Annals of the American Thoracic Society

Rationale: Eradication and suppression of Pseudomonas aeruginosa is a key priority in national guidelines for bronchiectasis and is a major focus of drug development and clinical trials. An accurate estimation of the clinical impact of P. aeruginosa in bronchiectasis is therefore essential.

Methods: Data derived from 21 observational cohort studies comparing patients with P. aeruginosa colonization with those without it were pooled by random effects meta-analysis. Data were collected for key longitudinal clinical outcomes of mortality, hospital admissions, exacerbations, and lung function decline, along with cross-sectional outcomes such as quality of life.

Measurements and Main Results: In the aggregate, the included studies comprised 3,683 patients. P. aeruginosa was associated with a highly significant and consistent increase in all markers of disease severity, including mortality (odds ratio [OR], 2.95; 95% confidence interval [CI], 1.98–4.40; P < 0.0001), hospital admissions (OR, 6.57; 95% CI, 3.19–13.51; P < 0.0001), and exacerbations (mean difference, 0.97/yr; 95% CI, 0.64–1.30; P < 0.0001). The patients with P. aeruginosa also had worse quality of life on the basis of their St. George’s Respiratory Questionnaire results (mean difference, 18.2 points; 95% CI, 14.7–21.8; P < 0.0001). Large differences in lung function and radiological severity were also observed. The definitions of colonization were inconsistent among the studies, but the findings were robust regardless of the definition used.

Conclusion: P. aeruginosa is associated with an approximately threefold increased risk of death and an increase in hospital admissions and exacerbations in adult bronchiectasis.

Bronchiectasis is a chronic inflammatory lung disease characterized by recurrent cough, sputum production, and recurrent respiratory tract infections (1). Failure of the mucociliary escalator and innate antimicrobial defenses leads to chronic bacterial colonization of the airways (2). Bacteria provoke an inflammatory response that can further drive airway inflammation and airway structural damage, leading to the well-described “vicious cycle” of bronchiectasis (2, 3).

Although the majority of patients with bronchiectasis may be colonized with organisms that are upper airway commensals, such as Haemophilus influenzae and Streptococcus pneumoniae, a proportion of patients become colonized with the opportunistic pathogen Pseudomonas aeruginosa (46). In cystic fibrosis (CF) bronchiectasis, it is well established that P. aeruginosa colonization leads to a more rapid deterioration in lung function and earlier mortality (7). Consequently, P. aeruginosa eradication is standard care in European CF centers (8, 9). The capability of P. aeruginosa to form biofilms provides it with physical and chemical protection from the immune system and reduces its exposure to systemically delivered antibiotics (10, 11). P. aeruginosa has the ability to rapidly adapt to chronic infection in the lung and readily develops antimicrobial resistance. Management of P. aeruginosa therefore represents a significant clinical challenge.

In the study of bronchiectasis, conflicting data have been published on the independent contribution of P. aeruginosa to long-term prognosis, and there remains a question whether P. aeruginosa drives disease progression or is simply a marker of existing severe disease (12, 13). Determining the importance of P. aeruginosa in relation to bronchiectasis morbidity and mortality is important, as there are few evidence-based treatments for bronchiectasis (14). Current therapeutic development is heavily influenced by CF and is therefore targeted largely toward treatment of P. aeruginosa infection (15, 16). Therefore, from clinical, drug development, and regulatory perspectives, a comprehensive understanding of the impact of P. aeruginosa on outcomes in bronchiectasis is important.

We undertook a systematic review to determine whether colonization with P. aeruginosa influences future prognosis and/or is associated with cross-sectional features of severity.

This systematic review and meta-analysis was conducted and is reported according to Meta-analysis of Observational Studies in Epidemiology guidelines (17).

