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PM11CH20-Boyton ARI 23 February 2016 13:8
Review in Advance first posted online

V I E W
E on March 2, 2016. (Changes may
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still occur before final publication
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online and in print.)
C E
I N
A
D V A
Bronchiectasis: Current
Concepts in Pathogenesis,
Immunology, and Microbiology
Annu. Rev. Pathol. Mech. Dis. 2016.11. Downloaded from www.annualreviews.org
Access provided by University of Pittsburgh on 03/04/16. For personal use only.
Rosemary J. Boyton1,2 and Daniel M. Altmann3

1
Lung Immunology Group, Department of Infectious Diseases and Immunity, Imperial College
London, London W12 0NN, United Kingdom; email: r.boyton@imperial.ac.uk
2
Department of Respiratory Medicine, Royal Brompton & Harefield NHS Foundation Trust,
London SW3 6NP, United Kingdom
3
Division of Immunology and Inflammation, Department of Medicine, Imperial College
London, London W12 0NN, United Kingdom
Annu. Rev. Pathol. Mech. Dis. 2016. 11:52354 Keywords

The Annual Review of Pathology: Mechanisms of lung, immunity, bacterial infection, microbiota
Disease is online at pathol.annualreviews.org
This articles doi: Abstract

10.1146/annurev-pathol-012615-044344
Bronchiectasis is a disorder of persistent lung inflammation and recur-
Copyright c 2016 by Annual Reviews. rent infection, defined by a common pathological end point: irreversible
All rights reserved
bronchial dilatation arrived at through diverse etiologies. This suggests an
interplay between immunogenetic susceptibility, immune dysregulation,
bacterial infection, and lung damage. The damaged epithelium impairs
mucus removal and facilitates bacterial infection with increased cough,
sputum production, and airflow obstruction. Lung infection is caused by
respiratory bacterial and fungal pathogens, including Pseudomonas aerugi-
nosa, Haemophilus, Aspergillus fumigatus, and nontuberculous mycobacteria.
Recent studies have highlighted the relationship between the lung micro-
biota and microbial-pathogen niches. Disease may result from environments
favoring interleukin-17-driven neutrophilia. Bronchiectasis may present in
autoimmune disease, as well as conditions of immune dysregulation, such as
combined variable immune deficiency, transporter associated with antigen
processingdeficiency syndrome, and hyperimmunoglobulin E syndrome.
Differences in prevalence across geography and ethnicity implicate an etio-
logical mix of genetics and environment underpinning susceptibility.
523
Changes may still occur before final publication online and in print
INTRODUCTION
Bronchiectasis is an obstructive lung disease that presents with chronic cough and sputum pro-
duction, recurrent bacterial infection, tiredness, and progressive lung damage. It is the result of
a complex interplay between host immunity, pathogen, and environment. The common patho-
logical correlate is bronchial wall dilatation and thickening. High-resolution computed tomogra-
phy (HRCT) of the thorax is the radiological investigation of choice to establish a diagnosis of
bronchiectasis (1). Bronchiectasis is, in essence, a pathological end point consisting of abnormal,
permanent dilatation of the bronchi and airway obstruction, as identified in lung-function studies
(24). This end point can be reached by many different routes (Table 1).
About 50% of individuals with bronchiectasis have no obvious or easily definable underlying
etiology (5). Disease in this group has been termed idiopathic, but it might better be termed
patho-inflammatory because there appears to be dysfunctional host immunity to viral, bacterial,
or fungal species, leading to chronic inflammation, lung remodeling, and lung damage associated
with recurrent infection and impaired pathogen clearance.

Bronchial wall dilatation was first described in 1819 by Laennec (6), and the term bronchiec-
tasis was introduced in Swaines 1846 translation of Hasse (7). With the advent of radiological
techniques in the 1920s, it became possible to diagnose less severe cases: Wall & Hoyle (8) de-
scribed 20 cases of bronchiectasis. A common finding was a clinical history of severe pneumonia
following measles, whooping cough, or influenza in childhood or young adulthood.
The current model of bronchiectasis pathophysiology originates with Coles vicious cycle
hypothesis (9). Cole described how chronic bronchial sepsis depended on an initially compro-
mised mucociliary clearance that allowed certain microbes to colonize the airway through their
ability to release factors that inhibit and damage the ciliated epithelium. Once established, this
microbial colonization prompted the host to respond with a nonspecific and immune inflamma-
tory responses that failed to clear the microbial flora but damaged the innocent bystander lung.
This further compromised bronchial clearance mechanisms in a vicious cycle of events with the
end result of progressive lung damage (10).
This hypothesis was proposed at a time when it was believed that the healthy lung was sterile
and before the relationship between the microbiota and host immunity had been considered (11
17). Nevertheless, the description of a perpetual cycle of recurrent or chronic lung infection,
progressive lung damage, and a persistent inflammatory response has served as a useful model on
which to incorporate current concepts (Figure 1).
The precise incidence, prevalence, and economic impact of bronchiectasis, both in terms lost
working days and health-care costs, are unknown and likely to be underestimated. There is con-
siderable variation in the documented incidence of bronchiectasis across ethnic groups. A high
prevalence has been reported in Alaskan Native children in the YukonKuskokwim region (11
20.5/1,000 births for the decades 1940 to 1980) (18), in New Zealand Pacific and Maori children
(respectively, 17.8/100,000 and 4.8/100,000) (19), and in central Australian Aboriginal children
(14.7/1,000) (20). These children have recurrent chest infections throughout childhood. These
increased prevalences are likely to arise from environmental factors, but may also indicate specific
immunogenetic susceptibility (21).
Bronchiectasis was common in the United Kingdom after the First World War, with reports
demonstrating that 1.3/1,000 population had bronchiectasis (22). Since then, severe bronchiectasis
has become less common in the West as socioeconomic conditions improved, and vaccination
against tuberculosis (TB), measles, and whooping cough were introduced, as were antibiotics (4).
However, over the past 20 years, studies indicate an increase in the burden of disease in terms
of morbidity and mortality, as evidenced by an increasing prevalence of bronchiectasis-associated
524 Boyton Altmann
Table 1 Underlying causes and associations of bronchiectasis

Cause Association
Idiopathic HLA-C 03 associated with increased susceptibility
HLA-C 06 associated with reduced susceptibility
Postinfectious: severe lower Bordetella pertussis (whooping cough)
respiratory tract infections due to Mycobacterium tuberculosis
pneumonia Nontuberculous mycobacteria (NTM)
Aspergillus species (allergic bronchopulmonary aspergillosis)
Viral (adenoviruses 3, 7, and 21; measles virus; influenza virus; HIV)
Mucociliary clearance defects Primary ciliary dyskinesia
Cystic fibrosis [CF transmembrane regulator (CFTR) mutation]
Youngs syndrome (azoospermia)
Sequelae of inhalation or aspiration Toxic gasses (e.g., chlorine, ammonia)
of toxics, or local bronchial Overdose (e.g., intravenous heroin)

obstruction Foreign body aspiration
External compression
Smoke inhalation
Immunodeficiencies, primary Hypogammaglobulinemia (common variable immune deficiency)
X-linked agammaglobulinemia
Immunoglobulin A deficiency
TAP deficiency syndrome
Specific antibody deficiency (e.g., bacterial capsular polysaccharides)
Immunodeficiencies, secondary Malignancy (e.g., chronic lymphocytic leukemia), chemotherapy, or
immune modulation (after transplantation)
Autoimmune disease Rheumatoid arthritis
Systemic sclerosis
Systemic lupus erythematosus
Ankylosing spondylitis
Sjogrens syndrome
Relapsing polychondritis
Inflammatory bowel disease (ulcerative colitis and Crohns disease)
Allergic hypersensitivity Allergic bronchopulmonary aspergillosis
Congenital conditions MounierKuhn syndrome (tracheobronchomegaly)
WilliamsCampbell syndrome (cartilage deficiency)
Marfans syndrome
EhlersDanlos syndrome
Late-presenting H-type tracheobronchial and esophagobronchial
fistula, lung malformation, or rib malformation
Primary bronchiolar disorders Obliterative bronchiolitis
Diffuse panbronchiolitis
Other Yellow nail syndrome
1-antitrypsin deficiency
Mercury poisoning
Fibrosis (fibrosing alveolitis, sarcoidosis, postirradiation)
Abbreviations: CF, cystic fibrosis; TAP, transporter associated with antigen processing.
www.annualreviews.org Bronchiectasis: Immunity and Microbiology 525
Lung
inflammation
and remodeling
Pathogenic
bacteria compete Neutrophilia
with local and neutrophil
microbiota activation
CD4
Competitive
changes in
Innate microbiome ecology CD8
recognition lead to immune
subset changes
IFN-
IL-17
Activating and
inhibitory KIR
IL-12 HLA-C
IL-18
NK cell
activation
Figure 1
The disrupted microbiota in the vicious cycle of chronic bacterial infection and inflammation in the lung.
Figure modified from Reference 12 with permission from the study authors; John Wiley & Sons, publisher
of Clinical and Experimental Immunology; and Ms. Rachel Scott, Medical Illustrator. Abbreviations: HLA,
human leukocyte antigen; IFN, interferon; IL, interleukin; KIR, killer immunoglobulin-like receptors;
NK, natural killer.
526 Boyton Altmann
hospital care in Germany and the United States (2325). The number of deaths from bronchiectasis
in England and Wales is reported to be increasing by 3% per year and was 1.68/100,000 population
in 2007 (26).
Data on mortality have demonstrated that bronchiectasis shortens life. Loebinger et al. (27)
described detailed, retrospective data from 91 individuals followed for 13 years in a specialist
tertiary referral hospital in London. About 30% died during follow-up (70% from respiratory
complications). The strongest predictors of mortality were age, male sex, colonization of the lung
by Pseudomonas aeruginosa, the ratio of residual volume (RV):total lung capacity (TLC), TLC,
and the transfer coefficient for the lung for carbon monoxide (KCO). Onen and colleagues (28)
followed 98 individuals with bronchiectasis for 4 years in Turkey; survival was 58% at 4 years.
Mortality was highly significantly associated with increasing age, low body mass index (BMI), and
increasing breathlessness. Vaccination against influenza and pneumococci was strongly associated
with improved survival (28). Patients with bronchiectasis associated with chronic obstructive
pulmonary disease (COPD) seemed to be at a significantly increased risk of death compared with
patients with bronchiectasis without COPD (29). A study following 245 newly diagnosed patients
in a specialist bronchiectasis clinic in Belgium found that during a median follow-up period of
5.12 years, mortality was 20.4% (29). The strongest risk factor for mortality was bronchiectasis
associated with COPD. Patients with bronchiectasis and associated COPD had a mortality rate
of 55% (29). Traffic-related air pollution also appeared to increase the risk of dying for patients
with bronchiectasis (30).
As discussed below, infective exacerbations are most commonly caused by Haemophilus influen-
zae and P. aeruginosa. Chronic infection by P. aeruginosa, nontuberculous mycobacteria (NTM),
Aspergillus fumigatus, or a combination of these is associated with accelerated, progressive lung
damage (3134).
Both for research and for clinical practice it is important to have a validated grading system
that can classify the severity of disease according to prognosis (32). Two such scoring systems
have recently been described: the FACED score and the Bronchiectasis Severity Index (BSI) (33,
34). The FACED score [for forced expiratory volume in 1 second (FEV1 ) % predicted, age, the
presence of chronic colonization by P. aeruginosa, radiological extension of disease (number of
lobes affected), and dyspnea (as measured using the Medical Research Councils scale)] predicts
the probability of all-cause 5-year mortality. The FACED score classifies bronchiectasis as mild,
moderate, or severe (33). The BSI score uses nine variables: age, BMI, FEV1 % predicted, number
of hospital admissions during the preceding year, number of exacerbations during the preceding
year, the Medical Research Councils dyspnea score, the presence of colonization with P. aerug-
inosa, colonization with other pathogens, and radiological severity. Individuals are classified as
having low, intermediate, or high BSI scores, and the scoring system identifies individuals at risk
of mortality, hospital admissions, and exacerbations (34).
A detailed summary of the diagnosis and management of bronchiectasis is described in the
British Thoracic Society Guideline for Non-CF Bronchiectasis (1). In brief, the aim is to start by
making the clinical diagnosis, assessing the severity of disease, and establishing whether there is
any known underlying cause. Bronchiectasis should be considered in all patients presenting with
persistent productive cough and recurrent chest infections.
Investigations should include a chest X-ray and HRCT; sputum microscopy culture and an-
tibiotic sensitivity testing, a smear test for acid-fast bacilli, and 8-week mycobacterial culture and
antibiotic sensitivity testing, fungal culture; and lung-function tests measuring lung volumes and
gas transfer, FEV1 , forced vital capacity, peak expiratory flow, RV, TLC, transfer factor of the
lung for carbon monoxide, KCO, and percent oxygen saturation in air.
Blood tests should include tests for serum immunoglobulins (IgG, IgA, and IgM) and serum
electrophoresis, as well as tests for serum IgE, an A. fumigates radioallergosorbent test, and tests
for aspergillus precipitins. Specific antibody levels should also be evaluated against tetanus toxoid
and the capsular polysaccharides of Streptococcus pneumoniae and H. influenzae type B, at baseline
and again if they are low following immunization.
Specialist immune investigation should be considered when there is clinical suspicion or a
family history of immune deficiency and where there is a history of unusual, persistent, severe, or
life-threatening infection. Screening investigations (sweat chloride measurement and analysis of
CFTR genetic mutation) should be carried out to determine a diagnosis of cystic fibrosis (CF). CF
should be considered in everybody up to the age of 40 years and if there is upper lobe disease, male
primary infertility, malabsorption, and persistent Staphylococcus aureus in the sputum in individuals
who are older than 40 years. Ciliary investigations, including the saccharin test and the exhaled
nitric oxide test, may be used to screen individuals to establish whether detailed ciliary function tests
are needed. Clinical features supporting further investigation of ciliary function include chronic
upper respiratory tract symptoms, chronic otitis media, predominantly middle lobe bronchiectasis,
infertility, and dextrocardia. Bronchoscopy is indicated in single lobe disease to exclude foreign-
body or proximal obstruction and in cases in which HRCT suggests NTM infection and sputum
culture is negative.
SPECTRUM OF INFECTIONS
This is a disease driven by a vicious cycle of persistent bacterial infection, leading to a dysregulated
inflammatory environment with accompanying tissue damage and impaired lung function, which
provides a favorable niche for bacterial infection. We consider these component parts, assessing
whether it is possible to gain insights into the entry point at which the cycle is initiated (9, 10).
Is this a disease in which stochastic episodes of respiratory infection work in some individuals to
establish an environment appropriate for perpetuation of the cycle, or is this a disease in which
some individuals are destined to respond abnormally to common respiratory pathogens due to
dysregulated immunity?
A common lesson from analyses of human immune system genotypephenotype correlates is
that although vital insights are gained from studying which microbial pathogens assume promi-
nence as a consequence of defects in any given pathway, the redundancy of the immune system
dictates that the pathogens one expects to dominate may in practice not. Mutations in interferon
(IFN)- receptors were initially noted through identifying a susceptibility to NTM (35). In famil-
ial hemophagocytic lymphohistiocytosis, perforin-deficiency macrophage hyperactivation is seen
rather than susceptibility to viruses (36). Defects in the activation pathways of natural killer (NK)
cells specifically cause susceptibility to herpesviruses (37). In bronchiectasis, we lack a unifying
view of the affected immuneinflammatory pathway. Perplexingly, this is a disease ensuing from
immune dysregulation, but it may involve elements of either immune hyper- or hyporeactivity.
What can be learned, then, by starting from the other end of the puzzle, since we have considerable
information about the most commonly isolated pathogens? This is a relatively finite list and shows
a very high degree of agreement across studies in patient cohorts from different countries.
The appraisal of the microbial spectrum in bronchiectasis, as in any disease, is subject to the
caveat that information can be drawn only from the laboratory tests that are commonly done. There
is considerable information from clinical microbiology, giving a relatively clear picture of the
bacteriology and mycology, with some additional information from analyses of 16S ribosomal RNA
(rRNA) of the wider lung microbiota. Fewer data are available with respect to viral susceptibility
or from serology.
528 Boyton Altmann
Bacterial Infection
Bronchiectasis has long been considered primarily a disease in which there is recurrent and persis-
tent infection, mainly (but not entirely) by gram-negative bacteria, associated with an exaggerated
and unresolving immuneinflammatory response that is predominantly neutrophilic. A compo-
nent of this response is mucus hypersecretion (38, 39), generating an enhanced microbial niche
for further colonization and persistence. Another hallmark of strongly bacterial-driven pulmonary
inflammation is the presence in sputum of high levels of neutrophil elastase, interleukin (IL)-17
and IL-8 (3842).
A conundrum is that if bronchiectasis is simply a consequence of heightened susceptibility to
respiratory pathogens and the inflammation driven by them, one might expect the list of common
pathogens to comprise those that are seasonally common, from S. pneumoniae to H. influenzae
and respiratory syncytial virus. However, the list of pathogens commonly seen in bronchiectasis
is rather specific and somewhat constrained. There is commonly a preponderance of environ-
mental, microbial organisms operating at the margins between commensalism and pathogenicity.
This is an area that poses tantalizing questions not extensively addressed by microbial immunol-
ogy: What is the nature of interactions between bacterial antigens and host innate and adaptive
immune receptors in healthy individuals who have daily environmental exposure to these same
microorganisms and yet operate a background level of immune recognition to ensure that encoun-
ters do not become symptomatic or inflammatory and that there is successful pathogen clearance?
What are the conditions that become established in the bronchiectatic lung that specifically favor
the pathogenicity of this subset of organisms, which are not primarily evolved for human infec-
tion and not normally associated with symptomatic lung disease? In the wake of developments
in research into the human microbiota there has been a reappraisal of the relationships between
terms such as microbe and pathogen, with the associated implication of intrinsic ability to cause
disease. We have previously proposed that it may be more informative to consider microbial and
environmental perceptogens (43), encompassing the notion that the perception of (rather than
protective immunity to) immune receptor microbial ligands can instruct immune programs and,
in turn, influence host immunity to incoming pathogens.
There is a high degree of consensus among studies, with H. influenzae found in approximately
half of sputum cultures from patients with bronchiectasis; P. aeruginosa in 1230%; and NTM,
Moraxella, Prevotella, and Veillonella each in approximately 810% (11, 13, 14, 24, 25, 4447).
Colonization by P. aeruginosa often comes later in the disease than colonization by H. influenzae,
and it is associated with exacerbations, lower FEV1 , and poorer outcomes (44, 4750) (Table 2).
Central to the consideration of bacterial infection in this disease is the patient-context-dependent
interface between what is a human pathogen and what is a commensal or environmental isolate. As
biomedical research has stumbled into the world of microbial ecology, there has been increasing
reference to the 1934 tenet of Baas Becking, very apt in this case, that everything is everywhere, but
the environment selects, with accompanying debate about the proper translation and provenance
of the aphorism (15, 51).
Why then should it be that in patients living in different geographic and climatic environments,
and with different host polymorphisms, there is such conservation of microbial pathogens in the
bronchiectatic lung? We would argue that this is because Baas Beckings tenet applies, and the
relevant environment for survival and evasion of host immunity by specific microbial species is
the microniche of the inflamed, mucoid, sometimes anaerobic, bronchi. Mucoidicity has diverse
impacts, encompassing access to nutrients and oxygen (52), and evasion of immunity, as well as
more nuanced effects. In the gut, for example, the mucin MUC2 imprints dendritic cells with
anti-inflammatory and tolerogenic properties, believed to facilitate noninflammatory encounters
with commensals and food allergens in the gut (53).
Table 2 Bacterial species most commonly isolated from sputum in studies of bronchiectasis cohorts
Cohort n location mean age % of sputum samples tested by
(SD)a standard microbiologya Comments Reference
Stable bronchiectasis 38 No bacterial growth 86% of Pseudomonas isolates were 197
n = 87 25 Pseudomonas aeruginosa mucoid
United Kingdom (London) 20 Haemophilus influenzae
54 years (13) 6 Streptococcus pneumoniae
5 Staphylococcus aureus
3 Moraxella
3 Coliforms
Stable bronchiectasis 35 Haemophilus influenzae Presence of Pseudomonas aeruginosa 5
n = 150 31 Pseudomonas aeruginosa correlated with low FEV1 (forced
United Kingdom (Cambridge) 23 No bacterial growth expiratory volume in 1 second);
53 years (15) 20 Moraxella persistent colonization was most
14 Staphylococcus aureus common for Haemophilus influenzae

