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Sputum Microbiota and the Association With Clinical Parameters in Steady-state, Acute Exacerbation and Convalescence of Bronchiectasis (BISER-2)

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ClinicalTrials.gov Identifier: NCT02315547
Recruitment Status : Recruiting
First Posted : December 12, 2014
Last Update Posted : August 1, 2019
Sponsor:
Information provided by (Responsible Party):
Weijie Guan, Guangzhou Institute of Respiratory Disease

Brief Summary:

Study 1 is a cross-sectional investigation. Patients with clinically stable bronchiectasis (symptoms, including cough frequency, sputum volume and purulence, within normal daily variations) will undergo baseline assessment consisting of history taking, routine sputum culture, 16srRNA pyrosequencing, measurement of sputum inflammatory markers, oxidative stress biomarkers and MMPs, and spirometry. Microbiota taxa will be compared between bronchiectasis patients and healthy subjects.

In study 2, patients inform investigators upon symptom deterioration. Following diagnosis of BEs, patients will undergo the aforementioned assessments as soon as possible. This entails antibiotic treatment, with slightly modified protocol, based on British Thoracic Society guidelines [16]. At 1 week after completion of 14-day antibiotic therapy, patients will undergo convalescence visit.

Study 3 is a prospective 1-year follow-up scheme in which patients participated in telephone or hospital visits every 3 months. For individual visit, spirometry and sputum culture will be performed, and BEs will be meticulously captured from clinical charts and history inquiry, with the final decisions adjudicated following group discussion.


Condition or disease Intervention/treatment Phase
Bronchiectasis Drug: Antibiotics Not Applicable

Detailed Description:

Bronchiectasis is a chronic airway disease characterized by airway infection, inflammation and destruction [1]. Bacteria are frequently responsible for the vicious cycle seen in bronchiectasis. Clinically, potentially pathogenic microorganisms (PPMs) primarily consisted of Hemophilus influenzae, Hemophilus parainfluenzae, Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pneumoniae and Moraxella catarrhalis [1]. These PPMs elicit airway inflammation [2-5] and biofilm formation [6] leading to and oxidative stress [7,8]. However, different PPMs harbor varying effects on bronchiectasis. For instance, P. aeruginosa has been linked to more pronounced airway inflammation and poorer lung function [9,10].

However, it should be recognized that routine sputum bacterial culture techniques could only effectively identify a small proportion of PPMs. The assay sensitivity and specificity could be significantly affected by the duration from sampling to culture, the culture media and environment. Pyrosequencing of the bacterial 16srRNA might offer more comprehensive assessment of the airway microbiota. Based on this technique, Goleva and associates [11] identified an abundance of gram-negative microbiota (predominantly the phylum proteobacteria) which might be responsible for corticosteroid insensitivity. The microbiome of airways in patients with asthma [11,12], idiopathic pulmonary fibrosis [13] and bronchiectasis [14,15] has also been characterized. Furthermore, the association between the "core microbiota" and clinical parameters (i.e., FEV1) has been demonstrated. However, previous studies suffered from relatively small sample size and lack of comprehensive sets of clinical parameters for further analyses.

Bronchiectasis exacerbations (BEs) are characterized by significantly worsened symptoms and (or) signs that warrant antibiotics therapy. The precise mechanisms responsible for triggering BEs have not been fully elucidated, but could be related to virus infection and increased bacterial virulence. However, it should be recognized that antibiotics, despite extensive bacterial resistance, remain effective for most BEs. This at least partially suggested that bacterial infection might have played a major role in the pathogenesis of BEs. Therefore, the assessment of sputum microbiota during steady-state, BEs and convalescence may unravel more insights into the dynamic variation in microbiota compositions and the principal microbiota phylum or species that account for BEs.

In the this study, the investigators seek to perform 16srRNA pyrosequencing to determine: 1) the differences in microbiota compositions between bronchiectasis patients and healthy subjects; 2) association between sputum microbiota compositions and clinical parameters, including systemic/airway inflammation, spirometry, disease severity, airway oxidative stress biomarkers and matrix metalloproteinase; 3) the microbiota compositions in patients who yielded "normal flora (commensals)", in particular those who produced massive sputum daily (>50ml/d); 4) dynamic changes in microbiota compositions during BEs and convalescence as compared with baseline levels; 5) the utility of predominant microbiota taxa in predicting lung function decline and future risks of BEs during 1-year follow-up.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Guangzhou Institute of Respiratory Disease
Study Start Date : January 2015
Estimated Primary Completion Date : December 2023
Estimated Study Completion Date : December 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Antibiotics

