The Pathogenesis of

B ro n c h i e c t a s i s
Mark L. Metersky, MDa,*, Alan F. Barker, MDb

KEYWORDS
 Bronchiectasis  Inflammation  Mucus  Pseudomonas aeruginosa
 Polymorphonuclear leukocyte

KEY POINTS
 Bronchiectasis is a condition with heterogeneous inciting factors that result in impaired ability to
clear bacteria from the airways, perpetuating ongoing inflammation, and resulting progressive dam-
age to the airways.
 Abnormal mucus clearance, from abnormalities in the mucus itself and/or impaired ability to clear
otherwise normal mucus, is a common initiating factor that facilitates chronic bacterial airway
infection.
 Direct inflammatory insults to the airway, from autoimmune-mediated inflammation, protease-anti-
protease imbalance, to noxious agents, can incite airway damage that results in bronchiectasis.
 Once chronic airway bacterial infection is in place, the resulting inflammatory response and direct
toxic substances elaborated by the bacteria promote further airway damage and resulting airway
dilatation.

INTRODUCTION Histopathology of Bronchiectasis

Bronchiectasis is defined as permanent dilatation Bronchiectasis was described by Laennec in
of the conducting airways and is generally associ- 1819,2 when it was most commonly seen as a
ated with symptoms of persistent cough, usually complication of pulmonary tuberculosis. In 1950,
productive of sputum and episodes of exacerba- Reid,3 examining postmortem and surgical speci-
tion characterized by several of the following: mens, described the loss of bronchial subdivisions
increased volume and/or purulence of sputum, and 3 types of bronchiectasis—cylindrical, vari-
shortness of breath, fatigue, chest pain, hemopty- cose, and saccular or cystic. These descriptions
sis, fever, or cough.1 In severely affected patients, have been adapted to the radiologic chest
progressive airways obstruction develops. How- computed tomographic (CT) imaging of bronchi-
ever, the severity of bronchiectasis is varied, with ectasis. Although these 3 manifestations do corre-
some patients demonstrating permanent yet late with the degree of airway destruction and
asymptomatic irreversible bronchial dilatation, symptoms, they provide little insight into the path-
whereas others have daily production of volumi- ophysiology of bronchiectasis. In 1952, Whitwell4
nous, purulent sputum, chronic infection with published the findings of a histopathologic study
pathogens such as Pseudomonas aeruginosa of 200 operative specimens resected due to bron-
(PA), and several exacerbations each year. chiectasis. He described the loss of cartilage,
chestmed.theclinics.com

There was no funding for this article.

a
Division of Pulmonary, Critical Care and Sleep Medicine, University of Connecticut School of Medicine, 263
Farmington Avenue, Farmington, CT 06030-1321, USA; b Division of Pulmonary and Critical Care Medicine,
UHN-67, Oregon Health and Science University, Portland, OR 97239, USA
* Corresponding author.
E-mail address: [email protected]

Clin Chest Med 43 (2022) 35–46

https://doi.org/10.1016/j.ccm.2021.11.003
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36 Metersky & Barker

muscle, elastic tissue, and in cystic bronchiec- of chronic infection, resulting inflammation,
tasis, of ciliated epithelium. He found lymphoid fol- impaired mucus clearance, and resulting airway
licles, enlarged lymph nodes (which he thought damage, leading to disease progression. More
contributed to airway obstruction in some cases), recently, Flume and colleagues7 proposed a vi-
inflammation with peribronchial fibrosis, and inter- cious vortex model that more completely illus-
stitial pneumonia. Inflammation in the bronchial trated the complexity of the chronic infection and
wall involved predominantly lymphocytes and the reality that in many patients the relationship
macrophages, whereas polymorphonuclear leu- of these factors is not unidirectional (Fig. 1B).
kocytes were predominant in the bronchial However, neither of these models provides a tem-
lumen.5 Published in 1986, Cole’s classic descrip- poral basis/context for the origin of bronchiectasis
tion of the vicious cycle of bronchiectasis6 in that neither identifies the initial events leading to
(Fig. 1A) has served us well, describing the role disease. Indeed, there is not widespread