13 Streptococcus pneumoniae and Pseudomonas aeruginosa
11 Coliforms
Stable bronchiectasis 55 Haemophilus influenzae 45
n = 77 26 Pseudomonas aeruginosa
Spain 12 Streptococcus pneumoniae
58 years (14)
Bronchiectasis longitudinal 70 Staphylococcus aureus 11
studya : stable and after 45 Streptococcus pneumoniae
exacerbation and antibiotic 33 Veillonella
course 30 Haemophilus influenzae
n = 40 25 Pseudomonas aeruginosa
United Kingdom (Belfast) 20 Rothia
66 years (7) 13 Neisseria
Bronchiectasis BLESS cohorta 32 Haemophilus influenzae-dominated H. influenzae-dominated and 14
n = 107 24 Pseudomonas aeruginosa-dominated P. aeruginosa-dominated groups had
Australia (Queensland) 44 Dominated by other taxa, most poorest lung function with high
63 years (10) commonly Veillonella and Prevotella C-reactive protein and interleukin-8
Indigenous children with 78 Nontypeable Haemophilus Data based on any growth from 198
bronchiectasis influenzae samples from bronchoalveolar lavage
n = 45 33 Streptococcus pneumoniae
Australia (Queensland) 27 Moraxella
2 years 0 Pseudomonas aeruginosa
a
Samples were tested using sequenced operational taxonomic units rather than standard microbiological tests.
Haemophilus influenzae and Pseudomonas aeruginosa. Studies on the microbiology of spu-

tum from bronchiectasis patients often identify H. influenzae as the most commonly iso-
lated species, which is often correlated with disease severity, with P. aeruginosa present in a
slightly smaller subset, but associated with the most severe disease (11, 13, 44, 45, 47). Most
H. influenzae infections in this group are nontypeable H. influenzae (NTHi)that is, unencapsu-
lated and not affected by H. influenzae type b vaccination.
H. influenzae may be regarded as an opportunistic pathogen of susceptible individuals. That
NTHi is encountered ubiquitously, visible to the immune system yet not normally pathogenic, is
suggested by the fact that bronchiectasis patients and controls show similar antibacterial antibody
titers (54). An interesting consideration in the context of bronchiectasis pathogenesis is NTHis
530 Boyton Altmann
possible role as a driver of neutrophilia. NTHi shows highly effective adaptations that enable it to
resist host innate oxidative stress responses (55). As a consequence of NTHi uptake by neutrophils,
it is the neutrophils that tend to die rather than the bacteria, leading to the release of neutrophil
elastase and IL-8 with, in turn, recruitment of further neutrophils (56). One study compared
CD4 T cell immunity to NTHi between bronchiectasis patients and healthy controls (57). The
study found a profound and pathogen-specific immune deviation in the CD4 T cell responses
of patients, with decreased IL-2 and IFN- and increased IL-10 and IL-4. Similar results were
observed in the T cell responses of children with chronic suppurative lung disease (58). In response
to a pathogen that can assume an intracellular lifestyle, CD8 and NK cell responses are also likely
to be important; it has been shown that live H. influenzae can induce these responses in healthy
controls, but the responses were impaired in patients with bronchiectasis (54).
A considerable challenge is posed by protective vaccination against NTHi, which, unlike en-
capsulated H. influenzae type B, lacks a polysaccharide capsule and shows extensive antigenic
variation among strains (59). In support of the notion that this would be a valuable endeavor,
children with chronic suppurative lung disease who received more than three doses of a conjugate
vaccine containing the candidate immunogen H. influenzae protein D, acquired antigen-specific
IFN- responses in the normal range (60).
Our lab assessed CD4 T cell immunity to P. aeruginosa in bronchiectasis patients (61). Infec-
tion is adapted for long-term survival in the airway lumen, locating in hypoxic masses associated
with a transcriptomic, morphotypic shift to a biofilm state involving the generation of a protec-
tive, alginate, exopolysaccharide coat (62, 63). This adaptation seemingly confers several survival
advantages on the bacterium, including resistance to high titers of neutralizing antibody, presum-
ably through physical inaccessibility. Various P. aeruginosa candidate vaccine immunogens have
been investigated in the course of studies in mouse, rat, and nonhuman primate models; there
have also been a limited number of trials in human vaccinees with or without CF (64, 65). Among
these candidate immunogens are flagellin, lipopolysaccharide O antigens, and the outer membrane
porins F and L (OprF and L). Of note, OprF is massively upregulated during anaerobic biofilm
growth, exposing it as a potential target for T cell recognition (66, 67). We recruited a cohort of
57 bronchiectasis patients, who were stratified according to the frequency with which P. aerug-
inosa was cultured from monthly, sputum samples as: never positive, sometimes positive (<50%
of cultures), or chronically colonized (50% of cultures). The aim was to start to unpack the
functional immune correlates that might distinguish otherwise similar patients, thus highlighting
how a subset of patients could succumb to chronic colonization with this opportunistic pathogen,
which confers such a negative effect on disease outcome. As predicted, patients with evidence of
chronic infection were far more likely to harbor mucoid isolates, and also showed reduced T cell
responses to OprF as measured by the frequency of antigen-specific cells. Furthermore, when
these T cell responses were mapped at the level of specific human leukocyte antigen (HLA) class
II-presented epitopes, the response of chronically infected patients was narrowed, being focused
on a small subset of the recognizable epitopes. However, the chronically infected group showed
enhanced innate immune responses with respect to a number of pathways, including pathways
involved in neutrophil recruitment (61).
Nontuberculous mycobacteria. CT and X-ray evidence of bronchiectatic changes may be the

result of old TB, possibly contributing to the high prevalence of bronchiectasis findings on CT
in countries where TB is relatively common (68). Such effects are distinct from the role of NTM
as opportunistic pathogens contributing to the microbial load in the pathogenesis of ongoing
bronchiectasis. A meta-analysis of NTM in bronchiectasis considered eight published studies
spanning Europe, Asia, and Australia (69). NTM was more common in the Asian studies, and the
most common NTM species were Mycobacterium avium complex (MAC) followed by M. abscessus
complex (MABSC), although the mycobacterial species identified varied somewhat by country.
Overall, the meta-analysis indicated an NTM prevalence of 9.3% in patients with bronchiectasis.
A study based on records from the US Medicare program found that bronchiectasis conferred a
raised risk for NTM infection of more than 50-fold (25). The term MAC includes M. avium and
M. intracellulare, and, outside of this specific context, susceptibility is generally expected in the
setting of immunodeficiency, such as in HIV infection. NTM co-infections may be seen in some
patients, and a US study reported that specimens from more than one-half of an MABSC cohort
also cultured MAC (70). The chicken or egg case for NTM as either cause or effect of bronchiectasis
has been comprehensively argued by Griffith & Aksamit (71), who concluded in favor of the latter
view. Host immunity to NTM has not been extensively characterized, but is likely to share key
features with immunity to other mycobacteria (72). That this is essentially a question of adaptive
immune mechanisms is evidenced by the fact that immune-deficient individuals with HIV show
enhanced susceptibility to MAC and other NTM (73).

Moraxella, Veillonella, and Prevotella. Moraxella catarrhalis is a gram-negative commensal of the

upper respiratory tract, but it has been implicated in significant crossover to human pathogenicity
in settings such as COPD and in pediatric infections, particularly otitis media (74). This clinical
recognition has driven a significant body of research on the characterization of human adaptive im-
mune responses to Moraxella, and to the evaluation of several candidate vaccine immunogens (75).
Moraxella features on the list of many analyses of common respiratory pathogens in bronchiectasis
(5, 11, 44, 46). There may be an argument for joining together the cases for vaccine development
for use in children, bronchiectasis, and COPD.
Veillonella are anaerobic gram-negative cocci, commonly identified by pyrosequencing of the
human oral and gut microbiomes. When specific anaerobic culture techniques have been applied,
Veillonella have been implicated in cases of human disease, including pediatric abscesses and aspi-
ration pneumonias (76). Tunney and colleagues (77) have proposed that the mucoidicity of a lung
with CF would confer an oxygen gradient encompassing regions favoring anaerobic microbial
growth, and so they used anaerobic culture conditions to show that CF sputum contains anaerobic
species including not only Veillonella but also Prevotella, Propionibacterium, and Actinomyces. This
was particularly the case in patients colonized with P. aeruginosa. In bronchiectasis, Rogers and
colleagues (13, 14) reported that, apart from presence of P. aeruginosa, the presence of Veillonella
was the best predictor of exacerbation frequency. Prevotella are a group of anaerobic species within
the Bacteroidetes, noted mainly in the context of 16S rRNA sequencing studies of human micro-
biota but also implicated in some disease studies, including correlations with periodontal disease
and rheumatoid arthritis (78, 79). Among immune interactions attributed to Prevotella species is
the ability to subvert immunity by degrading complement C3 (80).
Aspergillus
Current understanding of the mycobiome in the lung is in a less developed state than understand-
ing of the microbiome (81). From classical microbiology, the most common fungal pathogen of
relevance in patients with immune dysregulation is Aspergillus fumigatus. Infection by Aspergillus
in susceptible patients may be associated with a diverse spectrum of pathologiesdepending on
the interplay between host immunity and fungal transcriptionfrom invasive aspergillosis (IA)
through to chronic primary aspergillosis and Aspergillus bronchitis to allergic bronchopulmonary
aspergillosis (ABPA) (82). At one end of the spectrum, IA tends to be associated with immunode-
ficiency or immunosuppression and, at the other end, ABPA with atopic hyperactivity. Thus, as
532 Boyton Altmann
with environmental bacteria, this is an example of more or less ubiquitous fungal spores present
in the environment, which are seemingly cleared by innate mechanisms in healthy individuals but
that cause severe disease in susceptible individuals. Upper lobe bronchiectatic changes may be
seen in the context of severe ABPAthat is, Aspergillus sensitization as a cause of bronchiectasis
(83). However, individuals with bronchiectasis of any cause may become colonized by Aspergillus,
and individuals with cavitation may develop IA.
Viral Infections and Exacerbations

