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

Primary Purpose

Bronchiectasis

Status
Recruiting
Phase
Not Applicable
Locations
China
Study Type
Interventional
Intervention
Antibiotics
Sponsored by
Guangzhou Institute of Respiratory Disease
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional diagnostic trial for Bronchiectasis focused on measuring Microbiota, Airway infection, Bronchiectasis, Airway inflammation, Oxidative stress, Matrix metalloproteinase

Eligibility Criteria

18 Years - 85 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

  • Guangzhou Institute of Respiratory DiseaseRecruiting

Arms of the Study

Arm 1

Arm Type

Other

Arm Label

Antibiotics

Arm Description

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.

Outcomes

Primary Outcome Measures

relative abundance, diversity and richness of microbiota taxa
Sputum microbiota taxa compositions (at phylum and species levels, respectively), including the relative abundance, diversity and richness

Secondary Outcome Measures

Serum inflammatory indices
IL-8, TNF-α, WBC and CRP
Sputum sol phase inflammatory biomarkers
IL-8 and TNF-α
Sputum sol phase oxidative stress biomarkers or parameters
CAT, hydrogen peroxide, superoxide dismutase, MDA
Sputum sol phase matrix metalloproteinases
MMP-8, MMP-9, TIMP-1, MMP-9/TIMP-1 ratio
24-hour sputum volume
24-hour sputum volume, measured to the nearest 5 ml
Spirometry
FEV1, FVC, FEV1/FVC, MMEF
Bronchiectasis Severity Index
Sputum culture findings
normally reported as growth of a predominant potentially pathogenic microorganism or no bacterial growth
Sputum purulence
scale 1 to 8
SGRQ total score and the scores of individual domains
SGRQ total score and the scores of individual domains

Full Information

First Posted
December 8, 2014
Last Updated
July 31, 2019
Sponsor
Guangzhou Institute of Respiratory Disease
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1. Study Identification

Unique Protocol Identification Number
NCT02315547
Brief Title
Sputum Microbiota and the Association With Clinical Parameters in Steady-state, Acute Exacerbation and Convalescence of Bronchiectasis
Acronym
BISER-2
Official Title
Guangzhou Institute of Respiratory Disease
Study Type
Interventional

2. Study Status

Record Verification Date
July 2019
Overall Recruitment Status
Recruiting
Study Start Date
January 2015 (undefined)
Primary Completion Date
December 2023 (Anticipated)
Study Completion Date
December 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Guangzhou Institute of Respiratory Disease

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Bronchiectasis
Keywords
Microbiota, Airway infection, Bronchiectasis, Airway inflammation, Oxidative stress, Matrix metalloproteinase

7. Study Design

Primary Purpose
Diagnostic
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
120 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Antibiotics
Arm Type
Other
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Antibiotics
Intervention Description
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 Measure Information:
Title
relative abundance, diversity and richness of microbiota taxa
Description
Sputum microbiota taxa compositions (at phylum and species levels, respectively), including the relative abundance, diversity and richness
Time Frame
Jan 2015 to Dec 2017, up to 3 years
Secondary Outcome Measure Information:
Title
Serum inflammatory indices
Description
IL-8, TNF-α, WBC and CRP
Time Frame
Jan 2015 to Dec 2017, up to 3 years
Title
Sputum sol phase inflammatory biomarkers
Description
IL-8 and TNF-α
Time Frame
Jan 2015 to Dec 2017, up to 3 years
Title
Sputum sol phase oxidative stress biomarkers or parameters
Description
CAT, hydrogen peroxide, superoxide dismutase, MDA
Time Frame
Jan 2015 to Dec 2017, up to 3 years
Title
Sputum sol phase matrix metalloproteinases
Description
MMP-8, MMP-9, TIMP-1, MMP-9/TIMP-1 ratio
Time Frame
Jan 2015 to Dec 2017, up to 3 years
Title
24-hour sputum volume
Description
24-hour sputum volume, measured to the nearest 5 ml
Time Frame
Jan 2015 to Dec 2017, up to 3 years
Title
Spirometry
Description
FEV1, FVC, FEV1/FVC, MMEF
Time Frame
Jan 2015 to Dec 2017, up to 3 years
Title
Bronchiectasis Severity Index
Time Frame
Jan 2015 to Dec 2017, up to 3 years
Title
Sputum culture findings
Description
normally reported as growth of a predominant potentially pathogenic microorganism or no bacterial growth
Time Frame
Jan 2015 to Dec 2017, up to 3 years
Title
Sputum purulence
Description
scale 1 to 8
Time Frame
Jan 2015 to Dec 2017, up to 3 years
Title
SGRQ total score and the scores of individual domains
Description
SGRQ total score and the scores of individual domains
Time Frame
Jan 2015 to Dec 2017, up to 3 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Patients of either sex and age between 18 and 85 years Exclusion Criteria: Patient judged to have poor compliance Female patient who is lactating or pregnant Patients having concomitant severe systemic illnesses (i.e. coronary heart disease, cerebral stroke, uncontrolled hypertension, active gastric ulcer, malignant tumor, hepatic dysfunction, renal dysfunction) Miscellaneous conditions that would potentially influence efficacy assessment, as judged by the investigators 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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Wei-jie Guan, Ph.D.
Phone
+86-13826042052
Email
battery203@163.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nan-shan Zhong, MD
Organizational Affiliation
State Key Laboraotry of Respiratory Disease
Official's Role
Study Chair
Facility Information:
Facility Name
Guangzhou Institute of Respiratory Disease
City
Guangzhou
State/Province
Guangdong
ZIP/Postal Code
510120
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Nan-shan Zhong, MD
Email
nanshan@vip.163.com
First Name & Middle Initial & Last Name & Degree
Wei-jie Guan, MD
Phone
+86-13826042052
Email
battery203@163.com

12. IPD Sharing Statement

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

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