Fig. 1. (A) Cole’s6 vicious cycle of bronchiectasis pathogenesis. (B) Flume and colleagues’7 vicious vortex of bron-
chiectasis pathogenesis. (C) A proposed alternative version of the vicious vortex of bronchiectasis pathogenesis.
(From McShane PJ, Naureckas ET, Tino G, Strek ME. Non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med.
2013 Sep 15;188(6):647-56. Reprinted with permission of the American Thoracic Society. Copyright Ó 2021 Amer-
ican Thoracic Society. All rights reserved; and [B] From Flume PA, Chalmers JD, Olivier KN. Advances in bronchi-
ectasis: endotyping, genetics, microbiome, and disease heterogeneity. Lancet. 2018 Sep 8;392(10150):880-890.
Reproduced with permission of Elsevier. )

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 The Pathogenesis of Bronchiectasis 37

agreement as to whether there is a clinically Fig. 1B), we offer an alternate representation of

apparent precursor state to bronchiectasis in the vicious vortex. In doing so, we attempt to illus-
adults, or if there is one, what it looks like, although trate initiating factors and distinguish them from
logic would dictate that there must be. However, the perpetuating factors that continue to result in
some experts believe that the entity of protracted progressive airway damage, even in cases in
bacterial bronchitis (PBB) precedes the develop- which the initiating factor has resolved (Fig. 1C).
ment of bronchiectasis in some patients and that Table 1 illustrates some of the most common
the inflammation associated with persistent bacte- “causes” of bronchiectasis using this schema of
rial infection leads to the pathologic changes that initiating and perpetuating factors contributing
result in airway dilatation. Although PBB and its to the development and progression of
putative relationship to bronchiectasis has most bronchiectasis.
commonly been reported in children,8 the recent
report of several cases in adults who had underly- INITIATING FACTORS
ing conditions known to cause bronchiectasis, and
the observed progression from PBB to bronchiec- Although this section of the article lists several
tasis in one of the cases,9 lends credence to the causes of bronchiectasis, it is not meant to be an
suggestion that in at least some adults, PBB is a exhaustive recitation of all its causes. Rather, our
precursor to bronchiectasis. goal is to discuss the pathophysiologic mecha-
The mechanism by which chronic inflammation nisms leading to bronchiectasis, using some of
of the airway wall leads to bronchial dilatation is the most common underlying causes to illustrate
not completely understood. The destruction of these mechanisms. Readers will note that we
various components of the airway wall likely leads depart from how various causes have been cate-
to loss of structural integrity, with weaker, more gorized by prior authors, to group causes based
compliant airway walls and therefore, dilatation on their direct pathogenic effects on the airways.
at least in part based on circumferential “traction” For example, although cystic fibrosis (CF), primary
on the walls due to the elastic recoil of the sur- ciliary dyskinesia, and alpha-1-antitrypsin defi-
rounding lung parenchyma. Although the mecha- ciency are commonly grouped together as “ge-
nism might be similar, this should not be netic causes,” the mechanisms by which each
confused with “traction bronchiectasis,” in which results in bronchiectasis are completely different,
abnormally increased elastic recoil of the lung as described later.
due to interstitial disease results in dilatation of
Abnormalities of Mucus
otherwise normal airways. Traction bronchiec-
tasis usually does not result in clinically significant The production of normal mucus is crucial for the
consequences. Other potential mechanisms for maintenance of airway and lung homeostasis.
bronchial dilatation have been proposed, specif- Mice lacking a gene necessary for mucus synthe-
ically, increased intraluminal pressure due to sis die of pulmonary inflammation.10 Mucus cre-
mucus plugging and chronic cough. These ates a physical barrier that protects the airway
seem less likely to be important causes, given epithelium from inhaled particles and toxins.
the lack of bronchial dilatation in the vast majority Furthermore, glycoproteins, a major component
of patients who have chronic cough unassociated of mucus, is rich in carbohydrate moieties, which
with chronic infection. Furthermore, it is not un- provide binding sites for pathogenic bacteria,
common to discover an incidental finding of bron- preventing binding to the respiratory epithelium.
chiectasis in patients without significant cough or Mucous clearance, by either ciliary function or
mucus plugging. Similarly, the frequent finding of cough, promotes clearance of bacteria and
bronchial dilatation even in relatively proximal air- potentially damaging inhaled substances. Given
ways that likely never had been completely its importance, it is not surprising that the produc-
obstructed mitigates against increased luminal tion of abnormal mucus can result in bronchiec-
pressure being the cause of dilatation in most tasis. CF is the most well-known condition in
cases. On the other hand, the common findings this category, in which defects in the cystic
of proximal mucus plugging and bronchiectasis fibrosis transmembrane conductance regulator
in allergic bronchopulmonary aspergillosis sug- (CFTR) results in defective ion transport, thereby
gest that this hypothesis cannot be completely causing the airway mucus to be dry and viscous.
dismissed. Although other mechanisms may also play a role,
Building on the vicious cycle schema initially the water-deficient mucus leads to defective
suggested by Cole,6 (see Fig. 1A) refined by Flume clearance, bacterial overgrowth, and chronic
and colleagues7 to a vicious vortex reflecting the infection and inflammation.11 Less well known is
interrelationships of the contributing factors (see the epithelial sodium channel (ENaC), missense

