Article published online: 2021-07-14

499

Pathophysiology of Bronchiectasis
Holly R. Keir, BSc1 James D. Chalmers, MBChB, PhD, FRCPE, FERS1

1 Scottish Centre for Respiratory Research, University of Dundee, Address for correspondence Holly R. Keir, BSc, Division of Molecular
Dundee, United Kingdom and Clinical Medicine, Mailbox 12, Level 5, School of Medicine,
Ninewells Hospital and Medical School, Dundee DD1 9SY, United
Semin Respir Crit Care Med 2021;42:499–512. Kingdom (e-mail: [email protected]).

Abstract Bronchiectasis is a complex, heterogeneous disorder defined by both a radiological

abnormality of permanent bronchial dilatation and a clinical syndrome. There are
multiple underlying causes including severe infections, mycobacterial disease, auto-

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
immune conditions, hypersensitivity disorders, and genetic conditions. The patho-
physiology of disease is understood in terms of interdependent concepts of chronic
infection, inflammation, impaired mucociliary clearance, and structural lung damage.
Neutrophilic inflammation is characteristic of the disease, with elevated levels of
harmful proteases such as neutrophil elastase associated with worse outcomes. Recent
data show that neutrophil extracellular trap formation may be the key mechanism
leading to protease release and severe bronchiectasis. Despite the dominant of
neutrophilic disease, eosinophilic subtypes are recognized and may require specific
treatments. Neutrophilic inflammation is associated with elevated bacterial loads and
chronic infection with organisms such as Pseudomonas aeruginosa. Loss of diversity of
the normal lung microbiota and dominance of proteobacteria such as Pseudomonas and
Haemophilus are features of severe bronchiectasis and link to poor outcomes. Ciliary
dysfunction is also a key feature, exemplified by the rare genetic syndrome of primary
ciliary dyskinesia. Mucus symptoms arise through goblet cell hyperplasia and metapla-
Keywords sia and reduced ciliary function through dyskinesia and loss of ciliated cells. The
► bronchiectasis contribution of chronic inflammation, infection, and mucus obstruction leads to
► inflammation progressive structural lung damage. The heterogeneity of the disease is the most
► airway infection challenging aspect of management. An understanding of the pathophysiology of
► personalized disease and their biomarkers can help to guide personalized medicine approaches
medicine utilizing the concept of “treatable traits.”

Bronchiectasis is characterized by a dysregulated inflamma- chiectasis either in the advanced stages of disease or as part
tory response which results in lung damage; abnormal, of a specific underlying etiology, such as cystic fibrosis (CF) or
irreversible dilation of the bronchi; and recurrent bacterial primary ciliary dyskinesia (PCD),5,6 which, although useful,
infection. Although once considered an “orphan disease,” the means that our understanding of other stages and etiologies
incidence and prevalence of bronchiectasis has increased of bronchiectasis are still lacking.
40% in the past 10 years throughout the world, with rates of There are many underlying causes of bronchiectasis and
up to 566 per 100,000 population being reported.1,2 Despite in up 50% of patients, no cause is identified (summarized
this, the pathophysiology and underlying mechanisms of in ►Table 1).7 Causes can include postinfectious, bacterial
bronchiectasis are still poorly understood.3,4 The heteroge- infections, such as severe pneumonia or tuberculosis;
neity of bronchiectasis coupled with a lack of both experi- congenital conditions such as CF and PCD; aspiration syn-
mental and animal models has made research efforts more dromes; primary or secondary immunodeficiency; hyper-
challenging. Many previous studies have investigated bron- sensitivity disorders such as allergic bronchopulmonary

Issue Theme Bronchiectasis: Advances © 2021. Thieme. All rights reserved. DOI https://doi.org/
in Diagnosis and Treatment; Guest Thieme Medical Publishers, Inc., 10.1055/s-0041-1730891.
Editor: James D. Chalmers, MBChB, PhD, 333 Seventh Avenue, 18th Floor, ISSN 1069-3424.
FRCPE, FERS New York, NY 10001, USA
500 Pathophysiology of Bronchiectasis Keir, Chalmers

Table 1 Etiologies of bronchiectasis biology and pathophysiology of bronchiectasis is critical to

the development of new therapies.
Idiopathic
Postinfective
The Vicious Cycle and Vicious Vortex
Bacterial (e.g., pseudomonas, haemophilus)
The hypothesis of a “vicious cycle” of bronchiectasis was first
Viral (e.g., human immunodeficiency virus, influenzae
proposed by Cole in 1986.15 In this model, impaired mucocili-
virus, adenovirus)
ary clearance results in an accumulation of airway secretions
Mycobacterium tuberculosis
that disrupt normal host defenses, leaving the patient more
Aspergillus species
vulnerable to infection. Persistent infection triggers an inflam-
Secondary lung disease mation response which causes abnormal airway remodeling
Chronic obstructive pulmonary disease and structural damage. This cycle of events results in a persis-
Asthma tent and progressive process with an “entry point” that can be
related to the underlying etiology of bronchiectasis. For exam-
Allergic bronchopulmonary aspergillosis

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
ple, inflammatory bowel disease induces localized inflamma-
Interstitial lung disease
tion and structural damage; patients with CF and PCD have
Congenital condition impaired mucociliary clearance resulting in increased suscep-
Cystic fibrosis tibility to infections5; and immunodeficiency can result in
Primary ciliary dyskinesia chronic infections. It is important to note that the interactions
within the cycle are highly complex and will not always take
Marfan’s syndrome
place in a stepwise fashion; it is likely that each component of
Williams–Campbell syndrome the pathophysiology contributes to all others. This model was
Mounier–Kuhn syndrome therefore further revised by Flume et al to describe a vicious
Yellow nail syndrome vortex, where airway dysfunction, airway inflammation, in-
fection, and structural damage are linked.1 There is convincing
Young’s syndrome
evidence for this interconnected concept since, for example,
Immunodeficiency Pseudomonas aeruginosa infection induces neutrophilic in-
Alpha-1 antitrypsin deficiency flammation by promoting the release of chemotactic factors
Hypogammaglobulinemia such as CXCL-8 (chemokine [C-X-C motif] ligand 8), interleukin
(IL)-1β, and others, but also directly affects mucociliary clear-
Secondary to cancer (e.g., chronic lymphatic leukemia,
chemotherapy, or immune modulation) ance through the action of ciliotoxins such as pyocyanin which
slows down ciliary beat frequency. Pseudomonas elastase may
Inflammatory disease
direct damage lung structure. P. aeruginosa infection is there-
Rheumatoid arthritis fore only one example of why an interdependent vortex rather
Inflammatory bowel disease than cycle model is a more accurate representation of bron-
Crohn’s disease chiectasis pathophysiology (►Fig. 1).
This may explain why “breaking the cycle” with treatments
Connective tissue disease
for bronchiectasis has not consistently demonstrated clinical
Systemic lupus erythematosus benefits. Inhaled antibiotics and anti-inflammatory therapies
Aspiration/esophageal reflux are among the principle therapies for bronchiectasis, but when
Anatomical disruption used individually only target one aspect of the vicious vor-
tex.16,17 Although inhaled antibiotic treatments may reduce
Intraluminal airway obstruction (e.g., foreign body)
bacterial infection, other components of the vortex can main-
Intramural obstruction (e.g., complete cartilage rings)
tain inflammation and structural damage. Antibiotics do not
External airway compression (e.g., by tuberculous lymph appear to be disease modifying, as bacterial loads return to
nodes) baseline after discontinuation of antibiotics. This would sup-
port the need for multimodality treatment, as targeting only
one part of the vortex is not enough to disrupt the cycle and
halt the progression of lung damage.
aspergillosis (ABPA); bronchial obstruction; rheumatic con- This review will discuss the components of the vicious
ditions; or connective tissue diseases.7–13 Identifying the vortex and consider how they contribute to the disease
underlying cause of bronchiectasis is important, as it guides progression of bronchiectasis.
treatment strategy and management in patients. Although
there are guidelines available for the treatment of bronchi-
Mucociliary Function
ectasis,14 to date no medications have been approved by
regulatory bodies in Europe or the United States. This is The conducting airways are predominantly lined by ciliated
partly due to the complex, heterogenous nature of the epithelial cells, followed by secretory and goblet cells and
disease. Improving our understanding of the underlying finally a small number of “brush” and neuroendocrine

Seminars in Respiratory and Critical Care Medicine Vol. 42 No. 4/2021 © 2021. Thieme. All rights reserved.
 Pathophysiology of Bronchiectasis Keir, Chalmers 501

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Fig. 1 The vicious vortex of bronchiectasis with examples of etiology “entry points” which can lead to the development of bronchiectasis. ABPA, allergic
bronchopulmonary aspergillosis; IBD, inflammatory bowel disease; NTM, nontuberculosis mycobacterium. (Created with BioRender.com.)

cells.18 Motile cilia beat in a coordinated, continuous fashion response to bacterial infection but can also have detrimental
to clear overlying mucus from the airways. The mucociliary effects on the airway epithelium. NE is a biomarker of disease
escalator acts as one of the first lines of defense against severity and exacerbation in bronchiectasis and increases in
infection, as bacteria, viruses, and particles are trapped in the severe disease.24–26 NE can damage the extracellular matrix
mucus layer and transported by cilia to be expectorated or and reduce ciliary beat frequency, reducing effective clear-
swallowed. Dysfunctional mucociliary clearance can lead to ance.27–29 In vitro, NE increases the expression of MUC5AC
sputum retention in the airways, creating a harbor for from bronchial epithelial cells and studies in murine models
infection and inflammation. have demonstrated that NE increases mucus hypersecretion
A known etiology of bronchiectasis is PCD, an autosomal and goblet cell metaplasia, hampering effective mucociliary
recessive genetic disorder. Mutations in genes encoding pro- clearance.30,31 Mucus cell hyperplasia and metaplasia is
teins involved in ciliary biogenesis, structure, and function likely to be a key mechanism leading to mucus hypersecre-
result in a range of defects in which cilia are absent, immotile tion in bronchiectasis, as a study of bronchial biopsies by
or dysmotile, and leave the epithelium vulnerable to infec- Gaga et al found up to 40% of tissue in bronchiectasis biopsies
tion.19–21 Mutations in more than 40 genes have been identified were composed of mucus glands with no hyperplasia identi-
as pathogenic in PCD; however, genetic testing cannot confirm fied in control samples.32 Bacterial infection has also been
PCD in 20 to 25% of cases, indicating more genes are likely to be associated with reduced mucociliary clearance in patients
discovered.22 Due to suffering from recurrent infections, most with bronchiectasis. In vitro, high levels of Pseudomonas
patients with PCD develop bronchiectasis by adulthood.9,23 elastase have been demonstrated to be cytotoxic and cause
Ciliary dyskinesia can occur in bronchiectasis patients the detachment of epithelial cells from neighboring cells and
without known PCD. Both environmental and physiological the basement membrane.28 Bacterial products such as
factors are believed to reduce ciliary clearance. Neutrophil pyocyanin, a product of P. aeruginosa, reduce ciliary beat
elastase (NE) is a serine protease released by neutrophils in frequency, impacting effective clearance.28,33