Search Criteria

The present study was based on a search of the PubMed database for articles evaluating the prognostic impact of colonization with P. aeruginosa. The following search strategy was used: (“Pseudomonas” OR “aeruginosa”) AND (“bronchiectasis”), followed by (“prognosis” or “mortality”) AND (“bronchiectasis”). The search included articles published between January 1980 and January 2015. No language criteria were applied. Full-text articles of potentially appropriate abstracts were reviewed. Only peer-reviewed data were included. Conference abstracts were excluded. The search was repeated in the Embase and Web of Science databases to obtain any articles missed by the initial search. The search strategy was supplemented by review of reference lists, bibliographies including the British Thoracic Society guidelines, and investigator files.

Data Extraction

Studies deemed not relevant based on review of the title and abstract were excluded. Article review was performed independently by two investigators (among all five coauthors) who conducted data extraction from and quality assessment of studies meeting the inclusion criteria. All investigators have experience in meta-analysis and training in literature review. Any disagreement between investigators was resolved independently by a third investigator. Additional unpublished data were obtained from study authors where possible. Where data were presented only as medians, means with standard deviations were estimated according to the formula of Hozo and colleagues (18)

Study Inclusion and Exclusion Criteria

All studies were considered eligible if they fulfilled the following criteria: original publications, inclusion of a cohort of patients with bronchiectasis (not due to CF) diagnosed by computed tomography, inclusion of patients with P. aeruginosa colonization and a comparator population without P. aeruginosa colonization, and reporting of one of the study outcomes that was determined a priori (described below). Definitions of P. aeruginosa colonization were obtained from the source studies and were not prespecified.

As the aim of the present study was to compare patients with P. aeruginosa colonization with patients without P. aeruginosa colonization, we excluded any studies that provided data only for a single population. We also excluded case reports, review articles, editorials, and letters without original data.

Study Outcomes
Primary analysis

Our hypothesis was that cases with P. aeruginosa colonization would be associated with globally worse clinical outcomes than cases without P. aeruginosa colonization. Outcomes were split into longitudinal clinical outcomes determined during follow-up and cross-sectional outcomes. The primary longitudinal outcome was all-cause mortality. Secondary outcomes were hospital admissions, exacerbation frequency, decline in forced expiratory volume in 1 second (FEV1), and the prognostic impact of P. aeruginosa eradication therapy.

Cross-sectional outcomes were FEV1% predicted, forced vital capacity (FVC), radiological involvement, and quality of life (QoL). A descriptive analysis of the methods of defining P. aeruginosa colonization in the literature was also considered a prespecified secondary endpoint.

Anticipating that studies would have different lengths of follow-up to determine survival, we prespecified that data could be pooled where equal follow-up was demonstrated between patients colonized and those not colonized with P. aeruginosa.

Quality assessments

The quality of each study was independently assessed according to the criteria described by Hayden and coworkers, which are widely used for assessing the quality of observational studies in meta-analysis (19, 20). The agreement between two reviewers (among S.F., H.A.-L., and J.D.C.) was measured using the κ-statistic. Publication bias was determined by visual inspection of funnel plots and use of Egger’s test.

Sensitivity analysis

We identified possible factors a priori that may be major sources of bias and planned subanalyses for the following: (1) analysis according to different definitions of P. aeruginosa colonization (e.g., single isolate vs. multiple isolations), (2) comparisons of patients with P. aeruginosa versus H. influenzae colonization, and (3) data derived from high-quality and prospective studies.

Statistical Analysis

The primary outcome of the relationship between P. aeruginosa colonization and mortality was displayed as an odds ratio (OR) with 95% confidence interval (95% CI). ORs were pooled using a Mantel-Haenszel random effects model. The same analysis was used for hospital admissions.

Continuous variables such as QoL, lobar involvement, pulmonary function tests, and exacerbations were compared by pooling mean differences by the inverse of their variance. As described above, random effects meta-analysis was used because of expected heterogeneity between studies. To analyze for possible effect modifiers, such as study quality or definitions of colonization, we compared ORs using interaction testing as described.