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38 Metersky & Barker

Table 1
Initiating and perpetuating factors associated with common causes of bronchiectasis

Type of Factor Specific Factor Examples

Initiating factors Impaired mucociliary clearance Primary ciliary dyskinesia
Anatomic airway obstruction
Abnormalities of mucus Cystic fibrosis
ENaC mutations
Infection Tuberculosis
Nontuberculous mycobacteria
Acute pneumonia, measles, pertussis
Autoimmune airway inflammation
Inflammatory bowel diseases
Sjögren disease, rheumatoid arthritis, etc.
Systemic immunodeficiency
Common variable immunodeficiency
Lymphoma
Immunosuppressive therapy
Noninfectious (nonautoimmune)
inflammatory states
Alpha-1-antitrypsin deficiency
Gastroesophageal reflux?
Toxic inhalation-ammonia,
“mustard gas”
Asthma, allergic bronchopulmonary
aspergillosis, and chronic obstructive
pulmonary diseasea
Perpetuating Any of the above-mentioned
factors factors that persists
Bacterial products
Toxins
Biofilms
Host immune response
Cellular inflammatory products
Proteases
Abnormalities of mucus related
to immune response
mucus hypersecretion
Abnormal mucus due to products of
inflammation
Abnormal mucus clearance
Mucus plugging
Functional airway obstruction
Impaired ciliary function

Abbreviation: ENaC, epithelial sodium channel.

a
It is unclear to what extent the airway inflammation associated with these conditions, the resultant development of
mucus plugging, and/or the resulting airway bacterial infection drives the development of bronchiectasis.

mutations and polymorphisms of which can also in virtually every afflicted patient. Local airway
lead to defective sodium transport and increased obstruction from tumor or benign causes may
risk for bronchiectasis.12 also result in chronic infection and bronchiectasis.
Williams-Campbell syndrome, a rare congenital
condition manifested by lack of cartilage in the
Abnormalities of Mucus Clearance
conducting airways might result in bronchiectasis
Mechanisms
due to the resulting severe airways obstruction,
The most common example of this risk is primary which could impair cough clearance.13 It is un-
ciliary dyskinesia, which directly impairs mucocili- known to what extent severe airways obstruction
ary clearance, leading to retained mucus, chronic in asthma and chronic obstructive pulmonary dis-
bacterial infections, and ultimately bronchiectasis ease (COPD) might lead to increased risk for

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 The Pathogenesis of Bronchiectasis 39

bronchiectasis by this mechanism, or whether humoral immunodeficiencies, immunoglobulin