There are few data addressing whether there could be a role for respiratory viral infections in exac-
erbations of bronchiectasis. In the mid-twentieth century, a common description of bronchiectasis
etiology would have been productive cough following measles in early childhood (particularly
in what was described histopathologically as follicular bronchiectasis), but measles became un-
common as a source of infection following the introduction of vaccination programs in the 1970s
(84, 85). A recent analysis in China using a respiratory virus polymerase chain reaction panel
of samples from nasopharyngeal swabs and sputum from 100 exacerbations in 58 adult patients
during 1 year found significantly more virus-positive samples in exacerbations than at steady state
(86). However, more than one-half of exacerbations showed no evidence of any of the viruses
monitored. Of the virus-positive samples, coronavirus was identified in 39%, rhinovirus in 25%,
and influenza A or B viruses in 25%. Thus, common viral infections were statistically associated
with exacerbations, which is compatible with the notion that viral infection may be either the
cause or effect of exacerbations, but certainly, common viral infections were not necessary for
exacerbation.
An Australian study conducted a similar analysis of exacerbations in pediatric bronchiectasis,
finding respiratory viruses, most commonly rhinovirus, in 48% of exacerbations (87). Furthermore,
virus-positive exacerbations tended to be more severe. Thus, although there is evidence of a
contributory impact of common respiratory viruses on exacerbations of bronchiectasis, this does
not appear to be a condition driven by susceptibility to viral infection. Although the potential
of seasonal influenza to contribute to bronchiectasis has been flagged, no randomized controlled
trials using influenza vaccine in this group have been reported. We are unaware of reports explicitly
linking bronchiectasis exacerbations to seasonal influenza. However, in a bronchiectasis cohort of
98 individuals in Ankara, vaccination was a highly significant correlate of patient survival during a
5-year follow-up evaluating mortality: With respect to annual influenza vaccination and 5-yearly
pneumococcal vaccination, compliance was 96% in the survivor group and 45% in the nonsurvivor
group (28). This current picture contrasts with evidence from the early- to mid-twentieth century
when measles and influenza appear to have been significant drivers of the disease (22, 85).
INFLUENCE OF THE LUNG MICROBIOTA

As in several other respiratory diseases, there has been considerable interest in analyses of the lung
microbiota (1117). To date, this has encompassed pyrosequencing of bacterial 16S rRNA rather
than pyrosequencing of viral or fungal sequences. Recent analyses of the lung microbiota have over-
turned the dogma that the lower airways are normally sterile. Clearly, there are many perspectives
from which to view analyses of microbiota in a disease such as this. A simple starting point might be
that in a disease in which many exacerbations may be negative for bacterial isolates by conventional
microbiological sputum culture, sequencing-based approaches offer the chance of identifying pre-
viously implicated or additional bacterial species that are candidates for having a pathogenic role
(11). For example, sequencing identifies both P. aeruginosa and H. influenzae from a considerably
higher proportion of sputum samples from bronchiectasis patients than does conventional micro-
biology (13). A more common rationale would be to look for disturbances in the complexity of
microbial communitiesthat is, the notion of dysbiosis as a disease mechanism. In several inflam-
matory conditions, and prototypically in inflammatory bowel disease (IBD), a common finding is
of either a loss of microbial complexity associated with disease or of a disruption in the hierar-
chy of the most abundant phyla (88, 89). There are several possible models to explain how such
changes might impact on disease. The microbial niche of potentially pathogenic bacterial species
is subject to complex competition within the microbial ecology of the lung, encompassing host
antimicrobial peptides, bacterial quorum sensing, and simple competition for nutrients (90, 91).
Although terms such as commensal and symbiont may have once indicated tolerance of bacteria
that coexist in us, and unlike pathogens, are ignored by the immune system, this is now appreciated
not to be the case (9294). For example, evidence of immune surveillance comes from the obser-
vation that in individuals with HIV-dependent immunodeficiency but without symptomatic lung
disease, the lung microbiota shows a shift toward abundant Tropheryma whipplei, which decreases
after antiretroviral therapy (95). Furthermore, it is known from work in murine models, which
is as yet uncharted in other species, that particular bacterial species may be required in the gut
for proper differentiation of immune subsets. Thus, segmented filamentous bacteria are function-
ally implicated in the differentiation of Th17 cells, and clostridial species in the differentiation of
regulatory T cells (92, 93). A more complex model is offered by the observation that changes to
the fiber content of the diet modulate the ratio of gut Bacteroidaceae and Bifidobacteriaceae rel-
ative to Firmicutes, favoring fiber breakdown into short-chain fatty acids with anti-inflammatory
properties (96). Even in the mouse, it is unclear whether the lung microbiota can act to shape the
immune repertoire in the same way as seen in the gut. The trend in microbiota analysis is to focus
less on comparative lists of specific, abundant phyla and more on the analysis of shifts in common
mechanistic pathways conferred by differential microbial communities (9799). Another emerging
aspect of research on the lung microbiota is the nature of the interaction between different com-
munity members. For example, colonization by Pseudomonas in CF airways may be associated with
mucous plugs, in turn favoring a shift to anaerobic species such as Prevotella and Veillonella (100).
The lung microbiota of healthy individuals, being less accessible than the skin or gut micro-
biome, has been less commonly reported on and was not one of the niches reported on initially
by the Human Microbiome Project (101). Somewhat different findings have been reported for
bacterial analyses of oropharyngeal swabs, peribronchial brushing, bronchoalveolar lavage (BAL),
or induced sputum, the latter two approaches being favored in most studies as a means of sam-
pling the airways. Huffnagles group (102) compared the microbiota of the mouth, nose, lung, and
stomach in 28 healthy individuals. They found a simpler microbial complexity with BAL than in
the mouth or stomach, with about half the number of operational taxonomic units. The dominant
bacterial operational taxonomic units in the mouth, from BAL, and in the stomach were classified
as Prevotella species. It is noteworthy that studies of the lung microbiota in the mouse yield a
rather different hierarchy of dominant phyla, so that findings transferred between murine models
and human patients may carry some caveats (103). Other studies have raised the consideration
of whether, in a given context, Prevotella can ever be a source of inflammation and pathology in
the lungs (104). Looking at pulmonary inflammation in relation to the lung microbiota of current
or ex-smokers, enrichment for Prevotella and Veillonella sequences was associated with a raised
inflammation score, as judged by lymphocytes and neutrophils obtained by BAL.
A number of studies have considered the lung microbiota in bronchiectasis, with somewhat
varied findings (reviewed in 15, 16). In support of a dysbiosis model, Rogers and colleagues (13)
found a positive correlation between microbial complexity and FEV1 : That is, more severe disease
was associated with less complexity, related to greater dominance by P. aeruginosa or H. influenzae.
534 Boyton Altmann
They went on to propose patient stratification based on microbial communities that were either
P. aeruginosa-dominated, Haemophilus-dominated, or dominated by other taxa, with patients in
the first two groups (accounting for approximately two-thirds of their cohort) showing worse and
more inflammatory disease in terms of FEV1 , C-reactive protein (CRP), IL-8, and IL-1 (14).
Another study of the microbial community in the lungs of patients with bronchiectasis similarly
found less microbial complexity in patients colonized by P. aeruginosa, this correlating with lower
FEV1 (17). A key question is whether P. aeruginosa was able to gain hold due to the simplified
microbiota or whether P. aeruginosa outcompeted other species and caused the dysbiosis. A related
study compared the lung microbiota in a cohort of patients analyzed during stable bronchiectasis,
during exacerbations, and after antibiotic treatment (11). This study found no correlation between
lung function or disease exacerbation and microbial complexity, concluding that dysbiosis is not
a driver of bronchiectasis exacerbations. Antibiotic treatment was associated with a rather limited
change in overall microbial composition.
These types of analyses, their interpretation, and their implementation in translational thera-
peutics are in their infancy. It will be clear from the above that for this disease, there is some way to
go before one can even draw conclusions as to correlates of clinical outcome of differential species
within the microbiota beyond the points that were knowable from classical microbiology, such as
the impact of chronic colonization by P. aeruginosa. Colonization is correlated with exacerbations
and severe disease.
It has been clearly established for other niches, such as the gut, that there is competition between
dominant, commensal taxa (105). Even once we have greater clarity as to those species that may
be preferentially associated with protective or pathogenic outcomes, progress will depend on the
ability to define culture conditions, allow the manipulation of specific species, and analyze animal
models of immune recognition and disease (106, 107). It is credible that in the future all patients
will be analyzed using comprehensive sputum microbiota sequencing (in addition to mycobiome
and virome analysis), allowing a personalized-medicine approach to their antimicrobial therapy,
encompassing not simply an appropriate antibiotic regimen but also the potential for manipulating
any dysbiosis (or the consequences thereof ) with treatment using therapeutic bacterial species or
products.
RELATIONSHIP TO INFLAMMATORY BOWEL DISEASE

AND INFLAMMATORY REGULATION IN THE GUT
The human and mouse microbiome initiatives have been, to a large extent, led by analyses of the
gut microbiome, due both to the accessibility of fecal samples and the potential impact on research
into IBD (108110). Strong evidence from murine models has focused on the role of dysbiosis
in general, and specific bacterial species in particular, in modulating T cell subset differentiation
(92, 93). It is unclear whether this relationshipwith the gut microbiota shaping the immune
repertoire as sampled in the gut mucosais a special case affecting just the gut, whether changes
in the lung microbiota might similarly affect lung immune differentiation, or, indeed, if the gut
acts as mission control also for the lung. The gut microbiota seems special to some extent, with
respect to the size of the microbial community found there and the interface it has with the immune
system. Similar interactions must undoubtedly prevail at least to some extent at other mucosal
sites, but we lack the experimental models to dissect them. Certainly, there is some evidence for a
gutlung axis (96). It is likely that in time it will be possible to annotate the interaction among the
lung microbiota, immune subsets in the lung, and disease phenotypes. For example, it is clear that
changes in diet that impact the gut microbiota are also reflected in changes in the lung microbiota
(96). A possible pathological role of dysbiosis is suggested by the fact that one of the several
routes to bronchiectasis is colectomy for severe ulcerative colitis (UC) (111). Some 35 years ago,
Turner-Warwick, Cole, and colleagues (112) described seven patients with bronchiectasis, three
of whom had developed disease within 1 year of colectomy, and another two who had developed
it in association with an exacerbation of colitis (112). A meta-analysis considered 155 cases in the
literature of pulmonary manifestations in IBD, noting that bronchiectasis is the most common and
highlighting 9 cases, mainly with UC, who developed bronchiectasis within 1 year of colectomy
(113). Among the reports of IBD associated with bronchiectasis, the most prevalent appears to be
UC, with Crohns disease somewhat less common, and only a few reports in the context of celiac
disease (CD) (114). Nevertheless, it is of interest that bronchiectasis can occur also in the context
of CD, this being a rather well-characterized gut immunopathology, typically driven by CD4
T cells specific for a gliadin epitope presented by HLA-DQ2, in turn leading to inflammatory
damage to the intestinal epithelium (115). As an example of an inflammatory disease for which
the link among immunogenetics, T cell effector populations, and subsequent tissue damage has
been elucidated with molecular precision (116), the investigation of any link between CD and
bronchiectasis may offer valuable mechanistic insights.

Bronchiectasis is now considered the most common pulmonary manifestation of IBD, and the
phenomenon of the development of bronchiectasis (or exacerbation) within a short period after
colectomy has been widely acknowledged (113). The temporal association suggests a mechanistic
association, which may occur through a common microbialdysbiosis trigger or a common im-
munopathogenic pathway, or both. The turmoil wrought by colectomy on the microbial ecosystem
will have a profound effect on any control exerted by the gut microbiota on the systemic action of
immune subsets, but these effects have not yet been analyzed in experimental models or in patients.
In terms of immunopathogenic pathways, we showed that an IFN- polymorphism (T/A 874)
may be protective for development of bronchiectasis: no patients undergoing colectomy for UC
who subsequently developed bronchiectasis had a TT genotype (117); this appears to highlight a
role in protection for Th1 or Tc1 T cells.
One might propose a commonality in immune triggering between lung and gut inflammation
through shared features of microbial exposure (118), specific impact on inflammatory immune
subsets in the lung through programming in the gut (96), or a commonality in target antigens
through the shared embryonic origin of gut and lung epithelium. Since the initial observations of
Turner-Warwick, Cole and colleagues (112), much has been learned about the origins of IBD,
now considered to be a clear manifestation of immune subset dysregulation occurring in response
to dysbiosis.
OVERLAP WITH OTHER AUTOIMMUNE CONDITIONS