Statistical heterogeneity was assessed using Cochran’s Q (χ2) test and the Higgins I2 test. For the Cochran’s Q test, P < 0.1 was considered to represent significant heterogeneity. For the Higgins test, an I2 value less than 25% indicated low heterogeneity, 25–50% indicated moderate heterogeneity, and greater than 50% indicated severe heterogeneity. Analyses were conducted using Review Manager 5 (Cochrane Collaboration, London, UK) and IBM SPSS version 21 for Windows (IBM, Armonk, NY) software.

The process and results of the literature review are shown in Figure 1. The majority of studies were rejected because they did not deal specifically with patients with bronchiectasis not due to CF or did not evaluate severity or outcomes. Of 55 articles selected as relevant, 21 studies had valid data for inclusion and were pooled in the meta-analysis (6, 12, 13, 2136). One study contained data for 5 cohorts, and each cohort was considered separately for the purposes of this analysis on the basis that they were independent cohorts (total of 25 cohorts; to differentiate the independent cohorts reported in Chalmers et al. 2014, where other publications are not available to reference they have been referred to by the name of the principal investigator of the database used [Aliberti 2015, Chalmers 2015, and McDonnell 2015]) (24).

The characteristics of the 21 included studies are shown in Table 1. Ten studies were done in the United Kingdom (12, 21, 23, 24, 26, 28, 31, 32), and overall 16 cohorts were in Europe. There were no cohorts from North America.