other factors such as impaired local immunity or replacement leads to improved quality of life and
airway wall inflammation are more important. It is reduced exacerbation rate, directly linking the
also thought that the lymphoid follicles noted by antibody deficiency to the manifestations of airway
Whitwell4 in pathologic specimens may contribute infection. Defects of cell-mediated immunity such
to small airway obstruction, leading to impaired as in association with some hematologic malig-
mucus clearance and resulting chronic infection nancies and/or their treatment can also lead to
and inflammation.14 bronchiectasis. The relationship between bronchi-
ectasis and innate immune deficiency, specifically
Acute infection mannose-binding lectin deficiency, is more com-
In many cohorts, “postinfectious” is the most plex. Studies have not found a direct association
commonly identified cause of bronchiectasis. In between mannose-binding lectin deficiency and
some cases, it is a distant childhood acute infec- the occurrence of bronchiectasis, although the
tion such as pertussis or measles that is blamed. severity seems to be increased when it occurs.17
It is often unclear the extent to which the infection
is actually relevant to the bronchiectasis detected Autoimmune disease
many years later, as opposed to a previously Several autoimmune diseases that predominantly
healthy child who develops chronic cough after target other areas of the body may result in airway
an acute infection and is found to have bronchiec- inflammation with a continuum of manifestations
tasis. Although bronchiectasis is commonly that may be limited to chronic cough or bronchio-
mentioned as a result of an acute bacterial pneu- litis but also includes bronchiectasis. The most
monia, there is limited literature supporting this be- common autoimmune diseases that result in bron-
ing a frequent occurrence. In many patients who chiectasis appear to be rheumatoid arthritis, Sjög-
are found to have bronchiectasis after an acute ren disease, ulcerative colitis, and Crohn disease.
lower respiratory tract infection, careful “sleuth- It is unknown whether chronic inflammation
ing” reveals that the patient likely had preexisting directly due to the autoimmune disease is the initi-
bronchiectasis and the acute infection was a ating factor for the development of bronchial dila-
sequela of the bronchiectasis and not the cause. tation. The other possibility is that the perturbed
Although common in children, reversible airway environment due to the autoimmune-mediated
dilatation after acute infection can also occur in inflammation affects local host defenses, resulting
adults.15 in chronic infection. Although we are not aware of
supporting data, it is the authors’ clinical impres-
Chronic Infection sion, as well as that of other experts, that many
of these patients are symptomatic despite not hav-
Bronchiectasis has been increasingly recognized ing evidence of bacterial infection. Not unexpect-
in the setting of immunocompetent nontubercu- edly, dry cough, as opposed to cough productive
lous mycobacterial (NTM) infection, most of purulent secretions, seems to be more common
commonly Mycobacterium avium complex in these patients. Also, supporting the importance
(MAC). In identifying the potential causal direction of autoimmune-related inflammation driving at
of this association, there is a chicken-egg prob- least some of the symptoms, immunosuppressive
lem: does the MAC cause the bronchiectasis or therapy such as corticosteroids or anti-tumor ne-
does the bronchiectasis increase the risk for crosis factor (TNF) agents directed at the underly-
MAC, making it a complication of the preexisting ing condition may decrease the cough and even
bronchiectasis? There seems to be little doubt decrease exacerbation rates.18
that bronchiectasis increases the risk for NTM,16
similar to what is seen in CF; however, some pa- Asthma and Chronic Obstructive Pulmonary
tients seem to develop bronchiectasis in associa- Disease
tion with the MAC infection, not before.9
Both of these airway diseases predispose to bron-
Systemic immunodeficiency chiectasis, because it is seen in higher percent-
It is well known that systemic immune defects lead ages than among the general population. In
to bronchiectasis, almost surely by leading to many patients, the bronchiectasis seems to be
impaired bacterial clearance, chronic bacterial an incidental finding, with mild bronchial dilatation,
airway infection, and the resulting inflammatory but no clinical manifestations that distinguish
response; these may be purely genetic immuno- these patients from the typical patient with asthma
deficiencies, such as X-linked agammaglobulin- or COPD. Furthermore, in some patients with
emia, or acquired defects such as most cases of COPD with apparent airway dilatation, that
common variable immunodeficiency. With these appearance is actually due to narrowing or pruning

