[ Recent Advances in Chest Medicine ]

Bronchiectasis
Pamela J. McShane, MD; and Gregory Tino, MD

Bronchiectasis is an important clinical syndrome because of its increasing prevalence, sub-

stantial economic burden on health care, and associated morbidity. Until recently, the disease
was considered an orphan and essentially neglected from a therapeutic standpoint, but many
recent advances have been made in the field. Several national registries have formed to provide
databases from which to study patients with bronchiectasis. Experts published a consensus
definition of a bronchiectasis-specific exacerbation that will serve as a unified definition for
future clinical trials. Several inhaled antibiotic trials aimed at reducing exacerbation frequency
have been completed. Researchers have investigated nonculture techniques, such as 16S ri-
bosomal RNA (rRNA) and whole genome sequencing, to characterize the microbiological
characteristics. Studies of anti-Pseudomonas antibodies are providing interesting insight into
varying host responses to chronic Pseudomonas infection. After three successful trials
demonstrating that macrolides reduce exacerbations in bronchiectasis, other antiinflammatory
agents have been investigated, and a trial of a novel antiinflammatory drug is ongoing. A
relatively robust study has been published in airway clearance, a therapy that is accepted
universally as beneficial but that has never been accompanied by strong evidence. To build on
the successes with bronchiectasis thus far, investigators must develop better definitions of
phenotypes of bronchiectasis. In this regard, clinical tools have been developed to quantify
disease severity and predict prognosis. Studies of different clinical phenotypes of bronchiectasis
in patients with bronchiectasis have been published. With continued advances in the field of
bronchiectasis, there is hope that evidenced-based therapies will become available.
CHEST 2019; 155(4):825-833

KEY WORDS: airway clearance; bronchiectasis; inhaled antibiotics

Bronchiectasis has been an important bronchiectasis being termed an “orphan”

respiratory condition since it was first
described by Laënnec1 in 1819. This
syndrome of permanent airway dilatation,
characterized by chronic productive cough
and recurrent exacerbations, is notably a
heterogeneous entity, as was described in
1952.2 This heterogeneity resulted in
disease3 with a poor prognosis in need of
particular attention. In the past 2 decades,
bronchiectasis has received an increasing
focus. In 2013, Mandal and Hill4 published
an editorial that heralded the development of
therapeutic strategies to break the
paradigmatic cycle of inflammation and

ABBREVIATIONS: ACT = airway clearance technique; BSI = Bronchi-
ectasis Severity Index; CF = cystic fibrosis; ELTGOL = expiration with
the glottis opened in the lateral posture; FACED = FEV1, age, chronic
Pseudomonas colonization, extension of disease radiographically, dys-
pnea; LCQ = Leicester Cough Questionnaire; NTM = nontuberculous
mycobacteria; rRNA = ribosomal RNA; SGRQ = St. George’s Respi-
ratory Questionnaire
AFFILIATIONS: From the Section of Pulmonary and Critical Care
Medicine (Dr McShane), University of Chicago, Chicago, IL; and the
Section of Pulmonary and Critical Care Medicine (Dr Tino), Univer-
sity of Pennsylvania, Philadelphia, PA.
CORRESPONDENCE TO: Pamela J. McShane, MD, Section of Pulmo-
nary and Critical Care Medicine, University of Chicago, 5841 S
Maryland Ave, MC 6076, Chicago, IL 60637; e-mail: pmcshane@
medicine.bsd.uchicago.edu
Copyright Ó 2018 American College of Chest Physicians. Published by
Elsevier Inc. All rights reserved.
