Clinical Microbiology and Infection 26 (2020) 313e318

Contents lists available at ScienceDirect

Clinical Microbiology and Infection

journal homepage: www.clinicalmicrobiologyandinfection.com

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

a r t i c l e i n f o a b s t r a c t

Article history: Background: Pseudomonas aeruginosa is one of the most common pathogens isolated from respiratory
Received 17 May 2019 tract specimen in patients with bronchiectasis. It is considered highly responsible for pathogenicity,
Received in revised form progression and clinical outcomes of bronchiectasis.
4 July 2019
Aims: To summarize existing evidence on how different factors of Pseudomonas aeruginosa affect the
Accepted 8 July 2019
Available online 12 July 2019
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: for additional articles.
Drug resistance Content: This review focused on nonecystic fibrosis bronchiectasis and also provided some data on
Genomic diversity cystic fibrosis when studies in bronchiectasis were limited. We discussed various factors in relation to
Narrative review P. aeruginosa: virulence factors, drug resistance, regulatory systems, genomic diversity and transmission
Regulatory systems
of P. aeruginosa, as well as treatment for P. aeruginosa. Their impacts on bronchiectasis and its man-
Transmission
agement were discussed.
Treatment
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 2020;26:313
© 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)

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

Does P. aeruginosa affect the progression of bronchiectasis?

* Corresponding author. J.-F. Xu, Department of Respiratory and Critical Care
Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine,
Shanghai, China. Many studies have revealed the relationship between
E-mail address: jfxucn@gmail.com (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.
314 Y.-H. Chai, J.-F. Xu / Clinical Microbiology and Infection 26 (2020) 313e318
lung function, more exacerbations, increased mortality and a
deterioration of life quality in patients with bronchiectasis, trans-
lating into a higher economic burden both to individuals and to
society as a whole [3,9].
A comprehensive analysis published in 2015 including 21 cohort
studies found that P. aeruginosa was associated with a threefold
increased risk of death, an increase in hospital admissions rate,
more frequent exacerbations and worse quality of life [8]. Studies in
the following years also demonstrated that P. aeruginosa was
associated with worse lung function, more severe radiologic char-
acteristics and more frequent exacerbations in patients with
bronchiectasis [4,10e12]. Notably, patients with P. aeruginosa have
worse clinical outcomes compared to those with other microor-
ganisms [13,14].
Interestingly, there is an increasing trend to define different
phenotypes of bronchiectasis and to then explore their respective
outcomes [15]. Patients with P. aeruginosa tend to be of a particular
type (with no specific name yet assigned to this group) associated
with a much worse prognosis in bronchiectasis. However, whether
P. aeruginosa is associated with a decline in lung function or is only
a marker of severity cannot be concluded with certainty, according
to the conflicting results, since one study [9] showed that
P. aeruginosa did not accelerate the decline in pulmonary function
either before or after adjustment for baseline lung function, while
another [16] concluded that P. aeruginosa as an independent factor
was associated with progression of lung function impairment (odds
ratio 30.4; 95% confidence interval (CI) 3.8e39.4; p 0.005).
Is P. aeruginosa an independent factor for prognosis in bron-
chiectasis? A recent study assessing the independent impact of
P. aeruginosa found that P. aeruginosa was associated with higher
mortality (hazard ratio (HR) 2.02; 95% CI 1.53e2.66; p < 0.0001),
but not independently (HR 0.98; 95% CI 0.70e1.36; p 0.89) [17].
Compared to other indexes of prognosis (exacerbation frequency,
hospital admissions and quality of life), an independent impact of
P. aeruginosa on mortality occurred only in patients with frequent
exacerbations (two or more exacerbations a year). Therefore, we
did a brief summary to find out the possible independent role of
P. aeruginosa in bronchiectasis (Table 1). On univariate analysis,
there was no controversy regarding the negative effect of
P. aeruginosa on bronchiectasis outcomes, including mortality.
However, on multivariate analysis, which only half of the studies
we assessed conducted, results concerning other prognostic in-
dexes are much more consistent compared to mortality, which
showed an independent role of P. aeruginosa in poorer outcomes
except for mortality. Those having performed a multivariate anal-
ysis, mostly those with ideal sample sizes and prospective follow-
up designs, concluded quite heterogeneously, which suggested
that mortality is multifactorial and also strengthened the impor-
tance of tackling other factors (especially exacerbations) in bron-
chiectasis patients. Because P. aeruginosa itself can promote
exacerbations, the influence of P. aeruginosa on bronchiectasis
cannot be underestimated.