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40 Metersky & Barker

of the pulmonary artery and not dilatation of the could explain these findings is that these abnor-
bronchi.19 Nonetheless, in some patients the bron- malities, alone, are not sufficient to cause bronchi-
chiectasis is clinically significant, with accompa- ectasis, but they increase the susceptibility in
nying chronic airway infection by organisms not patients who have an additional risk factor,
typically seen in asthma or COPD. These patients whether it be another as yet undiscovered genetic
tend to have more severe asthma and COPD than abnormality or other intrinsic or environmental fac-
patients who do not develop bronchiectasis.20,21 tors, with these factors serving as a “second-hit.”
Of course, bronchiectasis is also a feature of This phenomenon is nicely demonstrated by the
allergic bronchopulmonary aspergillosis. It is un- interaction of common variable immunodeficiency
known whether the chronic inflammation and (CVID) and deficiency of mannose-binding lectin.
mucus plugging associated with these conditions Bronchiectasis is more common in patients with
leads to perturbation of local host defenses and CVID with mannose-binding lectin deficiency
then chronic airway infection, or whether a than in those without,30 but among the general
different mechanism, such as the mechanical ef- population, patients with mannose-binding lectin
fect of airways obstruction, plays a role. deficiency are no more likely than normals to
develop bronchiectasis.17 In this case, “the excep-
Noninfectious Inflammatory States tion may prove the rule,” as patients with
mannose-binding lectin deficiency who do
Patients with homozygous alpha-1-antitrypsin
develop bronchiectasis tend to have more severe
PiZZ deficiency have uncontrolled excessive pro-
disease than those without deficiency.17 Similarly,
tease activity that results in emphysema in some
patients with rheumatoid arthritis who have a sin-
patients, especially cigarette smokers. These pa-
gle CFTR mutation are more likely to have bronchi-
tients are also at high risk of developing bronchiec-
ectasis than patients with rheumatoid arthritis who
tasis, with 27% in one cohort of ZZ patients having
have normal CFTR.31
clinically significant bronchiectasis.22 Inhalation of
directly acting irritant substances may result in
PERPETUATING FACTORS
damage to the airways and resulting bronchiec-
Mucociliary Clearance
tasis; these include inhalational injuries from in-
dustrial accidents with ammonia23 and the The perpetuation and progression of bronchiec-
chemical warfare agent, “mustard gas.”24 Gastro- tasis, including the often-frequent exacerbations
esophageal reflux is more common in patients with and tissue destruction, is due to a complex combi-
bronchiectasis than in the general population, and nation of an uncontrolled inflammatory response,
direct acid injury of the airway may be a factor in chronic infection with potentially virulent bacteria,
this association; however, this is not yet clear, impaired mucociliary clearance, and resistance
and the relationship might be more complex.25 In to antibiotics.32 This section examines each of
one rat model, intratracheal nitric acid instillation the factors. As will be emphasized, almost every
resulted in several types of airway lesions, cell and secretory component has salutary effects
including bronchiectasis.26 Bronchiectasis has on bacterial killing and removal, but excessive
also been reported as a common sequela of bron- amounts or ineffectual clearing may also damage
chial thermoplasty.27 airway and lung tissue.33

Double-Hit Hypothesis Neutrophils and Neutrophil Elastase

There are several relevant genetic mutations that Normal airway secretions contain 95% macro-
do not seem to directly cause bronchiectasis in phages. In bronchiectasis, the predominant cell
heterozygotes or in those with milder mutations, is the neutrophil. Bacteria attract neutrophils via
because the vast majority of such patients never a variety of released chemokines including inter-
develop disease. However, these genetic abnor- leukin (IL)-8, IL-1, and TNF-alpha. Upon mobiliza-
malities are seen with greater frequency in patients tion to sites of infection, neutrophils release
with bronchiectasis than in individuals without potent enzymes including elastase and myeloper-
bronchiectasis, suggesting that they may oxidase. Neutrophil elastase (NE) is a 29-kDa
contribute to its pathophysiology; these include serine proteinase stored in neutrophil granules
heterozygotes with a single CFTR mutation,28 pa- and released into neutrophil extracellular traps
tients with milder alpha-1-antitrypsin mutations, (NETs) or at times of apoptosis. NE is highly inflam-
or those heterozygote for the Z allele.29 The finding matory and a potent neutralizer of bacteria. NE
that coexisting single CFTR mutations and ENaC also impairs ciliary motility and stimulates mucus
mutations increase the risk of bronchiectasis12 secretion. NE is neutralized by serum-derived
also supports this hypothesis. One theory that alpha-1 antitrypsin, secretory leukoproteinase

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 The Pathogenesis of Bronchiectasis 41