Rheumatoid Arthritis
In line with the concept of bronchiectasis as a disease of overexuberant inflammatory pathol-
ogy, it can also occur as part of a spectrum of pathologies in several different, systemic, autoim-
mune diseases. These include rheumatoid arthritis (RA), IBD, ankylosing spondylitis, systemic
lupus erythematosus (SLE), Sjogrens syndrome, systemic sclerosis, vasculitis, and autoimmune
polyendocrinopathycandidiasisectodermal dystrophy (APECED) (119126). Clearly, this list
encompasses highly diverse systems, etiologies, genetics, primary target autoantigens, and patholo-
gies. What can one learn from the observation that in a variable subset of cases, these diseases
can manifest in the form of bronchiectasis detected by HRCT, sometimes in the presence of
associated respiratory symptoms, and sometimes not? The first point to make is that although
these are highly diverse diseases, the age of disease genomics has taught lessons both about the
536 Boyton Altmann
unique details of predisposition to each disease and also about shared pathways (127). Thus, if
autoimmune diseases are now typically thought to result from an interplay between the environ-
ment and the combined, often weak, effects of scores of disease-susceptibility genes, which are
generally immune in nature, then groups of autoimmune diseases may share a variable number of
these genes in the Venn-diagram overlap. Examples of immune system polymorphisms that have
appeared in the genome-wide association studies of several different diseases include those im-
pacting HLA class II, CTLA-4, PTPN22, and interleukins. From this starting point, the appearance
of bronchiectatic changes common to many autoimmune conditions should be taken as evidence,
if not that bronchiectasis can be bracketed as a bona fide autoimmune disease (with the notion of
an autoimmune repertoire specifically targeting specific tissue antigens), then at least that Coles
vicious cycle contains a shared pathway leading to poorly controlled, pathogenic immunity.
We start by considering the case of the interplay between RA and bronchiectasis. RA is a rather
common disease with a prevalence of around 1% in many countries, and bronchiectasis is a much
rarer disease, so that the increased risk of bronchiectasis in patients with RA over controls can
readily be identified. This has been done in a large number of observational, prospective studies,
generally taking cohorts of patients before RA, with RA, or with long-established RA and looking
for respiratory disease using HRCT, as well as for evidence of symptoms of respiratory disease (120,
128130). The co-occurrence of these pathologies is associated with increased mortality, which
is higher in patients with both diseases than in patients with RA or bronchiectasis alone (131).
It has been repeatedly reported since the early 1950s that RA is associated with lung disease,
including bronchiectasis (132). Aronoff and colleagues (132) found bronchiectasis in 3% of a
series of 130 chest X-rays of RA patients and in 12% of postmortem investigations of patients
with RA. The subset of RA patients found to have bronchiectasis differed somewhat among studies,
according to country, cohort size, the nature of RA disease in the cohort, and whether the study
considered only HRCT changes or also took into account clinical symptoms. These studies have
been reviewed in detail (119). The data show a spread, from many studies identifying bronchiectasis
in the range of 510% of individuals with RA, to studies where the figure was as high as 30%
(133). An implication of this is that if RA has a prevalence of 1% and one-tenth to one-third
of these patients are found on HRCT to show bronchiectasis, then current estimates of the
prevalence of bronchiectasis are too low. A study in Japan identified a raised risk of developing
RA with bronchiectasis in individuals with the HLA-DRB1 0405 allele (although this allele is
rare outside of Asia) (134). A US study identified a particularly high prevalence of RA (29%)
in African-Americans with bronchiectasis, which is of interest because in the United States the
general prevalence of RA is similar in White and African-American individuals (135137).
It has long been known that pulmonary features tend to precede articular symptoms in patients
who go on to show both RA and bronchiectasis (138). Some studies have looked at bronchiectasis
by HRCT in pre-RA individuals, who are positive for rheumatoid factor (RF) or anticitrullinated
peptide antibodies (ACPA), or both. The conclusions from these studies have been that patho-
logical changes in the lung precede symptomatic RA. Demoruelle and colleagues (120) appraised
HRCT changes in 42 autoantibody-positive participants without RA in a Denver cohort and found
any airway changes in 76% and bronchiectasis in 14%.
Other studies have considered the relationship between these pathologies by asking whether
there is an increased prevalence of RA-diagnostic autoantibodies in bronchiectasis cohorts. Hilton
& Doyle (128) found that approximately one-half of their bronchiectasis cohort were positive for
RF. More recently, Perry and colleagues (139) analyzed serum samples from 122 bronchiectasis
patients; the prevalence of RF was nonspecifically increased in the bronchiectasis patient cohort.
Interestingly, four individuals were strongly positive for ACPA, and two of these developed RA
within 1 year.
Based on the observations described above, there are a number of hypotheses to consider in
unpacking the relationship between bronchiectasis and RA. A simple view would be the common-
autoimmune-pathways argument introduced earlier in this section; for example, both bronchiec-
tasis and RA are conditions in which a strong and possibly dysregulated Th17 response has been
flagged (140, 141). An alternative view starts from the observation that pulmonary disease tends
to precede articular disease and, thus, would make a case for the lung as one of the mucosal sites
at which the arthritogenic program is initiated (120, 139). Recent work on the etiology of RA has
supported a view of induction at mucosal sites, with emphasis, for example, on periodontal disease
and the impact on immune regulation of Porphyromonas gingivalis in the oral microbiota (78). A
posited contribution of oral P. gingivalis to pathogenesis is that it is able to citrullinate human
proteins, thus potentially targeting them for autoimmunity (142). Analyses of gut microbiota in
patients with recent-onset RA have implicated the presence of Prevotella copri as a correlate of
new disease (79); Prevotella is also among the common microbial species present in the lung in
bronchiectasis (11). Although it is early days in the establishment of functional relationships based
on microbiota sequencing, a current aim must be to test the hypothesis of a gutlungjoint axis
for mucosal priming by differential microbiotal bacterial species. These, it would be argued, may
have subtle effects in establishing immune subset programming and reactivity, including reactivity
to self-tissues. Under this model, those individuals who develop both RA and bronchiectasis do so
because of a common initiating event that occurs through immune programming by the oral or
gut microbiota. Supportive of the notion of an immune axis that functionally links the lung and the
joints, Rangel-Moreno and colleagues (143, 144) showed that in pulmonary complications of RA,
one can detect what has been termed iBALT (inducible bronchus-associated lymphoid tissue);
these are ectopic lymphoid follicles in the lung that contain Th17 cells, and depend on Th17
cells for their induction (143, 144). Although we lack definitive histopathological studies to define
whether iBALT formation is a feature of the pathological changes in bronchiectasis, the changes
are in some respects reminiscent of older studies of what was known as follicular bronchiectasis,
and more recent immunocytochemical studies (85, 145).
Ankylosing Spondylitis, Sjogrens Syndrome, Systemic Lupus Erythematosus,

and Systemic Sclerosis
Other diseases on the arthritic spectrum, including ankylosing spondylitis, Sjogrens syndrome,
and systemic sclerosis, can also present with pulmonary disease, including bronchiectasis. The
findings are summarized in Table 3.
There are no additional studies of which we are aware that specifically focus on potential
underlying mechanisms. It is worth adding that there have been case reports of bronchiectasis as
part of the pathological spectrum in APECED (126). This is a rare but devastating multisystem
Table 3 Bronchiectasis diagnosed by high-resolution computed tomography (HRCT) in patients with non-rheumatoid
arthritis arthritic disease
Number Number (%) with
Primary diagnosis Country evaluated Type of lung study bronchiectasis Reference
Scleroderma Greece 22 HRCT 13 (59) 124
Systemic lupus Ireland 34 HRCT, lung 7 (21) 123
erythematosus function
Ankylosing spondylitis Meta-analysis 303 HRCT 33 (11) 121
Sjogrens syndrome Spain 507 HRCT 41 (8) 122
538 Boyton Altmann
disease, but it is perhaps most noteworthy in this context because it might be regarded as being,
mechanistically, the ultimate disease of autoimmune etiology: It is caused by mutations in the
autoimmune regulator of expression (AIRE) gene, which normally functions to control expression
of self-proteins, allowing thymic self-tolerance (146). The presence of bronchiectasis in this disease
process argues either that it can occur as a consequence of direct autoimmune attack or may be a
downstream consequence of such an attack.
IMMUNE MECHANISMS AND EVIDENCE FOR

IMMUNE DYSREGULATION
In some respects, there may be a strong case for dropping the term idiopathic, which literally means
arising spontaneously or of unknown cause. To some extent, the term is a throwback to an earlier,
prevaccination era, when many cases could be causally linked to a specific episode of pertussis or
measles (85). However, proponents of this term might highlight the fact that this is a pathobiology
that poses exceptionally strong challenges: It is a disease process of immune dysregulation, yet one
that can occur against a backdrop of diverse causes of immune deficiency and equally diverse im-
mune hyperactivation. It has been proposed that the attribution idiopathic actually collates those
patients suffering from uncharacterized immunodeficiencies (147). How should a unifying hypoth-
esis of immune causality be attributed to a lung pathology that may be arrived at by predisposing
causes encompassing combined variable immunoglobulin deficiency on the one hand, and autoim-
mune hyperactivation on the other? In the following section we review the evidence for various
forms of immune dysregulation. It is helpful in this context to explore the argument that in our cur-
rent understanding of complex interactions among the interacting subsets, reciprocal controls, and
overlayered redundancies of the innate and adaptive immune system effector mechanisms, there are
points at which immunodeficiency in one pathway is a cause of immune hyperactivation in another.
Two such examples that can encompass bronchiectasis are transporter associated with antigen
processing (TAP)deficiency syndrome and Jobs syndrome, otherwise known as hyper-IgE syn-
drome. In TAP-deficiency syndrome, a mutation prevents the expression of the TAP gene product,
which is necessary for proper transport and loading into HLA class I molecules of antigenic pep-
tides in the endoplasmic reticulum. Although this is clearly a profound form of immunodeficiency,
leading particularly to susceptibility to NTM among other pathogens, it also encompasses hyperac-
tivation of some immune subsets, including T cells and NK cells (148). Hyper-IgE syndrome is
also classified as an immunodeficiency, involving as it does a mutation in the STAT3 transcription
factor (which is activated in response to IL-6 and IL-10) that is associated with increased suscepti-
bility to staphylococcal, candidal, and other infections, yet also involves pathological enhancements
to some immune pathways, including IgE class-switching and Th1 immunity, but with impaired
Th17 immunity (149). Chronic granulomatous disease may also be regarded as a disease with two
faces: immunodeficiency and inflammatory hyperactivation. This is a disease in which mutations
in the NADPH oxidase enzyme complex lead to defects in the innate response to specific bacteria
and fungi and also to inflammatory disease, including IBD and bronchiectasis (150). Viewed in this
light, we should perhaps concern ourselves less with defining whether bronchiectasis is a result of
either immune deficiency or immune excess and, rather, focus on it as a consequence of immune
dysregulation.
Due, perhaps, to limitations in accessing intact cellular populations from the sputum of
bronchiectasis patients, there is a paucity of data about lung immunology from this patient group.
It has long been known that neutrophils predominate in sputum or BAL fluid from patients with
bronchiectasis, and decrease after intravenous antibiotic therapy (39, 41, 151). Furthermore,
induced sputum from bronchiectasis patients has been shown to have elevated tumor necrosis
factor-, IL-8, and neutrophil elastase, which are reduced after treatment (41). A recent study
reported on the comprehensive analysis of cytokines from BAL and in endobronchial biopsy tissue
from a cohort of 41 patients with bronchiectasis (42). As might be expected, the study found highly
raised levels of innate cytokines, IL-8 and IL-1, and also much raised levels of cytokines in BAL
samples, implicating the Th17 pathway, IL-17, and IL-23. A caveat was that the study could not
identify any clear correlation between Th17 levels and lung function, disease severity, or infection.
For a disease process in which a strong index of suspicion points to the Th17neutrophilia
antibacterial pathway, further studies in this area are clearly warranted; there is resonance with
the proposed role for Th17 cells in CF, where high levels of IL-17 in the airways of patients with
CF precede P. aeruginosa infection (152). Although Th17 immunity was initially characterized in
the context of effector function in autoimmune models, it is now clear that the primary function
of this pathway is likely to be in antibacterial and antifungal host defense, but with considerable
potential for causing collateral inflammatory damage (153). An analysis of endobronchial biopsy
samples from 17 pediatric bronchiectasis patients showed large numbers of IL-17+ cells among
infiltrates, these comprising IL-17+ Th17 cells, invariant natural killer T (iNKT) cells, T
cells, and neutrophils (154). This was associated with the presence of IL-17 in samples from
BAL, which correlated with the degree of neutrophilia. This is in line with studies using murine
models, in which pulmonary IL-17 drives both neutrophilia and mucus hypersecretion (155).
Could it be then that the entry point to the vicious cycle is heightened susceptibility to the subset
of microbial species with the evolutionary ability to strongly stimulate the IL-17neutrophilia
pathway, thus fueling mucus hypersecretion and further colonization (Figure 2)?
King and colleagues (156) conducted an assessment of global, systemic immunity in a cohort of
103 adult patients with bronchiectasis. The key findings in their study were that when compared
with controls, the bronchiectasis group showed low IgG3, low B cells, low CD4 T cells, and,
most commonly, a reduced neutrophil oxidative burst. This study supports the central notion of
dysregulation in the interaction between CD4 T cells and neutrophil activation, but did not pursue
issues of local respiratory immunity or interactions of T cells and innate subsets. Other studies
have localized the most common IgG deficiency in bronchiectasis cohorts to the IgG2 subclass
(157) or found that IgG subclass deficiency was uncommon (158).
Silva and colleagues (159) conducted a study some 30 years ago of bronchial biopsies from nine
bronchiectasis patients. They highlighted the fact that in the tissue there was abundant lympho-
cytic infiltrate, with far more CD8 cells than CD4 and few neutrophils, these being more abundant
in the bronchial lumen. Many of the T cells were strongly HLA class IIpositive, arguing for an
activated T cell population. At that time, the CD8 antibody was used as a marker for suppressor and
cytotoxic T cells, but today a strongly CD8 infiltrate is more likely to be regarded as evidence of an
ongoing effector response to an intracellular pathogen. From the above, the most likely candidates
would be H. influenzae or NTM. Silva and colleagues manuscript contains relatively high-powered
views of lymphocytic infiltrates, but it is not possible to clarify whether any of these biopsies would
have shown evidence of Th17-dependent ectopic follicles. A more extensive study from this group
considered the immunocytochemistry of bronchial specimens from 22 patients with bronchiecta-
sis of mixed etiology (145). Again, the key finding was the large numbers of T cells infiltrating the
bronchial walls. The researchers made a distinction between the cell types present in follicular
and nonfollicular bronchial histopathology. In 15 of 22 samples, CD8 cells were the predominant
T cells. CD4 cells predominated in follicular samples, these structures containing largely CD4 T
cells and B cells. The follicular T cells were more strongly CD25+ , which, depending on bright-
ness, we would now regard either as a simple measure of effector T cell activation or of regulatory
T cells (160). The histopathological categorization of a variably follicular subset of disease harks
back to early studies from Engel (84) and Whitwell (85), who stated, the term follicular has been
540 Boyton Altmann
Mucus IL-8 MMP-1, MMP-8 IL-17 Neutrophil elastase 7
Neutrophil
Lung mucosa Th17 Th17 Mucus hypersecretion IL-8
Th17 Th17 elastase
Th17 neutrophil
6
Th17 Th17 Th17 Th17 Th17 AHR