Table 1. Characteristics of the 21 Included Studies

First Author, Year of PublicationStudy DesignLocation and Years of StudyAge, Mean or MedianDefinition of P. aeruginosa ColonizationNumber of Included PatientsPercentage with P. aeruginosa ColonizationStudy Follow-UpOutcomes Reported by or Obtained from Study AuthorsMain Aim of StudyComparator Population
Aliberti et al., 2014* (24)Prospective cohort studyMonza, Italy, 2011–201267 yr (58–74)A20139 (19.4%)1 yrExacerbations, FEV1, FVC, radiological severity, hospital admissions, mortalityValidation of the Bronchiectasis Severity IndexAll patients
Ergan Arsava and Cöplü, 2011 (35)Cohort studyAnkara, Turkey, January–December 2005Median, 51 yr (IQR, 43–60)H388 (21.1%)Cross-sectionalFEV1, FVC, radiological severityEvaluate systemic inflammation according to colonization statusAll patients (subgroup colonized with other pathogens)
Chalmers et al., 2014* (24)Prospective cohort studyEdinburgh, UK, 2008–201267 yr (58–75)A60870 (11.5%4 yrExacerbations, FEV1, FVC, QoL, radiological severity, hospital admissions, mortalityDerivation of the Bronchiectasis Severity IndexAll patients
Chalmers et al., 2014* (24)Prospective observational cohort studyDundee, UK, 2011–201468 yr (61–75)A28637 (14%)3 yrExacerbations, FEV1, FVC, QoL, radiological severity, hospital admissions, mortalityClinical and laboratory predictors of disease progression, validation of Bronchiectasis Severity IndexAll patients
Davies et al., 2006 (13)Consecutive cohort studyLondon, UK44–49 yr at first pulmonary function testF16314 (8.6%)Mean, 9–11 yrFEV1, decline in FEV1Evaluate the impact of P. aeruginosa colonization on FEV1 declineAll patients and intermittently colonized patients
Evans et al., 1996 (12)Retrospective cohort studyManchester, UKMean, 60–62 yrC5912 (20.3%)Mean, 9–10 yrFEV1, declines in FEV1, FVCEvaluate impact of P. aeruginosa on lung function in bronchiectasisAll patients
Goeminne et al., 2014 (25)Prospective cohort studyLeuven, Belgium, 2006–201268 yr (56–78)C25320 (7.9%)Median, 5.18 yrExacerbations, FEV1, FVC, radiological severity, hospital admissions, mortalityDefine predictors of mortalityAll patients
Hernández et al., 2002 (22)Prospective cohort studySpain, January 1999–December 200056 yr (17)X7014 (20%)Cross-sectionalFEV1, FVC, QoLAssess impact of colonization on outcomesAll patients
Hester et al., 2012 (31)Prospective cohort studyNewcastle, UKMedian, 60 yr (range, 16–83)A11712 (10.3%)Cross-sectionalFEV1Study fatigue in bronchiectasisAll patients without P. aeruginosa isolation
Kelly et al., 2003 (23)Random sampling of prospective cohortBelfast, UK57 yr (SEM 2)B10021 (21%)Cross-sectionalExacerbations, hospital admissionsDescribe patient characteristicsAll patients
King et al., 2007 (29)Prospective cohort studyMelbourne, Australia, 1990–200457 yr (14)D8927 (30.3%)Mean, 5.7 yrHospital admissions, exacerbations, radiological severity, FEV1, FVCMicrobiologic follow-up studyAll patients (subanalysis comparing with H. influenzae also included)
Loebinger et al., 2009 (26)Longitudinal follow-up of patients participating in a questionnaire validation studyLondon, UK, 1994–200951.7 yr (12.1) in 1994X9120 (22%)13 yrMortalityDefine predictors of mortalityAll patients
Martínez-García et al., 2014 (27)Retrospective multicenter cohort studySpain, “before December 31, 2005”58.7 yr (17.6)X819260 (31.8%)5 yrMortalityDerivation of a prediction toolAll patients
McDonnell et al., 2015 (21)Retrospective cohort studyNewcastle, UK
July 2007–June 2009
62.1 yr (12.4)A15547 (30.3%)Median, 4 yrFEV1, exacerbations, hospital admissions, mortalityCharacterization of patients with P. aeruginosaAll patients
McDonnell et al., 2014* (24)Retrospective cohort studyGalway, Ireland, January 2009–December 201463 yr (53–71)A21234 (16%)Mean, 5 yrExacerbations, hospital admissions, FEV1, FVC, radiological severity, mortalityDescribe characteristics of patients with bronchiectasisAll patients
Miszkiel et al., 1997 (32)Consecutive cohort studyLondon, UK, 1991–1993Mean, 44–54 yrG6722 (32.8%)Cross-sectionalRadiological severity, FEV1Evaluate impact of P. aeruginosa on basis of CT scan appearanceAll patients
Ho et al., 1998 (33)Prospective cohort studyHong Kong, 1996–199755.1 yr (16.7)B10033 (33%)Cross-sectionalFEV1, FVCImpact of P. aeruginosa on clinical parameters in stable bronchiectasisAll patients
Rogers et al., 2013 (36) and 2014 (6)Nested cohort studies within a randomized controlled trialQueensland, Australia, 2008–201162.9 yr (6.9)E41 in Study 1 (36), 62 in Study 2 (6)11 (27%) in Study 1 (36), 26 (42%) in Study 2 (6)12 moExacerbations, FEV1Correlation of the microbiome with disease severity in bronchiectasisAll patients
Tsang et al., 2000 (30)Prospective cohort studyHong Kong, December 1996–February 199848.5 yr (16.5)B3022 (73.3%)Cross-sectionalFEV1, FVC, exacerbations, radiological severityEvaluation of elastase as a biomarker in bronchiectasisAll patients
Wilson et al., 1997 (37)Prospective cohort studyLondon, UK, 199452 yr (13)B8722 (25.3%)Cross-sectionalFEV1, FVC, QoLDetermine impact of sputum bacteriology on QoLAll patients
Zheng et al., 2000 (34)Prospective cohort studyHong Kong, 1998–199949.1 yr (15)B3518 (51.4%)Cross-sectionalFEV1, FVC, radiological severityEvaluate endothelin 1 as a biomarker in bronchiectasisAll patients

Definition of abbreviations: CT = computed tomographic; H. influenzae = Haemophilus influenzae; IQR = interquartile range; P. aeruginosa = Pseudomonas aeruginosa; QoL = quality of life.