DOI: https://doi.org/10.1016/j.chest.2018.10.027

chestjournal.org 825
infection in bronchiectasis. The authors took a justifiably
optimistic stance. Studies had demonstrated that
reduction of bacterial load with nebulized antibiotics led
to a decline in measures of inflammation, critical to the
pathogenesis of bronchiectasis.5 Three clinical trials of
macrolide antibiotics demonstrated a significant
reduction in exacerbation frequency.6-8 In addition,
multicenter trials of inhaled antibiotics were
underway.9-11
Subsequent years, however, have brought a mix of
disappointment and hope. Phase III trials of inhaled
antibiotics, although they demonstrated effectiveness in
reducing bacterial load, failed to show benefit in
exacerbation frequency or quality of life. For all the
success of the macrolide trials, there remain nagging
concerns regarding adverse effects and the emergence of
bacterial resistance12 and macrolide resistance in
patients with covert nontuberculous mycobacteria
(NTM) infection. However, in the past several years,
there have been a number of advances in bronchiectasis.
Tools to characterize disease severity and predict
mortality such as the Bronchiectasis Severity Index (BSI)
and the FEV1, age, chronic Pseudomonas colonization,
extension of disease radiographically, dyspnea (FACED)
score have been developed and validated.13,14 American
and European registries have been formed to define
phenotypes of the disease and provide a database to
answer research questions.15-17 A working group
convened to establish a unified consensus definition of a
bronchiectasis exacerbation. Efforts to characterize the
microbiological characteristics of bronchiectasis more
accurately are progressing, and investigations of new
ways to combat inflammation are ongoing. This article
will capsulize the evidence supporting current therapies
in bronchiectasis not due to cystic fibrosis (CF), as well
as highlight recent advances in the field over the past
several years.
Epidemiologic Characteristics
The clinical course of bronchiectasis is punctuated by
episodes of worsening clinical status, referred to as
TABLE 1 ] Definition of a Bronchiectasis Pulmonary Exacerbation for Clinical Trials
Symptoms: Deterioration in Three or More
Cough Symptoms must be present
Sputum volume and/or consistency for at least 48 h
Sputum purulence
Breathlessness and/or exercise tolerance
Fatigue and/or malaise
Hemoptysis
Adapted with permission from Hill and colleagues.18
826 Recent Advances in Chest Medicine
“exacerbations.” A shortcoming of bronchiectasis trials
has been the lack of a unifying definition of an
exacerbation, making interpretation and comparison of
trials troublesome. In July 2016, an international group
of bronchiectasis investigators convened at the first
World Bronchiectasis Conference in Hannover,
Germany, to develop, by a three-round Delphi process, a
consensus definition of a clinically significant
exacerbation in adult patients with bronchiectasis.18
Table 1 outlines the consensus definition, which includes
both clinical symptoms and stipulation that an
intervention be made. The definition was developed for
use in clinical trial design but has considerable relevance
for clinical practice.
Using phenotypes or grouping patients on the basis of
common clinical characteristics is occurring in a variety
of pulmonary conditions, including COPD19 and
asthma.20 Defining phenotypes for these diseases has
clarified which patients have a higher risk of developing
exacerbations and mortality. As a heterogeneous disease
process, bronchiectasis may have the most to benefit
from careful definition of phenotypes. Deemed
“frequent exacerbators,” those with three or more
exacerbations per year are now seen as a distinct clinical
phenotype by Chalmers and colleagues21 after analysis
of 2,572 patients with bronchiectasis from 10 different
European clinical centers. A history of frequent
exacerbations was the strongest predictor of future
exacerbations over time. In addition, other independent
predictors of frequent exacerbations were the presence
of Haemophilus influenzae and Pseudomonas
aeruginosa, reduced FEV1, radiologic severity, and the
presence of coexisting COPD. By multivariate regression
model, each additional annual exacerbation per year was
associated with an independent 3.7-point increase in St.