Th17 Th17 7 chemotaxis
Th17
Th177 Th17
Th17 Th17
Th17
Th17Th17 Th17
Th17
Th17
Th17 Th17 Neutrophil
Th17 Th17 Th17 Innate
Th17 Th17 Th17
Th17 Th17 chemotaxis recognition
Th17Th17Th17
Th17 activation 5 (but impaired killing)
leads to formation
of ectopic lymphoid
follicles IL-17 Incoming
3 environmental
Th17 and pathogenic
Dendritic cell Th17 bacteria
Antigen
Th17 Th17
recognition
induction/ Th17 by adaptive
MyD88 polarization immunity 4
TLR/NLR
recognition 1 2 Bacterial
adaptations for
colonization
Lung microbiota
Figure 2
A proposed scheme for Th17 immunity in bronchiectasis. The figure depicts a hypothetical scheme based on the current literature for
Th17 immune dysregulation in immune bronchiectasis. Based on findings in gut mucosal immunity, it is assumed that different
microbiotal species, by producing different types and levels of microbial products, can interact with innate receptors including Toll-like
receptors (TLRs) and NOD-like receptors (NLRs) on local dendritic cells and other antigen-presenting cells (94, 196), ,
preferentially favoring induction and differentiation of Th17-polarized CD4 T cells (92); this may potentially encompass impacts on
bronchial immunity and also on the gut microbiota (96). These Th17 cells can recognize and respond to incoming bacteria, such as
Haemophilus influenzae or Pseudomonas aeruginosa by secretion of interleukin (IL)-17 (151). In the case of P. aeruginosa, transcriptional
changes or mutations may facilitate the development of adaptations for chronic colonization, such as mucoidicity and biofilm formation
(52). Neutrophils will be further drawn into lung tissue through chemotaxis in response to IL-8 release by epithelial cells; the innate
recognition and killing of bacteria by neutrophils may be impaired in patients with bronchiectasis (65). Excessive, chronic Th17
activation in bronchial tissue may result in the generation of ectopic lymphoid follicles containing primarily CD4 T cells and B cells
(159, 161163). An additional outcome of local IL-17 release is mucus hypersecretion and airway hyperreactivity (AHR) (154). As a
consequence of this inflammation and mucus hypersecretion, the airway becomes occupied with mucus that contains abundant
neutrophils, as well as IL-8, matrix metalloproteinase (MMP)-1, MMP-8, IL-17, and neutrophil elastase, potentially offering a positive
feedback loop for further inflammation and neutrophilia. Abbreviation: MyD88, myeloid-differentiation primary-response protein-88.
chosen because the prominent microscopic feature is an excessive formation of lymphoid tissue,
occurring as follicles and nodes, which are situated both in the walls of diseased bronchi and bron-
chioles . . . These lesions are usually associated with great enlargement of hilar lymph nodes (85).
These CD4- and B cellladen ectopic follicles appear highly reminiscent of the Th17-dependent
ectopic lymphoid follicles described in autoimmune target tissues in diverse autoimmune diseases,
including multiple sclerosis, RA, Sjogrens syndrome, and myasthenia gravis (161163).
Another bronchiectasis biopsy study looked at 12 patients with what was described as postinfec-
tive bronchiectasis, 6 of whom were being treated with inhaled steroids (39). Within the bronchial
mucosa, the study found raised numbers of CD4 T cells and neutrophils in patients compared
with controls, although it did not identify any increase in CD8 cells. Both the numbers of CD4
T cells and of IL-8+ cells were significantly reduced in the group being treated with steroids.
Although it would be foolhardy to attempt reinterpretation with hindsight of histopatholog-
ical studies at a distance of some 2060 years, they do appear to indicate clear histopathological
distinctions between types of bronchiectatic disease, possibly relating to disease-initiating pro-

cesses, with distinctions between the predominance or not of ectopic lymphoid follicles, these in
turn bearing on T cell bias toward CD4 or CD8 subsets. It would be difficult to rationalize such
differences except in relation to differences in disease-driving pathogens.
We approached immune susceptibility to bronchiectasis from an immunogenetic standpoint,
reporting in a cohort of 92 patients a raised relative risk for individuals with an HLA-DR1, DQ5
haplotype (164). In other studies, HLA-DR1 is noteworthy mainly for being the allele (after HLA-
DR4) most commonly associated with susceptibility to RA (165). We also noted an independent
effect on genetic susceptibility at the HLA-C locus (21). Because HLA-C molecules are ligands
for the activating and inhibitory KIR receptor (killer immunoglobulin-like receptor), we evaluated
HLA-CKIR interactions in our bronchiectasis cohort in some detail. A paradigm widely applied
to the analysis of infectious, inflammatory, and autoimmune susceptibility argues that carriage of
HLA-CKIR combinations may differentially modulate the rheostat of NK cell activation on a
spectrum from highly activated to highly regulated; susceptibility to microbial pathogens often
resides at the highly regulated end of the spectrum, and susceptibility to autoimmunity at the
highly activated end (166, 167). We found HLA-C group 1 homozygosity in general, and HLA-
Cw 03 alleles in particular, to confer increased susceptibility to idiopathic bronchiectasis, while
the presence of Cw 06 alleles conferred reduced susceptibility (21). Particularly noteworthy was
the increase in HLA-C group 1 homozygosity in disease; effects of this type are often interpreted
in terms of homozygotes lacking ligands for inhibitory receptors and, consequently, having fewer
NK cells under inhibitory control (12). In our patient cohort, we found an excess of individuals
expressing HLA-C group 1 with 2DS1 or 2DS2 stimulatory KIRs, or both. This is predicted
to support a highly activated NK cell program. The presence of these HLA-C allelespecific
associations in idiopathic bronchiectasis resulting in increased (HLA-Cw 03) or reduced (HLA-
Cw 06) susceptibility may result from different peptide loading onto the class I molecule, impacting
KIR binding and subsequent levels of NK cell activation. Note that the presence of NK cells
(including their expression of CD8) in lung infiltrates in bronchiectasis would be compatible with
the histopathologic picture reported by Silva and colleagues 30 years ago. One other study has
looked at HLA-C in a bronchiectasis cohort and did not find a significant association (168).
In view of the fact that NK cell recognition is classically associated with the response to viral
infection or tumors, it is worth pausing to evaluate the evidence for any role in its defense against
bacteria. Abundant data argue for a role of NK cells in bacterial sepsis, including immunity to
Pseudomonas, Haemophilus, and NTM (54, 169172). Both protective and pathogenic roles have
been ascribed to the NK cell response in these settings. NK cell activation in these infections may
542 Boyton Altmann
be driven largely by innate cytokines and may involve modulatory effects on T cells and other cell
types, rather than being limited to direct effects on infection.
Although the immunological phenotype in bronchiectasis remains less than fully resolved, we
perhaps know enough to put together a pathway of the underlying events. A range of immuno-
genetic or structural susceptibilities may lower the threshold for infection by a range of respiratory
pathogens, especially bacterial and fungal. The impact of IL-17 (whether from Th17 or activated
NK cells) on neutrophil chemoattraction and activation is likely to have an impact on abnor-
mal, unresolving neutrophil activation. However, as described above, although many strands of
evidence argue for neutrophil activation at the heart of this pathologyhigh neutrophil elastase
and IL-8 in sputum, and impaired neutrophil activation in diseaseneutrophils were not always
abundant in lung tissue in the reported specimens. The centrality of neutrophil chemotaxis to the
lung has been a given since studies in the early 1980s used in vivo tracking of Indium111 -labeled
neutrophils, which showed that nearly half of circulating neutrophils may be diverted to the lung
(173). It will be important to revisit this paradox with modern approaches and cell markers. Ensu-
ing from this scenario of underlying susceptibility is the dynamic interaction of microbial species.
This encompasses both the unknowns of what we define as a healthy lung microbiota, and how
the gut and lung microbiota might shape the immune repertoire. Colonization by Pseudomonas
appears to be decisive both in determining disease severity and in shaping microbial competi-
tion, for example, through the growth advantage offered to anaerobes profiting from low oxygen
concentrations in the mucoid respiratory environment.
PROSPECTS FOR NEW THERAPEUTICS

The British Thoracic Society Guideline for Non-CF Bronchiectasis provides a thorough sum-
mary of a general approach to managing bronchiectasis including airway clearance techniques,
exercise, and airway pharmacotherapy, as well as antibiotic therapy, surgery, and the management
of complications and advanced disease (1). An appraisal of management strategies is outside the
scope of this review and has recently been addressed and extensively reviewed by others (174181).
There is an urgent need in this patient group for new approaches to address research priorities
in studying the epidemiology, pathogenesis, and management of bronchiectasis. This is especially
important because the burden of disease is increasing. Audits in 2010 and 2011 in the United
Kingdom by the British Thoracic Society of patients attending secondary care with bronchiectasis
reported that the majority of patients were women (6162%), with a mean age of 6466 years, and
that the mean (SD) number of exacerbations was 2.6 (2.5), with 2126% of patients infected with
P. aeruginosa (182). Taken together with the possibility that COPD and bronchiectasis may coexist
as an overlapping syndrome associated with increased mortality, it seems likely that bronchiectasis
is a more common clinical problem than was previously thought (183, 184).
In light of the vicious-cycle hypothesis, there has been debate about the merits of long-term
antibiotic therapy, which reduces inflammation and the frequency and severity of exacerbations,
but brings an accompanying risk of antimicrobial resistance (185). Clinical trials have demon-
strated the beneficial effects of continuous treatment with macrolide antibiotics for 612 months
in patients with bronchiectasis (186188) and COPD (189). However, this clinical improvement
was accompanied by increased macrolide resistance among respiratory pathogens [H. influenzae,
S. aureus, and M. catarrhalis; Bronchiectasis and Long-term Azithromycin Treatment (BAT) study
(188)] and oral flora [oropharyngeal streptococci; Bronchiectasis and Low-dose Erythromycin
(BLESS) study (187)]. Long-term erythromycin treatment substantially changed the lung
microbiota in patients with bronchiectasis, as assessed by 16S rRNA gene sequencing (190).
Bronchiectasis is one of the respiratory diseases in which disease markers and severity are corre-
lated with vitamin D deficiency (191). Vitamin D deficiency is functionally linked to perturbation
of immune function through its impact on several different cell types and pathways (192). Thus,
this may be a disease in which there is a positive impact from vitamin D supplementation.
Faced with the evidence that vaccination against respiratory pathogens appears beneficial in
bronchiectasis (28), there would be benefit from utilizing a more comprehensive arsenal of respi-
ratory vaccines, both for prophylactic and therapeutic vaccination. To varying degrees, there are
experimental vaccine candidates available for many of the key pathogens discussed above, includ-
ing P. aeruginosa, NTHi, and Moraxella. Although it might be difficult to generate momentum for
vaccine trials for a relatively rare condition such as bronchiectasis, this issue may be more tractable
if it is bracketed with CF and COPD.
In both IBD and RA research, there is considerable enthusiasm for the notion of characterizing
the microbiotal communal interactions that might predispose either to disease or to the regulation
of pathology (79, 88). The hope is that this may lead in the future to new therapeutic strategies,
whether through the culture and transfer of beneficial microbial species, through the use of dietary
probiotics, or through the characterization and manipulation of functional pathways (96, 107).
With greater research into this area in chronic lung disease, such approaches would be equally
applicable. In one example, dietary supplementation with propionate, based on pathway analysis
from microbiota sequencing, might alleviate respiratory inflammation (96).
Armed with a greater understanding of immune subsets and immunopathogenic activation
programs, it will be important to look at candidate immunotherapeutics. Other lung-inflammatory
diseases are benefitting from new biologics that impact on pathogenic cytokine polarization (193).
A therapeutic monoclonal antibody against IL-8 has previously been tested in COPD (194). Anti-
IL-17 monoclonals have been tested in various conditions: brodalumab, an anti-IL-17R subunit A
monoclonal antibody was ineffective in treating asthma; secukinumab and ixekizumab have been
tested in RA; and ixekizumab has been found to be effective in treating psoriasis (195).
CONCLUDING REMARKS
Knowledge of bronchiectasis, as a pathological and clinical description encompassing chronic
cough, mucus hypersecretion, and irreversibly dilatated bronchi, was first described by Laennec
in 1819 (6). In the mid-twentieth century, bronchiectasis became a less common and less se-
vere clinical problem when pediatric vaccinationincluding the use of bacille CalmetteGuerin
(BCG), and vaccination against pertussis, measles, mumps, and rubellaimpacted on this extreme,
postinfectious manifestation of common childhood infections. However, in the early twenty-first
century, the burden from bronchiectasis appears to be increasing. As a disease process that encom-
passes features of susceptibility to common environmental bacteria and dysregulated inflammatory
responses, it may be considered a member of the group of inflammatory and autoimmune diseases
that are rising in incidence due to changes in environmental impacts on the programming of innate
and adaptive immunity. Bronchiectasis arising as a pulmonary complication of several autoimmune
diseases, including IBD and RA, is presumably a reflection of this. Diagnosis has improved with
the widespread availability of HRCT, and management has improved with the advent of better
antibiotic therapeutics to control infection and inflammation, such as the macrolides. There is
an improved grasp of the microbiology, immunology, and immunogenetics of bronchiectasis, but
this is far from comprehensive. Current studies indicate there is an interplay of bacterial commu-
nities, with a key role for colonization by Pseudomonas acting as a switch point in disease severity.
Although there are clues to the pathogenic part played by dysregulated neutrophil chemotaxis
through IL-8 and IL-17, this has not yet been clearly defined.
544 Boyton Altmann
SUMMARY POINTS
1. Bronchiectasis is a disorder characterized by chronic cough and sputum production;
recurrent chest infections, mainly caused by gram-negative bacteria; and progressive
lung damage, with irreversible bronchial dilatation and airflow obstruction.
2. Lung colonization with Pseudomonas aeruginosa, nontuberculous mycobacteria, and/or
Aspergillus fumigatus is associated with a poor outcome.
3. The disease burden seems to be increasing, and prevalence differs among populations.
4. This disorder results from a diverse etiology, ranging from infection, genetic or acquired
defects in host defense, autoimmunity, immune deficiencies, or immune hyperactivation.
5. The pathological end point has been considered as resulting from genetic predisposition
(including cases of cystic fibrosis, combined variable immunoglobulin deficiency, and
primary ciliary dyskinesia); from a specific initiating infectious event, such as pediatric
measles or pertussis; or, alternatively, from other etiologies, termed idiopathic. These
idiopathic cases might be better termed patho-inflammatory. The dysfunctional host
immunity to viral, bacterial, NTM, or fungal species leads to persistent inflammation,
lung remodeling, and lung damage associated with recurrent infection and impaired
pathogen clearance.
6. Pathogenesis is proposed to ensue from a vicious cycle in susceptible individuals, with
bacterial lung infection leading to an uncontrolled or inappropriate, unresolving respi-
ratory immune response, particularly involving neutrophil recruitment, thus creating an
altered, inflammatory niche and lung remodeling that, in turn, favors further infection.
FUTURE ISSUES
1. There is an urgent need to build a more comprehensive epidemiological picture of
bronchiectasis and attain clarity on its incidence and prevalence worldwide, and the
impact of geography and ethnicity.
2. Genomics will offer answers as to etiology, but for this disorder the need is to map how
diverse causalities feed into a common, pathogenic pathway, and this mapping will not be
readily resolved until sufficient data have been obtained to allow identification of these
pathways.
3. We are beginning to analyze the lung microbiota in stable bronchiectasis and in relapse,
and compare these with the microbiota in healthy controls, yet we still have little grasp of
the correlates of disease, the impacts on microbial competition and immune function, the
biology of culturable species from the lung microbiota, the nature of the lung mycobiome
and virome, and, thus, the potential for therapeutic manipulation.
4. There exists an exciting toolkit for analyzing lungimmune interactions at the level
of immune phenotype, immune repertoire, microbial interactions, and knockout and
reporter mice, which is yet to be fully applied to this research need.
5. The development of therapeutics, including preventative and treatment vaccines, and
immunomodulators, would offer improved options for managing disease in these patients.
6. As in many chronic, inflammatory, or autoimmune diseases, outcomes would be im-

