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

July 31, 2019 updated by: Weijie Guan, Guangzhou Institute of Respiratory Disease

Guangzhou Institute of Respiratory Disease

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Anticipated)

120

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • China
    • Guangdong
      • Guangzhou, Guangdong, China, 510120
        • Recruiting
        • Guangzhou Institute of Respiratory Disease
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 85 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: DIAGNOSTIC
  • Allocation: NA
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
OTHER: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
Jan 2015 to Dec 2017, up to 3 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Serum inflammatory indices
Time Frame: Jan 2015 to Dec 2017, up to 3 years
IL-8, TNF-α, WBC and CRP
Jan 2015 to Dec 2017, up to 3 years
Sputum sol phase inflammatory biomarkers
Time Frame: Jan 2015 to Dec 2017, up to 3 years
IL-8 and TNF-α
Jan 2015 to Dec 2017, up to 3 years
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
Jan 2015 to Dec 2017, up to 3 years
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
Jan 2015 to Dec 2017, up to 3 years
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
Jan 2015 to Dec 2017, up to 3 years
Spirometry
Time Frame: Jan 2015 to Dec 2017, up to 3 years
FEV1, FVC, FEV1/FVC, MMEF
Jan 2015 to Dec 2017, up to 3 years
Bronchiectasis Severity Index
Time Frame: Jan 2015 to Dec 2017, up to 3 years
Jan 2015 to Dec 2017, up to 3 years
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
Jan 2015 to Dec 2017, up to 3 years
Sputum purulence
Time Frame: Jan 2015 to Dec 2017, up to 3 years
scale 1 to 8
Jan 2015 to Dec 2017, up to 3 years
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
Jan 2015 to Dec 2017, up to 3 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Guangzhou Institute of Respiratory Disease

Investigators

  • Study Chair: Nan-shan Zhong, MD, State Key Laboraotry of Respiratory Disease

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2015

Primary Completion (ANTICIPATED)

December 1, 2023

Study Completion (ANTICIPATED)

December 1, 2023

Study Registration Dates

First Submitted

December 8, 2014

First Submitted That Met QC Criteria

December 9, 2014

First Posted (ESTIMATE)

December 12, 2014

Study Record Updates

Last Update Posted (ACTUAL)

August 1, 2019

Last Update Submitted That Met QC Criteria

July 31, 2019

Last Verified

July 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • GIRD-20141208-GWJ

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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