Does antibiotic resistance in P. aeruginosa affect the
progression of bronchiectasis?
The existence of multidrug-resistant P. aeruginosa (MDR-PA)
isolates is well known as a growing health threat worldwide.
However, evidence on the association between MDR-PA isolates
and prognosis in bronchiectasis is limited [3,5,6]. Most of the
published studies found risk factors for drug resistance, such as
hospitalization and more frequent exacerbations in the past year,
but rarely did they explore the prospective impact of MDR-PA
isolates on outcomes in bronchiectasis. A recent retrospective
study in China [18] found that MDR-PA isolates were not associated
with greater all-cause mortality in bronchiectasis during a 26-
month follow-up. This conclusion was in line with studies of
cystic fibrosis (CF). However, even in patients with CF, the evidence
is limited and conflicting. Although an analysis of 2267 patients
found that the absence of MDR-PA in adolescence was associated
with a substantial lung function decline in young adulthood [19],
there also exist some studies reporting on the poor outcomes of
patients with MDR-PA isolates. One cohort study of 75 adult CF
patients over a 4-year period found links between MDR-PA isolates
and a more rapid decline in forced expiratory volume in 1 second
(FEV1; 160 mL/year, p 0.003) as well as more possibilities of lung
transplantation (17.6 vs. 0, p 0.005) [20]. Because of the factor MDR-
PA itself usually reflects more aggressive interventions, and
whether the benefit or drug resistance those interventions brought
can dominate in the long-period impact on clinical outcomes is still
unclear, it is hard to draw a definite conclusion without dealing
with those confounding factors. Therefore, more well-designed and
high-quality studies are desperately needed.
Virulence factors, degradative enzymes and adaptation
If P. aeruginosa is generally associated with a worse outcome in
bronchiectasis, then what can explain it? Currently our under-
standing of bronchiectasis is mostly extrapolated from studies in
patients with CF. It is well established in CF and animal models that
virulence factors and degradative enzymes are associated with
pathogenicity and poor outcomes. We also searched for studies on
non-CF bronchiectasis and created a brief summary (Table 2) to find
associations between main factors of P. aeruginosa and pathoge-
nicity as well as clinical outcomes in bronchiectasis. However, the
evidence on bronchiectasis is still far too small. There were few
common contributing factors of P. aeruginosa recorded because
studies rarely covered both bronchiectasis and CF patients. Never-
theless, it is still reasonable to hypothesize that part of the factors
associated with CF can also affect the progression of non-CF
bronchiectasis.
In chronic infection, P. aeruginosa tends to undergo an evolu-
tional process, including loss of motility, decreased virulence fac-
tors and antibiotic resistance, all of which are well investigated in
CF [21]. After adaptation, the questions about the role of
P. aeruginosa become thornier. With reduced inflammasome li-
gands and motility, P. aeruginosa isolates from CF patients failed to
induce inflammasome activation, which resulted in inflammasome
evasion of this organism [22]. This is in line with other research that
found an association between the defective motility of P. aeruginosa
and pulmonary exacerbations in CF, the former of which was a
predictor for the latter [23].
There are also studies of P. aeruginosa adaptation in bronchiec-
tasis. Because CF and bronchiectasis are distinct kinds of diseases,
the phenotype and genotype of P. aeruginosa isolated from them
also differ to some extent. For example, one study in 2015 inves-
tigating the phenotypic and genotypic characteristics of a particular
P. aeruginosa strain in bronchiectasis represented a similar process
of adaptation both in bronchiectasis and CF patients, but also some
niche-specific phenotypic traits of PAHM4 (a non-CF bronchiectasis
isolate), which suggested differences between CF and non-CF
bronchiectasis [24].
Issues related to drug resistance and virulence
Regulatory systems
There exist a series of systems in P. aeruginosa which function as
networks to regulate many aspects of P. aeruginosa, including
virulence factors, biofilm formation and drug resistance, as a
 Y.-H. Chai, J.-F. Xu / Clinical Microbiology and Infection 26 (2020) 313e318 315

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
Hernandez 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 admissionsa
[51] retrospective cohort ePseudomonas spp.