proved by the early detection of at-risk individuals, which would allow pathogenesis to
be addressed at an early stage before the development of irreversible changes, in this
case, bronchial dilatation. This would argue for early treatment, both antimicrobial and
anti-inflammatory, to prevent establishment of the vicious cycle of bronchiectasis. Such
a course of action would depend on robust, predictive risk algorithms that might poten-
tially be based on genomics, serum and transcriptomic biomarkers, microbiology, and
clinical assessment.
DISCLOSURE STATEMENT
The authors are not aware of any affiliations, memberships, funding, or financial holdings that
might be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS
R.J.B. acknowledges the following for funding support: the Welton Foundation; the Medical
Research Council; the Biotechnology and Biological Sciences Research Council; the Wellcome
Trust; the National Institute of Allergy and Infectious Diseases, National Institutes of Health;
Arthritis Research UK; Asthma UK; MS Society UK; and the National Institute for Health
Research Imperial Biomedical Research Center. R.J.B. thanks Professor Sir Malcolm Green and
Professor Peter Cole for their support and mentorship. The authors thank Ms. Rachel Scott for
the illustration in Figure 1.
LITERATURE CITED
1. Pasteur MC, Bilton D, Hill AT, British Thoracic Society Bronchiectasis non-CF Guideline Group.
2010. British Thoracic Society guideline for non-CF bronchiectasis. Thorax 65:577
6. The father of the 2. Wilson R, Boyton RJ. 2006. Bronchiectasis. In Encyclopedia of Respiratory Medicine, Vol. 1, ed. GJ Laurent,
stethoscope includes SD Shapiro, pp. 25968. Oxford, UK: Elsevier
remarkably timeless and 3. Boyton RJ, Altmann DM. 2012. Immune regulation in idiopathic bronchiectasis. Ann. N. Y. Acad. Sci.
accurate descriptions of
1272:6872
bronchiectasis.
4. Boyton RJ. 2009. Regulation of immunity in bronchiectasis. Med. Mycol. 47(Suppl. 1):S17582
5. Pasteur MC, Helliwell SM, Houghton SJ, Webb SC, Foweraker JE, et al. 2000. An investigation into
9. Coles vicious-cycle causative factors in patients with bronchiectasis. Am. J. Respir. Crit. Care Med. 162:127784
hypothesis remains the 6. Laennec RTH. 1819. De lauscultation mediate ou Traite du Diagnostic des Maladies des Poumon et
bedrock of subsequent
du Coeur. Paris: Brosson & Chaude. 1st ed.
mechanistic iterations.
7. Hasse CE. 1846. An Anatomical Description of the Diseases of the Organs of Circulation and Respiration.
Transl. and ed. WE Swaine. London: Sydenham Soc.
8. Wall C, Hoyle JC. 1933. Observations on dry bronchiectasis. BMJ 1:597
11. Using 16S rRNA
microbiota sequencing 9. Cole PJ. 1986. Inflammation: a two-edged swordthe model of bronchiectasis. Eur. J. Respir.
in bronchiectasis Dis. Suppl. 147:615
brought new 10. Cole P. 1989. Host-microbe relationships in chronic respiratory infection. Respiration 55(Suppl. 1):5
perspectives on 8
microbial relationships 11. Tunney MM, Einarsson GG, Wei L, Drain M, Klem ER, et al. 2013. Lung microbiota and bac-
in the lung. terial abundance in patients with bronchiectasis when clinically stable and during exacerbation.
Am. J. Respir. Crit. Care Med. 187:111826
546 Boyton Altmann
12. Boyton RJ, Reynolds CJ, Quigley KJ, Altmann DM. 2013. Immune mechanisms and the impact of the
disrupted lung microbiome in chronic bacterial lung infection and bronchiectasis. Clin. Exp. Immunol.
171:11723
13. Rogers GB, van der Gast CJ, Cuthbertson L, Thomson SK, Bruce KD, et al. 2013. Clinical measures of
disease in adult non-CF bronchiectasis correlate with airway microbiota composition. Thorax 68:73137
14. Rogers GB, Zain NM, Bruce KD, Burr LD, Chen AC, et al. 2014. A novel microbiota stratification
system predicts future exacerbations in bronchiectasis. Ann. Am. Thorac. Soc. 11:496503
15. Dickson RP, Martinez FJ, Huffnagle GB. 2014. The role of the microbiome in exacerbations of chronic
lung diseases. Lancet 384:691702
16. Hurst JR. 2014. Microbial dysbiosis in bronchiectasis. Lancet Respir. Med. 2:94547
17. Purcell P, Jary H, Perry A, Perry JD, Stewart CJ, et al. 2014. Polymicrobial airway bacterial communities
in adult bronchiectasis patients. BMC Microbiol. 14:130
18. Singleton R, Morris A, Redding G, Poll J, Holck P, et al. 2000. Bronchiectasis in Alaska Native children:
causes and clinical courses. Pediatr. Pulmonol. 29:18287
19. Twiss J, Metcalfe R, Edwards E, Byrnes C. 2005. New Zealand national incidence of bronchiectasis too
high for a developed country. Arch. Dis. Child. 90:73740

20. Chang AB, Grimwood K, Mulholland EK, Torzillo PJ, Working Group on Indigenous Paediatric Res-
piratory Health. 2002. Bronchiectasis in indigenous children in remote Australian communities. Med. J.
Aust. 177:2004
21. Boyton RJ, Smith J, Ward R, Jones M, Ozerovitch L, et al. 2006. HLA-C and killer cell immunoglobulin-
like receptor genes in idiopathic bronchiectasis. Am. J. Respir. Crit. Care Med. 173:32733
22. Wynn-Williams N. 1953. Bronchiectasis: a study centred on Bedford and its environs. BMJ 1:119499
23. Ringshausen FC, de Roux A, Pletz MW, Hamalainen N, Welte T, et al. 2013. Bronchiectasis-associated
hospitalizations in Germany, 20052011: a population-based study of disease burden and trends. PLOS
ONE 8:e71109
24. Seitz AE, Olivier KN, Adjemian J, Holland SM, Prevots R. 2000. Trends in bronchiectasis among
Medicare beneficiaries in the United States, 2000 to 2007. Chest 142:43239
25. Seitz AE, Olivier KN, Steiner CA, Montes de Oca R, Holland SM, et al. 2010. Trends and burden of
bronchiectasis-associated hospitalizations in the United States, 19932006. Chest 138:94449
26. Roberts HJ, Hubbard R. 2010. Trends in bronchiectasis mortality in England and Wales. Respir. Med.
104:98185
27. Loebinger MR, Wells AU, Hansell DM, Chinyanganya N, Devaraj A, et al. 2009. Mortality in bronchiec-
tasis: a long-term study assessing the factors influencing survival. Eur. Respir. J. 34:84349
28. Onen ZP, Gulbay BE, Sen E, Yildiz OA, Saryal S, et al. 2007. Analysis of the factors related to mortality
in patients with bronchiectasis. Respir. Med. 101:139097
29. Goeminne PC, Nawrot TS, Ruttens D, Seys S, Dupont LJ. 2014. Mortality in non-cystic fibrosis
bronchiectasis: a prospective cohort analysis. Respir. Med. 108:28796
30. Goeminne PC, Bijnens E, Nemery B, Nawrot TS, Dupont LJ. 2014. Impact of traffic related air pollution
indicators on non-cystic fibrosis bronchiectasis mortality: a cohort analysis. Respir. Res. 15:108
31. Kunst H, Wickremasinghe M, Wells A, Wilson R. 2006. Nontuberculous mycobacterial disease and
Aspergillus-related lung disease in bronchiectasis. Eur. Respir. J. 28:35257
32. Poppelwell L, Chalmers JD. 2014. Defining severity in non-cystic fibrosis bronchiectasis. Expert Rev.
Respir. Med. 8:24962
33. Martnez-Garca MA, de Gracia J, Vendrell Relat M, Giron RM, Maiz Carro L, et al. 2014. Multidi-
mensional approach to non-cystic fibrosis bronchiectasis: the FACED score. Eur. Respir. J. 43:135767
34. Chalmers JD, Goeminne P, Aliberti S, McDonnell MJ, Lonni S, et al. 2014. The bronchiectasis severity
index: an international derivation and validation study. Am. J. Respir. Crit. Care Med. 189:57685
35. Dorman SE, Picard C, Lammas D, Heyne K, van Dissel JT, et al. 2004. Clinical features of dominant
and recessive interferon receptor 1 deficiencies. Lancet 364:211321
36. Jenkins MR, Rudd-Schmidt JA, Lopez JA, Ramsbottom KM, Mannering SI, et al. 2015. Failed CTL/NK
cell killing and cytokine hypersecretion are directly linked through prolonged synapse time. J. Exp. Med.
212:30717
37. Orange JS. 2013. Natural killer cell deficiency. J. Allergy Clin. Immunol. 132:51525
38. Potter JL, Matthews LW, Spector S, Lemm J. 1967. Studies on pulmonary secretions. II. Osmolality
and the ionic environment of pulmonary secretions from patients with cystic fibrosis, bronchiectasis, and
laryngectomy. Am. Rev. Respir. Dis. 96:8387
39. Gaga M, Bentley AM, Humbert M, Barkans J, OBrien F, et al. 1998. Increases in CD4+ T lymphocytes,
macrophages, neutrophils and interleukin 8 positive cells in the airways of patients with bronchiectasis.
Thorax 53:68591
40. Tsang KW, Chan K, Ho P, Zheng L, Ooi GC, et al. 2000. Sputum elastase in steady-state bronchiectasis.
Chest 117:42026
41. Watt AP, Brown V, Courtney J, Kelly M, Garske L, et al. 2004. Neutrophil apoptosis, proinflammatory
mediators and cell counts in bronchiectasis. Thorax 59:23136
42. Chen AC, Martin ML, Lourie R, Rogers GB, Burr LD, et al. 2015. Adult non-cystic fibrosis bronchiec-
tasis is characterised by airway luminal Th17 pathway activation. PLOS ONE 10:e0119325
43. Altmann D, Boyton R. 2015. Nomenclature: replace pathogens with perceptogens. Nature 518:35
44. King PT, Holdsworth SR, Freezer NJ, Villanueva E, Holmes PW. 2007. Microbiologic follow-up study
in adult bronchiectasis. Respir. Med. 101:163338

45. Angrill J, Agust C, de Celis R, Rano A, Gonzalez J, et al. 2002. Bacterial colonisation in patients with
bronchiectasis: microbiological pattern and risk factors. Thorax 57:1519
46. Hare KM, Binks MJ, Grimwood K, Chang AB, Leach AJ, et al. 2012. Culture and PCR detection of
Haemophilus influenzae and Haemophilus haemolyticus in Australian Indigenous children with bronchiec-
tasis. J. Clin. Microbiol. 50:244445
47. McDonnell MJ, Jary HR, Perry A, MacFarlane JG, Hester KL. 2015. Non cystic fibrosis bronchiectasis:
a longitudinal retrospective observational cohort study of Pseudomonas persistence and resistance. Respir.
Med. 109:71626
48. Miszkiel KA, Wells AU, Rubens MB, Cole PJ, Hansell DM. 1997. Effects of airway infection by Pseudo-
monas aeruginosa: a computed tomographic study. Thorax 52:26064
49. Davies G, Wells AU, Doffman S, Watanabe S, Wilson R. 2006. The effect of Pseudomonas aeruginosa on
pulmonary function in patients with bronchiectasis. Eur. Respir. J. 28:97479
50. Martnez-Garca MA, Soler-Cataluna JJ, Perpina-Tordera M, Roman-Sanchez P, Soriano J. 2007. Fac-
tors associated with lung function decline in adult patients with stable non-cystic fibrosis bronchiectasis.
Chest 132:156572
51. de Wit R, Bouvier T. 2006. Everything is everywhere, but, the environment selects; what did Baas Becking
and Beijerinck really say? Environ. Microbiol. 8:75558
52. Worlitzsch D, Tarran R, Ulrich M, Schwab U, Cekici A, et al. 2002. Effects of reduced mucus oxygen
concentration in airway Pseudomonas infections of cystic fibrosis patients. J. Clin. Investig. 109:31725
53. Shan M, Gentile M, Yeiser JR, Walland AC, Bornstein VU, et al. 2013. Mucus enhances gut homeostasis
and oral tolerance by delivering immunoregulatory signals. Science 342:44753
54. King PT, Ngui J, Farmer MW, Hutchinson P, Holmes PW, Holdsworth SR. 2008. Cytotoxic T lym-
phocyte and natural killer cell responses to non-typeable Haemophilus influenzae. Clin. Exp. Immunol.
152:54251
55. Harrison A, Baker BD, Munson RS Jr. 2015. Overlapping and complementary oxidative stress defense
mechanisms in nontypeable Haemophilus influenzae. J. Bacteriol. 197:27785
56. Naylor EJ, Bakstad D, Biffen M, Thong B, Calverley P. 2007. Haemophilus influenzae induces neutrophil
necrosis: a role in chronic obstructive pulmonary disease? Am. J. Respir. Cell Mol. Biol. 37:13543
57. King PT, Hutchinson PE, Johnson PD, Holmes PW, Freezer NJ, Holdsworth SR. 2003. Adaptive
immunity to nontypeable Haemophilus influenzae. Am. J. Respir. Crit. Care Med. 167:58792
58. Pizzutto SJ, Yerkovich ST, Upham JW, Hales BJ, Thomas WR, Chang AB. 2104. Children with chronic
suppurative lung disease have a reduced capacity to synthesize interferon- in vitro in response to non-
typeable Haemophilus influenzae. PLOS ONE 9:e104236
59. Murphy TF. 2015. Vaccines for nontypeable Haemophilus influenzae: The future is now. Clin. Vaccine
Immunol. 22:45966
60. Pizzutto SJ, Yerkovich ST, Upham JW, Hales BJ, Thomas WR, et al. 2015. Improving immunity to
Haemophilus influenzae in children with chronic suppurative lung disease. Vaccine 33:32126
548 Boyton Altmann
61. Quigley KJ, Reynolds CJ, Goudet A, Raynsford EJ, Sergeant R, et al. 2015. Chronic infection by mucoid
Pseudomonas aeruginosa associated with dysregulation in T-cell immunity to outer membrane porin F.
Am. J. Respir. Crit. Care Med. 191:125064
62. Jensen P, Givskov M, Bjarnsholt T, Moser C. 2010. The immune system versus Pseudomonas aeruginosa
biofilms. FEMS Immunol. Med. Microbiol. 59:292305
63. Gellatly SL, Hancock RE. 2013. Pseudomonas aeruginosa: new insights into pathogenesis and host defenses.
Pathog. Dis. 67:15973
64. Doring G, Pier GB. 2008. Vaccines and immunotherapy against Pseudomonas aeruginosa. Vaccine 26:1011
24
65. Doring G, Meisner C, Stern M, Flagella Vaccine Trial Study Group. 2007. A double-blind randomized
placebo-controlled phase III study of a Pseudomonas aeruginosa flagella vaccine in cystic fibrosis patients.
PNAS. 104:1102025
66. Cattoir V, Narasimhan G, Skurnik D, Aschard H, Roux D, et al. 2013. Transcriptional response of
mucoid Pseudomonas aeruginosa to human respiratory mucus. mBio 3:e0041012
67. Balasubramanian D, Mathee K. 2009. Comparative transcriptome analyses of Pseudomonas aeruginosa.
Hum. Genom. 3:34961

