Clinical Microbiology and Infection xxx (xxxx) xxx

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Clinical Microbiology and Infection

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Narrative review

How does Pseudomonas aeruginosa affect the progression of

bronchiectasis?
Y.-H. Chai, J.-F. Xu*
Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China

articleinfo
abstract
Article history:
Received 17 May 2019 Background: Pseudomonas aeruginosa is one of the most common pathogens isolated from respiratory
Received in revised form tract specimen in patients with bronchiectasis. It is considered highly responsible for pathogenicity,
4 July 2019 progression and clinical outcomes of bronchiectasis.
Accepted 8 July 2019 Aims: To summarize existing evidence on how different factors of Pseudomonas aeruginosa affect the
Available online xxx pathogenicity, progression and clinical outcomes of bronchiectasis, so as to provide possible insights for
clinical practice and related research in the future.
Editor: L. Leibovici
Sources: PubMed was searched for studies pertaining to bronchiectasis and P. aeruginosa published to
date, with no specific inclusion or exclusion criteria. Reference lists of retrieved reviews were searched
Keywords:
Drug resistance
for additional articles.
Genomic diversity Content: This review focused on nonecystic fibrosis bronchiectasis and also provided some data on
Narrative review cystic fibrosis when studies in bronchiectasis were limited. We discussed various factors in relation to
Regulatory systems P. aeruginosa: virulence factors, drug resistance, regulatory systems, genomic diversity and
Transmission transmission of P. aeruginosa, as well as treatment for P. aeruginosa. Their impacts on bronchiectasis
Treatment and its man- agement were discussed.
Virulence factors Implications: The impact of P. aeruginosa on bronchiectasis is definite, although conclusions in some
aspects are still vague. Faced with the worrying drug-resistance status and treatment bottleneck, indi-
vidualized management and novel therapies beyond the classic pathway are most likely to be a future
trend. To confirm the independent or integrated impact of various factors of P. aeruginosa on bronchi-
ectasis and to figure out all the problems mentioned, larger randomized control trials are truly needed in
the future. Y.-H. Chai, Clin Microbiol Infect 2019;▪:1
© 2019 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All
rights reserved.

Introduction
chronic colonization by P. aeruginosa (C), radiologic extension (E)
and dyspnea (D)) [5,6] and the newest E-FACED score (FACED plus
Pseudomonas aeruginosa is one of the most common
exacerbations) [7].
pathogens isolated from sputum in patients with bronchiectasis
Does P. aeruginosa really affect the progression of
both when clinically stable and during exacerbation [1,2]. It has
bronchiectasis, and which bacterial factors are responsible for its
been widely reported to be an important risk factor for the
progression? As a result of the high heterogeneity of definitions
severity and prog- nosis of bronchiectasis [3,4] and has been
when assessing the long-term impact of P. aeruginosa in different
included into several score systems for severity assessment of
studies [8], here we are going to simply talk about the presence
bronchiectasis, such as the Bronchiectasis Severity Index (BSI),
(cultured and identified at least once in respiratory specimen
FACED score (forced expiratory volume in 1 second, percentage
including sputum and bron- choalveolar lavage fluid) of P.
predicted (F), age (A), presence of aeruginosa and its impact on patients with bronchiectasis as well
as the management of this pathogen.

* Corresponding author. J.-F. Xu, Department of Respiratory and Critical Care Does P. aeruginosa affect the progression of bronchiectasis?
Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine,
Shanghai, China. Many studies have revealed the relationship between
E-mail address: [email protected] (J.-F. Xu).
P. aeruginosa and increased inflammation, greater impairment of