Davies 2006 Consecutive cohort study 163 Among 3 groupsb FEV1a (cross-sectional); decline in FEV1 Decline in FEV1
[9] (longitudinal)
Martínez- Prospective cohort study 76 P. aeruginosa, noneP. aeruginosa Decline in FEV1a Decline in FEV1a
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, no FEV1, FVC, radiologic severity, WBC count,
2011 [53] 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 FEV1, 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, exacerbations, Mortality,
2014 [6] up study pathogen SGRQa hospitalizationsa
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
a
McDonnell Retrospective and follow-up 155 P. aeruginosa, noneP. aeruginosa FEV1, hospital admissions 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, other Radiologic severity, exacerbation, FEV1a
2016 [12] pathogens
Faverio 2016 Prospective observational 261 NTM, P. aeruginosa, other pathogens BSI score, exacerbationa
[13] study
Aliberti 2016 Secondary analysis of five 1145 Among 4 clustersc Radiologic severity, inflammation, FEV1, QoL,
[15] prospective databases exacerbations, hospital admissions, mortalityd
Wang 2018 Retrospective and follow-up 1188 P. aeruginosa, noneP. aeruginosa FEV1, FVC, FEV1/FVC (cross-sectional); All-cause mortality
[4] study exacerbation, mortality (follow-up)a (fully adjusted)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
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,
their interactions are fairly tight and sophisticated, which enables
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].
316 Y.-H. Chai, J.-F. Xu / Clinical Microbiology and Infection 26 (2020) 313e318
Table 2
Associations between factors of Pseudomonas aeruginosa and CF as well as bronchiectasis
Study Factor Patient (CF or bronchiectasis)
Lanotte 2003 [58] PLC CF
Cobb 2004 [59] Flagellin
Smith 2006 [60] Protease IV CF
Ryall 2008 [61] Cyanide CF and bronchiectasis
Mowat 2011 [62] Pyocyanin CF
Rieber 2013 [63] Flagellin CF
Anstead 2013 [64] Alkaline protease, CF
exotoxin A
Tan 2014 [65] Type IV pilus
Minandri 2016 [66] Pyoverdine
Saint-Criq 2018 [67] Elastase CF
Luo 2018 [38] ExoU, PldA Bronchiectasis
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
of novel therapies have been showing potential, such as inhibition
of the CRISPR-Cas9 system in P. aeruginosa based on the new
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, a variable composition of 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 carbapenem-
resistant [33] and aztreonam-resistant strains [34], resulting in
better survival of this organism in the host. One of the reasonable
Association details
Associated with poor clinical status, may negatively affect pulmonary function
Have potential proinflammatory activity; may result in exacerbations in CF patients
Associated with pathogenicity of P. aeruginosa infection in lung
Associated with an impaired lung function in CF patients
Contributory factor for pulmonary exacerbations
Induce generation of MDSCs, which may be used to undermine T cell-mediated host defense
Seropositivity to alkaline protease and exotoxin A was significantly associated with
increased risk for recurrent P. aeruginosa isolation
Associated with resistance to antimicrobial activities of pulmonary surfactant protein A
Combine iron transport and virulence-inducing capabilities to cause lung infection
Modulate ion transport, immune response and tissue repair
Associated with exacerbations
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.
 Y.-H. Chai, J.-F. Xu / Clinical Microbiology and Infection 26 (2020) 313e318
Although it is well established that eradication of P. aeruginosa
correlates with better prognosis in CF, the evidence in 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-
lecular methods such as gene sequencing technology are quite
promising and may be utilized for more accurate testing results. For
317
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.
References
[1] Lin JL, Xu JF, Qu JM. Bronchiectasis in China. Ann Am Thorac Soc 2016;13:
609e16.
[2] Tunney MM, Einarsson GG, Wei L, Drain M, Klem ER, Cardwell C, et al. Lung
microbiota and bacterial abundance in patients with bronchiectasis when
clinically stable and during exacerbation. Am J Respir Crit Care Med 2013;187:
1118e26.
[3] Loebinger MR, Wells AU, Hansell DM, Chinyanganya N, Devaraj A, Meister M,
et al. Mortality in bronchiectasis: a long-term study assessing the factors
influencing survival. Eur Respir J 2009;34:843e9.
