Role of Pseudomonas Aeruginosa Biofilms in Exacerbations in Patients With Bronchiectasis With and Without Chronic Obstructive Pulmonary Disease

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Brief Title

Role of Pseudomonas Aeruginosa Biofilms in Exacerbations in Patients With Bronchiectasis With and Without Chronic Obstructive Pulmonary Disease

Official Title

Role of Pseudomonas Aeruginosa Biofilms in Exacerbations in Patients With Bronchiectasis With and Without Chronic Obstructive Pulmonary Disease

Brief Summary

      Exacerbations, in particular during chronic Pseudomonas aeruginosa (PA) infection, are very
      important in the prognosis of patients with non-cystic fibrosis bronchiectasis (BE). In
      Cystic Fibrosis patients, PA biofilms are associated with chronic respiratory infections and
      are the primary cause of their increased morbidity and mortality. However, the presence and
      role in exacerbations of PA biofilms, microbiome dysbiosis and inflammatory biomarkers has
      not been studied in depth in BE patients. Our aim is to determine the association between PA
      chronic infection and its biofilms with the number of exacerbations in the next year (primary
      outcome), time until next exacerbation, quality of life, FEV1 and inflammatory biomarkers
      (secondary outcomes) in BE patients with or without chronic obstructive pulmonary disease
      (COPD). The investigators will include and follow up during 12 months post study inclusion,
      48 patients with BE and 48 with BE-COPD, with a positive sputum culture of PA. During
      stability and follow up (and in each exacerbation) The investigators will collect 4 sputum, 4
      serum samples, perform spirometry, and quality of life tests every three months. For the
      biomarkers subproject, 4 additional serum samples will be collected at: exacerbation, 3-5
      days after treatment, at 30 days and three months post-exacerbation. Biomarkers will be
      measured by commercial kits and Luminex. The investigators will quantify PA colony forming
      units (CFU)/mL, their resistance pattern, their mutation frequency and isolate mucoid and
      non-mucoid colonies. In each sputum, the investigators will analyze by Confocal Laser
      Scanning Microscopy (CLSM) and Fluorescent in situ Hybridizatrion (FISH) PA biofilms, their
      size, bacterial density and their in situ growth rate. Specific serum antibodies against PA
      will be determined through Crossed Immunoelectrophoresis. In addition, the investigators will
      indentify potential respiratory microbiome and gene expression patterns predictive for
      exacerbations, or with a protective role against chronic PA infection, as well as their
      association with biofilms. Microbiome analysis will be performed through the Illumina Miseq
      platform. Finally, the investigators will explore the antimicrobial activity of novel
      combinations of antibiotics against PA, both in in vitro planktonic cultures and in a biofilm
      model, and will include testing of antibiotic-containing alginate nanoparticles.

Detailed Description

      This project will study the association between chronic PA infection in the airways and the
      formation of biofilms in the following patient populations: 1-bronchiectasis not associated
      with cystic fibrosis (BQ) and 2-bronchiectasis with chronic obstructive pulmonary disease
      (BQ-EPOC). The primary objective is to determine the association between chronic infection by
      PA, presence of biofilms of PA and the worst evolution of the disease measured mainly by the
      number of exacerbations per year (primary outcome) days until the next exacerbation, quality
      of Life and Forced Expiratory Volume (FEV1), and inflammatory biomarkers (secondary
      outcomes). For this, these parameters will be compared in patients with chronic infection by
      PA and with the presence of biofilms of PA in the sputum (identified by FISH-CLSM) vs those
      with PA without chronic infection and without biofilms (control negative) in each study
      population (BE and BE-COPD). The investigators will analyze, to the recruitment and
      sequentially (3 determinations), various aspects of the biofilms that are detailed in the
      methodology. In addition, by comparing the microbiome before, during and after each
      exacerbation, the investigators will try to identify those microbial patterns that entail a
      higher risk of exacerbation, those with a protective role against chronic PA infection and
      its relationship with biofilms.