George’s Respiratory Questionnaire (SGRQ) score
(95% CI, 2.58-4.87; P < .0001), indicating worse quality
of life. The patients also required more frequent
hospitalizations and had a higher mortality. This group
may be the optimal target population for future clinical
trials and may be the most appropriate candidates for
Time Course Additional Criteria That Must Be Present
Physician determines that a change in
treatment is required
Other potential causes of clinical
deterioration have been discounted
[ 155#4 CHEST APRIL 2019 ]
currently available treatments, including long-term use
of macrolides and inhaled antibiotics.22
Other phenotypic groups have been proposed, such as
those patients with dry bronchiectasis vs those with daily
sputum production.23 Defining phenotypes of
bronchiectasis in patients with bronchiectasis is still in its
early stages but has emerged as a major research priority
within the field of bronchiectasis. The goal is to apply
emerging technologies of proteomics, metabolomics, and
genomics to well-characterized groups of patients with
bronchiectasis to understand better exact causes and
identify targets for future therapies.24
Another important advance in the area of
bronchiectasis has been the development of clinical
prediction tools for disease severity and prognosis that
can be applied to clinical research as well as clinical
practice. The BSI was derived from a prospective
Diagnostic Methods
Microbiological Characteristics
Chronic bacterial infection is an integral part of the pathogenesis of
bronchiectasis.26 Data show that even in the nonexacerbated state,
antibiotics reduce bacterial load and systemic inflammation.
International guidelines27-30 recommend surveillance sputum
cultures and culture-directed antibiotic therapy. However,
traditional culture techniques may be limited by factors such as
sputum volume, time from expectoration to incubation, and the
fastidiousness of the pathogen. Culture-independent techniques
such as nucleic acid-based technologies like pyrosequencing can
be applied directly to sputum or BAL samples. These techniques
have uncovered limitations of traditional sputum culture, have
shown important nuances of the microbial community and its
behavior, and have revealed potential vulnerabilities that could be
targets for future therapies.31
32
Byun and colleagues compared traditional quantitative sputum and
BAL culture techniques to 16S rRNA sequencing in adult patients
with both clinically stable and exacerbated bronchiectasis. They
found that typical sputum or BAL cultures yielded only dominant
organisms and, in some patients, no pathogenic organism at all. In
contrast, 16S rRNA sequencing identified bacteria in all study
subjects and identified a broader number of potentially pathogenic
bacteria per patient. In instances in which the sputum or BAL
culture findings were negative, 16S rRNA sequencing revealed at
least three organisms, and in abundance. In some instances, the
dominant organisms present in the culture were scarce at 16S rRNA
sequencing. Importantly and unexpectedly, 16S rRNA sequencing of
BAL samples revealed no significant differences in relative
abundance and distribution of taxa between the stable and
exacerbated states. This finding contradicts those in a sentinel study
in COPD that implicated acquisition of new strains of bacteria in the
genesis of exacerbations33 and highlights that bronchiectasis differs
from other airways diseases.
Cox and colleagues34 analyzed the longitudinal variability of the lung
microbiome by using 16S rRNA sequencing on a monthly basis for
6 months in patients with predominantly idiopathic or postinfectious
bronchiectasis. Traditional microbiological sputum cultures were
chestjournal.org
cohort study in 608 patients in the United Kingdom
and was validated in several independent cohorts.13
The index is composed of nine clinical parameters,
including lung function and chronic Pseudomonas
infection, among others. Higher BSI scores predict
higher mortality, more frequent hospital admissions
and exacerbations, and worse quality of life.
Independent predictors of mortality include older age,
low FEV1, lower BMI, previous hospitalizations, and
> three exacerbations in the previous year. Another
such tool is the FACED score that classifies severity
according to prognosis. It was derived from an
observational study from 819 patients in Spain by using
five variables and a 7-point score. Higher FACED
scores predict 5-year all-cause mortality.14 In one study
that compared BSI vs FACED in a 91-patient cohort,
both scores were similarly predictive of 5-year and 15-
year mortality.25
obtained in parallel for comparison. The sputum samples were
obtained at defined states in the patient’s clinical course: baseline,
stable, exacerbated, during treatment for exacerbation, and during
recovery. The results showed a richness of organisms revealed by
16S rRNA sequencing: 352 operational taxonomic units in the
baseline samples, mostly in very low abundance. H influenzae was
the most abundant operational taxonomic unit overall, followed by P
aeruginosa, and Streptococcus. In contrast, parallel sputum cultures
grew P aeruginosa most commonly, followed by Staphylococcus
aureus and H influenzae. Culture findings that were negative were
commonly positive with 16S rRNA. If 16S rRNA were the gold
standard, the culture sensitivity for P aeruginosa was 52% and for H
influenzae was only 18%. Conversely, Pseudomonas species and S
aureus were sometimes present in culture but not detected with
sequencing.