[4] Wang H, Ji XB, Mao B, Li CW, Lu HW, Xu JF. Pseudomonas aeruginosa isolation
in patients with nonecystic fibrosis bronchiectasis: a retrospective study. BMJ
Open 2018;8:e014613.
[5] Martínez-García MA, de Gracia J, Vendrell Relat M, Giron RM, Maiz Carro L, de
la Rosa Carrillo D, et al. Multidimensional approach to nonecystic fibrosis
bronchiectasis: the FACED score. Eur Respir J 2014;43:1357e67.
[6] Chalmers JD, Goeminne P, Aliberti S, McDonnell MJ, Lonni S, Davidson J, et al.
The Bronchiectasis Severity Index. An international derivation and validation
study. Am J Respir Crit Care Med 2014;189:576e85.
[7] Martínez-García MA, Athanazio RA, Giron R, Maiz-Carro L, de la Rosa D,
Olveira C, et al. Predicting high risk of exacerbations in bronchiectasis: the E-
FACED score. Int J Chron Obstruct Pulmon Dis 2017;12:275e84.
[8] Finch S, McDonnell MJ, Abo-Leyah H, Aliberti S, Chalmers JD. A comprehensive
analysis of the impact of Pseudomonas aeruginosa colonization on prognosis in
adult bronchiectasis. Ann Am Thorac Soc 2015;12:1602e11.
[9] Davies G, Wells AU, Doffman S, Watanabe S, Wilson R. The effect of Pseudo-
monas aeruginosa on pulmonary function in patients with bronchiectasis. Eur
Respir J 2006;28:974e9.
[10] Mao B, Yang JW, Lu HW, Xu JF. Asthma and bronchiectasis exacerbation. Eur
Respir J 2016;47:1680e6.
[11] Park J, Kim S, Lee YJ, Park JS, Cho YJ, Yoon HI, et al. Factors associated with
radiologic progression of nonecystic fibrosis bronchiectasis during long-term
follow-up. Respirology 2016;21:1049e54.
[12] Dimakou K, Triantafillidou C, Toumbis M, Tsikritsaki K, Malagari K, Bakakos P.
Non CF-bronchiectasis: aetiologic approach, clinical, radiological, microbio-
logical and functional profile in 277 patients. Respir Med 2016;116:1e7.
[13] Faverio P, Stainer A, Bonaiti G, Zucchetti SC, Simonetta E, Lapadula G, et al.
Characterizing non-tuberculous mycobacteria infection in bronchiectasis. Int J
Mol Sci 2016;17.
[14] McDonnell MJ, Jary HR, Perry A, MacFarlane JG, Hester KL, Small T, et al. Non
cystic fibrosis bronchiectasis: a longitudinal retrospective observational
cohort study of Pseudomonas persistence and resistance. Respir Med
2015;109:716e26.
[15] Aliberti S, Lonni S, Dore S, McDonnell MJ, Goeminne PC, Dimakou K, et al.
Clinical phenotypes in adult patients with bronchiectasis. Eur Respir J
2016;47:1113e22.
[16] Martínez-García MA, Soler-Cataluna JJ, Perpina-Tordera M, Roman-Sanchez P,
Soriano J. Factors associated with lung function decline in adult patients with
stable nonecystic fibrosis bronchiectasis. Chest 2007;132:1565e72.
[17] Araújo D, Shteinberg M, Aliberti S, Goeminne PC, Hill AT, Fardon TC, et al. The
independent contribution of Pseudomonas aeruginosa infection to long-term
318 Y.-H. Chai, J.-F. Xu / Clinical Microbiology and Infection 26 (2020) 313e318
clinical outcomes in bronchiectasislong-term clinical outcomes in bronchi-
ectasis. Eur Respir J 2018;51.
[18] Gao YH, Guan WJ, Zhu YN, Chen RC, Zhang GJ. Antibiotic-resistant Pseudo-
monas aeruginosa infection in patients with bronchiectasis: prevalence, risk
factors and prognostic implications. Int J Chron Obstruct Pulmon Dis 2018;13:
237e46.
[19] Vandenbranden SL, McMullen A, Schechter MS, Pasta DJ, Michaelis RL,
Konstan MW, et al. Lung function decline from adolescence to young adult-
hood in cystic fibrosis. Pediatr Pulmonol 2012;47:135e43.
