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

Bronchiectasis Clinical Trial

— BISER-2  

Official title:

Guangzhou Institute of Respiratory Disease

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02315547
• Other study ID #: GIRD-20141208-GWJ
• Status: Recruiting
• Phase: N/A
• Start date: January 2015
• Est. completion date: December 2023

Study information

• Verified date: July 2019
• Source: Guangzhou Institute of Respiratory Disease
• Contact: Wei-jie Guan, Ph.D.
• Phone: +86-13826042052
• Email: battery203[@]163.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 120
• Est. completion date: December 2023
• Est. primary completion date: December 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

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

Related Conditions & MeSH terms

• Bronchiectasis

Intervention

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.

Locations

Country	Name	City	State
China	Guangzhou Institute of Respiratory Disease	Guangzhou	Guangdong

Sponsors (1)

Lead Sponsor	Collaborator
Guangzhou Institute of Respiratory Disease

Country where clinical trial is conducted

China, 

References & Publications (20)

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Horvath I, Loukides S, Wodehouse T, Kharitonov SA, Cole PJ, Barnes PJ. Increased levels of exhaled carbon monoxide in bronchiectasis: a new marker of oxidative stress. Thorax. 1998 Oct;53(10):867-70. — View Citation

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Pasteur MC, Bilton D, Hill AT; British Thoracic Society Bronchiectasis non-CF Guideline Group. British Thoracic Society guideline for non-CF bronchiectasis. Thorax. 2010 Jul;65 Suppl 1:i1-58. doi: 10.1136/thx.2010.136119. Review. — View Citation

Pasteur MC, Helliwell SM, Houghton SJ, Webb SC, Foweraker JE, Coulden RA, Flower CD, Bilton D, Keogan MT. An investigation into causative factors in patients with bronchiectasis. Am J Respir Crit Care Med. 2000 Oct;162(4 Pt 1):1277-84. — View Citation

Rogers GB, van der Gast CJ, Cuthbertson L, Thomson SK, Bruce KD, Martin ML, Serisier DJ. Clinical measures of disease in adult non-CF bronchiectasis correlate with airway microbiota composition. Thorax. 2013 Aug;68(8):731-7. doi: 10.1136/thoraxjnl-2012-203105. Epub 2013 Apr 6. — View Citation

Ryall B, Davies JC, Wilson R, Shoemark A, Williams HD. Pseudomonas aeruginosa, cyanide accumulation and lung function in CF and non-CF bronchiectasis patients. Eur Respir J. 2008 Sep;32(3):740-7. doi: 10.1183/09031936.00159607. Epub 2008 May 14. — View Citation

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Tunney MM, Einarsson GG, Wei L, Drain M, Klem ER, Cardwell C, Ennis M, Boucher RC, Wolfgang MC, Elborn JS. Lung microbiota and bacterial abundance in patients with bronchiectasis when clinically stable and during exacerbation. Am J Respir Crit Care Med. 2013 May 15;187(10):1118-26. doi: 10.1164/rccm.201210-1937OC. — View Citation

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* Note: There are 20 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Jan 2015 to Dec 2017, up to 3 years
Secondary	Serum inflammatory indices	IL-8, TNF-a, WBC and CRP	Jan 2015 to Dec 2017, up to 3 years
Secondary	Sputum sol phase inflammatory biomarkers	IL-8 and TNF-a	Jan 2015 to Dec 2017, up to 3 years
Secondary	Sputum sol phase oxidative stress biomarkers or parameters	CAT, hydrogen peroxide, superoxide dismutase, MDA	Jan 2015 to Dec 2017, up to 3 years
Secondary	Sputum sol phase matrix metalloproteinases	MMP-8, MMP-9, TIMP-1, MMP-9/TIMP-1 ratio	Jan 2015 to Dec 2017, up to 3 years
Secondary	24-hour sputum volume	24-hour sputum volume, measured to the nearest 5 ml	Jan 2015 to Dec 2017, up to 3 years
Secondary	Spirometry	FEV1, FVC, FEV1/FVC, MMEF	Jan 2015 to Dec 2017, up to 3 years
Secondary	Bronchiectasis Severity Index		Jan 2015 to Dec 2017, up to 3 years
Secondary	Sputum culture findings	normally reported as growth of a predominant potentially pathogenic microorganism or no bacterial growth	Jan 2015 to Dec 2017, up to 3 years
Secondary	Sputum purulence	scale 1 to 8	Jan 2015 to Dec 2017, up to 3 years
Secondary	SGRQ total score and the scores of individual domains	SGRQ total score and the scores of individual domains	Jan 2015 to Dec 2017, up to 3 years