The study also suggested that long-term use of suppressive antibiotics
caused a more homogeneous community of bacteria.34 Alpha diversity,
the number of different species within an individual patient, was
significantly lower in patients who were receiving prophylactic
antibiotics. Diversity of bacterial species did not correlate with
severity of disease in terms of lung function, number of years since
first P aeruginosa isolation, or treatment with steroids. The patient’s
microbial profile was undisturbed by antibiotic treatment for
exacerbation or by clinical state: 16S rRNA gene quantitative
polymerase chain reaction measurement demonstrated no significant
difference in bacterial load for the baseline, exacerbation, treatment,
or recovery states.
Although provocative, the role of 16S rRNA vs that of traditional
sputum culture in the clinical setting remains to be determined.
Nonculture techniques have been studied in small numbers of
patients with bronchiectasis, so they are probably not yet
representative of the entire affected population. Given the speed of
this technology’s evolution, however, nonculture techniques may
arrive in the clinical setting sooner than expected.
Culture-independent techniques also have been used to investigate
whether bacterial cross infection occurs. Under the premise that
genetically similar Pseudomonas isolates in two patients from a
827
shared facility is representative of cross infection rather than
independent acquisition, Mitchelmore and colleagues35 performed a
cross-sectional study of Pseudomonas strains identified in
unsegregated CF and non-CF bronchiectasis cohorts. Multilocus
sequencing was used to obtain strains from unique Pseudomonas
profiles. These strains were characterized further to the isolate level
by using whole genome sequencing. They found that Pseudomonas
strains between the CF and non-CF cohorts were completely
divergent from one another and therefore unlikely to have been
acquired by cross infection. In contrast, two shared strains of
Pseudomonas within the CF group (strain ST146, known as the
“Liverpool epidemic strain”) were found in sibling patients. The
strains differed from each other by only 31 single nucleotide
polymorphisms, demonstrating high genetic relatedness and, in
combination with known personal contact between siblings, were
presumed to be indicative of cross infection. In the non-CF cohort, a
shared strain identified in three unrelated patients was highly
similar, differing by only four to 12 single nucleotide
polymorphisms, consistent with cross infection.
In a position statement from the European Multicentre Bronchiectasis
Audit and Research Collaboration, Chalmers and colleagues36
acknowledged that although cross infection occurs but is rare. The
clinical significance of these events also is unknown, particularly
because clinical deterioration has not been linked to cross infection
and segregation of patients with bronchiectasis is logistically
impractical and unfounded based on currently available data.
Whole Genome Sequencing
Whole genome sequencing has revolutionized medicine in recent years
and is becoming increasingly available. The technique is particularly
relevant in bronchiectasis because it may describe the modus
operandi of key bacteria in the disease. P aeruginosa is a particularly
important pathogen in bronchiectasis and is associated with worse
quality of life and higher rates of hospitalization and mortality.37
Hilliam and colleagues38 performed comparative whole genome
sequencing on 189 P aeruginosa isolates from sputum samples from
93 patients with bronchiectasis with chronic Pseudomonas infection.
Their work revealed several characteristics of Pseudomonas in
chronic infection, including the following:
1. In addition to diversity of strains between individual patients, there
are multiple distinct clonal lineages of P aeruginosa within the same
patient (multilineage infection), which has implications for deter-
mining the source of acquisition.
2. Mutations that enhance adaptation to the lung environment, such as
conversion to mucoidy, quorum sensing, and production of
Treatment
Inhaled Antibiotics
Despite the failure of multicenter trials of inhaled
antibiotics to demonstrate reduction in exacerbation
frequency, these agents continue to be used by
physicians for some patients with bronchiectasis. In a
recent report from the US Bronchiectasis Research
Registry of management across US centers, aerosolized
antibiotics were used in 10% of patients.15 In addition,
international guidelines endorse the use of inhaled
antibiotics for patients with chronic P aeruginosa
infection and in selected patients with frequent
828 Recent Advances in Chest Medicine
exopolysaccharides that contribute to biofilm formation were
identified. These mutations overlap somewhat with those from
bacteria in CF, but overall the mutations were specific to Pseudo-
monas in bronchiectasis. Again, the data showed that bronchiectasis
is unique compared with other chronic obstructive airways diseases.