[20] Lechtzin N, John M, Irizarry R, Merlo C, Diette GB, Boyle MP. Outcomes of
adults with cystic fibrosis infected with antibiotic-resistant Pseudomonas
aeruginosa. Respiration 2006;73:27e33.
[21] Winstanley C, O’Brien S, Brockhurst MA. Pseudomonas aeruginosa evolutionary
adaptation and diversification in cystic fibrosis chronic lung infections. Trends
Microbiol 2016;24:327e37.
[22] Huus KE, Joseph J, Zhang L, Wong A, Aaron SD, Mah TF, et al. Clinical isolates of
Pseudomonas aeruginosa from chronically infected cystic fibrosis patients fail
to activate the inflammasome during both stable infection and pulmonary
exacerbation. J Immunol 2016;196:3097e108.
[23] Mayer-Hamblett N, Rosenfeld M, Gibson RL, Ramsey BW, Kulasekara HD,
Retsch-Bogart GZ, et al. Pseudomonas aeruginosa in vitro phenotypes distin-
guish cystic fibrosis infection stages and outcomes. Am J Respir Crit Care Med
2014;190:289e97.
[24] Varga JJ, Barbier M, Mulet X, Bielecki P, Bartell JA, Owings JP, et al. Genotypic
and phenotypic analyses of a Pseudomonas aeruginosa chronic bronchiectasis
isolate reveal differences from cystic fibrosis and laboratory strains. BMC
Genomics 2015;16:883.
[25] Burr LD, Rogers GB, Chen AC, Hamilton BR, Pool GF, Taylor SL, et al. Macrolide
treatment inhibits Pseudomonas aeruginosa quorum sensing in nonecystic
fibrosis bronchiectasis. An analysis from the Bronchiectasis and Low-Dose
Erythromycin Study trial. Ann Am Thorac Soc 2016;13:1697e703.
[26] Imamura Y, Yanagihara K, Mizuta Y, Seki M, Ohno H, Higashiyama Y, et al.
Azithromycin inhibits MUC5AC production induced by the Pseudomonas
aeruginosa autoinducer N-(3-oxododecanoyl) homoserine lactone in NCI-
H292 cells. Antimicrob Agents Chemother 2004;48:3457e61.
[27] Hoyland-Kroghsbo NM, Paczkowski J, Mukherjee S, Broniewski J, Westra E,
Bondy-Denomy J, et al. Quorum sensing controls the Pseudomonas aeruginosa
CRISPR-Cas adaptive immune system. Proc Natl Acad Sci U S A 2017;114:131e5.
[28] Song D, Meng J, Cheng J, Fan Z, Chen P, Ruan H, et al. Pseudomonas aeruginosa
quorum-sensing metabolite induces host immune cell death through cell
surface lipid domain dissolution. Nat Microbiol 2019;4:97e111.
[29] Goswami M, Espinasse A, Carlson EE. Disarming the virulence arsenal of
Pseudomonas aeruginosa by blocking two-component system signaling. Chem
Sci 2018;9:7332e7.
[30] Stover CK, Pham XQ, Erwin AL, Mizoguchi SD, Warrener P, Hickey MJ, et al.
Complete genome sequence of Pseudomonas aeruginosa PAO1, an opportu-
nistic pathogen. Nature 2000;406:959e64.
[31] Macia MD, Blanquer D, Togores B, Sauleda J, Perez JL, Oliver A. Hypermutation
is a key factor in development of multiple-antimicrobial resistance in Pseu-
domonas aeruginosa strains causing chronic lung infections. Antimicrob
Agents Chemother 2005;49:3382e6.
[32] Henrichfreise B, Wiegand I, Pfister W, Wiedemann B. Resistance mechanisms
of multiresistant Pseudomonas aeruginosa strains from Germany and corre-
lation with hypermutation. Antimicrob Agents Chemother 2007;51:4062e70.
[33] Skurnik D, Roux D, Cattoir V, Danilchanka O, Lu X, Yoder-Himes DR, et al.
Enhanced in vivo fitness of carbapenem-resistant oprD mutants of Pseudo-
monas aeruginosa revealed through high-throughput sequencing. Proc Natl
Acad Sci U S A 2013;110:20747e52.