Definitions of Pseudomonas aeruginosa colonization: A = two positive cultures at least 3 mo apart over a 12-mo period; B = single culture; C = Leeds criteria; D = isolation either at baseline or during the study; E = study included isolation of P. aeruginosa by culture, polymerase chain reaction, and pyrosequencing; F = classified as Pseudomonas colonized if all cultures positive for P. aeruginosa and intermittent if some cultures negative; G = isolation of P. aeruginosa from sputum within 3 mo of CT scan; H = quantitative culture of more than 105 colony-forming units per milliliter in a single sample; X = unclear.

*To differentiate the independent cohorts reported in Chalmers et al. 2014, where other publications are not available to reference they have been referred to by the name of the principal investigator of the database used (Aliberti 2015, Chalmers 2015, and McDonnell 2015).

Dates of study not reported.

Comparing Pseudomonas (n = 26) with group dominated by another genus (n = 36). N = 60 for comparisons between Pseudomonas (n = 26) vs. Haemophilus influenzae (n = 34).

Definitions of chronic P. aeruginosa colonization were highly heterogeneous. The most frequent definition used was two positive cultures at least 3 months apart over the course of 12 months. Five studies reported patients with a single positive culture as being “colonized.” In all, eight different methods of defining P. aeruginosa colonization were identified; in addition, the definition used was not stated in three studies. According to the quality assessment, six studies were rated as high quality, eight as intermediate quality, and seven as low quality (κ = 0.73). None of the analyses showed evidence of publication bias.

The total number of patients studied was 3,683, and the rate of P. aeruginosa colonization (according to study definitions) was 21.4%. Comparator populations were almost universally mixed populations of bronchiectasis not colonized with P. aeruginosa.

Association of P. aeruginosa with Longitudinal Outcomes
Primary outcome: all-cause mortality

Mortality was available as an outcome in eight cohorts (2427), five of which were derived from a single study (24). Follow-up duration ranged from 1 to 14 years. Mortality for patients with P. aeruginosa ranged from 7.7% at 1 year, to 13.6% at 2 years, to 30–50% at 5 years. Corresponding mortality rates for patients without P. aeruginosa were 0% at 1 year, 7% at 2 years, and 9–15% at 5 years. All studies showed a higher risk of mortality associated with P. aeruginosa colonization. The pooled OR for mortality was 2.95 (95% CI, 1.98–4.40; P < 0.0001). The results of heterogeneity tests were not statistically significant. These data are shown in Figure 2. Subanalyses confirmed this association in high-quality studies (OR, 3.64; 95% CI, 1.75–7.55; P = 0.0005; n = 1,433) and in prospective studies and excluding studies with less than 3 years (OR, 2.82; 95% CI, 1.94–4.11; P < 0.0001; n = 1,994) and more than 6 years (OR, 3.14; 95% CI, 1.83–5.33; P < 0.0001; n = 1,894) of follow-up.

Hospital admissions

This analysis included 7 cohorts with an aggregate of 1,628 participants (23, 24, 29). Hospital admission rates for patients with P. aeruginosa varied from 41% at 1 year to 75% at 4 years. Corresponding hospital admission rates in patients without P. aeruginosa were 15% at 1 year and 28.5% at 4 years. P. aeruginosa was associated with a marked increase in the risk of hospital admissions (pooled OR, 6.57; 95% CI, 3.19–13.51; P < 0.0001). There was significant heterogeneity that was not resolved when we limited studies by quality, prospective design, or length of follow-up. Insufficient data were available to evaluate additional impacts such as length of hospital stay or economic impact of hospitalization. The hospital admissions data are shown in Figure 3.