Anti-Pseudomonas IgG Antibodies
Suarez-Cuartin and colleagues39 evaluated the significance of anti-
Pseudomonas IgG antibodies by using a commercially available
enzyme-linked immunosorbent assay kit in 408 patients with
clinically stable bronchiectasis. Sixty patients (14.7%) were identified
as having chronic P aeruginosa infection, defined by two or more
positive sputum samples at least 3 months apart and/or failure to
clear P aeruginosa after eradication treatment. Those with chronic P
aeruginosa infection had significantly more severe bronchiectasis as
measured by means of BSI and FACED scores, more exacerbations,
lower lung function, and worse Medical Research Council dyspnea
scores and quality of life scores than did the group without chronic
P aeruginosa infection. Patients with chronic Pseudomonas infection
had higher baseline anti-Pseudomonas IgG levels than did those
without Pseudomonas (median, 6.2 vs 1.3 units; P < .001). The
antibody level was > 2.96 units (the cutoff for a positive value) in
95% of the patients with chronic P aeruginosa infection. Twenty-five
percent of the patients without chronic P aeruginosa infection had
an antibody level > 2.96 units and were considered to have false-
positive findings. Of this group, 11.2% had a history of P aeruginosa
positivity in the prior year or went on to meet criteria for chronic
infection, suggesting that this assay may be predictive. Higher
antibody levels correlated with worse disease severity as evidenced by
BSI (r ¼ 0.281; P < .001), frequent prior exacerbations (r ¼ 0.169;
P < .001), quality of life according to SGRQ score (r ¼ 0.152; P <
.006), and inflammatory markers such as neutrophil elastase (r ¼
0.228; P < .001) and myeloperoxidase (r ¼ 0.168; P < .001).
The most provocative aspect of anti-P aeruginosa IgG levels, however,
was that they may predict how successful an eradication attempt will
be. Patients with a first isolation of P aeruginosa during the study
period were separated into those with positive test results and those
with negative test results.39 Individuals whose antibody level was
negative achieved eradication (defined as absence of P aeruginosa
isolation in sputum after 3 and 12 months) 89.5% of the time,
whereas only 15.8% of those who had a positive antibody level
achieved eradication. One potential limitation of anti-P aeruginosa
antibodies is that some cross-reactivity with H influenzae was
identified. In instances in which the antibodies were determined to
be false-positive findings, 37% were due to reactivity with H influenzae.
exacerbations.27-30 Even though all trials of inhaled
antibiotics, except one of inhaled gentamicin, have failed
to reduce exacerbations, there is evidence to support
inhaled antibiotics for certain patients with
bronchiectasis. For example, a randomized, placebo-
controlled study of inhaled colistin included 144 patients
from 35 centers in the United Kingdom, Russia, and
Ukraine. Post hoc analysis evaluating subjects who were
80% adherent to treatment showed a median time to
exacerbation of 168 days in the colistin group
vs 103 days in the placebo group (P ¼ .028). Compared
with participants treated with placebo, participants
treated with colistin also had improved quality-of-life
[ 155#4 CHEST APRIL 2019 ]
scores according to the SGRQ and had reductions in P
aeruginosa colony-forming units (with no emergence of
colistin-resistant strains).40
The Aztreonam for inhalation solution in patients with
non-cystic fibrosis bronchiectasis (AIR-BX-2) trial
assessed inhaled aztreonam 75 mg thrice daily for
1 month on and 1 month off over 4 months. The study
included 274 multinational patients randomly assigned
to receive either inhaled aztreonam (n ¼ 136) or placebo
(n ¼ 138). For patients with a baseline FEV1 < 50%,
aztreonam improved the Quality of Life Questionnaire-
Bronchiectasis respiratory symptoms score compared
with placebo results (the difference between treatment
group and placebo was 13.4 points [95% CI, 7.0-19.7];
P < .0001).41 The number of patients with gram-
negative organisms (including Pseudomonas, Klebsiella,
Escherichia, and Enterobacter) decreased compared with
findings with placebo in both AIR-BX2 and its identical
companion trial AIR-BX1.