Seminars in Respiratory and Critical Care Medicine Vol. 42 No. 4/2021 © 2021. Thieme. All rights reserved.
502 Pathophysiology of Bronchiectasis Keir, Chalmers

It is unlikely that bacteria and NE are the only modulators there is no relationship between mutations of CFTR and
of cilia function in bronchiectasis; although secondary ciliary bronchiectasis.48 However, conflicting studies have reported
dyskinesia has not been extensively studied in this disease, that CFTR mutations can occur in 36% of non-CF bronchiec-
there is emerging evidence of an association with other lung tasis patients.49 Bienvenu and colleagues evaluated the
conditions. Studies utilizing exome sequencing have identi- association between CFTR heterozygosity and CFTR protein
fied that genes associated with PCD further disease progres- dysfunction in 122 patients with diffuse bronchiectasis. They
sion in CF and that abnormal cilia genes contribute to found that bronchiectasis patients had a high rate of CFTR
idiopathic nontuberculosis mycobacterium (NTM) infec- mutations and abnormal nasal potential difference measure-
tion.34,35 It is possible that future studies will identify that ments compared with healthy control individuals.50 It is
both primary and secondary cilia dysfunctions are involved notable that the average age of patients in the study by
in bronchiectasis. Bienvenu et al was 45 years, approximately 20 years younger
The efficiency of mucociliary clearance is determined by than most published bronchiectasis series suggesting
both the action of ciliated epithelium and the characteristics a degree of selection bias. These studies highlight that the
of the overlying mucus. There is evidence of abnormal mucus role of CFTR in bronchiectasis remains contentious and that

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
hydration and rheology in bronchiectasis. Ramsey et al further multicenter studies on larger cohorts of patients are
studied a cohort of patients with the BLESS randomized needed to resolve this debate.
controlled trial. Sputum from patients with bronchiectasis Defective mucus clearance can also occur due to anatomi-
on average had 20-fold higher DNA concentrations than cal changes to the airway such as congenital tracheobron-
control subjects, and elevated levels of total mucins, com- chomegaly, tracheomalacia, and bronchomalacia.51,52
posed primarily of MUC5AC and MUC5B. Mucus from bron-
chiectasis patients was dehydrated and more viscous.36
Inflammation
Mucus hydration and viscosity are regulated by epithelial
ion channels. The epithelial sodium channel (ENaC) regulates Chronic inflammation is a key component of bronchiectasis
composition of airway surface liquid via sodium reabsorp- pathophysiology. Patients have extensive infiltration of the
tion on the epithelial surface.37 Functional CF transmem- airways by inflammatory cells, particularly in severe disease.
brane conductance regulator (CFTR) downregulates ENaC; in Sputum and bronchoalveolar lavage (BAL) samples from
CF, upregulation contributes to excess mucus which is cen- bronchiectasis patients have high numbers of inflammatory
tral to the pathophysiology of the disease. Transgenic mice cells and inflammatory mediators.53–55 The inflammatory
that overexpress ENaC develop CF-like lung disease38 and it response comprises a complex cytokine network that acti-
has been proposed that hyperactive ENaC may contribute to vates and deploys cells involved in host defense. Levels of
the development of bronchiectasis.39 Patients who carry the inflammation are controlled by interactions between upre-
p.W493R-SCNN1A, a variant that encodes for a hyperactive gulated proinflammatory cytokines, and anti-inflammatory
ENaC channel, have been identified as being at a higher risk of cytokine and cytokine inhibitors, which are released to
developing bronchiectasis.40 In 2008 and 2009, Fajac and dampen the immune response. An imbalance between
colleagues investigated whether a defective ENaC protein pro- and anti-inflammatory signaling occurs leading to
could be involved in the development of bronchiectasis. They recruitment of inflammatory cells and ultimately a self-
analyzed ENaC-beta and -gamma genes in 55 subjects who perpetuating cycle of inflammation.3,56,57
had idiopathic bronchiectasis without two mutations in the
coding regions of CFTR. Of the 10 patients identified to have Neutrophils
an ENaC mutation, 6 had functional abnormalities suggesting Neutrophils are among the first immune cells to be recruited
impaired sodium transport.41,42 These studies suggest that in response to an infection but are also regarded as a key
mutations in ENaC-beta and -gamma genes may disrupt component in the pathophysiology of bronchiectasis. Bron-
ENaC function and lead to bronchiectasis. Downregulating chiectasis is typically considered to be a neutrophilic dis-
ENaC has been suggested as a potential therapeutic strategy ease; however, recent studies have suggested that
in both CF and PCD to reduce mucus viscosity and improve eosinophilic inflammation may be prevalent in up to a third
airway clearance.43–45 of patients.58,59
The role of CFTR and CFTR mutations in bronchiectasis Neutrophils are recruited to the lung by several mediators,
remains under debate in the literature, with conflicting including CXCL-8, IL-1β, IL-17, leukotriene B4, and tumor
studies being published. A study of 100 patients with idio- necrosis factor-α (TNF-α).54,60,61 Once neutrophils reach the
pathic bronchiectasis in an Australian cohort found that the airways, these chemoattractants induce neutrophil activa-
rate of classical CFTR mutations was 1:25, the same frequen- tion. The inflamed airways of bronchiectasis patients contain
cy as found in the general population.46 These results were high levels of neutrophil granule products, such as myelo-
supported in a study of 19 Serbian patients with disseminat- peroxidase, NE, heparin-binding protein, resistin, and matrix
ed bronchiectasis, published shortly after.47 Analysis of the metalloproteinases.62–65 Sputum proteomics has demon-
whole coding region of the CFTR gene, its flanking regions, strated that patients with severe disease have an upregula-
and the promoter in 47 patients with diffuse bronchiectasis tion of neutrophil proteins in the airways, compared with
and 47 controls identified CFTR variants in 24 bronchiectasis higher levels of antiproteases and epithelial proteins in the
subjects and 27 in control subjects. This study suggested that sputum of mild patients.65

Seminars in Respiratory and Critical Care Medicine Vol. 42 No. 4/2021 © 2021. Thieme. All rights reserved.
 Pathophysiology of Bronchiectasis Keir, Chalmers 503

The main stimulant of neutrophil migration into the longed viability.56 A study in CF patients found that neutro-
airway is believed to be bacterial colonization. Bacterial phils had a longer life span, which resulted in increased NET
load is associated with markers of airway inflammation formation.72
such as the key chemoattractants described earlier, and We recently observed in a series of independent interna-
treatment with short- and long-term antibiotic therapies tional bronchiectasis cohorts that NET formation was a key
reduce markers of airway and systemic inflammation and component of bronchiectasis pathophysiology.
therefore reduces neutrophil recruitment to the airway.66 NETs are highly ordered, web-like structures released by
However, subgroups of patients have been identified for neutrophils in response to multiple stimuli including bacte-
whom inflammation occurred without bacterial infection.54 rial infection. The webs contain antimicrobial neutrophil
This would align with the vortex model of bronchiectasis; granule proteins including NE and histones which are also
neutrophilic inflammation is not induced solely by bacterial toxin to microbes. It is likely that NET formation represents
infection, meaning antibiotic treatments alone are insuffi- the dominant mechanism of NE release into the bronchiec-
cient to break the cycle of inflammation in all patients. tasis airway. It remains controversial whether NETs are truly
Once recruited to the site of infection, neutrophils deploy antimicrobial or are only able to trap bacteria and prevent

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
several host defense mechanisms including phagocytosis, infection from being disseminated. Our study found that
degranulation, production of reactive oxygen species, proin- NETs were present in sputum of patients with bronchiectasis
flammatory cytokine production, and neutrophil extracellu- and correlated with increasing severity, mortality, severe
lar trap (NET) formation. In blood, bacterial killing by exacerbation, and a reduction in time to next exacerbation.
neutrophils occurs primarily through phagocytosis, an effi- Additionally, NET levels can be reduced through antibiotic
cient intercellular pathway of killing where the cell uses its treatment with patients who had the largest reduction in
plasma membrane to engulf particles, resulting in minimal NET concentrations showing the greatest clinical benefit.65
damage to the host. Neutrophil phagocytosis is dependent on This study indicates that NETs may actively contribute to the
the binding of IgG and complement (C3b/Cb4 and iC3b)- pathophysiology of bronchiectasis. A central role for neutro-
coated microbial targets to Fcγ and complement receptors. phil serine proteases and NETs in the pathophysiology of
The cleavage of these receptors by NE, or the cleavage of bronchiectasis is suggested by the recent demonstration of
complement and Ig receptors from the surface of pathogens, prolonged time to next exacerbation and reduced frequency
is thought to impair phagocytosis in the bronchiectasis of exacerbations in patients treated with two doses of a novel
airway.3,67,68 A study by Voglis et al demonstrated that dipeptidyl peptidase-1 (DPP1/cathepsin-C) inhibitor com-
neutrophils isolated from sputum of bronchiectasis patients pared with placebo in 256 patients with bronchiectasis. The
displayed defective phagocytosis which correlated with high WILLOW trial showed marked reductions in NE with treat-
human neutrophil peptide (HNP) concentrations in the lung. ment that correlated with clinical response. DPP1 directly
The study showed that HNP decreased phagocytic capacity of promotes NETosis and indirectly promotes NETosis through
healthy neutrophils through intracellular calcium and actin the action of NE. Neutrophils from individuals with Papillon–
cytoskeleton remodeling.55 Both of these observations sug- Lefevre syndrome, a congenital syndrome arising through
gest a negative feedback loop whereby failure of bacterial genetic absence of DPP1, cannot make NETs but have pre-
phagocytosis leads to extracellular release of NE and HNPs, served bacterial killing. The results of the WILLOW study
which further impair phagocytosis. demonstrate the potential importance of neutrophil serine
Several studies have demonstrated that neutrophils in the proteases in bronchiectasis exacerbations as well as the
blood display normal phagocytic function, oxidative burst, potential for translating basic research findings into novel
and expression of activation receptors.12,55,69,70 However, a therapies.73
study in 2018 of 24 patients with bronchiectasis (8 mild, 8
moderate, and 8 severe), blood neutrophils had impaired Macrophages
neutrophil phagocytosis and killing of PAO1 increased acti- Macrophages play a critical role in immune response and are
vation, prolonged viability, and reduced apoptosis compared involved in the detection, phagocytosis, and eradication of
with healthy controls. Furthermore, bronchiectatic airway pathogens as well as the initiation of the inflammatory
neutrophils had significantly reduced bacterial killing and response through cytokine release.74 In bronchiectasis, mac-
phagocytosis compared with matched autologous blood rophages in the lung are increased compared with healthy
neutrophils.71 This study is surprising, as bronchiectasis controls.32,75 Macrophages are responsible for regulating
patients do not exhibit an increased risk in nonpulmonary neutrophil numbers in the airway through efferocytosis,
infections which would be expected with a major systemic the clearance of apoptotic neutrophils, and the release of
defect of neutrophils, and P. aeruginosa infections impact on neutrophil chemoattractants. Phagocytosis of apoptotic neu-
only a subset of bronchiectasis patients. Further studies are trophils by macrophages, before they undergo secondary
needed to fully understand systemic neutrophil function in necrosis, prevents the release of inflammatory cytokine,
patients with bronchiectasis. proteases, and oxygen radicals which exacerbate tissue
It is likely that the reduced functional properties of injury and inflammation.76,77 Several studies have shown
bacterial killing and phagocytosis are perpetuating the vi- indirect evidence that apoptosis and apoptotic cell clearance
cious vortex. Additionally, Watt et al demonstrated that are reduced in bronchiectasis.72,78,79 Watt et al investigated
bronchiectasis neutrophils have delayed apoptosis and pro- the effects of antibiotic treatment for exacerbations on