[34] Jorth P, McLean K, Ratjen A, Secor PR, Bautista GE, Ravishankar S, et al. Evolved
aztreonam resistance is multifactorial and can produce hypervirulence in
Pseudomonas aeruginosa. MBio 2017;8.
[35] Wong-Beringer A, Wiener-Kronish J, Lynch S, Flanagan J. Comparison of type
III secretion system virulence among fluoroquinolone-susceptible and
-resistant clinical isolates of Pseudomonas aeruginosa. Clin Microbiol Infect
2008;14:330e6.
[36] Agnello M, Wong-Beringer A. Differentiation in quinolone resistance by
virulence genotype in Pseudomonas aeruginosa. PLoS One 2012;7:e42973.
[37] Sullivan E, Bensman J, Lou M, Agnello M, Shriner K, Wong-Beringer A. Risk of
developing pneumonia is enhanced by the combined traits of fluoroquinolone
resistance and type III secretion virulence in respiratory isolates of Pseudo-
monas aeruginosa. Crit Care Med 2014;42:48e56.
[38] Luo RG, Miao XY, Luo LL, Mao B, Yu FY, Xu JF. Presence of pldA and exoU in mucoid
Pseudomonas aeruginosa is associated with high risk of exacerbations in
nonecystic fibrosis bronchiectasis patients. Clin Microbiol Infect 2019;25:601e6.
[39] Kidd TJ, Soares Magalhaes RJ, Paynter S, Bell SC. The social network of cystic
fibrosis centre care and shared Pseudomonas aeruginosa strain infection: a
cross-sectional analysis. Lancet Respir Med 2015;3:640e50.
[40] McCallum SJ, Gallagher MJ, Corkill JE, Hart CA, Ledson MJ, Walshaw MJ. Spread
of an epidemic Pseudomonas aeruginosa strain from a patient with cystic
fibrosis (CF) to non-CF relatives. Thorax 2002;57:559e60.
[41] Orriols R, Hernando R, Ferrer A, Terradas S, Montoro B. Eradication therapy
against Pseudomonas aeruginosa in nonecystic fibrosis bronchiectasis. Respi-
ration 2015;90:299e305.
[42] White L, Mirrani G, Grover M, Rollason J, Malin A, Suntharalingam J. Outcomes
of Pseudomonas eradication therapy in patients with nonecystic fibrosis
bronchiectasis. Respir Med 2012;106:356e60.
[43] Hill AT, Sullivan AL, Chalmers JD, De Soyza A, Elborn SJ, Floto AR, et al. British
Thoracic Society guideline for bronchiectasis in adults. Thorax 2019;74(Suppl
1):1e69.
[44] Polverino E, Goeminne PC, McDonnell MJ, Aliberti S, Marshall SE,
Loebinger MR, et al. European Respiratory Society guidelines for the man-
agement of adult bronchiectasis. Eur Respir J 2017;50.
[45] Murray MP, Turnbull K, Macquarrie S, Hill AT. Assessing response to treatment
of exacerbations of bronchiectasis in adults. Eur Respir J 2009;33:312e8.
[46] Fan LC, Lin JL, Yang JW, Mao B, Lu HW, Ge BX, et al. Macrolides protect against
Pseudomonas aeruginosa infection via inhibition of inflammasomes. Am J
Physiol Lung Cell Mol Physiol 2017;313:L677e86.
[47] Waters EM, Neill DR, Kaman B, Sahota JS, Clokie MRJ, Winstanley C, et al.
Phage therapy is highly effective against chronic lung infections with Pseu-
domonas aeruginosa. Thorax 2017;72:666e7.
[48] Mao YX, Xu JF, Seeley EJ, Tang XD, Xu LL, Zhu YG, et al. Adipose tissueederived
mesenchymal stem cells attenuate pulmonary infection caused by Pseudo-
monas aeruginosa via inhibiting overproduction of prostaglandin E2. Stem
Cells 2015;33:2331e42.
[49] Zheng L, Tipoe G, Lam WK, Ho JC, Shum I, Ooi GC, et al. Endothelin-1 in stable
bronchiectasis. Eur Respir J 2000;16:146e9.
[50] Hernandez C, Abreu J, Jimenez A, Fernandez R, Martin C. [Pulmonary function
and quality of life in relation to bronchial colonization in adults with bron-
chiectasis not caused by cystic fibrosis]. Med Clin (Barc) 2002;118:130e4.