https://doi.org/10.1016/j.cmi.2019.07.010
1198-743X/© 2019 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Please cite this article as: Chai Y-H, Xu J-F, How does Pseudomonas aeruginosa affect the progression of bronchiectasis?, Clinical Microbiology
and Infection, https://doi.org/10.1016/j.cmi.2019.07.010
lung function, more exacerbations, increased mortality and a
with greater all-cause mortality in bronchiectasis during a 26-
deterioration of life quality in patients with bronchiectasis, trans-
month follow-up. This conclusion was in line with studies of
lating into a higher economic burden both to individuals and to
cystic fibrosis (CF). However, even in patients with CF, the evidence
society as a whole [3,9].
is limited and conflicting. Although an analysis of 2267 patients
A comprehensive analysis published in 2015 including 21 cohort
found that the absence of MDR-PA in adolescence was associated
studies found that P. aeruginosa was associated with a threefold
with a substantial lung function decline in young adulthood [19],
increased risk of death, an increase in hospital admissions rate,
there also exist some studies reporting on the poor outcomes of
more frequent exacerbations and worse quality of life [8]. Studies
patients with MDR-PA isolates. One cohort study of 75 adult CF
in the following years also demonstrated that P. aeruginosa was
patients over a 4-year period found links between MDR-PA isolates
associated with worse lung function, more severe radiologic char-
and a more rapid decline in forced expiratory volume in 1 second
acteristics and more frequent exacerbations in patients with
(FEV1; 160 mL/year, p 0.003) as well as more possibilities of lung
bronchiectasis [4,10e12]. Notably, patients with P. aeruginosa have
transplantation (17.6 vs. 0, p 0.005) [20]. Because of the factor
worse clinical outcomes compared to those with other microor-
MDR- PA itself usually reflects more aggressive interventions, and
ganisms [13,14].
whether the benefit or drug resistance those interventions brought
Interestingly, there is an increasing trend to define different
can dominate in the long-period impact on clinical outcomes is still
phenotypes of bronchiectasis and to then explore their respective
unclear, it is hard to draw a definite conclusion without dealing
outcomes [15]. Patients with P. aeruginosa tend to be of a particular
with those confounding factors. Therefore, more well-designed and
type (with no specific name yet assigned to this group) associated
high-quality studies are desperately needed.
with a much worse prognosis in bronchiectasis. However, whether
P. aeruginosa is associated with a decline in lung function or is only
Virulence factors, degradative enzymes and adaptation
a marker of severity cannot be concluded with certainty, according
to the conflicting results, since one study [9] showed that
If P. aeruginosa is generally associated with a worse outcome in
P. aeruginosa did not accelerate the decline in pulmonary function
bronchiectasis, then what can explain it? Currently our under-
either before or after adjustment for baseline lung function, while
standing of bronchiectasis is mostly extrapolated from studies in
another [16] concluded that P. aeruginosa as an independent factor
patients with CF. It is well established in CF and animal models that
was associated with progression of lung function impairment (odds
virulence factors and degradative enzymes are associated with
ratio 30.4; 95% confidence interval (CI) 3.8e39.4; p 0.005).
pathogenicity and poor outcomes. We also searched for studies on
Is P. aeruginosa an independent factor for prognosis in bron-
non-CF bronchiectasis and created a brief summary (Table 2) to
chiectasis? A recent study assessing the independent impact of
find associations between main factors of P. aeruginosa and
P. aeruginosa found that P. aeruginosa was associated with higher
pathoge- nicity as well as clinical outcomes in bronchiectasis.
mortality (hazard ratio (HR) 2.02; 95% CI 1.53e2.66; p < 0.0001),