Seminars in Respiratory and Critical Care Medicine Vol. 42 No. 4/2021 © 2021. Thieme. All rights reserved.
504 Pathophysiology of Bronchiectasis Keir, Chalmers

neutrophil apoptosis and necrosis in 15 patients with idiopathic biopsies by Gaga et al found increased infiltration of CD4þ T
bronchiectasis.56 Neutrophil apoptosis and necrosis were ana- lymphocytes in the airways of bronchiectasis patients.32 It is
lyzed using morphology and flow cytometry, on sputum sam- clear that patients with abnormal B- and T-cell function are
ples taken on day 1 of an exacerbation and again after 2 weeks of at increased risk of bronchiectasis. Chronic lymphocytic
antibiotic treatment. The study found that bronchiectasis leukemia and transporter antigen presentation deficiency
patients had a significantly lower percentage of macrophages syndrome are both disorders with abnormal T-cell functions
present in their sputum and a significantly higher percentage which are associated with bronchiectasis.84,85 HIV has also
of secondary necrotic cells compared with healthy controls on been implicated in the development of bronchiectasis.86
day 14, suggesting impaired efferocytosis possibly due to low Patients with common variable immunodeficiency (CVID)
numbers of macrophages.56 Impaired efferocytosis may also be have a lack of general and local protective humoral immunity
caused by cleavage of the phosphatidylserine receptor by NE, a due to reduced levels of Ig. The progression of bronchiectasis
potential mechanism of the reduced phagocytosis of apoptotic development can be slowed down by Ig replacement thera-
cells.79 In the study of Watt et al, no relationship was seen pies in CVID patients.87–89 The advancement in genomic and
between NE and the percentage of secondary necrotic cells, direct approaches is likely to improve our understanding and

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
suggesting that the mechanisms of efferocytosis are not fully identify new mechanisms of immune dysfunction in bron-
understood. The impairment of efferocytosis in bronchiectasis is chiectasis pathogenesis.
likely to contribute to pathophysiology through the increase in In patients with established bronchiectasis, there are
the release of molecules which damage lung tissue and aggra- limited published data. One study found lower T-cell
vate inflammation. responses, measured using interferon-gamma release, to
bacterial pathogens in bronchiectasis patients compared
Eosinophils with healthy volunteers. Interestingly, a negative correlation
Although bronchiectasis is classically thought of as a neutro- was observed between the bronchiectasis severity index and
philic disease, emerging evidence suggests the presence of an T-cell responses to Haemophilus influenzae, the most com-
eosinophilic subtype of bronchiectasis. Up to 30% of bron- mon bronchiectasis pathogen in northern Europe, indicating
chiectasis patients show airway eosinophilia in sputum that patients with more severe disease had impaired to
using established cut-offs such as 3% eosinophils.11,58,59 reduced T-cell immunity to H. influenzae.90
Gaga et al also found increased infiltration of eosinophils Quigley et al studied T-cell responses to OprF, an outer
into bronchial biopsies from bronchiectasis patients com- membrane protein of P. aeruginosa as the other critical
pared with controls. Inhaled corticosteroid (ICS) use is not pathogen in this disease. They found that patients with
recommended in the treatment of bronchiectasis, out with chronic P. aeruginosa surprisingly had reduced T-cell immu-
ABPA or severe asthma which are both T-helper (Th) type 2 nity to OprF determined by interferon-gamma release but
cell/eosinophil-driven conditions.14 ICS use has been dem- had enhanced release of multiple cytokines and chemokines
onstrated to be associated with an increased risk of hospi- involved in neutrophil, monocyte, and NK cell recruitment,
talized respiratory infections80 in the general bronchiectasis with additionally an increase in release of interleukin-4.
population; however, the identification of eosinophilic sub- These data suggest T-cell responses may be important in
types in bronchiectasis may be useful to guide personalized the impaired immune response permitting chronic P. aeru-
treatment. In chronic obstructive pulmonary disease (COPD), ginosa infection while additionally promoting the chronic
eosinophilia is a recognized endotype which can be used to neutrophilic inflammation that accompanies it.91
predict response to ICS.81,82 A recent post hoc analysis of two
randomized controlled trials of ICS use, which stratified
Epithelial Inflammation
patients according to blood eosinophil count, found that
patients with peripheral eosinophilia of
4% had a signifi- The role of epithelial cells in the immune response is not
cant reduction in number of exacerbations during follow-up limited to mucus clearance; they also release several inflam-
compared with patients with noneosinophilic inflammation matory factors which induce, amplify, and modulate ongoing
on ICS treatment. As a post hoc analysis, this study did have inflammation. Bronchial epithelial cells synthesize and re-
limitations, including differences in ICS treatment type and lease proinflammatory mediators, including CXCL-8 and
doses, but does, however, highlight the potential benefits of TNF-α, which trigger neutrophil migration to the site of
personalized treatment approaches surrounding ICS use in inflammation.92,93 ET-1 production by epithelial cells, which
bronchiectasis.83 promotes neutrophil adhesion to endothelial cells and mi-
gration to areas of inflammation, is increased in the serum of
Immunodeficiency bronchiectasis patients with P. aeruginosa infection.94–96
Immunodeficiency has been identified as part of the under- Both epithelial cell communication and interactions with
lying etiology of bronchiectasis in several conditions. bacteria cause bronchial epithelial cells to express ICAM-1.97
ICAM-1 plays multiple roles in the modulation of inflamma-
tion, including upregulating airway response to pathogens
Lymphocytes
and inducing neutrophil adhesion to airway epithelial cells
Less is known about B- and T-cell function in bronchiectasis, through neutrophil surface receptors CD11/CD18.97–100 The
but the previously mentioned study examining bronchial release of antimicrobial peptides from epithelial cells, such

Seminars in Respiratory and Critical Care Medicine Vol. 42 No. 4/2021 © 2021. Thieme. All rights reserved.
 Pathophysiology of Bronchiectasis Keir, Chalmers 505

as LL-37, has been shown to be higher in patients with more aureus or Streptococcus pneumoniae. Proteobacteria dysbio-
severe disease, although LL-37 can also be neutrophil de- sis of the microbiome is associated with more severe disease
rived.101,102 A study by Sibila et al identified that patients and worse clinical outcomes.6,65,111–113
with severe bronchiectasis had raised levels of the proin- P. aeruginosa is the most commonly identified pathogen
flammatory mediators lactoferrin and cathelicidin LL-37 and in bronchiectasis patients worldwide and has been associ-
reduced levels of anti-inflammatory secretory leucocyte ated with increased exacerbation frequency, reduced quali-
protease inhibitor (SLPI). Raised LL-37 coupled with lower ty of life, and increased mortality.112,114,115 The frequency
SLPI levels was associated with a reduction in forced expira- of P. aeruginosa colonization is likely due to its ability to
tory volume in 1 second (FEV1), P. aeruginosa infection, and evade killing by inflammatory cells and antimicrobial pep-
reduced time to next exacerbation. This study highlights a tides. Hilliam and colleagues used whole-genome sequenc-
subgroup of bronchiectasis patients who have dysregulated ing to characterize P. aeruginosa adaptations in
antimicrobial peptide levels which are associated with dis- bronchiectasis.116 In total, 191 isolates from the sputum
ease severity.102 Bronchial epithelial release of secretory of 91 bronchiectasis patients were sequenced and revealed
leukocyte protease inhibitor may be an important mecha- that during infection, P. aeruginosa populations adapt by

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
nism of defense against chronic neutrophilic inflammation. accumulating loss-of-function mutations which lead to
Our proteomic analysis found that higher levels of SLPI in changes in biofilm formation and nutrient acquisition,
sputum were among the strongest predictors of a benign suggesting adaption of the organism to survive in the
disease course, and an independent study by Sibila et al hostile lung environment. A separate study of P. aeruginosa
found that among antimicrobial peptides, SLPI was most isolated from 40 patients with bronchiectasis found that
strongly associated with outcomes. In particular, lower SLPI pathogen virulence reduced over time, an adaption that has
was associated with a higher risk of exacerbation. SLPI is the also been identified in CF that enables the organism to hide
dominant inhibitor of NE in secretions (in contrast to α-1 from the immune system and establish a chronic infec-
antitrypsin which is thought to be the dominant inhibitor in tion.117,118 Both the studies conducted by Hilliam et al and
tissues and blood). The study by Sibila et al also showed that Woo et al found that patients can experience multiple
elastase exposure blocked release of SLPI from epithelial cells infections with P. aeruginosa where they acquire different
through a mechanism that was independent of its protease lineages over time.116,117 P. aeruginosa may also evade
activity. This is supported by our recent findings using killing by inflammatory cells through the stimulation of
proteomics which saw that response to intravenous antibi- NET formation.65 Numerous studies have found that P.
otic treatment was associated with reductions in NE and aeruginosa can mediate NETosis through multiple stimu-
increases in SLPI and other epithelial antiproteases. This lants including LPS, flagellum, and release of virulence
supports a model in which severe disease is associated factors.119–122 The induction of NET formation gives P.
with an imbalance of proteases and proinflammatory medi- aeruginosa a survival advantage, as NET formation inhibits
ators which suppress epithelial anti-inflammatory, antipro- and kills competitor microorganisms, while P. aeruginosa
tease, and antimicrobial responses, while successful persists due to an ability to degrade NETs and a resistance to
treatment is associated with a restoration of normal epithe- killing.123–125 The induction and evasion of NETs is not
lial defense.102 limited to P. aeruginosa. Pathogens H. influenzae and S.
aureus are also able to induce and evade NETosis. H.
influenzae, S. aureus, Streptococcus suis and group A Strep-
Airway Infection
tococcus all release nucleases as part of NET resistance,
Bacterial Infection which may account in part for their colonization of the
Airways infection is believed to be key to the pathophysi- airways.126,127
ology of bronchiectasis, through both direct structural H. influenzae is a common but less well studied pathogen
damage and contributing to the chronic cycle of inflamma- in bronchiectasis. Infection with H. influenzae results in a
tion. Bacterial colonization is one of the main drivers of complex interactions between multiple microbial adhesins,
neutrophil migration into the airway and is thought to be a host responses to microbial antigens, and both mucosal and
major driver of disease progression.103–105 Bacterial load systemic immune responses which takes place intra- and
has been directly correlated with markers of airway inflam- extracellularly.128–131 Nontypeable H. influenzae (NTHi) is
mation, which can be reduced through short- and long- typically found in the upper respiratory tracts of healthy
term antibiotic treatment.66 Although bacterial pathogens individuals, but can cause a strong adaptive immune re-
are most commonly discussed clinically, virus, fungi, and sponse if infection occurs in the lower airway of patients
mycobacteria have also been identified in the airways of with bronchiectasis.132 H. influenzae have been associated
bronchiectasis patients and likely further disease with a loss of microbial diversity and the formation of
progression.106–110 NETs65,133 as well as an increase in serum CRP, sputum IL-
The most common organisms that chronically colonize 1β, and CXCL-8.54,134,135 In addition to a failure of neutrophil
the airways of bronchiectasis patients are the gram-negative killing, it is likely that pathogenesis H. influenzae is also
pathogens from the Proteobacteria phylum such as P. aeru- dependent on ciliary dysfunction. Several studies have found
ginosa, H. influenzae, Moraxella catarrhalis, and Enterobac- that NTHi can reduce ciliary beat frequency and cause
teriaceae, or Firmicutes pathogens such as Staphylococcus damage to epithelial cells in the respiratory tract, and it is