[51] Kelly MG, Murphy S, Elborn JS. Bronchiectasis in secondary care: a compre-
hensive profile of a neglected disease. Eur J Intern Med 2003;14:488e92.
[52] King PT, Holdsworth SR, Freezer NJ, Villanueva E, Holmes PW. Microbiologic
follow-up study in adult bronchiectasis. Respir Med 2007;101:1633e8.
[53] Ergan Arsava B, Coplu L. Does airway colonization cause systemic inflam-
mation in bronchiectasis? Tuberk Toraks 2011;59:340e7.
[54] Goeminne PC, Scheers H, Decraene A, Seys S, Dupont LJ. Risk factors for
morbidity and death in nonecystic fibrosis bronchiectasis: a retrospective
cross-sectional analysis of CT diagnosed bronchiectatic patients. Respir Res
2012;13:21.
[55] Hester KL, Macfarlane JG, Tedd H, Jary H, McAlinden P, Rostron L, et al. Fatigue
in bronchiectasis. QJM 2012;105:235e40.
[56] Rogers GB, Zain NM, Bruce KD, Burr LD, Chen AC, Rivett DW, et al. A novel
microbiota stratification system predicts future exacerbations in bronchiec-
tasis. Ann Am Thorac Soc 2014;11:496e503.
[57] Goeminne PC, Nawrot TS, Ruttens D, Seys S, Dupont LJ. Mortality in
nonecystic fibrosis bronchiectasis: a prospective cohort analysis. Respir Med
2014;108:287e96.
[58] Lanotte P, Mereghetti L, Lejeune B, Massicot P, Quentin R. Pseudomonas aer-
uginosa and cystic fibrosis: correlation between exoenzyme production and
patient’s clinical state. Pediatr Pulmonol 2003;36:405e12.
[59] Cobb LM, Mychaleckyj JC, Wozniak DJ, Lopez-Boado YS. Pseudomonas aeru-
ginosa flagellin and alginate elicit very distinct gene expression patterns in
airway epithelial cells: implications for cystic fibrosis disease. J Immunol
2004;173:5659e70.
[60] Smith L, Rose B, Tingpej P, Zhu H, Conibear T, Manos J, et al. Protease IV
production in Pseudomonas aeruginosa from the lungs of adults with cystic
fibrosis. J Med Microbiol 2006;55(Pt 12):1641e4.
[61] Ryall B, Davies JC, Wilson R, Shoemark A, Williams HD. Pseudomonas aerugi-
nosa, cyanide accumulation and lung function in CF and non-CF bronchiectasis
patients. Eur Respir J 2008;32:740e7.
[62] Mowat E, Paterson S, Fothergill JL, Wright EA, Ledson MJ, Walshaw MJ, et al.
Pseudomonas aeruginosa population diversity and turnover in cystic fibrosis
chronic infections. Am J Respir Crit Care Med 2011;183:1674e9.
[63] Rieber N, Brand A, Hector A, Graepler-Mainka U, Ost M, Schafer I, et al.
Flagellin induces myeloid-derived suppressor cells: implications for Pseudo-
monas aeruginosa infection in cystic fibrosis lung disease. J Immunol
2013;190:1276e84.
[64] Anstead M, Heltshe SL, Khan U, Barbieri JT, Langkamp M, Doring G, et al.
Pseudomonas aeruginosa serology and risk for re-isolation in the EPIC trial.
J Cyst Fibros 2013;12:147e53.
[65] Tan RM, Kuang Z, Hao Y, Lau GW. Type IV pilus of Pseudomonas aeruginosa
confers resistance to antimicrobial activities of the pulmonary surfactant
protein-A. J Innate Immun 2014;6:227e39.
[66] Minandri F, Imperi F, Frangipani E, Bonchi C, Visaggio D, Facchini M, et al. Role
of iron uptake systems in Pseudomonas aeruginosa virulence and airway
infection. Infect Immun 2016;84:2324e35.
[67] Saint-Criq V, Villeret B, Bastaert F, Kheir S, Hatton A, Cazes A, et al. Pseudo-
monas aeruginosa LasB protease impairs innate immunity in mice and humans
by targeting a lung epithelial cystic fibrosis transmembrane regulatoreIL-
6eantimicrobial-repair pathway. Thorax 2018;73:49e61.