448x. DOI: 10.1183/1025448x.10004810
Microbiology
A better understanding of the role of bacteria and how they interact with epithelial cells
and viruses [8] is likely to permit more targeted treatments and more effective prophylaxis.
Nonculture-based microbial detection methods [9] are likely to provide mechanistic insights into
the possible protective role of commensal microbial flora, the role of anaerobic and intracellular
organisms and the dynamic interplay between bacterial species in specific lung niches. For fungal
diseases [10] and nontuberculous mycobacterial infection [11], future research into the basic
mechanisms of disease may permit development of novel diagnostic tools and more effective
treatment strategies.
Mucociliary clearance
Recent work has suggested that nonclassical or secondary ciliary dysfunction [12] and epithelial
channel mutations [13] may be important determinants in compromising mucociliary clearance
(MCC) and, thus, predisposing to bronchiectatic damage. Novel developments in lung imaging [14], including quantification of global and regional MCC, may permit more detailed
investigation of bronchiectasis patients and assessment of the impact of specific physiotherapy
techniques and mucolytic therapies.
Novel genetic approaches
1) Genome-wide association scans (GWAS) may, as in other conditions [15], identify novel
disease-associated, single-nucleotide polymorphisms and potentially uncover critical pathways
involved in bronchiectasis in an unbiased, hypothesis-free way. Challenges in undertaking
GWAS studies include the large number of patient DNA samples required (usually several
thousand), as well as the problem of multiple initiators for the development of bronchiectasis
leading to reduced signal discrimination.
R.A. FLOTO
There are potentially three ways in which new developments in genetics might be exploited to
better understand the patho-physiology of non-CF bronchiectasis.
2) Candidate gene approaches could also be used to identify diseased-associated polymorphisms in

more well defined subsets of patients. Obvious candidates would include known genetic modifiers
of CF [16], genes involved in lung inflammation and those encoding proteins that are critical for
epithelial cell function.
3) Whole exome analysis using massive parallel sequencing can now permit rapid sequencing
of the entire expressed genome of individuals [17], potentially permitting detection of gene
mutations in small cohorts of patients with familial disease.
Can we improve the treatment of patients with non-CF

bronchiectasis?
It is reasonable to anticipate a number of future developments which may impact on the
management of patients with non-CF bronchiectasis.
New antibiotic strategies
259
As highlighted in the chapter by HAWORTH [18], the development of new nebulised or inhaled
formulations of single or combination antibiotics may significantly impact on our ability to
provide adequate prophylaxis for patients. In addition, a number of novel approaches are being
developed for the treatment of Pseudomonas aeruginosa which may prove useful, including novel
b-lactamase inhibitors, blockers of bacterial efflux pumps (which normally remove otherwise toxic
antibiotics), antimicrobial peptides and species-specific bacteriophage-based therapy [19].
Novel anti inflammatory agents

As discussed in the chapter by SMITH et al. [20], anti-inflammatory therapy may be of considerable
benefit in bronchiectasis. Novel agents that may have a future role include nonantibiotic macrolides,
HMG-CoA inhibitors (statins) and peroxisome proliferator-activated receptor-c agonists. The
difficulty will be to balance control of inflammation with compromise of host defence.
Mucolytic strategies
The potential benefits of improved airway clearance [21] are likely to be vast. Future therapies that
reduce mucus viscosity (by altering mucin production or blocking subsequent cross-linking),
increase airway-surface liquid (through osmosis or altered epithelial channel activity) or improve
ciliary function may all have potential benefit.
Surgery and lung repair
260
FUTURE DEVELOPMENTS
More research will be needed to define the precise role of surgery in the management of non-CF
bronchiectasis [22]. Anticipated improvement in surgical techniques and reductions in perioperative morbidity will impact on when surgery in considered and in whom. Future
developments in stem cell biology (including studies re-programming induced pluripotent stem
cells and overcoming engraftment difficulties) may open the door for therapeutic lung repair and
regeneration.
Over the next few years we can optimistically look forward to greater advances in our understanding
of the patho-physiology and genetic determinants of non-CF bronchiectasis, the development of
more sophisticated methods for investigation of patients and an increasing number of clinical trials
focusing on improving evidence-based treatment of this challenging condition.
None declared.
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17. Lehne B, Lewis CM, Schlitt T. Exome localisation of complex disease association signals. BMC Genomics 2011;
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19. Page MG, Heim J. Prospects for the next anti-pseudomonas drug. Curr Opin Pharmacol 2009; 9; 558565.
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52: 239247.
22. Mauchley DC, Mitchell JD. Surgery for bronchiectasis. Eur Respir Mon 2011; 52: 248257.

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Eur Respir Mon 2011. 52, v.

ronchiectasis has been a well-known disease for a long time. Following

Keywords: Aetiology, bronchiectasis, epidemiology, non-cystic

*Dept of Cystic Fibrosis, Royal

D. BILTON AND A.L. JONES

Bronchiectasis remains a significant cause of morbidity and

Eur Respir Mon 2011. 52, 110.

EPIDEMIOLOGY AND CAUSES

The lungs are continuously exposed to

Structural lung conditions

Table 1. Aetiology of bronchiectasis

D. BILTON AND A.L. JONES

Inflammation within the bronchial wall

GERD: gastro-oesophageal reflux disease; COPD: chronic

WilliamsCampbell syndrome was first

MounierKuhn syndrome (tracheobronchomegaly) is characterised by dilatation of the trachea

Obstructive airways disease

EPIDEMIOLOGY AND CAUSES

Defects of mucociliary clearance

Primary ciliary dyskinesia

D. BILTON AND A.L. JONES

Secondary ciliary dyskinesia

Allergic bronchopulmonary aspergillosis

EPIDEMIOLOGY AND CAUSES

Common variable immune deficiency

Chronic granulomatous disease

Antibody deficiency with normal Igs

A number of childhood respiratory infections have been implicated in the pathogenesis of

Nontuberculous mycobacterial infection

D. BILTON AND A.L. JONES

Bronchiectasis in systemic diseases

The development of bronchiectasis in patients with ulcerative colitis is a well recognised

Connective tissue diseases

EPIDEMIOLOGY AND CAUSES

Yellow nail syndrome

D. BILTON AND A.L. JONES

EPIDEMIOLOGY AND CAUSES

Over recent years there has been a tremendous increase in the

Keywords: Bronchiectasis, inflammatory mechanisms,

*Dept of Pulmonary Medicine,

B.N. LAMBRECHT ET AL.

Eur Respir Mon 2011. 52, 1121.

ronchiectasis is a chronic disorder characterised by permanent dilatation of the bronchi

Mechanical and physical pulmonary defence mechanisms

PULMONARY DEFENCE AND IMMUNITY

Humoral innate immune mechanisms in the lung

Cellular innate immune mechanisms in the lung

B.N. LAMBRECHT ET AL.

PULMONARY DEFENCE AND IMMUNITY

Induction of innate immune responses in the lung

Adaptive cellular immunity

B.N. LAMBRECHT ET AL.

Induction of adaptive cellular immunity by DCs

Constituents of adaptive cellular immunity

complex helminths, and at the same

The precise signals that induce

PULMONARY DEFENCE AND IMMUNITY

Figure 2. T-cell polarisation induced by dendritic cells (DCs) and

Humoral immune mechanisms in the lung

B.N. LAMBRECHT ET AL.

Organised lymphoid structures and bronchiectasis

The organised accumulation of lymphocytes in lymphoid organs serves to optimise both

PULMONARY DEFENCE AND IMMUNITY