Seminars in Respiratory and Critical Care Medicine Vol. 42 No. 4/2021 © 2021. Thieme. All rights reserved.
506 Pathophysiology of Bronchiectasis Keir, Chalmers

among the most common pathogens isolated from patients immune response, local nutrient availability, and ciliary
with PCD.132,136–138 function. There is also evidence to suggest that long-term
NTM can be a cause or a consequence of bronchiectasis and antibiotic therapy may change the microbiome. A post hoc
is thought to occur in approximately 9% of patients.139 Myco- analysis of the BLESS study, a randomized controlled trial of
bacterium avium complex (MAC) is the most frequently isolat- erythromycin, found that in patients without P. aeruginosa
ed NTM species in bronchiectasis.109,140 Patients with NTM infection, treatment reduced H. influenzae resulting in an
may have unique body and immune phenotypes including increase in macrolide-tolerant pathogens including P. aeru-
pectus excavatum, scoliosis, and mitral valve prolapse and are ginosa.149 The authors suggest caution in long-term eryth-
often tall, slender females.141,142 The genetic components romycin treatment in patients without P. aeruginosa
involved in NTM infection are complex; patients with NTM infection. There are still many unanswered questions around
have low-frequency genetic variants in immune, cilia, connec- the effect of antibiotic treatment on the microbiome in
tive tissue, and CFTR genes compared with healthy control bronchiectasis and more longitudinal studies are needed
individuals.35 Patients with NTM often have coinfection with P. to answer these questions.
aeruginosa and Aspergillus-related lung disease, which sug- 16S sequencing is limited to the study of bacteria which

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
gests there may be a shared susceptibility across different ignores potential contributions to the microbiome from virus,
infections.140,143 Treatment of bronchiectasis patients with fungi, mycobacteria, and potential other microorganisms.
NTM is complicated by concerns that long-term macrolide Studies of other kingdoms are limited by the availability of
therapy can increase the risk of macrolide-resistant MAC,144 sequencing technologies and reference databases. There are
which is problematic as several randomized controlled studies relatively few studies of viruses in bronchiectasis, but Gao et al
have shown benefits of long-term macrolide treatment.14,145 found viruses in 49% of bronchiectasis exacerbations com-
A preliminary study of 410 patients from the United States pared with 18.9% of patients in stable state. This suggests a
Bronchiectasis Research Registry found low rates of NTM contribution of respiratory viruses to bronchiectasis exacer-
positivity in patients receiving long-term macrolide therapy, bations.151 The first study of the lung microbiome in bronchi-
suggesting that long-term therapy could be protective against ectasis was the CAMEB (Cohort of Asian and Marched
NTM infection.108 European Bronchiectasis), published in 2018. The study ana-
The advent of next-generation sequencing technologies lyzed sputum from 238 Asian and matched European bron-
has allowed researchers to look at the microbiome in bron- chiectasis patients. Candida, Saccharomyces, and Penicillium
chiectasis in more detail than was previously available were the most frequently detected genera in bronchiectasis
through culture. 16S rRNA sequencing is the most commonly and healthy controls, while differentially abundant, bronchi-
used technique and several studies have identified dominant ectasis genera included Aspergillus, Cryptococcus, and Clavis-
organisms which are concordant with those found using pora. High frequencies of Aspergillus-associated disease
culture-based approaches, such as Pseudomonas and Hae- including sensitization and allergic bronchopulmonary Asper-
mophilus.146–148 The bronchiectasis microbiome is heterog- gillus were detected, with Aspergillus terreus–dominant pro-
enous and highly complex, with multiple bacterial files associating with an increase in exacerbations.107 The
genera.146,149 Woo et al conducted a longitudinal study of major clinical manifestations of fungal disease in bronchiecta-
29 bronchiectasis patients over 16 years and demonstrated a sis is ABPA which affects up to 10% of patients with bronchiec-
strong stability of the microbiome over time.148 Loss of tasis. ABPA is unusual, in the normally neutrophil-dominant
microbial diversity has been associated with a reduction in inflammatory profile of bronchiectasis syndromes, being
FEV1 and lung function decline, while dominance of Proteo- dominated by a Th2-driven, hypersensitivity response with
bacteria Pseudomonas and Haemophilus has been associated elevated levels of total and specific IgE and eosinophilic
with increased exacerbations and neutrophilic inflammation inflammation. Patients often have frequent exacerbations
including NET formation.65,134,147,150 Real-time quantitative and thick tenacious mucus.152,153 Testing for ABPA is mandat-
polymerase chain reaction can be used to determine bacte- ed by international guidelines because it requires specific
rial load as 16S rRNA sequencing is not quantitative. A study treatment with corticosteroids with or without antifungal
by Cox et al found that bacterial remained relatively consis- drugs.14,154 The earlier-mentioned CAMEB study suggested
tent between baseline and during an exacerbation in 76 that ABPA may be underdiagnosed.
patients with bronchiectasis. Additionally, the microbiome
composition remained relatively stable between baseline
Implications of Pathophysiology for
and exacerbation.146 This suggests current clinical concepts
Treatment
that exacerbations are caused by bacterial infections or
changes in bacterial load are likely overly simplistic. There The concept of identifying individual pathophysiological
are still important limitations to sequencing that are worth mechanisms in each individual with bronchiectasis and
considering, including a limited resolution in terms of defin- then targeting treatment to the appropriate part of the cycle
ing bacterial species and a loss of low abundance taxa which is known as the “treatable traits” approach and is summa-
may be identified by culture.146 rized in ►Fig. 2. New treatable traits are being identified
The mechanisms leading to pathogenic changes in the regularly, but the figure below summarizes pathophysiologi-
microbiome are complex and are likely to be derived from cal mechanisms that are linked to exacerbation and may be
several factors including pathogen virulence, dysregulated targetable by treatment.

Seminars in Respiratory and Critical Care Medicine Vol. 42 No. 4/2021 © 2021. Thieme. All rights reserved.
 Pathophysiology of Bronchiectasis Keir, Chalmers 507

IL-5 or anti-IL-5 receptor blockers or emerging options such

as anti-TSLP (thymic stromal lymphopoietin). Targeting
neutrophilic inflammation has been more challenging be-
cause most approaches historically have attempted to block
neutrophil recruitment to the lung. Drugs such as CXCR2
antagonists have effectively done this, but have been associ-
ated with increased infections or exacerbations, as illustrat-
ed by AZD5069 which was tested in a 28-day study in
bronchiectasis,156 and by a recent larger study in COPD
with the CXCR2 antagonist danirixin.157 Similar results
were obtained with leukotriene B4 antagonism in CF where
it was tested in adults and children and while associated with
reduced neutrophilic inflammation this produced an in-
crease in exacerbations and a worsening of lung function.158

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Subsequent studies in mice found increased translocation of
P. aeruginosa into the blood and increased airway P. aerugi-
nosa loads indicating the risks associated with reducing
neutrophils in the airways.159 NE inhibition has been tested
in two randomized studies in bronchiectasis. One study by
Stockley et al missed its primary endpoint but had encour-
Fig. 2 Summary of the underlying pathophysiological mechanisms of aging trends including a 100-mL improvement in FEV1 and
bronchiectasis that could be targeted in a “treatable traits” approach to an improvement in St Georges Respiratory Questionnaire.160
treatment in bronchiectasis. CFTR, CF transmembrane conductance The second study by Watz et al enrolled 94 patients and,
regulator; NTM, nontuberculosis mycobacterium. (Created with BioRender. despite showing reductions in elastase activity in blood,
com.)
found no clinical benefits.161
These data suggest that antineutrophil treatment is chal-
lenging. The ideal antineutrophil strategy would reprogram
Infection dysfunctional bronchiectasis neutrophils before they reach
As described earlier, sputum culture is a critical component the lung and would not impair neutrophil recruitment or
in the assessment of patients. It enables the identification of neutrophil function once they arrive in lung, while still
organisms such as P. aeruginosa, which has a worse progno- reducing harmful neutrophilic inflammation. Encouraging
sis, and organisms such as NTM which require specific results with DPP1 inhibition as noted earlier suggest the
treatment (or avoidance of specific treatment such as macro- potential for this type of immune modulation, but results of a
lide monotherapy). Culture is insensitive and future applica- phase 3 trial are awaited.73
tion of molecular techniques may improve detection of There are therefore significant challenges in implement-
infection and therefore treatment. As an example of a ing anti-inflammatory treatment in bronchiectasis, as it is
treatable trait, patients with P. aeruginosa infection respond not immediately obvious how to identify patients with
better to macrolide therapy than patients without P. aerugi- eosinophilic disease in clinical practice. Blood eosinophils
nosa infection according to an individual participant data counts are validated in COPD and asthma,162–165 but more
meta-analysis of three randomized trials in bronchiectasis work is needed to validate them in bronchiectasis. Sputum
patients.145 In vivo, we found that macrolides reduce NETs in counts are not practical to implement in widespread clinical
patients with P. aeruginosa infection, suggesting an anti- care. Nevertheless, work is underway to establish the opti-
inflammatory effect may be responsible for this beneficial mal treatment for eosinophilic bronchiectasis. Our increas-
effect.65 Higher bacterial loads of P. aeruginosa and other ing understanding of the inflammatory pathways in different
pathogens are associated response with inhaled antibiotics subtypes of bronchiectasis is likely to lead to the emergence
and in future bacterial load may be a useful biomarker of of multiple new anti-inflammatory therapies.
response. Other potential contributors to exacerbation under
the heading of infection are dealt with in the earlier section. Mucociliary Clearance
Future directions in this area may include vaccination Airway clearance exercises are the mainstays of treatment
against specific pathogens (e.g., H. influenzae). and should be practiced by all patients. Many patients are
unable to control their disease with just airway clearance
Inflammation exercises, but the role of mucoactive drugs or adjuncts is
As noted, eosinophilia in the airway or blood identifies not established. Trials that have attempted to address
patients more likely to respond to inhaled corticosteroid mucociliary clearance in bronchiectasis have had mixed
treatment in COPD and asthma and there are emerging data results with some suggesting benefit and others suggesting
that show this is also true in bronchiectasis.155 In the future, no benefit or potential harm in the case of recombinant
this may allow treatment of bronchiectasis patients with DNAse.166 This is likely due to the extremely heterogeneity
Th2-mediated inflammation with specific drugs such as anti- of the patient population. The recent study by Ramsey et al

