Clinical trial NCT02315547: Sputum Microbiota and the Association With Clinical Parameters in Steady-state, Acute Exacerbation and Convalescence of Bronchiectasis
Official title: Guangzhou Institute of Respiratory Disease
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Bronchiectasis
Keywords: Microbiota
Airway infection
Bronchiectasis
Airway inflammation
Oxidative stress
Matrix metalloproteinase
Lead sponsor: Guangzhou Institute of Respiratory Disease
Sponsor class: OTHER
First posted: 2014-12-12
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: DIAGNOSTIC

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.

Eligibility 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

Primary outcomes:
measure: relative abundance, diversity and richness of microbiota taxa
timeFrame: Jan 2015 to Dec 2017, up to 3 years
Secondary outcomes:
measure: Serum inflammatory indices
timeFrame: Jan 2015 to Dec 2017, up to 3 years
measure: Sputum sol phase inflammatory biomarkers
timeFrame: Jan 2015 to Dec 2017, up to 3 years
measure: Sputum sol phase oxidative stress biomarkers or parameters
timeFrame: Jan 2015 to Dec 2017, up to 3 years
measure: Sputum sol phase matrix metalloproteinases
timeFrame: Jan 2015 to Dec 2017, up to 3 years
measure: 24-hour sputum volume
timeFrame: Jan 2015 to Dec 2017, up to 3 years
measure: Spirometry
timeFrame: Jan 2015 to Dec 2017, up to 3 years
measure: Bronchiectasis Severity Index
timeFrame: Jan 2015 to Dec 2017, up to 3 years
measure: Sputum culture findings
timeFrame: Jan 2015 to Dec 2017, up to 3 years
measure: Sputum purulence
timeFrame: Jan 2015 to Dec 2017, up to 3 years
measure: SGRQ total score and the scores of individual domains
timeFrame: Jan 2015 to Dec 2017, up to 3 years
Other outcomes:
Locations:
city: Guangzhou
country: China
facility: Guangzhou Institute of Respiratory Disease
state: Guangdong
Study officials:
affiliation: State Key Laboraotry of Respiratory Disease
name: Nan-shan Zhong, MD
role: STUDY_CHAIR
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