However, the evidence on bronchiectasis is still far too small. There
but not independently (HR 0.98; 95% CI 0.70e1.36; p 0.89) [17].
were few common contributing factors of P. aeruginosa recorded
Compared to other indexes of prognosis (exacerbation frequency,
because studies rarely covered both bronchiectasis and CF patients.
hospital admissions and quality of life), an independent impact of
Never- theless, it is still reasonable to hypothesize that part of the
P. aeruginosa on mortality occurred only in patients with frequent
factors associated with CF can also affect the progression of non-CF
exacerbations (two or more exacerbations a year). Therefore, we
bronchiectasis.
did a brief summary to find out the possible independent role of
In chronic infection, P. aeruginosa tends to undergo an evolu-
P. aeruginosa in bronchiectasis (Table 1). On univariate analysis,
tional process, including loss of motility, decreased virulence fac-
there was no controversy regarding the negative effect of
tors and antibiotic resistance, all of which are well investigated in
P. aeruginosa on bronchiectasis outcomes, including mortality.
CF [21]. After adaptation, the questions about the role of
However, on multivariate analysis, which only half of the studies
P. aeruginosa become thornier. With reduced inflammasome li-
we assessed conducted, results concerning other prognostic in-
gands and motility, P. aeruginosa isolates from CF patients failed to
dexes are much more consistent compared to mortality, which
induce inflammasome activation, which resulted in inflammasome
showed an independent role of P. aeruginosa in poorer outcomes
evasion of this organism [22]. This is in line with other research
except for mortality. Those having performed a multivariate anal-
that found an association between the defective motility of P.
ysis, mostly those with ideal sample sizes and prospective follow-
aeruginosa and pulmonary exacerbations in CF, the former of
up designs, concluded quite heterogeneously, which suggested
which was a predictor for the latter [23].
that mortality is multifactorial and also strengthened the impor-
There are also studies of P. aeruginosa adaptation in bronchiec-
tance of tackling other factors (especially exacerbations) in bron-
tasis. Because CF and bronchiectasis are distinct kinds of diseases,
chiectasis patients. Because P. aeruginosa itself can promote
the phenotype and genotype of P. aeruginosa isolated from them
exacerbations, the influence of P. aeruginosa on bronchiectasis
also differ to some extent. For example, one study in 2015 inves-
cannot be underestimated.
tigating the phenotypic and genotypic characteristics of a particular
Does antibiotic resistance in P. aeruginosa affect the P. aeruginosa strain in bronchiectasis represented a similar process
of adaptation both in bronchiectasis and CF patients, but also some
progression of bronchiectasis?
niche-specific phenotypic traits of PAHM4 (a non-CF
The existence of multidrug-resistant P. aeruginosa (MDR-PA) bronchiectasis isolate), which suggested differences between CF
isolates is well known as a growing health threat worldwide. and non-CF bronchiectasis [24].
However, evidence on the association between MDR-PA isolates
Issues related to drug resistance and virulence
and prognosis in bronchiectasis is limited [3,5,6]. Most of the
published studies found risk factors for drug resistance, such as
Regulatory systems
hospitalization and more frequent exacerbations in the past year,
but rarely did they explore the prospective impact of MDR-PA
There exist a series of systems in P. aeruginosa which function
isolates on outcomes in bronchiectasis. A recent retrospective
as networks to regulate many aspects of P. aeruginosa, including
study in China [18] found that MDR-PA isolates were not associated
virulence factors, biofilm formation and drug resistance, as a
 Y.-H. Chai, J.-F. Xu / Clinical Microbiology and Infection xxx (xxxx) xxx
3
Table 1
Associations between Pseudomonas aeruginosa and bronchiectasis