Seminars in Respiratory and Critical Care Medicine Vol. 42 No. 4/2021 © 2021. Thieme. All rights reserved.
508 Pathophysiology of Bronchiectasis Keir, Chalmers

which examined mucus properties in patients with bron- are increasingly recognized, particularly the concept of persis-
chiectasis gives some clues as to why drug approaches to tent bacterial bronchitis in children which has also been
mucociliary clearance have been so challenging.36 Hyper- reported in adults.171,172 It is highly likely that inflammation
tonic saline treatment hydrates mucus and is widely used, and infection precede structural lung damage in a majority of
but evidence of its benefit is lacking. Ramsey et al showed cases, as has been observed in CF.173 Further studies are
profound diversity in mucus properties across a bronchiec- needed to understand the mechanisms preceding the devel-
tasis patient population with some having severely dehy- opment of structural bronchiectasis, but it is tempting to
drated mucus and others having mucus properties within speculate that anti-inflammatory or immunomodulatory
the normal range.36 These data are consistent with our own approaches early in the disease could prevent the develop-
clinical experience that patients have very different mucus ment of chronic disease. Studies of early and pre-bronchiecta-
properties and therefore responses to mucoactive drugs. sis are urgently needed.
Similarly, DNA concentrations in sputum varied in the study
of Ramsey et al by more than 1,000-fold in the bronchiec- Conflict of Interest
tasis population indicating remarkable diversity. It is highly None declared.

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
likely that patients at the extremes of this distribution
would have very different responses to DNAse therapy.
References
Patients with CF derive benefit, and it is reasonable to
1 Flume PA, Chalmers JD, Olivier KN. Advances in bronchiectasis:
assume some patients with a “CF-like phenotype” with endotyping, genetics, microbiome, and disease heterogeneity.
bronchiectasis may also respond. The reasons why DNAse Lancet 2018;392(10150):880–890
did not work in bronchiectasis have been the subject of 2 Quint JK, Millett ER, Joshi M, et al. Changes in the incidence,
much debate, but likely it is explained by the different prevalence and mortality of bronchiectasis in the UK from 2004
mucus properties between CF and non-CF bronchiectasis, to 2013: a population-based cohort study. Eur Respir J 2016;47
(01):186–193
and greater heterogeneity in mucus properties. Release of
3 Chalmers JD, Hill AT. Mechanisms of immune dysfunction and
proteases entrapped within DNA has been shown to be bacterial persistence in non-cystic fibrosis bronchiectasis. Mol
enhanced by DNAse treatment,167 suggesting a potential Immunol 2013;55(01):27–34
mechanism for harm in those with neutrophilic inflamma- 4 Fuschillo S, De Felice A, Balzano G. Mucosal inflammation in
tion but without highly viscose mucus as is commonly the idiopathic bronchiectasis: cellular and molecular mechanisms.
Eur Respir J 2008;31(02):396–406
case in bronchiectasis.
5 Ratjen F, Waters V, Klingel M, et al. Changes in airway inflam-
All of this argues for a personalized medicine or “treatable mation during pulmonary exacerbations in patients with cystic
traits” approach to mucoactive therapy. Biomarkers of mucus fibrosis and primary ciliary dyskinesia. Eur Respir J 2016;47(03):
properties are currently not easily available in clinical prac- 829–836
tice, but there is early evidence supporting this approach. In a 6 Poppelwell L, Chalmers JD. Defining severity in non-cystic fibrosis
post hoc analysis of the mannitol trials, Gao et al showed that bronchiectasis. Expert Rev Respir Med 2014;8(02):249–262
7 Gao YH, Guan WJ, Liu SX, et al. Aetiology of bronchiectasis in
the presence of increased symptoms, a surrogate of more
adults: a systematic literature review. Respirology 2016;21(08):
difficult mucus in bronchiectasis, was associated with re- 1376–1383
sponse.168 In keeping with the aforementioned hypothesis, 8 Araújo D, Shteinberg M, Aliberti S, et al. Standardised classifica-
there was a trend to more exacerbations in patients who had tion of the aetiology of bronchiectasis using an objective algo-
few baseline symptoms. Further research into this area is rithm. Eur Respir J 2017;50(06):50
needed, as mucociliary clearance is the least researched area 9 Shoemark A, Ozerovitch L, Wilson R. Aetiology in adult patients
with bronchiectasis. Respir Med 2007;101(06):1163–1170
of bronchiectasis pathophysiology. Exciting future directions
10 Anwar GA, McDonnell MJ, Worthy SA, et al. Phenotyping adults
in this area include the potential for CFTR modulation in with non-cystic fibrosis bronchiectasis: a prospective observa-
bronchiectasis which will shortly be tested in a phase 2 trial tional cohort study. Respir Med 2013;107(07):1001–1007
(NCT04396366). 11 Lonni S, Chalmers JD, Goeminne PC, et al. Etiology of non-cystic
fibrosis bronchiectasis in adults and its correlation to disease
severity. Ann Am Thorac Soc 2015;12(12):1764–1770
Structural Lung Disease
12 Pasteur MC, Helliwell SM, Houghton SJ, et al. An investigation
Currently, there are no therapies shown to reverse bronchiec-
into causative factors in patients with bronchiectasis. Am J Respir
tasis once established, although there are early-phase studies Crit Care Med 2000;162(4, Pt 1):1277–1284
of regenerative medicine approaches reported on internation- 13 Bush A, Floto RA. Pathophysiology, causes and genetics of
al clinical trial registries.169 Most approaches therefore aim to paediatric and adult bronchiectasis. Respirology 2019;24(11):
deal with the consequences of structural lung damage, such as 1053–1062
14 Polverino E, Goeminne PC, McDonnell MJ, et al. European
treating airflow obstruction with bronchodilators or in ex-
Respiratory Society guidelines for the management of adult
treme cases removing damaging areas of the lung through bronchiectasis. Eur Respir J 2017;50(03):50
surgery.170 In the future, it would be nice to think that there 15 Cole PJ. Inflammation: a two-edged sword–the model of bron-
may be approaches to reverse established lung damage. In the chiectasis. Eur J Respir Dis Suppl 1986;147:6–15
medium, the most likely approach to reduce this would be to 16 Stirling RG, Nicolson CH, Button BM, Wilson JW. Airway clear-
introduce preventative measures that reduce the likelihood of ance in bronchiectasis: breaking the infection-inflammation
cycle. Am J Respir Crit Care Med 2012;185(02):226
development of bronchiectasis. Pre-bronchiectasis syndromes

Seminars in Respiratory and Critical Care Medicine Vol. 42 No. 4/2021 © 2021. Thieme. All rights reserved.
 Pathophysiology of Bronchiectasis Keir, Chalmers 509

17 Donovan T, Felix LM, Chalmers JD, Milan SJ, Mathioudakis AG, 37 Hanukoglu I, Hanukoglu A. Epithelial sodium channel (ENaC)
Spencer S. Continuous versus intermittent antibiotics for bron- family: Phylogeny, structure-function, tissue distribution, and
chiectasis. Cochrane Database Syst Rev 2018;6:CD012733 associated inherited diseases. Gene 2016;579(02):95–132
18 Whitsett JA. Airway epithelial differentiation and mucociliary 38 Mall M, Grubb BR, Harkema JR, O’Neal WK, Boucher RC. Increased
clearance. Ann Am Thorac Soc 2018;15(Suppl 3):S143–S148 airway epithelial Naþ absorption produces cystic fibrosis-like
19 Knowles MR, Daniels LA, Davis SD, Zariwala MA, Leigh MW. lung disease in mice. Nat Med 2004;10(05):487–493
Primary ciliary dyskinesia. Recent advances in diagnostics, ge- 39 Azad AK, Rauh R, Vermeulen F, et al. Mutations in the amiloride-
netics, and characterization of clinical disease. Am J Respir Crit sensitive epithelial sodium channel in patients with cystic
Care Med 2013;188(08):913–922 fibrosis-like disease. Hum Mutat 2009;30(07):1093–1103
20 Collins SA, Walker WT, Lucas JS. Genetic testing in the diagnosis 40 Rademacher J, Schulz A, Hedtfeld S, et al. Nasal potential differ-
of primary ciliary dyskinesia: state-of-the-art and future per- ence of carriers of the W493R ENaC variant with non-cystic
spectives. J Clin Med 2014;3(02):491–503 fibrosis bronchiectasis. Eur Respir J 2016;47(01):322–324
21 Mirra V, Werner C, Santamaria F. Primary ciliary dyskinesia: an 41 Fajac I, Viel M, Sublemontier S, Hubert D, Bienvenu T. Could a
update on clinical aspects, genetics, diagnosis, and future treat- defective epithelial sodium channel lead to bronchiectasis.
ment strategies. Front Pediatr 2017;5:135 Respir Res 2008;9:46
22 Lucas JS, Davis SD, Omran H, Shoemark A. Primary ciliary 42 Fajac I, Viel M, Gaitch N, Hubert D, Bienvenu T. Combination of