Exacerbations per year

All available data were presented as mean exacerbations per patient per year. The nine cohorts in which this information was recorded gave a pooled increased frequency of just under one exacerbation per patient per year (mean difference, 0.97; 95% CI, 0.64–1.30; P < 0.0001) with no significant heterogeneity (6, 23, 24, 29, 30). This is shown in Figure 4. No significant differences in effect were observed in high-quality studies or prospective studies or in subanalyses based on the definition of P. aeruginosa.

Lung function decline

There were limited data available on lung function decline. One study group reported lower lung function in patients colonized with P. aeruginosa but no differences in long-term lung function decline (13). Another study team reported a mean decline of 52 milliliters per year in patients with P. aeruginosa colonization (12), and a further study group reported a mean decline of 123 milliliters per year (38). The available data included only 41 patients with P. aeruginosa colonization. Consequently, no attempt was made to pool the data.

Pseudomonas eradication treatment

No randomized studies of P. aeruginosa eradication treatment were identified. The authors of a nonrandomized observational study (n = 30) reported an initial eradication success rate of 80% that declined to 43% after a median of 6 months (39). This was associated with a reduction in exacerbations from 3.93 per year to 2.03 per year. No control population was available for comparison, and thus no data were reported on the spontaneous clearance rate that would have occurred without treatment.

Cross-sectional Association between P. aeruginosa and Markers of Severe Disease
Patient characteristics

In cross-sectional studies, we observed that patients with P. aeruginosa infection were 3 years older, on average, than patients not colonized with P. aeruginosa (mean difference, 3.1 yr; 95% CI, 0.9–5.4; P = 0.007; I2 = 48%). Interestingly there was a statistically significant association between male sex and P. aeruginosa colonization (OR, 1.39; 95% CI, 1.09–1.75; P = 0.009; I2 = 0%).

Quality of life

The only data available for QoL were based on the St. George’s Respiratory Questionnaire (SGRQ). The SGRQ is a validated questionnaire in patients with bronchiectasis that has been widely used, with an accepted increment of 4 points demonstrating clinical significance (37). The authors of four studies reported data for SGRQ, with a mean difference of 18.2 points (95% CI, 14.7–21.8; P < 0.0001; n = 1,041) (22, 24, 28). There was no heterogeneity between studies (I2 = 0%). No data were available for other questionnaires, including the Quality of Life–Bronchiectasis questionnaire.

Lung function: FEV1 and FVC

As expected, patients with P. aeruginosa colonization had worse cross-sectional lung function than patients without P. aeruginosa. Valid data for FEV1 were reported in 17 studies, with all showing worse lung function in the P. aeruginosa group, ranging from −1.4% to −29% (6, 12, 13, 21, 22, 24, 2831, 33, 34, 36). The pooled mean difference was 15.0% (95% CI, −18.7 to −11.3; P < 0.0001). This is shown in Figure 5. There was significant heterogeneity, but this was no longer statistically significant after exclusion of one study that defined P. aeruginosa presence by polymerase chain reaction (PCR) (6). Data for FVC were presented in nine cohorts, with a pooled mean difference of −9.4% (95% CI, −14.3 to −4.5%; P = 0.005, n = 1,453) (12, 24, 28, 29, 33, 34).

Radiological severity

Although multiple severity scoring systems have been used in bronchiectasis, the only variable that was studied in more than one study was the number of involved lobes visualized by computed tomography. These data were available in nine cohorts (24, 29, 30, 32, 34, 35). The mean difference between patients with and without P. aeruginosa colonization was 1.4 lobes (95% CI, 0.93–1.86; P < 0.0001). Nevertheless, worse radiological severity in patients with P. aeruginosa colonization was reported in all studies.

Sensitivity analyses

Limiting the analysis to only those studies that used the most robust definition of P. aeruginosa colonization, requiring at least two positive sputum samples over a 12-month period, showed results very similar to the primary analysis, with ORs of 3.46 for mortality (95% CI, 1.96–0.6.08; P < 0.0001) and 7.22 for hospital admissions (95% CI, 2.88–18.09; P   <   0.0001) and a mean difference of 0.87 for exacerbations (95% CI, 0.59–1.15; P < 0.0001). P > 0.5 when we used ORs in interactions testing compared with the overall cohort.