The RESPIRE 1 trial (ciprofloxacin dry powder
inhalation, 32.5 mg twice daily) enrolled 416
multinational patients and demonstrated a statistically
significant delay in time to first exacerbation and
reduced frequency of exacerbations in patients with
bronchiectasis with $ 2 exacerbations and chronic
infection not only with P aeruginosa but also with other
pathogenic bacteria.42 In the 14-day on/off regimen,
ciprofloxacin dry powder inhalation led to an
exacerbation rate ratio of 0.61 (95% CI, 0.40-0.91) and
an overall reduction in exacerbation frequency of 24%.10
However, these results were not replicated in the
identical concurrent RESPIRE 2 trial.
The ORBIT 4 trial, which assessed inhaled liposomal
ciprofloxacin in a once-daily regimen 28 days on and
28 days off,43 achieved its primary end point in delaying
time to first exacerbation in patients with bronchiectasis
with P aeruginosa (hazard ratio, 0.72; 95% CI, 0.53-0.97;
P ¼ .03) and reduced exacerbation frequency (rate ratio,
0.63; 95% CI, 0.48-0.82; P ¼ .0006). However, these
results were not replicated in the identical concurrent
ORBIT 3 trial.
These trials suggest that inhaled antibiotics may be
beneficial for some patients with bronchiectasis. The
final chapter regarding the role of inhaled antibiotics in
bronchiectasis is yet to be written. The key will be to
perform future trials with more stringent subject
selection.44 There are additional inhaled antibiotic trials
underway, specifically a multicenter, international trial
of inhaled colistin.
chestjournal.org
Macrolides
Given the role of inflammation in the pathogenesis of
bronchiectasis, there is a focus on strategies to
attenuate the inflammatory pathway. There is
scientific plausibility for macrolide therapy in
bronchiectasis. Macrolides exert immunomodulatory
effects on innate and adaptive immune responses in a
biphasic manner, initially by promoting host defense
by stimulating immune and epithelial cells and later
by reducing tissue injury by interactions with
structural cells, leukocytes, and modulation of
transcription factors to promote inflammation
resolution.45 Three well-conducted clinical trials have
demonstrated statistically significant reduction in
exacerbations.6-8 However, macrolide use is associated
with adverse effects, including QT interval
prolongation, GI symptoms, ototoxicity, and bacterial
resistance. In addition, macrolides should be used with
great caution in patients with known or strongly
suspected pulmonary NTM infection, and experts
recommend that physicians be keen to rule out NTM
prior to and perhaps during administration.46,47
Statins
Statins have received recent attention because, in
addition to their lipid-lowering effects, they also have
antiinflammatory properties, including repressing
activation of T lymphocytes dependent on major
histocompatibility complex class II.48 The ability of
statins to attenuate inflammation in vivo was shown in a
study in healthy volunteers who received inhaled
lipopolysaccharide to induce pulmonary inflammation.
Simvastatin reduced lung neutrophils (both amount and
activity), as well as other markers of inflammation
(tumor necrosis factor-alpha and matrix
metalloproteinases 7, 8, and 9).49 Chalmers and
colleagues50 showed that patients who were receiving
statins prior to admission for community-acquired
pneumonia had reduced markers of systemic
inflammation and reduced 30-day mortality.
In a proof-of-concept study in bronchiectasis, Mandal
and colleagues51 administered 6 months of daily
atorvastatin, the most powerful statin to repress major
histocompatibility complex class II, vs a lactose placebo
in adult patients with less severe bronchiectasis as
characterized by the absence of chronic Pseudomonas
infection. The primary outcome, Leicester Cough
Questionnaire (LCQ) scores (measured at baseline,
3 months, and 6 months) improved significantly at 3
and 6 months in patients receiving atorvastatin. Reduced
829
levels of IL-8, also called “CXCL8,” a neutrophil
chemotactic factor, and C-reactive protein also were
noted in the atorvastatin group.