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
dyskinesia in the genomics age. Lancet Respir Med 2020;8 ENaC and CFTR mutations may predispose to cystic fibrosis-like
(02):202–216 disease. Eur Respir J 2009;34(03):772–773
23 Shah A, Shoemark A, MacNeill SJ, et al. A longitudinal study 43 Regan KH, Hill AT. Emerging therapies in adult and paediatric
characterising a large adult primary ciliary dyskinesia popula- bronchiectasis. Respirology 2018;23(12):1127–1137
tion. Eur Respir J 2016;48(02):441–450 44 Goss CH, Jain R, Seibold W, et al. An innovative phase II trial to
24 Brusselle GG, Van Braeckel E. Sputum neutrophil elastase as a establish proof of efficacy and optimal dose of a new inhaled
biomarker for disease activity in bronchiectasis. Am J Respir Crit epithelial sodium channel inhibitor BI 1265162 in adults and
Care Med 2017;195(10):1289–1291 adolescents with cystic fibrosis: BALANCE-CF TM 1. ERJ Open Res
25 Shoemark A, Cant E, Carreto L, et al. A point-of-care neutrophil 2020;6(04):6
elastase activity assay identifies bronchiectasis severity, airway 45 Shei RJ, Peabody JE, Kaza N, Rowe SM. The epithelial sodium
infection and risk of exacerbation. Eur Respir J 2019;53(06):53 channel (ENaC) as a therapeutic target for cystic fibrosis. Curr
26 Gramegna A, Amati F, Terranova L, et al. Neutrophil elastase in Opin Pharmacol 2018;43:152–165
bronchiectasis. Respir Res 2017;18(01):211 46 King PT, Freezer NJ, Holmes PW, Holdsworth SR, Forshaw K, Sart
27 Smallman LA, Hill SL, Stockley RA. Reduction of ciliary beat DD. Role of CFTR mutations in adult bronchiectasis. Thorax
frequency in vitro by sputum from patients with bronchiectasis: 2004;59(04):357–358
a serine proteinase effect. Thorax 1984;39(09):663–667 47 Divac A, Nikolic A, Mitic-Milikic M, et al. CFTR mutations and
28 Amitani R, Wilson R, Rutman A, et al. Effects of human neutrophil polymorphisms in adults with disseminated bronchiectasis: a
elastase and Pseudomonas aeruginosa proteinases on human controversial issue. Thorax 2005;60(01):85
respiratory epithelium. Am J Respir Cell Mol Biol 1991;4(01): 48 Bergougnoux A, Viart V, Miro J, et al. Should diffuse bronchiec-
26–32 tasis still be considered a CFTR-related disorder? J Cyst Fibros
29 Tosi MF, Zakem H, Berger M. Neutrophil elastase cleaves C3bi on 2015;14(05):646–653
opsonized pseudomonas as well as CR1 on neutrophils to create 49 Casals T, De-Gracia J, Gallego M, et al. Bronchiectasis in adult
a functionally important opsonin receptor mismatch. J Clin patients: an expression of heterozygosity for CFTR gene muta-
Invest 1990;86(01):300–308 tions? Clin Genet 2004;65(06):490–495
30 Koga H, Miyahara N, Fuchimoto Y, et al. Inhibition of neutrophil 50 Bienvenu T, Sermet-Gaudelus I, Burgel PR, et al. Cystic fibrosis
elastase attenuates airway hyperresponsiveness and inflamma- transmembrane conductance regulator channel dysfunction in
tion in a mouse model of secondary allergen challenge: neutro- non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med
phil elastase inhibition attenuates allergic airway responses. 2010;181(10):1078–1084
Respir Res 2013;14:8 51 Falconer M, Collins DR, Feeney J, Torreggiani WC. Mounier-Kuhn
31 Gehrig S, Duerr J, Weitnauer M, et al. Lack of neutrophil elastase syndrome in an older patient. Age Ageing 2008;37(01):115–116
reduces inflammation, mucus hypersecretion, and emphysema, 52 George J, Jain R, Tariq SM. CT bronchoscopy in the diagnosis of
but not mucus obstruction, in mice with cystic fibrosis-like lung Williams-Campbell syndrome. Respirology 2006;11(01):117–119
disease. Am J Respir Crit Care Med 2014;189(09):1082–1092 53 Drost N, D’silva L, Rebello R, Efthimiadis A, Hargreave FE, Nair P.
32 Gaga M, Bentley AM, Humbert M, et al. Increases in CD4þ T Persistent sputum cellularity and neutrophils may predict bron-
lymphocytes, macrophages, neutrophils and interleukin 8 posi- chiectasis. Can Respir J 2011;18(04):221–224
tive cells in the airways of patients with bronchiectasis. Thorax 54 Angrill J, Agustí C, De Celis R, et al. Bronchial inflammation and
1998;53(08):685–691 colonization in patients with clinically stable bronchiectasis. Am
33 Nair C, Shoemark A, Chan M, et al. Cyanide levels found in J Respir Crit Care Med 2001;164(09):1628–1632
infected cystic fibrosis sputum inhibit airway ciliary function. 55 Voglis S, Quinn K, Tullis E, et al. Human neutrophil peptides and
Eur Respir J 2014;44(05):1253–1261 phagocytic deficiency in bronchiectatic lungs. Am J Respir Crit
34 Blue E, Louie TL, Chong JX, et al; U.S. National Heart, Lung, and Care Med 2009;180(02):159–166
Blood Institute “Grand Opportunity” Exome Sequencing Project 56 Watt AP, Brown V, Courtney J, et al. Neutrophil apoptosis,
(LungGO) Variation in cilia protein genes and progression of lung proinflammatory mediators and cell counts in bronchiectasis.
disease in cystic fibrosis. Ann Am Thorac Soc 2018;15(04): Thorax 2004;59(03):231–236
440–448 57 Dente FL, Bilotta M, Bartoli ML, et al. Neutrophilic bronchial
35 Szymanski EP, Leung JM, Fowler CJ, et al. Pulmonary nontuber- inflammation correlates with clinical and functional findings in
culous mycobacterial infection: a multisystem, multigenic dis- patients with noncystic fibrosis bronchiectasis. Mediators
ease. Am J Respir Crit Care Med 2015;192(05):618–628 Inflamm 2015;2015:642503
36 Ramsey KA, Chen ACH, Radicioni G, et al. Airway mucus hyper- 58 Coman I, Pola-Bibián B, Barranco P, et al. Bronchiectasis in severe
concentration in non-cystic fibrosis bronchiectasis. Am J Respir asthma: clinical features and outcomes. Ann Allergy Asthma
Crit Care Med 2020;201(06):661–670 Immunol 2018;120:409–413

Seminars in Respiratory and Critical Care Medicine Vol. 42 No. 4/2021 © 2021. Thieme. All rights reserved.
510 Pathophysiology of Bronchiectasis Keir, Chalmers

59 Tsikrika S, Dimakou K, Papaioannou AI, et al. The role of non- 79 Vandivier RW, Fadok VA, Hoffmann PR, et al. Elastase-mediated
invasive modalities for assessing inflammation in patients with phosphatidylserine receptor cleavage impairs apoptotic cell
non-cystic fibrosis bronchiectasis. Cytokine 2017;99:281–286 clearance in cystic fibrosis and bronchiectasis. J Clin Invest
60 Tan HL, Regamey N, Brown S, Bush A, Lloyd CM, Davies JC. The 2002;109(05):661–670
Th17 pathway in cystic fibrosis lung disease. Am J Respir Crit 80 Henkle E, Curtis JR, Chen L, et al. Comparative risks of chronic
Care Med 2011;184(02):252–258 inhaled corticosteroids and macrolides for bronchiectasis. Eur
61 Mikami M, Llewellyn-Jones CG, Bayley D, Hill SL, Stockley RA. The Respir J 2019;54(01):54
chemotactic activity of sputum from patients with bronchiecta- 81 Kerkhof M, Sonnappa S, Postma DS, et al. Blood eosinophil count
sis. Am J Respir Crit Care Med 1998;157(3, Pt 1):723–728 and exacerbation risk in patients with COPD. Eur Respir J 2017;
62 Chalmers JD, Moffitt KL, Suarez-Cuartin G, et al. Neutrophil 50(01):50
elastase activity is associated with exacerbations and lung 82 Siva R, Green RH, Brightling CE, et al. Eosinophilic airway
function decline in bronchiectasis. Am J Respir Crit Care Med inflammation and exacerbations of COPD: a randomised con-
2017;195(10):1384–1393 trolled trial. Eur Respir J 2007;29(05):906–913
63 Gray RD, MacGregor G, Noble D, et al. Sputum proteomics in 83 Martinez-Garcia MA, Posadas T, Sotgiu G, Blasi F, Saderi L,
inflammatory and suppurative respiratory diseases. Am J Respir Aliberti S. Role of inhaled corticosteroids in reducing exacerba-
Crit Care Med 2008;178(05):444–452 tions in bronchiectasis patients with blood eosinophilia pooled