Eight cohorts provided data that could be used to directly compare the outcomes of patients colonized with P. aeruginosa versus those colonized with H influenzae. The findings were highly consistent with the main analysis, with increases associated with P. aeruginosa in mortality (OR, 4.00; 95% CI, 2.28–7.02; P < 0.001), rate of hospital admissions (OR, 6.75; 95% CI, 3.98–11.45; P < 0.001), and exacerbations (mean difference, 0.99; 95% CI, 0.54–1.43; P < 0.0001), as well as lower FEV1 (mean difference, −11.4; 95% CI, −14.8 to −7.9; P < 0.0001).

The management of patients with bronchiectasis with P. aeruginosa colonization is challenging, and a large proportion of the current therapeutic development in bronchiectasis is focused on management of P. aeruginosa infection (1416). In particular, there are intensive efforts in the field of inhaled antibiotics to develop a licensed therapy for P. aeruginosa infection in bronchiectasis (15, 16). Therefore, an accurate assessment of the prognostic impact of P. aeruginosa in bronchiectasis is important for clinicians, drug developers, and regulators. Our present analysis provides detailed insight into the impact that P. aeruginosa colonization has on key clinical outcomes in bronchiectasis. In addition, P. aeruginosa colonization was associated with multiple cross-sectional markers of disease severity. It can therefore be said that P. aeruginosa colonization is both a marker of severe disease and associated with a worse long-term prognosis in patients with bronchiectasis.

Bronchiectasis has historically been a neglected condition, described in the European Lung White Book as one of the most neglected diseases in respiratory medicine (40). As a result, there have been few large cohort studies of this disease. The value of meta-analysis in this setting, therefore, is to combine the available data from existing small studies to give a more accurate estimate of the disease’s impact.

The most striking finding within this analysis is the impact of P. aeruginosa on all-cause mortality. In our analysis, we identified a threefold increase in the risk of death associated with P. aeruginosa colonization. P. aeruginosa was also associated with a greatly increased the risk of hospital admissions and also increased exacerbation frequency by a rate of one exacerbation per patient per year. This finding was robust regardless of the definition used and was consistent across all cohorts. These results strengthen the view that patients with P. aeruginosa require specific treatment to reduce the risk of long-term morbidity and mortality and that P. aeruginosa colonization status should play a key role in the assessment of disease severity (14).

The increased exacerbation frequency and hospital admissions demonstrate a measurable healthcare cost associated with P. aeruginosa colonization. Each additional exacerbation results in further antibiotic use with associated risks and side effects as well as increased potential for the development of antimicrobial resistance. Exacerbations are associated with reduced productivity through absence from work and are associated with poorer QoL and potential lung function decline (24, 38, 41). Hospital admissions may reflect more severe exacerbations or the development of resistance to oral antibiotic agents necessitating intravenous antibiotic therapy (24). The ability of P. aeruginosa to develop antibiotic resistance is inevitably enhanced by repeated antibiotic exposure (29).

Our analyses of QoL, lung function, and radiological severity were cross-sectional and can therefore only be considered hypothesis generating in terms of the impact of P. aeruginosa on these outcomes over the long term. Nevertheless, the impact on QoL demonstrated in this analysis is striking. The 18-point decrement in the SGRQ demonstrated in patients with P. aeruginosa colonization reflects a dramatic worsening of QoL. Given our observation that patients with P. aeruginosa had reduced lung function and more widespread radiological disease as evaluated by imaging, it is difficult to determine what proportion of this difference in QoL is directly attributable to P. aeruginosa. All of the analyses described herein are subject to the same limitation—that P. aeruginosa may be to some extent a reflection of the severity of underlying disease rather than a direct cause of disease progression. The only way to conclusively prove or quantify the independent effects of P. aeruginosa on outcome is likely to be through a large randomized controlled trial of P. aeruginosa eradication treatment, which has been highlighted as a clear priority for the bronchiectasis research community (42). Demonstrating that mortality, hospital admissions, exacerbations, QoL, and lung function are improved or cease to decline after successful eradication would clearly demonstrate the independent impact of P. aeruginosa. A strength of our analysis is that it provides the most precise estimates to date of P. aeruginosa prevalence and has sufficient impact to power future trials.