68. Kwak HJ, Moon JY, Choi YW, Kim TH, Sohn JW, et al. 2010. High prevalence of bronchiectasis in
adults: analysis of CT findings in a health screening program. Tohoku J. Exp. Med. 222:23742
69. Chu H, Zhao L, Xiao H, Zhang Z, Zhang J, et al. 2014. Prevalence of nontuberculous mycobacteria in
patients with bronchiectasis: a meta-analysis. Arch. Med. Sci. 10:66168
70. Jarand J, Levin A, Zhang L, Huitt G, Mitchell JD, Daley CL. 2011. Clinical and microbiologic outcomes
in patients receiving treatment for Mycobacterium abscessus pulmonary disease. Clin. Infect. Dis. 52:56571
71. Griffith DE, Aksamit TR. 2012. Bronchiectasis and nontuberculous mycobacterial disease. Clin. Chest
Med. 33:28395
72. Jasenosky LD, Scriba TJ, Hanekom WA, Goldfeld AE. 2015. T cells and adaptive immunity to My-
cobacterium tuberculosis in humans. Immunol. Rev. 264:7487
73. Young LS. 1993. Mycobacterial diseases and the compromised host. Clin. Infect. Dis. 17 (Suppl. 2):S436
41
74. Murphy TF, Brauer BJ, et al. 2005. Moraxella catarrhalis in chronic obstructive pulmonary disease: burden
of disease and immune response. Am. J. Respir. Crit. Care Med. 172:19599
75. Yang M, Johnson A, Murphy TF. 2011. Characterization and evaluation of the Moraxella catarrhalis
oligopeptide permease A as a mucosal vaccine antigen. Infect. Immun. 79:84657
76. Brook I. 2011. Anaerobic infections in children. Adv. Exp. Med. Biol. 697:11752
77. Tunney MM, Field TR, Moriarty TF, Patrick S, Doering G, et al. 2008. Detection of anaerobic bacteria
in high numbers in sputum from patients with cystic fibrosis. Am. J. Respir. Crit. Care Med. 177:9951001
78. Scher JU, Ubeda C, Equinda M, Khanin R, Buischi Y, et al. 2012. Periodontal disease and the oral
microbiota in new-onset rheumatoid arthritis. Arthritis Rheum. 64:308394
79. Scher JU, Sczesnak A, Longman RS, Segata N, Ubeda C, et al. 2013. Expansion of intestinal 79. An example from a
Prevotella copri correlates with enhanced susceptibility to arthritis. eLife 2:e01202 cohort of patients with
80. Potempa M, Potempa J, Kantyka T, Nguyen KA, Wawrzonek K. 2009. Interpain A, a cysteine proteinase rheumatoid arthritis
demonstrated that the
from Prevotella intermedia, inhibits complement by degrading complement factor C3. PLOS Pathog.
microbiota correlates
5:e1000316
with disease and
81. Nguyen LD, Viscogliosi E, Delhaes L. 2015. The lung mycobiome: an emerging field of the human
mechanism.
respiratory microbiome. Frontiers Microbiol. 16:89
82. Kosmidis C, Denning DW. 2015. The clinical spectrum of pulmonary aspergillosis. Thorax 70:27077
83. Moss RB. 2015. Fungi in cystic fibrosis and non-cystic fibrosis bronchiectasis. Semin. Respir. Crit. Care
Med. 36:20716 85. Provides a definitive
84. Engel S. 1947. The Childs Lung. London: Arnold piece of bronchiectasis
85. Whitwell F. 1952. A study of the pathology and pathogenesis of bronchiectasis. Thorax 7:21339 history, documenting
86. Gao Y, Guan W, Xu G, Lin Z, Tang Y, et al. 2015. The role of viral infection in pulmonary exacerbations pathological findings in
of bronchiectasis in adults: a prospective study. Chest 147:163543 a large cohort.
87. Kapur N, Mackay IM, Sloots TP, Masters IB, Chang AB. 2014. Respiratory viruses in exacerbations of
non-cystic fibrosis bronchiectasis in children. Arch. Dis. Child. 99:74953
88. Huttenhower C, Kostic AD, Xavier RJ. 2014. Inflammatory bowel disease as a model for translating the
microbiome. Immunity 40:84354
89. Cox MJ, Allgaier M, Taylor B, Baek MS, Huang YJ, et al. 2010. Airway microbiota and pathogen
abundance in age-stratified cystic fibrosis patients. PLOS ONE 5:e11044
90. Mansour SC, Pena OM, Hancock RE. 2014. Host defense peptides: front-line immunomodulators.
Trends Immunol. 35:44350
91. Pernet E, Guillemot L, Burgel PR, Martin C, Lambeau G, et al. 2014. Pseudomonas aeruginosa eradicates
Staphylococcus aureus by manipulating the host immunity. Nat. Commun. 5:5105
92. Presents the first 92. Ivanov II, Atarashi K, Manel N, Brodie EL, et al. 2009. Induction of intestinal Th17 cells by
demonstration that a segmented filamentous bacteria. Cell 139:48598
defined microbiota 93. Atarashi K, Tanoue T, Oshima K, Suda W, Nagano Y, et al. 2013. Treg induction by a rationally selected
species could shape mixture of Clostridia strains from the human microbiota. Nature 500:23236
Th17 differentiation.
94. Larsen JM, Musavian HS, Butt TM, Ingvorsen C, Thysen AH. 2015. Chronic obstructive pulmonary
disease and asthma-associated Proteobacteria, but not commensal Prevotella spp., promote Toll-like
receptor 2-independent lung inflammation and pathology. Immunology 144:33342

95. Lozupone C, Cota-Gomez A, Palmer BE, Linderman DJ, Charlson ES, et al. 2013. Widespread colo-
nization of the lung by Tropheryma whipplei in HIV infection. Am. J. Respir. Crit. Care Med. 187:1110
17
96. Provided evidence 96. Trompette A, Gollwitzer ES, Yadava K, Sichelstiel AK, Sprenger N. 2014. Gut microbiota
that diet can alter both metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat. Med.
the gut and the lung 20:15966
microbiota, with
97. Walker AW, Duncan SH, Louis P, Flint HJ. 2104. Phylogeny, culturing, and metagenomics of the
impacts on lung
human gut microbiota. Trends Microbiol. 22:26774
inflammation.
98. Integrative HMP (iHMP) Research Network Consortium. 2014. The Integrative Human Microbiome
Project: dynamic analysis of microbiome-host omics profiles during periods of human health and disease.
Cell Host Microbe 16:27689
99. Abubucker S, Segata N, Goll J, Schubert AM, Izard J, et al. 2012. Metabolic reconstruction for metage-
nomic data and its application to the human microbiome. PLOS Comput. Biol. 8:e1002358
100. Ostedgaard LS, Meyerholz DK, Chen JH, Pezzulo AA, Karp PH, et al. 2011. The F508 mutation
causes CFTR misprocessing and cystic fibrosis-like disease in pigs. Sci. Transl. Med. 3:74ra24
101. Human Microbiome Project Consortium. 2102. Structure, function and diversity of the healthy human
microbiome. Nature 486:20714
102. Provided a 102. Bassis CM, Erb-Downward JR, Dickson RP, Freeman CM, Schmidt TM, et al. 2015. Analysis
comprehensive analysis of the upper respiratory tract microbiotas as the source of the lung and gastric microbiotas in
of the microbiota of the healthy individuals. mBio 6:e00037
healthy human lung.
103. Barfod KK, Roggenbuck M, Hansen LH, Schjrring S, Larsen ST, et al. 2013. The murine lung micro-
biome in relation to the intestinal and vaginal bacterial communities. BMC Microbiol. 13:303
104. Segal LN, Alekseyenko AV, Clemente JC, Kulkarni R, Wu B, et al. 2013. Enrichment of lung microbiome
with supraglottic taxa is associated with increased pulmonary inflammation. Microbiome 1:19
105. Faust K, Sathirapongsasuti JF, Izard J, Segata N, Gevers D, et al. 2012. Microbial co-occurrence rela-
tionships in the human microbiome. PLOS Comput. Biol. 8:e1002606
106. Faith JJ, Ahern PP, Ridaura VK, Cheng J, Gordon JI. 2014. Identifying gut microbehost phenotype
relationships using combinatorial communities in gnotobiotic mice. Sci. Transl. Med. 6:220ra11
107. Lawley TD, Clare S, Walker AW, Stares MD, Connor TR, et al. 2012. Targeted restoration of the
intestinal microbiota with a simple, defined bacteriotherapy resolves relapsing Clostridium difficile disease
in mice. PLOS Pathog. 8:e1002995
108. Cho I, Blaser MJ. 2012. The human microbiome: at the interface of health and disease. Nat. Rev. Genet.
13:26070
109. Brown EM, Sadarangani M, Finlay BB. 2013. The role of the immune system in governing hostmicrobe
interactions in the intestine. Nat. Immunol. 14:66067
110. Morgan XC, Tickle TL, Sokol H, Gevers D, et al. 2012. Dysfunction of the intestinal microbiome in
inflammatory bowel disease and treatment. Genome Biol. 13:R79
550 Boyton Altmann
111. Eaton TE, Lambie N, Wells AU. 1998. Bronchiectasis following colectomy for Crohns disease. Thorax
53:52931
112. Butland RJ, Cole P, Citron KM, Turner-Warwick M. 1981. Chronic bronchial suppuration and 112. Presented the first
inflammatory bowel disease. Q JM. 50:6375 detailed description of
113. Black H, Mendoza M, Murin S. 2007. Thoracic manifestations of inflammatory bowel disease. Chest bronchiectasis in a
131:52432 cohort with
114. Mahadeva R, Flower C, Shneerson J. 1998. Bronchiectasis in association with coeliac disease. Thorax inflammatory bowel
53:52729 disease (IBD).
115. Sollid LM. 2000. Molecular basis of celiac disease. Annu. Rev. Immunol. 18:5381
116. Fallang LE, Bergseng E, Hotta K, Berg-Larsen A, Kim CY, Sollid LM. 2009. Differences in the risk
of celiac disease associated with HLA-DQ2.5 or HLA-DQ2.2 are related to sustained gluten antigen
presentation. Nat. Immunol. 10:1096101
117. Boyton RJ, Reynolds C, Wahid FN, Jones MG, Ozerovitch L, et al. 2006. IFN and CXCR-1 gene
polymorphisms in idiopathic bronchiectasis. Tissue Antigens 68:32530
118. Stockley RA. 1998. Commentary: bronchiectasis and inflammatory bowel disease. Thorax 53:52627
119. Wilczynska MM, Condliffe AM, McKeon DJ. 2013. Coexistence of bronchiectasis and rheumatoid
arthritis: revisited. Respir. Care 58:694701
120. Demoruelle MK, Weisman MH, Simonian PL, Lynch DA, et al. 2012. Brief report: airways abnormalities
and rheumatoid arthritis-related autoantibodies in subjects without arthritis: early injury or initiating
site of autoimmunity? Arthritis Rheum. 64:175661
121. El Maghraoui A, Dehhaoui M. 2012. Prevalence and characteristics of lung involvement on high res-
olution computed tomography in patients with ankylosing spondylitis: a systematic review. Pulm. Med.
2012:965956
122. Soto-Cardenas MJ, Perez-De-Lis M, Bove A, Navarro C, Brito-Zeron P, et al. 2010. Bronchiectasis in
primary Sjogrens syndrome: prevalence and clinical significance. Clin. Exp. Rheumatol. 28:64753
123. Fenlon HM, Doran M, Sant SM, Breatnach E. 1996. High-resolution chest CT in systemic lupus
erythematosus. Am. J. Roentgenol. 166:3017
124. Andonopoulos AP, Yarmenitis S, Georgiou P, Bounas A, Vlahanastasi C. 2001. Bronchiectasis in systemic
sclerosis: a study using high resolution computed tomography. Clin. Exp. Rheumatol. 19:18790
125. Homma S, Suzuki A, Sato K. 2013. Pulmonary involvement in ANCA-associated vasculitis from the
view of the pulmonologist. Clin. Exp. Nephrol. 17:66771
126. De Luca F, Valenzise M, Alaggio R, Arrigo T, Crisafulli G, et al. 2008. Sicilian family with autoimmune
polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) and lethal lung disease in one of the
affected brothers. Eur. J. Pediatr. 167:128388
127. Farh KK, Marson A, Zhu J, Kleinewietfeld M, Housley WJ, et al. 2015. Genetic and epigenetic fine
mapping of causal autoimmune disease variants. Nature 518:33743
128. Hilton AM, Doyle L. 1978. Immunological abnormalities in bronchiectasis with chronic bronchial sup-
puration. Br. J. Dis. Chest 72:20716
129. Demoruelle MK, Deane KD, Holers VM. 2014. When and where does inflammation begin in rheumatoid
arthritis? Curr. Opin. Rheumatol. 26:6471
130. Willis VC, Demoruelle MK, Derber LA, Chartier-Logan CJ, Parish MC. 2013. Sputum autoantibodies
in patients with established rheumatoid arthritis and subjects at risk of future clinically apparent disease.
Arthritis Rheum. 65:254554
131. Puechal X, Genin E, Bienvenu T, Le Jeunne C, Dusser DJ. 2014. Poor survival in rheumatoid arthritis
associated with bronchiectasis: a family-based cohort study. PLOS ONE 9:e110066 135. Provided a detailed
analysis of the
132. Aronoff A, Bywaters E, Fearnley G. 1955. Lung lesions in rheumatoid arthritis. BMJ 2:22832
epidemiology of
133. Allain J, Saraux A, Guedes C, Valls I, Devauchelle V. 1997. Prevalence of symptomatic bronchiectasis
bronchiectasis in
in patients with rheumatoid arthritis. Rev. Rhum. Engl. Ed. 64:53137 relation to ethnicity and
134. Mori S, Koga Y, Sugimoto M. 2012. Different risk factors between interstitial lung disease and airway microbiology in the
disease in rheumatoid arthritis. Respir. Med. 106:159199 United States.
135. McShane PJ, Naureckas ET, Strek ME. 2012. Bronchiectasis in a diverse US population: effects
of ethnicity on etiology and sputum culture. Chest 142:15967
136. McShane PJ, Naureckas ET, Tino G, Strek ME. 2013. Non-cystic fibrosis bronchiectasis. Am. J. Respir.
Crit. Care Med. 188:64756
137. Helmick CG, Felson DT, Lawrence RC, Gabriel S, Hirsch R, et al. 2008. Estimates of the prevalence
of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum. 58:1525
138. Despaux J, Toussirot E, Wendling D. 1997. Bronchectasies et polyarthrite rhumatode. Frequence et as-
pects etiopathogeniques. Revue de la litterature [Bronchiectasis and rheumatoid arthritis. Incidence and
etiopathogenic aspects. Review of the literature]. Rev. Med. Intern. 18:14452
139. Perry E, Stenton C, Kelly C, Eggleton P, Hutchinson D, De Soyza A. 2014. RA autoantibodies as
predictors of rheumatoid arthritis in non-cystic fibrosis bronchiectasis patients. Eur. Respir. J. 44:1082
85
140. Chen AC, Martin ML, Lourie R, Rogers GB, Burr LD, et al. 2015. Adult non-cystic fibrosis bronchiec-
tasis is characterised by airway luminal Th17 pathway activation. PLOS ONE 10:e0119325
141. Sherlock JP, Taylor PC, Buckley CD. 2015. The biology of IL-23 and IL-17 and their therapeutic
targeting in rheumatic diseases. Curr. Opin. Rheumatol. 27:7175
142. Wegner N, Wait R, Sroka A, Eick S, Nguyen KA. 2010. Peptidylarginine deiminase from Porphyromonas
gingivalis citrullinates human fibrinogen and -enolase: implications for autoimmunity in rheumatoid
arthritis. Arthritis Rheum. 62:266272
143. Rangel-Moreno J, Hartson L, Navarro C, Gaxiola M, Selman M, et al. 2006. Inducible bronchus-
associated lymphoid tissue (iBALT) in patients with pulmonary complications of rheumatoid arthritis.
J. Clin. Investig. 116:318394
144. Rangel-Moreno J, Carragher DM, de la Luz Garcia-Hernandez M, Hwang JY, Kusser K, et al. 2011.
The development of inducible bronchus-associated lymphoid tissue depends on IL-17. Nat. Immunol.
12:63946
145. Eller J, Lapa e Silva JR, Poulter LW, Lode H, Cole PJ. 1994. Cells and cytokines in chronic bronchial
infection. Ann. N. Y. Acad. Sci. 725:33145
146. Mathis D, Benoist C. 2009. Aire. Annu. Rev. Immunol. 27:287312
147. Chalmers JD, Hill AT. 2013. Mechanisms of immune dysfunction and bacterial persistence in non-cystic
fibrosis bronchiectasis. Mol. Immunol. 55:2734
148. Gadola SD, Moins-Teisserenc HT, Trowsdale J, Gross WL, Cerundolo V. 2000. TAP deficiency syn-
drome. Clin. Exp. Immunol. 121:17378
149. Paulson ML, Freeman AF, Holland SM. 2008. Hyper IgE syndrome: an update on clinical aspects and
the role of signal transducer and activator of transcription 3. Curr. Opin. Allergy Clin. Immunol. 8:52733
150. Holland SM. 2010. Chronic granulomatous disease. Clin. Rev. Allergy Immunol. 38:310
151. Fuschillo S, De Felice A, Balzano G. 2008. Mucosal inflammation in idiopathic bronchiectasis: cellular
and molecular mechanisms. Eur. Respir. J. 31:396406
152. Tiringer K, Treis A, Fucik P, Gona M, Gruber S, et al. 2013. A Th17- and Th2-skewed cytokine profile
in cystic fibrosis lungs represents a potential risk factor for Pseudomonas aeruginosa infection. Am. J. Respir.
153. Way EE, Chen K, Kolls JK. 2013. Dysregulation in lung immunitythe protective and pathologic Th17
response in infection. Eur. J. Immunol. 43:311624
154. Tan HL, Regamey N, Brown S, Bush A, Lloyd CM, et al. 2011. The Th17 pathway in cystic fibrosis
lung disease. Am. J. Respir. Crit. Care Med. 184:25258
155. Fogli LK, Sundrud MS, Goel S, Bajwa S, Jensen K, et al. 2013. T cell-derived IL-17 mediates epithelial
changes in the airway and drives pulmonary neutrophilia. J. Immunol. 191:310011
156. King PT, Hutchinson P, Holmes PW, Freezer NJ, Bennett-Wood V, et al. 2006. Assessing immune
function in adult bronchiectasis. Clin. Exp. Immunol. 144:44046
157. De Gracia J, Rodrigo MJ, Morell F, Vendrell M, Miravitlles M, et al. 1996. IgG subclass deficiencies
associated with bronchiectasis. Am. J. Respir. Crit. Care Med. 153:65055
158. Hill SL, Mitchell JL, Burnett D, Stockley RA. 1998. IgG subclasses in the serum and sputum from
patients with bronchiectasis. Thorax 53:46368
159. Silva JR, Jones JA, Cole PJ, Poulter LW. 1989. The immunological component of the cellular inflam-
matory infiltrate in bronchiectasis. Thorax 44:66873
552 Boyton Altmann
160. Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA. 2004. Loss of functional suppression by
CD4+ CD25+ regulatory T cells in patients with multiple sclerosis. J. Exp. Med. 199:97179
161. Magliozzi R, Howell O, Vora A, Serafini B, Nicholas R, et al. 2007. Meningeal B-cell follicles in secondary
progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain
130(Pt. 4):1089104
162. Peters A, Pitcher LA, Sullivan JM, Mitsdoerffer M, Acton SE, et al. 2011. Th17 cells induce ectopic
lymphoid follicles in central nervous system tissue inflammation. Immunity 35:98696
163. Pitzalis C, Jones GW, Bombardieri M, Jones SA. 2014. Ectopic lymphoid-like structures in infection,
cancer and autoimmunity. Nat. Rev. Immunol. 14:44762
164. Boyton RJ, Smith J, Jones M, Reynolds C, Ozerovitch L, et al. 2008. Human leucocyte antigen class II
association in idiopathic bronchiectasis, a disease of chronic lung infection, implicates a role for adaptive
immunity. Clin. Exp. Immunol. 152:95101
165. Suarez-Almazor ME, Tao S, Moustarah F, Russell AS, Maksymowych W. 1995. HLA-DR1, DR4, and
DRB1 disease related subtypes in rheumatoid arthritis: association with susceptibility but not severity in
a city wide community based study. J. Rheumatol. 22:202733