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
64 Garratt LW, Sutanto EN, Ling KM, et al; Australian Respiratory post-hoc analysis of 2 randomized clinical trials. Respir Med
Early Surveillance Team for Cystic Fibrosis (AREST CF) Matrix 2020;172:106127
metalloproteinase activation by free neutrophil elastase con- 84 Carmier D, Dartigeas C, Mankikian J, et al. Serious bronchopul-
tributes to bronchiectasis progression in early cystic fibrosis. Eur monary involvement due to chronic lymphocytic leukaemia. Eur
Respir J 2015;46(02):384–394 Respir Rev 2013;22(129):416–419
65 Keir HR, Shoemark A, Dicker AJ, et al. Neutrophil extracellular 85 Gadola SD, Moins-Teisserenc HT, Trowsdale J, Gross WL, Cer-
traps, disease severity, and antibiotic response in bronchiectasis: undolo V. TAP deficiency syndrome. Clin Exp Immunol 2000;121
an international, observational, multicohort study. Lancet Respir (02):173–178
Med 2021:S2213-2600(20)30504-X 86 Holmes AH, Trotman-Dickenson B, Edwards A, Peto T, Luzzi GA.
66 Chalmers JD, Smith MP, McHugh BJ, Doherty C, Govan JR, Hill AT. Bronchiectasis in HIV disease. Q J Med 1992;85(307-
Short- and long-term antibiotic treatment reduces airway and 308):875–882
systemic inflammation in non-cystic fibrosis bronchiectasis. Am 87 Eden E, Choate R, Barker A, et al. The clinical features of
J Respir Crit Care Med 2012;186(07):657–665 bronchiectasis associated with alpha-1 antitrypsin deficiency,
67 Chalmers JD, Ma A, Turnbull K, Doherty C, Govan JR, Hill A. common variable immunodeficiency and primary ciliary
Impaired neutrophil phagocytosis and receptor expression in dyskinesia–results from the U.S. Bronchiectasis Research
non-CF bronchiectasis. Eur Respir J 2013;42:2065 Registry. Chronic Obstr Pulm Dis (Miami) 2019;6(02):145–153
68 Keir HR, Fong CJ, Dicker AJ, Chalmers JD. Profile of the ProAxsis 88 Verma N, Grimbacher B, Hurst JR. Lung disease in primary
active neutrophil elastase immunoassay for precision medicine antibody deficiency. Lancet Respir Med 2015;3(08):651–660
in chronic respiratory disease. Expert Rev Mol Diagn 2017;17 89 Bouvry D, Mouthon L, Brillet PY, et al; Groupe Sarcoïdose
(10):875–884 Francophone. Granulomatosis-associated common variable
69 King PT, Hutchinson P, Holmes PW, et al. Assessing immune immunodeficiency disorder: a case-control study versus sar-
function in adult bronchiectasis. Clin Exp Immunol 2006;144 coidosis. Eur Respir J 2013;41(01):115–122
(03):440–446 90 Jaat FG, Hasan SF, Perry A, et al. Anti-bacterial antibody and T cell
70 Ruchaud-Sparagano MH, Gertig H, Hester KL, et al. Effect of responses in bronchiectasis are differentially associated with
granulocyte-macrophage colony-stimulating factor on neutro- lung colonization and disease. Respir Res 2018;19(01):106
phil function in idiopathic bronchiectasis. Respirology 2013;18 91 Quigley KJ, Reynolds CJ, Goudet A, et al. Chronic infection by
(08):1230–1235 mucoid Pseudomonas aeruginosa associated with dysregulation
71 Bedi P, Davidson DJ, McHugh BJ, Rossi AG, Hill AT. Blood neu- in T-cell immunity to outer membrane porin F. Am J Respir Crit
trophils are reprogrammed in bronchiectasis. Am J Respir Crit Care Med 2015;191(11):1250–1264
Care Med 2018;198(07):880–890 92 Devalia JL, Campbell AM, Sapsford RJ, et al. Effect of nitrogen
72 Gray RD, Hardisty G, Regan KH, et al. Delayed neutrophil dioxide on synthesis of inflammatory cytokines expressed by
apoptosis enhances NET formation in cystic fibrosis. Thorax human bronchial epithelial cells in vitro. Am J Respir Cell Mol
2018;73(02):134–144 Biol 1993;9(03):271–278
73 Chalmers JD, Haworth CS, Metersky ML, et al; WILLOW Inves- 93 Khair OA, Davies RJ, Devalia JL. Bacterial-induced release of
tigators. Phase 2 trial of the DPP-1 inhibitor brensocatib in inflammatory mediators by bronchial epithelial cells. Eur Respir
bronchiectasis. N Engl J Med 2020;383(22):2127–2137 J 1996;9(09):1913–1922
74 Sibille Y, Reynolds HY. Macrophages and polymorphonuclear 94 López Farré A, Riesco A, Espinosa G, et al. Effect of endothelin-1
neutrophils in lung defense and injury. Am Rev Respir Dis 1990; on neutrophil adhesion to endothelial cells and perfused heart.
141(02):471–501 Circulation 1993;88(03):1166–1171
75 Zheng L, Shum H, Tipoe GL, et al. Macrophages, neutrophils and 95 Elferink JG, de Koster BM. Endothelin-induced activation of neu-
tumour necrosis factor-alpha expression in bronchiectatic air- trophil migration. Biochem Pharmacol 1994;48(05):865–871
ways in vivo. Respir Med 2001;95(10):792–798 96 Zheng L, Tipoe G, Lam WK, et al. Endothelin-1 in stable bronchi-
76 Fadok VA, Bratton DL, Guthrie L, Henson PM. Differential effects of ectasis. Eur Respir J 2000;16(01):146–149
apoptotic versus lysed cells on macrophage production of cyto- 97 Humlicek AL, Pang L, Look DC. Modulation of airway inflamma-
kines: role of proteases. J Immunol 2001;166(11):6847–6854 tion and bacterial clearance by epithelial cell ICAM-1. Am J
77 Fadok VA, Henson PM. Apoptosis: getting rid of the bodies. Curr Physiol Lung Cell Mol Physiol 2004;287(03):L598–L607
Biol 1998;8(19):R693–R695 98 Frick AG, Joseph TD, Pang L, Rabe AM, St Geme JW III, Look DC.
78 Hodge S, Upham JW, Pizzutto S, et al. Is alveolar macrophage Haemophilus influenzae stimulates ICAM-1 expression on respi-
phagocytic dysfunction in children with protracted bacterial ratory epithelial cells. J Immunol 2000;164(08):4185–4196
bronchitis a forerunner to bronchiectasis? Chest 2016;149 99 Hayashi F, Means TK, Luster AD. Toll-like receptors stimulate
(02):508–515 human neutrophil function. Blood 2003;102(07):2660–2669

Seminars in Respiratory and Critical Care Medicine Vol. 42 No. 4/2021 © 2021. Thieme. All rights reserved.
 Pathophysiology of Bronchiectasis Keir, Chalmers 511

100 Look DC, Rapp SR, Keller BT, Holtzman MJ. Selective induction of cystic fibrosis lung. Microbiology (Reading) 2013;159(Pt
intercellular adhesion molecule-1 by interferon-gamma in hu- 11):2354–2363
man airway epithelial cells. Am J Physiol 1992;263(1, Pt 1): 119 Pieterse E, Rother N, Yanginlar C, Hilbrands LB, van der Vlag J.
L79–L87 Neutrophils discriminate between lipopolysaccharides of differ-
101 Chalmers JD, McHugh BJ, Docherty C, Govan JR, Hill AT. Vitamin- ent bacterial sources and selectively release neutrophil extra-
D deficiency is associated with chronic bacterial colonisation cellular traps. Front Immunol 2016;7:484
and disease severity in bronchiectasis. Thorax 2013;68(01): 120 Martínez-Alemán S, Bustamante AE, Jimenez-Valdes RJ, Gonzá-
39–47 lez GM, Sánchez-González A. Pseudomonas aeruginosa isolates
102 Sibila O, Perea L, Cantó E, et al. Antimicrobial peptides, disease from cystic fibrosis patients induce neutrophil extracellular
severity and exacerbations in bronchiectasis. Thorax 2019;74 traps with different morphologies that could correlate with their
(09):835–842 disease severity. Int J Med Microbiol 2020;310(07):151451
103 Mizgerd JP, Skerrett SJ. Animal models of human pneumonia. Am 121 Rada B, Jendrysik MA, Pang L, et al. Pyocyanin-enhanced neutro-
J Physiol Lung Cell Mol Physiol 2008;294(03):L387–L398 phil extracellular trap formation requires the NADPH oxidase.
104 Sibila O, Suarez-Cuartin G, Rodrigo-Troyano A, et al. Secreted PLoS One 2013;8(01):e54205
mucins and airway bacterial colonization in non-CF bronchiec- 122 Floyd M, Winn M, Cullen C, et al. Swimming motility mediates
tasis. Respirology 2015;20(07):1082–1088 the formation of neutrophil extracellular traps induced by

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
105 Tunney MM, Einarsson GG, Wei L, et al. Lung microbiota and flagellated Pseudomonas aeruginosa. PLoS Pathog 2016;12(11):
bacterial abundance in patients with bronchiectasis when clini- e1005987
cally stable and during exacerbation. Am J Respir Crit Care Med 123 Young RL, Malcolm KC, Kret JE, et al. Neutrophil extracellular trap
2013;187(10):1118–1126 (NET)-mediated killing of Pseudomonas aeruginosa: evidence of
106 Poh TY, Tiew PY, Lim AYH, et al. Increased chitotriosidase is acquired resistance within the CF airway, independent of CFTR.
associated with Aspergillus and frequent exacerbations in South- PLoS One 2011;6(09):e23637
East Asian patients with bronchiectasis. Chest 2020;158(02): 124 Mulcahy H, Charron-Mazenod L, Lewenza S. Extracellular DNA
512–522 chelates cations and induces antibiotic resistance in Pseudomo-
107 Mac Aogáin M, Chandrasekaran R, Lim AYH, et al. Immunological nas aeruginosa biofilms. PLoS Pathog 2008;4(11):e1000213
corollary of the pulmonary mycobiome in bronchiectasis: the 125 Wilton M, Halverson TWR, Charron-Mazenod L, Parkins MD,
CAMEB study. Eur Respir J 2018;52(01):52 Lewenza S. Secreted phosphatase and deoxyribonuclease are
108 Metersky ML, Choate RBronchiectasis and NTM Research Regis- required by Pseudomonas aeruginosa to defend against neutro-
try Investigators. The association of long-term macrolide thera- phil extracellular traps. Infect Immun 2018;86(09):86
py and nontuberculous mycobacterial culture positivity in 126 Pilsczek FH, Salina D, Poon KK, et al. A novel mechanism of rapid
patients with bronchiectasis. Chest 2021:S0012-3692(21) nuclear neutrophil extracellular trap formation in response to
00283-X Staphylococcus aureus. J Immunol 2010;185(12):7413–7425
109 Fowler SJ, French J, Screaton NJ, et al. Nontuberculous mycobac- 127 Juneau RA, Pang B, Weimer KE, Armbruster CE, Swords WE.
teria in bronchiectasis: prevalence and patient characteristics. Nontypeable Haemophilus influenzae initiates formation of neu-
Eur Respir J 2006;28(06):1204–1210 trophil extracellular traps. Infect Immun 2011;79(01):431–438
110 Mitchell AB, Mourad B, Buddle L, Peters MJ, Oliver BGG, Morgan 128 Murphy TF. Immunity to nontypeable Haemophilus influenzae:
LC. Viruses in bronchiectasis: a pilot study to explore the elucidating protective responses. Am J Respir Crit Care Med
presence of community acquired respiratory viruses in stable 2003;167(04):486–487
patients and during acute exacerbations. BMC Pulm Med 2018; 129 Ketterer MR, Shao JQ, Hornick DB, Buscher B, Bandi VK, Apicella
18(01):84 MA. Infection of primary human bronchial epithelial cells by
111 Tiew PY, Jaggi TK, Chan LLY, Chotirmall SH. The airway micro- Haemophilus influenzae: macropinocytosis as a mechanism of
biome in COPD, bronchiectasis and bronchiectasis-COPD over- airway epithelial cell entry. Infect Immun 1999;67(08):4161–4170
lap. Clin Respir J 2021;15(02):123–133 130 van Schilfgaarde M, Eijk P, Regelink A, et al. Haemophilus influ-
112 Chalmers JD, Aliberti S, Filonenko A, et al. Characterization of the enzae localized in epithelial cell layers is shielded from anti-
“frequent exacerbator phenotype” in bronchiectasis. Am J Respir biotics and antibody-mediated bactericidal activity. Microb
Crit Care Med 2018;197(11):1410–1420 Pathog 1999;26(05):249–262
113 Chalmers JD, Goeminne P, Aliberti S, et al. The bronchiectasis 131 Forsgren J, Samuelson A, Ahlin A, Jonasson J, Rynnel-Dagöö B,
severity index: an international derivation and validation study. Lindberg A. Haemophilus influenzae resides and multiplies in-
Am J Respir Crit Care Med 2014;189(05):576–585 tracellularly in human adenoid tissue as demonstrated by in situ
114 Hill AT, Haworth CS, Aliberti S, et al; EMBARC/BRR Definitions hybridization and bacterial viability assay. Infect Immun 1994;
Working Group. Pulmonary exacerbation in adults with bron- 62(02):673–679
chiectasis: a consensus definition for clinical research. Eur Respir 132 King PT, Hutchinson PE, Johnson PD, Holmes PW, Freezer NJ,
J 2017;49(06):49 Holdsworth SR. Adaptive immunity to nontypeable Haemophilus
115 Choate R, Aksamit TR, Mannino D, et al. Pseudomonas aeruginosa influenzae. Am J Respir Crit Care Med 2003;167(04):587–592
associated with severity of non-cystic fibrosis bronchiectasis 133 Dicker AJ, Crichton ML, Pumphrey EG, et al. Neutrophil extracel-
measured by the modified bronchiectasis severity score (BSI) lular traps are associated with disease severity and microbiota
and the FACED: The US bronchiectasis and NTM Research diversity in patients with chronic obstructive pulmonary dis-
Registry (BRR) study. Respir Med 2020;177:106285 ease. J Allergy Clin Immunol 2018;141(01):117–127
116 Hilliam Y, Moore MP, Lamont IL, et al. Pseudomonas aeruginosa 134 Taylor SL, Rogers GB, Chen AC, Burr LD, McGuckin MA, Serisier DJ.
adaptation and diversification in the non-cystic fibrosis bron- Matrix metalloproteinases vary with airway microbiota compo-
chiectasis lung. Eur Respir J 2017;49(04):49 sition and lung function in non-cystic fibrosis bronchiectasis.
117 Woo TE, Duong J, Jervis NM, Rabin HR, Parkins MD, Storey DG. Ann Am Thorac Soc 2015;12(05):701–707
Virulence adaptations of Pseudomonas aeruginosa isolated from 135 Richardson H, Dicker AJ, Barclay H, Chalmers JD. The microbiome
patients with non-cystic fibrosis bronchiectasis. Microbiology in bronchiectasis. Eur Respir Rev 2019;28(153):28
(Reading) 2016;162(12):2126–2135 136 Read RC, Wilson R, Rutman A, et al. Interaction of nontypable
118 Harmer C, Alnassafi K, Hu H, et al. Modulation of gene expression Haemophilus influenzae with human respiratory mucosa in vitro.
by Pseudomonas aeruginosa during chronic infection in the adult J Infect Dis 1991;163(03):549–558