Study Study design No. of Comparator groups Univariate association Adjusted

patients multivariate
association

Zheng 2000
Prospective cohort study 35 P. aeruginosa, noneP. aeruginosa Radiologic severity, sputum volume,
[49]
serum ET-1a
Herna´ndez Prospective cohort study 70 P. aeruginosa, other organisms, no FEV1, FVC, QoLa
2002 [50] microorganism
Kelly 2003 Random sampling of 100 Pseudomonas spp. vs. non Antibiotic burden, hospital admissions a
[51] retrospective cohort ePseudomonas spp.
Davies 2006 Consecutive cohort study 163 Among 3 groupsb FEV1 a (cross-sectional); decline in FEV1 Decline in FEV1
[9] (longitudinal)
Martínez- Prospective cohort study 76 P. aeruginosa, noneP. aeruginosa Decline in FEV1a Decline in FEV 1a
García 2007
[16]
King 2007 Prospective cohort study 89 Haemophilus influenzae, P. aeruginosa, Hospital admissions, exacerbations,
[52] no pathogen radiologic severity, FEV1, FVCa
Loebinger Longitudinal follow-up study 91 P. aeruginosa, noneP. aeruginosa Mortalitya Mortalitya
2009 [3]
Ergan Arsava Cohort study 38 P. aeruginosa, other organisms, FEV1, FVC, radiologic severity, WBC count,
2011 [53] no pathogen fibrinogen levela
Goeminne Retrospective cross-sectional 539 P. aeruginosa, noneP. aeruginosa Exacerbations, lung function,a mortality
2012 [54] study
Hester 2012 Prospective cohort study 117 Among 3 groupsb FEV 1, MRCDa
[55]
Martínez- Multicentre observational and 819 P. aeruginosa, other organisms, no 5-year all-cause mortalitya 5-year all-cause
García 2014 follow-up study pathogen mortalitya
[5]
Chalmers Prospective cohort and follow- 608 P. aeruginosa, other organisms, no 4-year mortality, hospitalizations, Mortality,
exacerbations,
2014 up study pathogen SGRQ a
hospitalizationsa
[6]
Rogers 2014 Nested cohort study within a 107 P. aeruginosa dominated, H. influenzae FEV1, exacerbationsa Exacerbationsa
[56] randomized controlled trial dominated, other taxa dominated
Goeminne Prospective cohort study 245 Never, free, intermittent, chronic Mortalitya Mortality
2014 [57] infection
McDonnell Retrospective and follow-up 155 P. aeruginosa, noneP. aeruginosa FEV1, hospital admissionsa FEV1a
2015 [14] study
Mao 2016 Retrospective cohort study 463 P. aeruginosa, noneP. aeruginosa Exacerbationa
[10]
Park 2016 Retrospective cohort study 155 P. aeruginosa, noneP. aeruginosa Radiologic severity changea Radiologic severity
[11] changea
Dimakou Prospective cohort study 277 P. aeruginosa, normal flora, Radiologic severity, exacerbation, FEV a1
2016 [12] other
pathogens
Faverio 2016 Prospective observational 261 NTM, P. aeruginosa, other pathogens BSI score, exacerbationa
[13] study
Aliberti Secondary analysis of five 1145 Among 4 clustersc Radiologic severity, inflammation, FEV1, QoL,
2016 prospective databases exacerbations, hospital admissions,
[15] Retrospective and follow-up mortalityd All-cause mortality
Wang 2018 study 1188 P. aeruginosa, noneP. aeruginosa FEV1, FVC, FEV1/FVC (cross-sectional); (fully adjusted)a
[4] exacerbation, mortality (follow-up)a
Araújo 2018 Multicentre prospective study 2596 P. aeruginosa, noneP. aeruginosa, other Exacerbations, hospital admissions, QoL, Exacerbations,
[17] pathogens mortalitya hospital
admissions, QoL,a
mortality
Empty cells indicate data are not available.
BSI, Bronchiectasis Severity Index; ET-1, endothelin 1; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; MRCD, Medical Research Council dyspnea
score; NTM, non-tuberculous mycobacteria; QoL, quality of life; SGRQ, St George's Respiratory Questionnaire.
a
Statistically significant (including preceding indexes not latter one when there is more than one index associated with P. aeruginosa).
b
Group 1 (‘never infected’ with P. aeruginosa); group 2 (P. aeruginosa isolated at least once, but not on all occasions, ‘intermittently isolated’); group 3 (P. aeruginosa in
all cultures, ‘chronically infected’). Group 2 included a subgroup of patients developing chronic isolation of P. aeruginosa during follow-up.
c
‘Pseudomonas’ (chronically infected with P. aeruginosa), ‘other chronic infection’ (chronically infected with pathogens other than P. aeruginosa), ‘daily sputum,’ ‘dry-
bronchiectasis’ (no chronic infection and no daily sputum).
d
Overall significant p value with worst radiologic and highest inflammatory patterns, lowest lung function status, worst life quality, most frequent hospitalizations and
highest mortality in ‘Pseudomonas’ cluster.