The same group of investigators then went on to
evaluate the efficacy of atorvastatin to reduce cough in
patients with more severe bronchiectasis, as defined by
chronic infection with P aeruginosa, in a 3-month
crossover trial.52 This time, LCQ scores were not
statistically different in the treatment group vs placebo,
but the study was smaller and shorter than the first
proof-of-concept study. There was a trend toward
improved cough in the patients receiving atorvastatin:
12 of 27 patients had a significant improvement in
cough compared with only five patients receiving
placebo. Quality of life as measured by means of SGRQ
improved significantly in the atorvastatin group (5.62;
95% CI, 10.13 to 1.13; P ¼ .016 during treatment).
Significant differences in the activity domain of the
SGRQ also were seen in the treatment group. As in the
prior study, IL-8 declined during treatment with
atorvastatin as did tumor necrosis factor and
intercellular adhesion molecule 1. Even in the context of
the reduced neutrophil-specific inflammation, fewer
patients had a sputum sample positive for P aeruginosa
in the atorvastatin group than did those in the placebo
arm. None of the patients in either study had to
withdraw due to high creatine kinase levels or myositis,
but treatment-limiting adverse effects such as headache;
diarrhea; and, in one case, abnormal alanine
aminotransferase levels were more frequent with
atorvastatin. For this reason, the most recent European
Multicentre Bronchiectasis Audit and Research
Collaboration bronchiectasis guidelines do not currently
recommend statin therapy in patients with
bronchiectasis.27 As is the case with inhaled antibiotics,
however, future studies may identify specific groups of
patients who may benefit from statins safely.
Novel Therapies
A phase II randomized, double-blind, placebo-
controlled, multinational study to assess the efficacy,
safety, and tolerability of an antiinflammatory agent,
INS 1007,53 is currently recruiting and is estimated to
complete in 2020. The drug inhibits neutrophil serine
proteases (neutrophil elastase, proteinase 3, and
cathepsin), which, in high levels, have detrimental effects
in lung tissue, particularly in bronchiectasis.54,55 The
study’s primary outcome is time to first exacerbation,
830 Recent Advances in Chest Medicine
and secondary outcomes are rate of exacerbation,
quality-of-life measures, FEV1, and change in neutrophil
elastase concentration.
Airway Clearance Techniques
Airway clearance techniques (ACTs) are not new to
bronchiectasis. ACTs have been recommended in the
management of bronchiectasis since the 1800s.56
Table 257 outlines the different airway clearance
modalities. However, only 56% of US patients are
prescribed nonpharmacologic measures to improve
bronchial hygiene.15 One reason for this may be the lack
of large, randomized, controlled trials to support the use
of ACTs. Nevertheless, all published guidelines for the
management of bronchiectasis promote ACTs as a
standard of treatment.27,28,30,58 Therefore, although
ACTs are not recent advances in the field of
bronchiectasis, it is appropriate for physicians who care
for patients with bronchiectasis to advance their practice
to include these techniques.
More substantial evidence is emerging to confirm the
benefits of ACTs. For example, Munoz and colleagues59
performed a 1-year placebo-controlled trial on slow
expiration with the glottis opened in the lateral posture
(ELTGOL) in patients with bronchiectasis with long-
term sputum production of 10 mL/d or more. Patients
were assigned to ELTGOL twice daily or upper
extremity stretching exercises twice daily. A total of 44
patients were randomly assigned (22 to each group).
Sputum volume was the primary end point of the trial
and was significantly higher in the patients who
received ELTGOL; the effect was noted from the first
day of intervention throughout the trial. The
intervention group demonstrated a mean difference in
SGRQ score of 6.8 from baseline to the end of the
study period (minimum clinically important difference
was 4, with lower scores indicating better health-related
quality of life) and improved LCQ scores (mean
difference from baseline to end of trial, 1.96; minimum
clinically important difference, 1.3; higher scores
indicate improved cough). The placebo group scored
worse in both measures when end-of-trial scores were
compared with baseline scores. There was a small but
significant improvement in exacerbation frequency in
the ELTGOL group compared with the placebo group,
and adherence was slightly better in the ELTGOL
group. No adverse effects of ELTGOL were observed
throughout the trial.