Seminars in Respiratory and Critical Care Medicine Vol. 42 No. 4/2021 © 2021. Thieme. All rights reserved.
512 Pathophysiology of Bronchiectasis Keir, Chalmers

137 Bernstein JM, Hard R, Cui ZD, So N, Fisher J, Ogra PL. Human 155 Ferri S, Crimi C, Campisi R, et al. Impact of asthma on bronchiectasis
adenoidal organ culture: a model to study nontypable Haemo- severity and risk of exacerbations. J Asthma 2020;9;1–11
philus influenzae (NTHI) and other bacterial interactions with 156 De Soyza A, Pavord I, Elborn JS, et al. A randomised, placebo-
nasopharyngeal mucosa–implications in otitis media. Otolar- controlled study of the CXCR2 antagonist AZD5069 in bronchi-
yngol Head Neck Surg 1990;103(5, Pt 1):784–791 ectasis. Eur Respir J 2015;46(04):1021–1032
138 Janson H, Carl n B, Cervin A, et al. Effects on the ciliated 157 Lazaar AL, Miller BE, Donald AC, et al; for 205724 Investigators.
epithelium of protein D-producing and -nonproducing nontype- CXCR2 antagonist for patients with chronic obstructive pulmo-
able Haemophilus influenzae in nasopharyngeal tissue cultures. J nary disease with chronic mucus hypersecretion: a phase 2b
Infect Dis 1999;180(03):737–746 trial. Respir Res 2020;21(01):149
139 Chu H, Zhao L, Xiao H, et al. Prevalence of nontuberculous 158 Konstan MW, Döring G, Heltshe SL, et al; Investigators and
mycobacteria in patients with bronchiectasis: a meta-analysis. Coordinators of BI Trial 543.45. A randomized double blind,
Arch Med Sci 2014;10(04):661–668 placebo controlled phase 2 trial of BIIL 284 BS (an LTB4 receptor
140 Aksamit TR, O’Donnell AE, Barker A, et al; Bronchiectasis Re- antagonist) for the treatment of lung disease in children and
search Registry Consortium. Adult patients with bronchiectasis: adults with cystic fibrosis. J Cyst Fibros 2014;13(02):148–155
a first look at the US Bronchiectasis Research Registry. Chest 159 Döring G, Bragonzi A, Paroni M, et al. BIIL 284 reduces neutrophil
2017;151(05):982–992 numbers but increases P. aeruginosa bacteremia and inflamma-

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
141 Chan ED, Iseman MD. Slender, older women appear to be more tion in mouse lungs. J Cyst Fibros 2014;13(02):156–163
susceptible to nontuberculous mycobacterial lung disease. Gend 160 Stockley R, De Soyza A, Gunawardena K, et al. Phase II study of a
Med 2010;7(01):5–18 neutrophil elastase inhibitor (AZD9668) in patients with bron-
142 Kartalija M, Ovrutsky AR, Bryan CL, et al. Patients with non- chiectasis. Respir Med 2013;107(04):524–533
tuberculous mycobacterial lung disease exhibit unique body and 161 Watz H, Nagelschmitz J, Kirsten A, et al. Safety and efficacy of the
immune phenotypes. Am J Respir Crit Care Med 2013;187(02): human neutrophil elastase inhibitor BAY 85-8501 for the treat-
197–205 ment of non-cystic fibrosis bronchiectasis: a randomized con-
143 Kunst H, Wickremasinghe M, Wells A, Wilson R. Nontuberculous trolled trial. Pulm Pharmacol Ther 2019;56:86–93
mycobacterial disease and Aspergillus-related lung disease in 162 Zhu S, Lv X, Cai W. Predictive value of blood eosinophil count in
bronchiectasis. Eur Respir J 2006;28(02):352–357 COPD. Respirology 2021;26(05):504
144 Griffith DE, Brown-Elliott BA, Langsjoen B, et al. Clinical and 163 Ko FWS, Chan KP, Ngai J, et al. Blood eosinophil count as a
molecular analysis of macrolide resistance in Mycobacterium predictor of hospital length of stay in COPD exacerbations.
avium complex lung disease. Am J Respir Crit Care Med 2006;174 Respirology 2020;25(03):259–266
(08):928–934 164 Hastie AT, Mauger DT, Denlinger LC, et al. Mixed sputum
145 Chalmers JD, Boersma W, Lonergan M, et al. Long-term macro- granulocyte longitudinal impact on lung function in the Severe
lide antibiotics for the treatment of bronchiectasis in adults: an Asthma Research Program. Am J Respir Crit Care Med 2021;203
individual participant data meta-analysis. Lancet Respir Med (07):882–892
2019;7(10):845–854 165 Sposato B, Scalese M, Ricci A, Rogliani P, Paggiaro POmalizumab
146 Cox MJ, Turek EM, Hennessy C, et al. Longitudinal assessment of Italian Study Group. Persistence of both reversible airway
sputum microbiome by sequencing of the 16S rRNA gene in non- obstruction and higher blood eosinophils may predict lung
cystic fibrosis bronchiectasis patients. PLoS One 2017;12(02): function decline in severe asthma. Clin Respir J 2021;15(02):
e0170622 237–243
147 Rogers GB, van der Gast CJ, Cuthbertson L, et al. Clinical measures 166 O’Donnell AE, Barker AF, Ilowite JS, Fick RB. Treatment of
of disease in adult non-CF bronchiectasis correlate with airway idiopathic bronchiectasis with aerosolized recombinant hu-
microbiota composition. Thorax 2013;68(08):731–737 man DNase I. rhDNase Study Group. Chest 1998;113(05):
148 Woo TE, Lim R, Heirali AA, et al. A longitudinal characterization 1329–1334
of the non-cystic fibrosis bronchiectasis airway microbiome. Sci 167 Dubois AV, Gauthier A, Bréa D, et al. Influence of DNA on the
Rep 2019;9(01):6871 activities and inhibition of neutrophil serine proteases in cystic
149 Rogers GB, Bruce KD, Martin ML, Burr LD, Serisier DJ. The effect of fibrosis sputum. Am J Respir Cell Mol Biol 2012;47(01):80–86
long-term macrolide treatment on respiratory microbiota com- 168 Gao YH, Abo Leyah H, Finch S, et al. Relationship between
position in non-cystic fibrosis bronchiectasis: an analysis from symptoms, exacerbations, and treatment response in bronchiec-
the randomised, double-blind, placebo-controlled BLESS trial. tasis. Am J Respir Crit Care Med 2020;201(12):1499–1507
Lancet Respir Med 2014;2(12):988–996 169 Chalmers JD, Chotirmall SH. Bronchiectasis: new therapies and
150 Zemanick ET, Sagel SD, Harris JK. The airway microbiome in new perspectives. Lancet Respir Med 2018;6(09):715–726
cystic fibrosis and implications for treatment. Curr Opin Pediatr 170 Fan LC, Liang S, Lu HW, Fei K, Xu JF. Efficiency and safety of
2011;23(03):319–324 surgical intervention to patients with non-cystic fibrosis bron-
151 Gao YH, Guan WJ, Xu G, et al. The role of viral infection in chiectasis: a meta-analysis. Sci Rep 2015;5:17382
pulmonary exacerbations of bronchiectasis in adults: a prospec- 171 Ruffles TJC, Marchant JM, Masters IB, et al. Outcomes of pro-
tive study. Chest 2015;147(06):1635–1643 tracted bacterial bronchitis in children: a 5-year prospective
152 Lu HW, Mao B, Wei P, et al. The clinical characteristics and cohort study. Respirology 2021;26(03):241–248
prognosis of ABPA are closely related to the mucus plugs in 172 Wang G, Hallberg J, Um Bergström P, et al. Assessment of chronic
central bronchiectasis. Clin Respir J 2020;14(02):140–147 bronchitis and risk factors in young adults: results from BAMSE.
153 Patel G, Greenberger PA. Allergic bronchopulmonary aspergillo- Eur Respir J 2021;57(03):57
sis. Allergy Asthma Proc 2019;40(06):421–424 173 Sly PD, Gangell CL, Chen L, et al; AREST CF Investigators. Risk
154 Suarez-Cuartin G, Chalmers JD, Sibila O. Diagnostic challenges of factors for bronchiectasis in children with cystic fibrosis. N Engl J
bronchiectasis. Respir Med 2016;116:70–77 Med 2013;368(21):1963–1970

Seminars in Respiratory and Critical Care Medicine Vol. 42 No. 4/2021 © 2021. Thieme. All rights reserved.