consequence of which this disease-causing microbe is able to fit their interactions are fairly tight and sophisticated, which enables
well in diverse conditions. One of the most important regulatory
systems is a bacterial cellecell communication mechanism orga-
nized in a multilayered hierarchy, termed quorum sensing (QS). To
date, QS consists of at least four signalling mechanisms: las, iqs,
pqs and rhl. While the las system was traditionally thought to be at
the top of the signalling hierarchy, increasing evidence has found
mutations and displacement of las system, which hints at the
complexity of the whole system. No matter what links they have,
Please cite this article as: Chai Y-H, Xu J-F, How does Pseudomonas aeruginosa affect the progression of bronchiectasis?, Clinical Microbiology
and Infection, https://doi.org/10.1016/j.cmi.2019.07.010
 Y.-H. Chai, J.-F. Xu / Clinical Microbiology and Infection xxx (xxxx) xxx
4 P. aeruginosa to fit different environmental and biological
stresses. Therefore, it could be promising to develop therapies
against the bacterial infections beyond a classical antimicrobial or
anti- inflammatory pathway. For example, there was a short
subgroup analysis [25] performed as part of the BLESS trial
which showed inhibition of P. aeruginosa QS without a reduction
in bacterial load in non-CF bronchiectasis patients receiving
erythromycin, which was in line with another study that found
alternative therapeutic mechanism of macrolides through
inhibiting production of a mucin protein induced by a QS signal
molecule [26].

Please cite this article as: Chai Y-H, Xu J-F, How does Pseudomonas aeruginosa affect the progression of bronchiectasis?, Clinical Microbiology
and Infection, https://doi.org/10.1016/j.cmi.2019.07.010
Table 2
Associations between factors of Pseudomonas aeruginosa and CF as well as bronchiectasis

Study Factor Patient (CF or bronchiectasis) Association details

Lanotte 2003 [58] PLC CF Associated with poor clinical status, may negatively affect pulmonary function
Cobb 2004 [59] Flagellin Have potential proinflammatory activity; may result in exacerbations in CF patients
Smith 2006 [60] Protease IV CF Associated with pathogenicity of P. aeruginosa infection in
lung Ryall 2008 [61] Cyanide CF and bronchiectasis Associated with an impaired lung function in CF patients
Mowat 2011 [62] Pyocyanin CF Contributory factor for pulmonary exacerbations
Rieber 2013 [63] Flagellin CF Induce generation of MDSCs, which may be used to undermine T cell-mediated host defense
Anstead 2013 [64] Alkaline protease, CF Seropositivity to alkaline protease and exotoxin A was significantly associated with
exotoxin A increased risk for recurrent P. aeruginosa isolation
Tan 2014 [65] Type IV pilus Associated with resistance to antimicrobial activities of pulmonary surfactant protein A
Minandri 2016 [66] Pyoverdine Combine iron transport and virulence-inducing capabilities to cause lung infection
Saint-Criq 2018 [67] Elastase CF Modulate ion transport, immune response and tissue repair
Luo 2018 [38] ExoU, PldA Bronchiectasis Associated with exacerbations

Study was conducted in laboratory conditions either in vitro or in vivo, without clinical samples.
CF, cystic fibrosis; MDSC, myeloid-derived suppressor cell; PLC, phospholipase C.

With tireless efforts in the past decades, an increasing number carbapenem- resistant [33] and aztreonam-resistant strains [34],
of novel therapies have been showing potential, such as inhibition resulting in better survival of this organism in the host. One of the
of the CRISPR-Cas9 system in P. aeruginosa based on the new reasonable
finding that the QS system activated it [27]. One study has found
that the metabolite of the P. aeruginosa QS system can induce the
death of immune cells in the host through lipid domain dissolution
on the cell surface [28], which revealed an uncommon mechanism
of pathogenehost communication and also provided new ideas for
the treatment of P. aeruginosa.
Another novel therapy could be the implementation of a large
repertoire of two-component regulatory systems involving
numerous proteins, such as PhoP-PhoQ, GacA-GacS and RetS.
Many studies have found their influence on antibiotic resistance as
well as links with metal transport systems and QS systems.
However, related therapies with this system seem to be in their
infancy. One study revealed the potential of blocking two-
component system signalling to inhibit infection of P. aeruginosa
[29]. Although it was designed in burn wound P. aeruginosa
isolates, it also hints at the promising design of novel therapies in
bronchiectasis.