inhibitor, and epithelial cell-derived syndecan-1. bacterial infection but may allow tissue
NE is the main culprit causing alveolar damage destruction.37
via destruction of elastin in COPD, including Elevated levels of PZP were found in patients
alpha-1 antitrypsin deficiency. Studies have found with bronchiectasis who had worse severity as
very high levels of NE in the sputum of patients measured by the BSI, exacerbation rate, and the
with CF and bronchiectasis.34 presence of PA. In patients who had an exacerba-
In a single-center study from Scotland, higher tion with an increased quantitative bacterial load,
sputum levels of NE highly correlated with disease PZP levels increased. After antibiotic administra-
severity, categorized by impairment of pulmonary tion sputum PZP levels declined. Another finding
function or forced expiratory volume in the first was that analysis of the microbiota by 16S ribo-
second of expiration (FEV1), scores on St. some sequencing showed high levels of PZP in
George’s Respiratory Questionnaire and the Bron- the sputum of patients with common virulent path-
chiectasis Severity Index (BSI), and extent of bron- ogens including PA, Stenotrophomonas, and
chiectasis on chest CT by the Reiff score. High Staphylococcus aureus (SA) and lower levels in
levels of NE also correlated with the presence of patients with Streptococcus, Haemophilus, and
and quantity of pathogenic bacteria including PA Veillonella. These data suggest PZP is a marker
and other gram-negative bacteria. During longitu- of enhanced inflammation, but it is not yet clear
dinal assessments, individuals with the highest whether it contributes to the ongoing airway
levels of NE had increased frequencies of exacer- destruction or is merely a marker.38
bations and shorter time to any subsequent exac-
erbation, but not mortality. In a small subset of 26 Macrophages
patients with exacerbations, sputum NE increased After contact with an airway irritant, macrophages
from baseline at the beginning of an exacerbation, recruit neutrophils by release of IL-8. Macro-
decreased at the end of 2 weeks of antibiotic phages are key components of phagocytosis and
administration, but remained at a higher level bacterial clearance via opsonizing antibodies and
than baseline sputum NE 6 months after resolution nonopsonizing mechanisms. PA via quorum
of the exacerbation.35 sensing (QS) interferes with this clearance via
Interest in NE as a biomarker and proinflamma- release of virulence factors including pyocyanin.
tory mediator has been heightened with the recent These virulence factors also neutralize humoral
phase 2 results of the study of the oral drug, bren- antibodies and interfere with ingestion of PA into
socatib, an inhibitor of dipeptidyl peptidase-1, also macrophages.
known as cathepsin C (the enzyme that activates
serine proteases). Brensocatib treatment pro- Lymphocytes
longed the time to first exacerbation and reduced
the number of exacerbations compared with pla- Lymphocytes are also recruited to the airway. QS
cebo. Sputum levels of elastase were significantly interferes with this recruitment as well as the for-
lower in the brensocatib-treated subjects, sup- mation of the key bronchus-associated lymphoid
porting the role of NE in the pathophysiology of tissue (BALT), a component of innate immunity.
bronchiectasis.36 BALT provides a major secondary reinforcing de-
fense via dendritic cells ingesting invasive bacte-
ria. BALT recruits both B and T lymphocytes that
Neutrophil Extracellular Traps and Neutrophil are directly responsible for the immune response
Zone Protein to invasive bacteria. Animal models have demon-
Pregnancy zone protein (PZP) is a glycoprotein strated that a tardy or ineffective BALT immunity
found mainly in the cytoplasm of PMNs and also contributes to lung injury and mortality.39
eosinophils. PZP has broad immunosuppressive
Eosinophils
and antiprotease properties. PZP was originally
found in pregnant women and thought to prevent Blood and sputum eosinophils play a role in the
fetal rejection. PZP is one of the products extruded major obstructive lung diseases, asthma and
from neutrophils as part of the NET formation. COPD.40 Emerging evidence is accumulating that
NETs trap and neutralize pathogens (also elastase they may be a biomarker indicating a role for spe-
and myeloperoxidase). Recently PZP has been cific treatments.41 Lung tissue attraction of eosin-
found to be elevated in the sputum (not blood) of ophils is stimulated by IL-5 and to a lesser extent
patients with bronchiectasis. PZP is not found in IL-4, IL-13, and chemokines where they release
airway epithelial cells, and only low levels are major basic protein, a toxin to bronchial epithelial
found in monocytes. NETs are intriguing because cells. Other eosinophilic proteases are found in
there is evidence that like NE, they may reduce excess in airways (sputum) of patients with