Arm Intervention/treatment
Antibiotics
Patients will be given antibiotics based on sputum microbiology during steady-state bronchiectasis. The methodology has been described in the British Thoracic Society guideline [16]. Briefly, for first-line therapy, patients isolated with Hemophilus influenzae, Hemophilus parainfluenzae, Streptoccus pneumoniae and Moraxella catarrhalis at baseline will be treated with amoxicillin clavulanate potassium (625mg bid); patients isolated with Klebsela pneumonae or Pseudomonas aeruginosa at baseline will be treated with fluoroquinolones. Levofloxacin (500mg qd) will be empirically employed for antibiotic treatment in those who tested negative to sputum microbiology. Severe BEs could be prescribed with intravenous antibiotics therapy at the discretion of study investigators, either in the out-patient department or hospitalized for intensive systemic treatment. Hospitalized patients will not be included in the exacerbation cohort.
Drug: Antibiotics
Patients will be given antibiotics based on sputum microbiology during steady-state bronchiectasis. The methodology has been described in the British Thoracic Society guideline [16]. Briefly, for first-line therapy, patients isolated with Hemophilus influenzae, Hemophilus parainfluenzae, Streptoccus pneumoniae and Moraxella catarrhalis at baseline will be treated with amoxicillin clavulanate potassium (625mg bid); patients isolated with Klebsela pneumonae or Pseudomonas aeruginosa at baseline will be treated with fluoroquinolones. Levofloxacin (500mg qd) will be empirically employed for antibiotic treatment in those who tested negative to sputum microbiology. Severe BEs could be prescribed with intravenous antibiotics therapy at the discretion of study investigators, either in the out-patient department or hospitalized for intensive systemic treatment. Hospitalized patients will not be included in the exacerbation cohort.




Primary Outcome Measures :
  1. relative abundance, diversity and richness of microbiota taxa [ Time Frame: Jan 2015 to Dec 2017, up to 3 years ]
    Sputum microbiota taxa compositions (at phylum and species levels, respectively), including the relative abundance, diversity and richness


Secondary Outcome Measures :
  1. Serum inflammatory indices [ Time Frame: Jan 2015 to Dec 2017, up to 3 years ]
    IL-8, TNF-α, WBC and CRP

  2. Sputum sol phase inflammatory biomarkers [ Time Frame: Jan 2015 to Dec 2017, up to 3 years ]
    IL-8 and TNF-α

  3. Sputum sol phase oxidative stress biomarkers or parameters [ Time Frame: Jan 2015 to Dec 2017, up to 3 years ]
    CAT, hydrogen peroxide, superoxide dismutase, MDA

  4. Sputum sol phase matrix metalloproteinases [ Time Frame: Jan 2015 to Dec 2017, up to 3 years ]
    MMP-8, MMP-9, TIMP-1, MMP-9/TIMP-1 ratio

  5. 24-hour sputum volume [ Time Frame: Jan 2015 to Dec 2017, up to 3 years ]
    24-hour sputum volume, measured to the nearest 5 ml

  6. Spirometry [ Time Frame: Jan 2015 to Dec 2017, up to 3 years ]
    FEV1, FVC, FEV1/FVC, MMEF

  7. Bronchiectasis Severity Index [ Time Frame: Jan 2015 to Dec 2017, up to 3 years ]
  8. Sputum culture findings [ Time Frame: Jan 2015 to Dec 2017, up to 3 years ]
    normally reported as growth of a predominant potentially pathogenic microorganism or no bacterial growth

  9. Sputum purulence [ Time Frame: Jan 2015 to Dec 2017, up to 3 years ]
    scale 1 to 8

  10. SGRQ total score and the scores of individual domains [ Time Frame: Jan 2015 to Dec 2017, up to 3 years ]
    SGRQ total score and the scores of individual domains



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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Patients of either sex and age between 18 and 85 years

Exclusion Criteria:

  1. Patient judged to have poor compliance
  2. Female patient who is lactating or pregnant
  3. Patients having concomitant severe systemic illnesses (i.e. coronary heart disease, cerebral stroke, uncontrolled hypertension, active gastric ulcer, malignant tumor, hepatic dysfunction, renal dysfunction)
  4. Miscellaneous conditions that would potentially influence efficacy assessment, as judged by the investigators
  5. Participation in another clinical trial within the preceding 3 months

Inclusion criteria for healthy subjects include all of the above criteria except for known respiratory diseases

It is estimated that 120 patients will be recruited in the study. Some of the patients in the BISER study (currently still ongoing, No.: NCT01761214) who are eligible for the current study will undergo assessments de novo, with the index date deemed as the the date of recruitment


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02315547


Contacts
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Contact: Wei-jie Guan, Ph.D. +86-13826042052 battery203@163.com

Locations
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China, Guangdong
Guangzhou Institute of Respiratory Disease Recruiting
Guangzhou, Guangdong, China, 510120
Contact: Nan-shan Zhong, MD       nanshan@vip.163.com   
Contact: Wei-jie Guan, MD    +86-13826042052    battery203@163.com   
Sponsors and Collaborators
Guangzhou Institute of Respiratory Disease
Investigators
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Study Chair: Nan-shan Zhong, MD State Key Laboraotry of Respiratory Disease

Publications:

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Responsible Party: Weijie Guan, physician, Guangzhou Institute of Respiratory Disease
ClinicalTrials.gov Identifier: NCT02315547     History of Changes
Other Study ID Numbers: GIRD-20141208-GWJ
First Posted: December 12, 2014    Key Record Dates
Last Update Posted: August 1, 2019
Last Verified: July 2019
Keywords provided by Weijie Guan, Guangzhou Institute of Respiratory Disease:
Microbiota
Airway infection
Bronchiectasis
Airway inflammation
Oxidative stress
Matrix metalloproteinase
Additional relevant MeSH terms:
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Bronchiectasis
Bronchial Diseases
Respiratory Tract Diseases
Anti-Bacterial Agents
Antibiotics, Antitubercular
Anti-Infective Agents
Antitubercular Agents