Genomic diversity and plasticity

The large genetic repertoire of P. aeruginosada conserved core of

at least 4000 genes, avariable compositionof various gene islands
and a small set of rare genesddetermines the versatility of this
organism [30]. Meanwhile, accessory genes of plasmid and phage,
which carry various antibiotic and virulence genes, also contribute
to the genomic diversity, which is highly dynamic and plastic. With
all this, it is no surprise that P. aeruginosa thrives in diverse
environments.
Many studies have revealed that hypermutation is a key
factor for antimicrobial resistance of P. aeruginosa in chronic
infection. Hypermutable strains (an increased spontaneous
mutation rate up to 1000-fold) were found in a quite high
proportiond53% in one study [31], and 11 of 12 strains and 3 of
10 strains from CF patients and non-CF patients, respectively, in
another [32]. With direct as- sociations between hypermutable
strains and overall drug- resistance rates being observed, there is
no doubt about the key role hypermutation plays in drug
resistance. However, there is only a low prevalence of
hypermutation in acute infection, which sug- gests that these
two conditions require different management.
Another issue attributable to genetic factors is the interplay be-
tween virulence and drug resistance. It has been commonly
accepted that antibiotic resistance is associated with a fitness cost
and reduced virulence. However, with the advances in molecular
tech- nology, a series of studies surprisingly found enhanced
virulence in antibiotic-resistant P. aeruginosa strains, including
explanations for this phenomenon is called coselection or
coevolu- tion of virulence and drug resistance. A typical
representative is exoU (major virulence factor secreted by type
III secretion system (T3SS) of
P. aeruginosa) and fluoroquinolone resistance. Many studies
have already revealed the possibility of coevolution of exoU and
fluo- roquinolone resistance on the basis of the consistent result
that isolates with the more virulent exoU genotype were more
likely to be fluoroquinolone resistant compared to exoS
(another virulence factor secreted by T3SS which is mutually
exclusive with exoU) strains [35,36]. Thereafter, the combined
traits of exoU genotype and fluoroquinolone resistance were
found to be significantly associated with the development of
pneumonia, providing further evidence of the link between
virulence and resistance, and their negative effect on disease
[37]. For bronchiectasis, we previously reported that the
presence of the exoU gene was an actual risk factor for
prognosis in bronchiectasis [38].
According to all these conclusions, we can imagine what
cose- lection will bring to patients with bronchiectasis.

Transmission and ecology implications

A recent cross-sectional study [39] assessed movement of

patients with CF infected with P. aeruginosa and suggested the
connectivity of CF centres as a relevant risk factor for the trans-
mission of P. aeruginosa strains, which emphasized the
necessity of infection control interventions such as molecular
surveillance and strict infection control precautions because
transmission can plausibly amplify any problem mentioned
above, especially drug resistance. On the one hand, because
cross-infection with
P. aeruginosa in non-CF bronchiectasis is less common than in
CF, stringent hygiene strategiesdalready carried out clinically in
CFdare not routinely implemented in bronchiectasis. Even
so, a multidisciplinary hygiene approach including patient
education and self-management is still recommended to
bronchiectasis patients. On the other hand, with the evidence
[40] supporting cross-infection between CF and bronchiectasis
patients, we recommend stringent hygiene measures to be
taken when they are in the same space and have a chance to
contact with each other, including isolation precautions in
hospitals, disinfection and sterilization in healthcare facilities,
hand hygiene, and edu- cation for patients and their families.

Does treatment for P. aeruginosa affect the progression of

bronchiectasis?