[ 155#4 CHEST APRIL 2019 ]
chestjournal.org

TABLE 2 ] Airway Clearance Techniques

Device dependent/
independent
Device independent
Device dependent
Maneuver
Active cycle of
breathing with
autogenic drainage
Postural positioning
Exercise
PEP
PEP with oscillation
High-frequency chest
wall oscillation
Technique or Device Rationale
Performed in seated position Thoracic expansion uses interdependence (expanded alveoli assist in
1) Breathing control: gentle relaxed expanding neighboring collapsed alveoli by exerting a traction force
breaths through elasticity of interstitium)
2) Thoracic expansion exercises: several Breath hold improves ventilation and reduces atelectasis by allowing air to
slow, deep inspirations with a brief hold move from unobstructed lung units to obstructed regions (pendelluft flow)
at full inspiration Forced exhalation (huff) exploits the equal pressure point theory and
3) Mild to moderate forced exhalation accelerates the expiratory airflow, resulting in high linear velocities that
(huff) with open glottis so as to fog a shear mucus from the airway walls
mirror
4) Expiratory airflow velocity is maximized
without causing dynamic compression
of the airways
Supine Positioning the patient to improve ventilation to affected areas of the lungs
Right or left lateral decubitus position
Ad lib Increasing mobility, oxygen demand increases, resulting in increased minute
ventilation and lung volumes, improving interdependence and collateral
ventilation
Threshold PEP (Philips) Maximizes collateral ventilation
PEP mask
TheraPEP (Smiths Medical)
Acapella (Smiths Medical) Incorporates collateral ventilation with oscillations to decrease viscoelastic
Flutter valve (Allergan) and spinnability properties of mucus leading to increased sputum clearance
Aerobika (Monaghan Medical)
Cornet (Curaplex)
Various vendors Enhance mucociliary transport by altering rheological properties of mucus
and creating expiratory flow bias to promote proximal movement of mucus
Enhance ciliary beat frequency
Does not provide collateral ventilation as with PEP

No one airway clearance technique has been proven to be superior to another. Some form of airway clearance should be initiated for all patients with bronchiectasis. Selection of airway clearance methods should be
based on patient preference and tolerance. Nebulized 7% sodium chloride (3% if 7% is not tolerated) and bronchodilators (if indicated for bronchospasm or if associated with subjective improvement in clinical
symptoms) are administered prior to airway clearance techniques. Data proving the benefit of nebulized agents in bronchiectasis are lacking. These agents are recommended by international guidelines nonetheless.
PEP ¼ positive expiratory pressure. Adapted with permission from McIlwaine and colleagues.57
831
Conclusions
Bronchiectasis is an impactful clinical syndrome,
associated with significant morbidity and mortality and
for which there are relatively few proven and effective
therapies. The past decade, however, finally has
witnessed renewed interest in the disease to refine it
further and define its phenotype as a clinical entity,
improve diagnostic accuracy, and develop new
treatment strategies. This review has focused on recent
advances in techniques to identify pathogens more
accurately, define exacerbations more precisely, develop
validated tools to assess both severity and natural
history, and provide treatment options. It is our hope,
and that of other investigators and patients, that this
momentum continues to accelerate until, as has been the
case with CF and pulmonary hypertension, for example,
evidence-based, effective therapies emerge.
Acknowledgments
Financial/nonfinancial disclosures: The authors have reported to
CHEST the following: P. J. M. is participating in a clinical trial for
Insmed and has served on advisory boards for Aradigm, Bayer, Grifols,
Hill-Rom, and Insmed. G. T. has received research funding from the
National Bronchiectasis and NTM Research Registry and has served as
a consultant and advisory board member for Aradigm, Bayer, and
Grifols.
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