      The diagnosis of biofilms is not yet routinely implemented in clinical practice for Chronic
      Obstructive Pulmonary Disease (COPD) and NonCF Bronchiectasis (BE) infections. The first
      guidelines for the diagnosis and treatment of biofilm infections were published in 2015 and
      included many biofilm-associated infections, but not COPD or BE. There are in fact very few
      studies on the presence of PA biofilms in these populations and on their potential role in
      exacerbations. However, there is sound scientific evidence that PA biofilms are associated
      with chronic respiratory infections in Cystic Fibrosis (CF) patients, and are the primary
      cause of their increased morbidity and mortality. It has been reported that during chronic PA
      lung infection in CF, PA adapts to different niches in the lungs. Both mucoid (biofilms) and
      non-mucoid (planktonic) bacteria are present in sputum. Cells with higher mutation rate
      develop multi-resistance to many antibiotics and their in situ growth rate is lower, since
      bacteria decrease their metabolism conditioned by high polymorphonuclear oxygen consumption,
      As yet, however, none of this has been described in patients with BE; in fact, there are very
      few studies on the presence of PA biofilms in these populations, and their role in the
      exacerbations has not been demonstrated. In addition, there is little evidence of the
      association of the microbiome dysbiosis with chronic colonization by PA and during

      Chronic colonization by PA is present in 12-27% of patients with BE and BE-COPD, and entails
      a worse prognosis (a 3-fold increase in mortality risk) and up to a 7-fold increase in the
      risk of hospital admission, with an average of one additional exacerbation per patient and
      per year. In these patients, eradication of PA is difficult, despite the fact that an
      adequate antimicrobial treatment reduces the bacterial load and the number of exacerbations
      and improves lung function and quality of life. One of the main challenges in patients with
      BE is the eradication of PA, especially during the early stages of colonization by this
      pathogen. In this situation, aggressive antibiotic treatment is recommended. However, this
      eradication fails in a notable percentage of cases. In addition to the increase in
      multiresistance in PA, even against quinolones, its ability to produce biofilms and survive
      in them is one of the reasons for the failed eradication. Although the presence of PA in
      sputum is a factor of poor prognosis in BE, biofilms have not yet been identified and
      characterized (i.e., their presence, size, amount of alginate and metabolic status) in sputum
      of these populations. Recently, the presence of biofilms in bronchoalveolar lavage (BAL)
      samples has been described by confocal laser scanning microscopy (CLSM) in pediatric patients
      with BE, even in those samples in which the culture was negative. This finding draws
      attention to the lack of studies on biofilm in BE and the importance of improving diagnostic
      tools for detection in respiratory samples, especially in patients with recurrent
      exacerbations despite antibiotic treatment.

      Between 30 and 50% of patients with moderate or severe COPD have BE. Its prevalence increases
      with the severity of COPD, while 5-10% of patients with BE have COPD. Patients with COPD and
      BE form a clinical group with its own characteristics (increased sputum production and
      purulence, greater dyspnea and number of exacerbations), worse prognosis, possible
      therapeutic implications and higher mortality. Although the causes of exacerbations are not
      yet well understood, bacterial infections are thought to be involved in approximately
      one-half of cases PA is one of the most frequent pathogens isolated from these exacerbations
      and is associated with higher mortality. PA from sputum of chronically infected COPD patients
      tends to be less cytotoxic and motile and produces more biofilm than PA from blood samples.
      Therefore, some authors suggest that COPD, BE and CF present similar patterns of infection
      and evolution. Following this reasoning, our hypothesis is that PA biofilms could be one of
      the pathogenic mechanisms associated with both the persistence of infections and the
      frequency and severity of exacerbations in patients with BE (with or without COPD). However,
      further research using the recommendations of the current guidelines is needed to confirm
      this hypothesis.

      Some authors who have studied microbial dysbiosis in COPD exacerbations have seen that, along
      with eosinophilic inflammation, it is associated with more severe exacerbations and a greater
      fall in lung function. Longitudinal studies of the microbiome in the sputum of patients with
      BE suggest that the management of chronic bronchial infection can be improved with a therapy
      that is specific for its microbiome, taking into account the burden of the pathogen, the
      stability of the community, and acute and chronic community responses to antibiotics.
      However, the fluctuations in the microbiome and its predictive role in the exacerbations of
      bronchiectasis have not yet been studied in depth. The study of variations in the microbiome
      before and during the exacerbation could reveal novel therapeutic targets that may have an
      impact on the management of patients. The results could help to determine the need to
      administer antimicrobial treatment in patients with negative microbiological cultures during
      the exacerbation. There is evidence that a balanced oral flora could have a protective role
      against the colonization of saliva by PA; however, a microbiome pattern with a protective
      effect on the upper respiratory tract against PA in BE patients and its relationship with PA
      biofilms has not yet been described.