Treatment for P. aeruginosa in bronchiectasis can be

considered in three instances: initial isolation, during
exacerbation and chronic infection.
 Although it is well established that eradication of P. aeruginosa lecular methods such as gene sequencing technology are quite
correlates with better prognosis in CF, the evidence in promising and may be utilized for more accurate testing results. For
bronchiectasis was not so robust. Although spontaneous clearing of
P. aeruginosa hardly happens in CF, it may be not uncommon in
bronchiectasis [14]. So is an eradication treatment beneficial for
long-term prog- nosis in bronchiectasis? There is only one
randomized controlled trial and one retrospective study evaluating
outcomes of eradication at the first isolation of P. aeruginosa.
While the 15-month random- ized study [41] found a global
improvement of a series of parameters in patients treated with 3
months of nebulized tobramycin after a 14- day intravenous
treatment with antibiotics compared to the placebo group, the 6-
year retrospective study [42] displayed a 80.0% initial eradication
ratio of P. aeruginosa in sputum, and demonstrated that
eradication at the first isolation of P. aeruginosa prolonged
clearance of this organism as well as reduced exacerbation rates.
However, the quality of evidence is low, as the former study was
observational and the latter lacked a control group. Given the lack of
sufficient evi- dence, the newest British Thoracic Society (BTS)
guidelines [43] still emphasize the necessity of feasible eradication
treatment, which is in line with the European Respiratory Society
(ERS) guidelines [44], which takes into consideration the poor
outcomes related to
P. aeruginosa and data in CF.
Faced with exacerbation caused by P. aeruginosa, there is
usually no control group that did not accept antibiotic therapy [43].
We have almost no evidence to confirm the impact of treatment
during exacerbation in bronchiectasis. Several studies only
recorded improvement of microbiologic outcomes but without
further clin- ical benefits recorded. A prospective cohort study in
2009 compared outcomes between exacerbations due to P.
aeruginosa and those due to other pathogens after 14 days of
intravenous antibiotics and found significant improvement in 24-
hour sputum volume, microbial clearance, C-reactive protein and
St George's Respiratory Questionnaire, independent of the
pathogenic organ- ism [45]. However, this study also lacked a
control group that did not receive antibiotic therapy.
There are relatively more studies on long-term treatment of
chronic P. aeruginosa infection. Both of the ERS [44] and BTS [43]
guidelines recommend inhaled colistin or gentamicin for patients
with P. aeruginosa as a result of their efficacy and good impact on
progression in bronchiectasis. Treatment with macrolides has also
been reported to have good clinical outcomes for bronchiectasis,
although they are not typically bactericidal against P. aeruginosa.
Macrolides, with a potential mechanisms of therapeutic impact
beyond a classical antimicrobial pathway [25,46], are recom-
mended as a second-line option for patients with P. aeruginosa.
However, with the increasing prevalence of resistance to antibi-
otics, other therapies for P. aeruginosa also need to be developed.
One study reported the efficacy of phage therapy in a lung model of
chronic P. aeruginosa infection and demonstrated the potential for
phage therapy [47]. Another study revealed the potential of adipose
tissueederived mesenchymal stem cells to improve functions of
macrophages by inhibiting production of PGE2 in a murine model
of
P. aeruginosa pneumonia, which might be of interest in bronchi-
ectasis as well [48].
More research is needed to improve the management of pa-
tients with bronchiectasis infected or colonized by P. aeruginosa.
The impact of P. aeruginosa on outcomes of patients with bron-
chiectasis is quite well defined. However, conditions may vary
noticeably among ages (adults or children), regions (different na-
tions) and frequency (persistent or intermittent infection) in pa-
tients with P. aeruginosa. We should define this impact in a more
personalized fashion. Because all studies use sputa from patients
who can provide samples, we might create biased estimates. Mo-
treatment, we need antimicrobial therapies beyond the classic
pathway, including those targeted by phage or regulatory systems.
Another practical, important management is good hygiene,
although its evidence in bronchiectasis is not currently robust.
In summary, the existence of P. aeruginosa is an actual risk
factor for worse outcomes in bronchiectasis, although issues on
many as- pects remain to be solved. To confirm the independent
or integrated impact of various factors of P. aeruginosa on
bronchiectasis, and to figure out solutions to all the problems
mentioned, larger random- ized controlled trials are needed. This
further emphasizes the importance of the establishment of the
Bronchiectasis Registry and Research Collaboration, as well as the
need for further clinical trials.

Acknowledgements

Supported in part by the National Science Foundation of

China (NSFC81670006), China; Shanghai Leading Talent
Program (2016036), China and the Project of the Shanghai
Hospital Devel- opment Center (16CR3036A), China.

Transparency Declaration

All authors report no conflicts of interest relevant to this article.

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