166. Khakoo SI, Carrington M. 2006. KIR and disease: a model system or system of models? Immunol. Rev.
214:186201
167. Boyton RJ, Altmann DM. 2007. Natural killer cells, killer immunoglobulin-like receptors and human
leucocyte antigen class I in disease. Clin. Exp. Immunol. 149:18
168. McDonnell MJ, Anwar GA, Rutherford RM, De Soyza A, Worthy S, et al. 2014. Lack of association
between KIR and HLA-C type and susceptibility to idiopathic bronchiectasis. Respir. Med. 108:112733
169. Wesselkamper SC, Eppert BL, Motz GT, Lau GW, Hassett DJ, et al. 2008. NKG2D is critical for NK
cell activation in host defense against Pseudomonas aeruginosa respiratory infection. J. Immunol. 181:5481
89
170. Giamarellos-Bourboulis EJ. 2014. Natural killer cells in sepsis: detrimental role for final outcome. Crit.
Care Med. 42:157980
171. Miyazaki S, Ishikawa F, Shimizu K, Ubagai T, Edelstein PH, Yamaguchi K. 2007. Gr-1high poly-
morphonuclear leukocytes and NK cells act via IL-15 to clear intracellular Haemophilus influenzae in
experimental murine peritonitis and pneumonia. J. Immunol. 179:540714
172. Lu CC, Wu TS, Hsu YJ, Chang CJ, et al. 2014. NK cells kill mycobacteria directly by releasing perforin
and granulysin. J. Leukoc. Biol. 96:111929
173. Currie DC, Saverymuttu SH, Peters AM, Needham SG, George P, et al. 1987. Indium-111-labelled
granulocyte accumulation in respiratory tract of patients with bronchiectasis. Lancet 329:133539
174. Chalmers JD, Aliberti S, Blasi F. 2015. Management of bronchiectasis in adults. Eur. Respir. J. 45:144662
175. Chang AB, Marsh RL, Smith-Vaughan HC, Hoffman LR. 2015. Emerging drugs for bronchiectasis: an
update. Expert Opin. Emerg. Drugs 20:27797
176. Main E, Grillo L, Rand S. 2015. Airway clearance strategies in cystic fibrosis and non-cystic fibrosis
bronchiectasis. Semin. Respir. Crit. Care Med. 36:25166
177. Tay GT, Reid DW, Bell SC. 2015. Inhaled antibiotics in cystic fibrosis (CF) and non-CF bronchiectasis.
Semin. Respir. Crit. Care Med. 36:26786
178. Chalmers JD, Loebinger M, Aliberti S. 2015. Challenges in the development of new therapies for
bronchiectasis. Expert Opin. Pharm. 16:83350
179. Sidhu MK, Mandal P, Hill AT. 2015. Developing drug therapies in bronchiectasis. Expert Opin. Investig.
Drugs 24:16981
180. De Soyza A, Brown JS, Loebinger MR, Bronchiectasis Research & Academic Network. 2013. Research
priorities in bronchiectasis. Thorax 68:69596
181. Bilton D, Loebinger MR, Wilson R. 2014. Non-cystic fibrosis bronchiectasis: an evidence-base for new
therapies. Lancet Respir. Med. 2:95860
182. Hill AT, Welham S, Reid K, Bucknall CE, British Thoracic Society. 2012. British Thoracic Society
national bronchiectasis audit 2010 and 2011. Thorax 67:92830
183. Blasi F, Chalmers JD, Aliberti S. 2014. COPD and bronchiectasis: phenotype, endotype or co-morbidity?
COPD 11:6034
184. Hurst JR, Elborn JS, De Soyza A, BRONCH-UK Consortium. 2015. COPDbronchiectasis overlap
syndrome. Eur. Respir. J. 45:31013
185. Chalmers JD, Smith MP, McHugh BJ, Dohery C, Govan JR, et al. 2012. Short- and long-term antibiotic
treatment reduces airway and systemic inflammation in non-cystic fibrosis bronchiectasis. Am. J. Respir.
186. Wong C, Jayaram L, Karalus N, Eaton T, Tong C, et al. 2012. Azithromycin for prevention of exacerba-
tions in non-cystic fibrosis bronchiectasis (EMBRACE): a randomised, double-blind, placebo-controlled
trial. Lancet 380:66067
187. Serisier DJ, Martin ML, McGuckin MA, Lourie R, Chen AC, et al. 2013. Effect of long-term, low-dose
erythromycin on pulmonary exacerbations among patients with non-cystic fibrosis bronchiectasis: the
BLESS randomized controlled trial. JAMA 309:12607
188. Altenburg J, de Graaff CS, Stienstra Y, Sloos JH, van Haren EH, et al. 2013. Effect of azithromycin main-
tenance treatment on infectious exacerbations among patients with non-cystic fibrosis bronchiectasis:
the BAT randomized controlled trial. JAMA 309:125159
189. Albert RK, Connett J, Bailey WC, Casaburi R, Cooper JA Jr, et al. 2011. Azithromycin for prevention
of exacerbations of COPD. N. Engl. J. Med. 365:68998

190. Rogers GB, Bruce KD, Martin ML, Burr LD, Serisier DJ. 2014. The effect of long-term macrolide
treatment on respiratory microbiota composition in non-cystic fibrosis bronchiectasis: an analysis from
the randomised, double-blind, placebo-controlled BLESS trial. Lancet Respir. Med. 2:98896
191. Chalmers JD, McHugh BJ, Docherty C, Govan JR, Hill AT. 2013. Vitamin-D deficiency is associated
with chronic bacterial colonisation and disease severity in bronchiectasis. Thorax 68:3947
192. Hewison M. 2012. An update on vitamin D and human immunity. Clin. Endocrinol. 76:31525
193. Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, et al. 2014. Mepolizumab treatment in
patients with severe eosinophilic asthma. N. Engl. J. Med. 371:1198207
194. Mahler DA, Huang S, Tabrizi M, Bell GM. 2004. Efficacy and safety of a monoclonal antibody recog-
nizing interleukin-8 in COPD: a pilot study. Chest 126:92634
195. van den Berg WB, McInnes IB. 2013. Th17 cells and IL-17a focus on immunopathogenesis and
immunotherapeutics. Semin. Arthritis Rheum. 43:15870
196. Clarke TB. 2014. Early innate immunity to bacterial infection in the lung is regulated systemically by
the commensal microbiota via Nod-like receptor ligands. Infect. Immun. 82:4596606
197. Wilson CB, Jones PW, OLeary CJ, Hansell DM, Cole PJ, et al. 1997. Effect of sputum bacteriology on
the quality of life of patients with bronchiectasis. Eur. Respir. J. 10:175460
198. Hare KM, Grimwood K, Leach AJ, Smith-Vaughan H, Torzillo PJ, et al. 2010. Respiratory bacterial
pathogens in the nasopharynx and lower airways of Australian indigenous children with bronchiectasis.
J. Pediatr. 157:10015
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PM11CH20-Boyton ARI 23 February 2016 13:8

Review in Advance first posted online

still occur before final publication

Rosemary J. Boyton1,2 and Daniel M. Altmann3

Annu. Rev. Pathol. Mech. Dis. 2016. 11:52354 Keywords

This articles doi: Abstract

with recurrent infection and impaired pathogen clearance.

524 Boyton Altmann

Table 1 Underlying causes and associations of bronchiectasis

of toxics, or local bronchial Overdose (e.g., intravenous heroin)

www.annualreviews.org Bronchiectasis: Immunity and Microbiology 525

526 Boyton Altmann

www.annualreviews.org Bronchiectasis: Immunity and Microbiology 527

528 Boyton Altmann

www.annualreviews.org Bronchiectasis: Immunity and Microbiology 529

14 Staphylococcus aureus common for Haemophilus influenzae

Haemophilus influenzae and Pseudomonas aeruginosa. Studies on the microbiology of spu-

530 Boyton Altmann

Nontuberculous mycobacteria. CT and X-ray evidence of bronchiectatic changes may be the

www.annualreviews.org Bronchiectasis: Immunity and Microbiology 531

enhanced susceptibility to MAC and other NTM (73).

Moraxella, Veillonella, and Prevotella. Moraxella catarrhalis is a gram-negative commensal of the

532 Boyton Altmann

Viral Infections and Exacerbations

INFLUENCE OF THE LUNG MICROBIOTA

www.annualreviews.org Bronchiectasis: Immunity and Microbiology 533

534 Boyton Altmann

RELATIONSHIP TO INFLAMMATORY BOWEL DISEASE

www.annualreviews.org Bronchiectasis: Immunity and Microbiology 535

bronchiectasis may offer valuable mechanistic insights.

OVERLAP WITH OTHER AUTOIMMUNE CONDITIONS

536 Boyton Altmann

www.annualreviews.org Bronchiectasis: Immunity and Microbiology 537

Ankylosing Spondylitis, Sjogrens Syndrome, Systemic Lupus Erythematosus,

538 Boyton Altmann

IMMUNE MECHANISMS AND EVIDENCE FOR

www.annualreviews.org Bronchiectasis: Immunity and Microbiology 539

540 Boyton Altmann

Mucus IL-8 MMP-1, MMP-8 IL-17 Neutrophil elastase 7

Th17 Th17 Th17 Th17 Th17 AHR

www.annualreviews.org Bronchiectasis: Immunity and Microbiology 541

distinctions between types of bronchiectatic disease, possibly relating to disease-initiating pro-

542 Boyton Altmann

PROSPECTS FOR NEW THERAPEUTICS

www.annualreviews.org Bronchiectasis: Immunity and Microbiology 543

544 Boyton Altmann

www.annualreviews.org Bronchiectasis: Immunity and Microbiology 545

6. As in many chronic, inflammatory, or autoimmune diseases, outcomes would be im-

might be perceived as affecting the objectivity of this review.

546 Boyton Altmann

high for a developed country. Arch. Dis. Child. 90:73740

www.annualreviews.org Bronchiectasis: Immunity and Microbiology 547

in adult bronchiectasis. Respir. Med. 101:163338

548 Boyton Altmann

Hum. Genom. 3:34961

www.annualreviews.org Bronchiectasis: Immunity and Microbiology 549

receptor 2-independent lung inflammation and pathology. Immunology 144:33342

550 Boyton Altmann

www.annualreviews.org Bronchiectasis: Immunity and Microbiology 551

552 Boyton Altmann

a city wide community based study. J. Rheumatol. 22:202733

www.annualreviews.org Bronchiectasis: Immunity and Microbiology 553

of exacerbations of COPD. N. Engl. J. Med. 365:68998