      Simultaneously, systemic biomarkers and inflammatory cytokines determine the potential
      importance of chronic PA infection and the productions of biofilms. Systemic CRP has been
      shown to be correlated with higher BE scores such as FACED and BSI. However, there are no
      longitudinal studies evaluating the intensity and duration of systemic inflammation caused by
      chronic PA infection.

      The spread of antibiotic resistance and increasing prevalence of biofilm-associated
      infections is driving demand for new means to treat such difficult to eradicate bacterial
      infections. Recently, the WHO published a list of bacteria for with research on new
      antibiotics is urgently needed. Drug discovery and development is a tedious, long and costly
      endeavour that can take hundreds of millions EUR and 10-15 years from the bench discovery to
      the bedside. Chronic PA infections associated to BE are typically treated with combinations
      of up to three antimicrobials. Despite periodic courses of multidrug therapy, effective cure
      for these diseases is below optimal levels. It is clear then that new therapeutic options are
      needed to improve positive outcomes in these patients. Our approach focuses on the concept of
      synergy, i.e. identifying synergistic combinations of antibiotics, being together more
      effective that when used alone. The investigators aim to systematically evaluate the
      synergistic interactions of currently used antibiotics and explore the introduction of other
      clinically approved antibiotics. Since their pharmacology and toxicity has been already well
      documented, any potential synergistic antibiotic combination could progress to clinical
      trials at fraction of the standard development cost and in much shorter period of time. Along
      with this, the nanocarrier-mediated delivery strategy has been suggested as a promising
      approach in treatment of drug resistant infections. Nanotechnology may provide an innovative
      platform for addressing the challenge of PA chronic infections associated to bronchiectasis,
      with potential to manage difficult to treat infections involving multidrug-resistant (MDR)
      bacteria. In particular, polysaccharide (PS)-based nanocarriers are ideal vehicles for
      encapsulation of antimicrobials and alginate is an ideal carrier for pulmonary administration
      due to its mucoadhesive properties.

Study Type


Primary Outcome

Number of exacerbations per year

Secondary Outcome

 Levels of inflammatory biomarkers during the follow up and in exacerbations




Microbial biofilm diagnose


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status

Diagnostic Test

Estimated Enrollment


Start Date

March 1, 2018

Completion Date

December 1, 2021

Primary Completion Date

January 1, 2021

Eligibility Criteria

        Inclusion Criteria:

          -  BE criteria (with and without COPD)

          -  Isolation of PA in sputum in the stable phase. * A prospective screening of BQ
             patients in outpatient consultations will be conducted to prospectively detect those
             with isolation of PA in the sputum.

        Exclusion Criteria:

          -  CF

          -  Immunosuppression (primary and secondary, with the exception of cases of IgG
             deficiency in stable substitution treatment)

          -  Sarcoidosis

          -  Tuberculosis, active infection by nontuberculous mycobacteria

          -  Diffuse interstitial lung disease

          -  Altered state of consciousness or disability to understand the study and perform the
             tests provided by it, involving the patient in another intervention study (clinical

               -  Patients with CF are excluded because the role of PA biofilms in CF has been
                  extensively studied, as argued in the background of the present proposal and the
                  selected literature. It is also a totally different disease from the one we
                  intend to study, with patients of much younger ages. Finally, this is a very
                  vulnerable population in which it would be very difficult to obtain all the
                  samples sequentially.




18 Years - N/A

Accepts Healthy Volunteers



Fernández-Barat Laia, 932275400, [email protected]

Location Countries


Location Countries


Administrative Informations



Organization ID

v.11 27/02/18

Responsible Party


Study Sponsor

Hospital Clinic of Barcelona



Study Sponsor

Fernández-Barat Laia, Principal Investigator, Hospital Clinic of Barcelona

Verification Date

March 2021