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42 Metersky & Barker

obstructive lung disease.42 Emerging experience exhibiting the almost pathognomonic 3-layered
in bronchiectasis suggests that inhaled corticoste- sputum that is observed when sputum is collected
roids and IL-5 antagonists may play a role in in a vessel.
reducing eosinophilic presence in some patients There are therapeutic implications of the
with bronchiectasis with blood eosinophilia. aqueous dehydration, as the administration of
nebulized normal or hypertonic saline may assist
Airway Epithelial Cells rehydration in addition to a mechanical action of
loosening tenacious adherent mucus plaques
Bronchial epithelial cells and overlying mucin pro-
from epithelial surfaces. The drug DNase or dor-
vide the major physical, immune, and chemical
nase alpha that breaks down the increased DNA
protective barrier against microbe invasion. This
in vitro and in patients with CF does not improve
barrier can be disrupted by physical trauma such
clinical outcomes in non-CF bronchiectasis.45
as an endotracheal tube or suctioning, chemical
insults such as acid aspiration, or chronic infection
Bacteria
in bronchiectasis. Bacteria (PA, the most virulent)
interacts with epithelial cells by attaching to mu- The bacterial flora in bronchiectatic airways are
cins and cell surface receptors via flagella and different from those in asthma and COPD. In indi-
pili. PA directly injects effector molecules that viduals with bronchiectasis and bacteria present in
allow internalization.43 QS signaling molecules sputum cultures, PA and Hemophilus influenza are
directly break down mucins and stimulate mucus each present 25% to 30% of the time, SA and
production and slow the coordinated beating of Streptococcus pneumoniae each 9% to 12%,
cilia, contributing to ineffective bacterial clear- and Moraxella catarrhalis 5% to 8%. PA is the
ance. Yet, epithelial cells resist infection by most virulent, contributing to increased morbidity,
secreting lactoferrin and enzymes that interfere accelerated decline in FEV1, increased exacerba-
with bacterial biofilm formation and allow entry of tions and hospitalizations, and mortality.46,47 The
inflammatory cell cytokines and chemokines to presence of PA is considered to represent infec-
attack virulent bacteria. tion and never a saprophyte or commensal.
Although bacteremia does not usually occur in
Mucociliary Clearance bronchiectasis, even during exacerbations, the in-
vasion of epithelial cells by bacteria and endo-
Transport occurs by a combination of coordinated
toxins allows release of cytokines into the
ciliary beating and cough. The mucociliary system
circulation that contributes to the systemic mani-
protects the respiratory system (upper and lower
festations including fever, chills, rigors, excessive
airways) from noxious inhaled substances by trap-
fatigue, and even pleuritic chest pain. PA virulence
ping deposited particles and clears invading path-
factors is discussed in detail.
ogens via an elaborate transport process. Mucus
that lines epithelial surfaces is composed of an
Pseudomonas
aqueous component (98% water), ions, glycopro-
teins, and mucin macromolecules, primarily the PA is fascinating and very complex with a variety
mucin polymers, MUC5B and MUC5AC. In bron- of injurious endotoxins and exotoxins, and one of
chiectasis the gelatinous component and inflam- the most invasive and damaging airway and some-
matory debris are increased, leading to the times systemic pathogens. PA rarely infects an
trapping of bacteria, and also impairing transport, immunocompetent host without structural lung
thereby leading to airway obstruction, and mucus damage, rather PA infection most often occurs in
plugging. Mucins consist of a viscoelastic gel pro- the setting of a systemic compromise such as se-
duced by epithelial surface secretory cells and vere burns, diabetes mellitus, organ transplants, or
submucosal glands connected to the lumen by cancer as examples. In lung disease, PA requires a
ciliary ducts. In airway diseases, mucin production damaged airway with breaks in the epithelial
and secretion is stimulated by infectious and other mucosal barrier, altered local or systemic immu-
noxious agents, reducing elasticity. The higher nity, and often a host that has received multiple,
mucin concentration augments the osmotic load, prolonged, and/or often broad-spectrum antibi-
increasing competition for water with the aqueous otics. These factors are present in the patient
layer, contributing to epithelial surface dehydra- with bronchiectasis. Other respiratory diseases
tion.44 Less elasticity of the mucin overlying ciliary prone to PA infection have similar characteristics
cells reduces proximal transport and loss of including CF, ventilator-associated pneumonia,
beating coordination. Expectorated sputum in pa- and advanced COPD.48
tients with bronchiectasis contains inflammatory PA is a gram-negative rod, facultative aerobe
debris (DNA, neutrophils and NETs) and bacteria, that adheres to airway epithelium via a single