Current national guidelines for bronchiectasis recommend eradication treatment for new isolation of P. aeruginosa, based largely on recommendations for CF (8, 14, 43). Data in bronchiectasis are limited to date, and further research is greatly needed.

Important gaps in the literature identified through this analysis include an absence of data available outside Europe and Australasia, with a large proportion of included data being from the United Kingdom. Broad, representative registries of patients with bronchiectasis are needed internationally. Few studies of lung function decline were identified, and those that were found were small and produced inconsistent results. We recommend further large studies of lung function decline in bronchiectasis. There is a lack of data describing the impact of organisms other than P. aeruginosa in bronchiectasis and in particular comparing the outcomes of patients colonized P. aeruginosa with those colonized with the most common bronchiectasis pathogens, such as H. influenzae or Moraxella catarrhalis. Such data would be valuable, as recent reports suggest that these patients do have worse outcomes than patients without colonization, but to a lesser extent than those colonized with P. aeruginosa (24). For example, in the Bronchiectasis Severity Index, 3 points are awarded to patients with P. aeruginosa colonization and 1 point is given to patients colonized with other pathogens (24). In the present meta-analysis, we were able to identify eight cohorts with data to compare outcomes between patients colonized with P. aeruginosa and those colonized with H. influenza, and the data for these cohorts confirmed the significantly worse clinical outcomes associated with P. aeruginosa.

There is a need from both a clinical and a research perspective to define chronic bacterial colonization in bronchiectasis, as in this analysis we identified eight different methods of defining P. aeruginosa colonization in bronchiectasis studies. The most frequently used definition was two or more positive cultures at least 3 months apart in a 12-month span. This should be standardized across studies to increase our ability to generalize results between studies and healthcare systems. Our data were based almost entirely on traditional bacterial culture, and recent studies have increasingly used quantitative PCR or characterization of the microbiome through sequencing of the 16S ribosomal RNA subunit to determine bacterial colonization status (6, 36, 44). This method is significantly more sensitive for the detection of P. aeruginosa, with Rogers and colleagues demonstrating very poor correlation between culture and PCR for P. aeruginosa detection. Of 107 patients in their study, 91 were positive for P. aeruginosa by PCR compared with 31 by culture (6). For this reason, further studies of the role of PCR in P. aeruginosa detection and to confirm eradication would be beneficial.

The word colonization in this context is perhaps misleading. Colonization implies a benign state defined by absence of tissue invasion or tissue damage. The term chronic infection may be more appropriate, given the clearly established association between the presence of bacteria and airway inflammation and the worse clinical outcomes observed in the presence of P. aeruginosa.

In summary, P. aeruginosa colonization is associated with increased mortality, hospital admissions, and exacerbations, as well as with worse QoL. As such, new isolation of P. aeruginosa should be considered a highly significant clinical event and followed with repeated cultures and attempts to eradicate it in line with guideline recommendations.

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Correspondence and requests for reprints should be addressed to James D. Chalmers, M.B.Ch.B., Ph.D., College of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK. E-mail:

Supported by the European Bronchiectasis Network (EMBARC). EMBARC is a European Respiratory Society Clinical Research Collaboration and has received funding from the European Respiratory Society, Bayer HealthCare, and Aradigm Corporation.

Author Contributions: All authors participated in the conception of the study, data collection, and drafting and revising of the manuscript.

Author disclosures are available with the text of this article at www.atsjournals.org.

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