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 The Pathogenesis of Bronchiectasis 43

flagellum, pili, and components of the outer biofilms. Other factors contributing to antibiotic
plasma membrane. Flagella home into damaged resistance inside biofilms include the relative lower
epithelial cells via released glycophospholipids. metabolic activity of PA and the low oxygen envi-
For this adherence, there needs to be a breach ronment. QS and subsequent biofilm formation
in tight junctions or focal concentrations of the may be reduced with several natural compounds
bacteria, both present in bronchiectasis.49 Bacte- including ajoene (in garlic), iberin (horseradish),
riophages specific for each bacteria interfere with and eugenol (clove). No large clinical studies have
this adherence and reduce inflammation. Bacte- been accomplished with these agents. Chronic
riophages, because of actions against toxins macrolide antibiotic administration is the only man-
including pyocyanin and lipopolysaccharide agement strategy that has been proved to reduce
(LPS) may be an emerging alternative or adjunctive exacerbations in bronchiectasis. In addition to
treatment of PA infection, in addition to reducing neutrophilic inflammation, other mecha-
antibiotics.50 nisms may be downregulating or inhibiting QS
The outer membrane of PA exhibits low perme- and biofilm formation.51,52
ability because of the expression of porins and li-
poproteins. This outer membrane containing Staphylococcus aureus
porin F provides resistance to influx of solutes
Individuals with CF were originally thought to have
and small molecules such as antibiotics. PA inter-
a predominant SA microbial load and later ac-
nal efflux pumps also externalize antibiotics that
quired PA. More recent studies with quantitative
enter the bacteria. Key components of a bacteria’s
cultures of sputum suggest that in adults both
virulence is their secretory system, expressing fac-
SA and PA coexist and contribute to worse
tors directly into cells or the airway space. Potent
outcomes than either organism alone. In contra-
exotoxins include proteases such as elastase
distinction to CF, in bronchiectasis methicillin-
and lipases that can be efficiently injected into
resistant SA may not be a more virulent pathogen
epithelial cells. The outer membrane also contains
than methicillin-sensitive SA as evidenced by the
LPS, an important PA virulence factor that upon
rate of decline in FEV1 and exacerbations.53
release is partly responsible for the systemic
symptomatic manifestations of PA infection.
Microbiome
Quorum Sensing Traditional microbiologic cultures usually identify
gram-negative PA, H influenza, and pathogens
QS is a form of bacterial cell-to-cell communica-
among others; however, they may miss fastidious
tion that regulates gene expression and through
potentially pathogenic bacteria. Anaerobic cultures
a series of biochemical reactions induces the pro-
are rarely performed. Quantitative bacterial cultures
duction of several of the virulence factors including
offer some advantages, but they are not readily
proteases, pyocyanin (is also a pigment that pro-
available and their utility in sputum versus broncho-
vides the blue-green color to PA in culture), and
scopic lavage has been controversial. Newer molec-
LPS. In essence, QS allows bacteria to limit
ular methodologies have emerged to help focus
expression of certain genes to times when there
targets for antimicrobial management. The most
is a high-enough population of bacteria that such
straightforward definition is that the microbiome en-
expression will be beneficial (eg, biofilm or toxin
compasses all the microorganism-derived genetic
production). QS and the ability to sense and
material in an environment. The microbiome meth-
respond to the environment and development of
odology used most frequently in bronchiectasis to
biofilms are fundamental to the initiation, propaga-
date is 16S ribosomal RNA amplicon sequencing.
tion, and maintenance of PA.
Key phyla identified included Proteobacteria
(including Pseudomonas and Haemophilus), Firmi-
Biofilms
cutes, and Bacteroidetes. The microbiome of the
Biofilms are structured and organized communities healthy airway is much different than in the bron-
of bacteria (PA) surrounded by an extracellular chiectatic airway. In bronchiectasis there is altered
polymeric matrix that provides stability and resis- mucociliary clearance and often dilated and
tance against surrounding host defense cells, pro- tortuous airways with pockets allowing harboring
teins, and antimicrobial agents. This surrounding of bacteria that may not be easily captured in
matrix is composed of polysaccharides, lipids, pro- large-enough quantities for traditional culture tech-
teins, and DNA produced by the bacteria. Biofilms niques. Because microbiome studies allow identifi-
enhance the bacterial virulence through QS com- cation of genetic material from all species and an
munications. Antibiotic resistance is partially due inability to quantitate the number of organisms, the
to lack of penetrance of antimicrobials through utility will depend on trends and relevance of

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44 Metersky & Barker

organisms identified in stable versus exacerbation sponsored by Insmed. Dr A.F. Barker has no finan-
clinical states. Although this analytical technology cial conflicts of interest to report.
is not new, only recently have trends emerged that
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