The sputum microbiome and clinical outcomes in patients with bronchiectasis: a prospective observational study
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Study information
-
Quality control
- Retracted paper
- Contamination issues suspected
- Batch effect issues suspected
- Uncontrolled confounding suspected
- Results are suspect (various reasons)
- Tags applied
study design
Citation
PMID PubMed identifier for scientific articles.
DOI Digital object identifier for electronic documents.
Authors
Dicker AJ, Lonergan M, Keir HR, Smith AH, Pollock J, Finch S, Cassidy AJ, Huang JTJ, Chalmers JD
Journal
The Lancet. Respiratory medicine
Year
2021
BACKGROUND: Infection is a key component of bronchiectasis pathophysiology. Characterisation of the microbiome offers a higher degree of sensitivity and resolution than does traditional culture methods. We aimed to evaluate the role of the microbiome in determining the risk of exacerbation and long-term outcomes, including all-cause mortality, in bronchiectasis. METHODS: We did a prospective observational cohort study of patients with bronchiectasis from eastern Scotland. Patients were enrolled from Sept 11, 2012, to Dec 21, 2015, and followed until Jan 8, 2019, for long-term outcomes. Patients were included if they were aged 18 years or older, and had a high-resolution CT-confirmed diagnosis of bronchiectasis and clinical symptoms consistent with the disease. Sputum samples were obtained when patients were clinically stable. Repeat sputum samples were taken at stable and exacerbation visits during follow-up. The V3-V4 region of the bacterial 16S rRNA gene was sequenced using the Illumina MiSeq platform. The dominant bacterial genus in each sample was assigned on the basis of a previously published method. Microbiome characteristics were analysed for their association with measures of clinical disease severity and long-term outcomes using PERMANOVA, random forest, and survival analyses. FINDINGS: Sequencing data were obtained from the sputum samples of 281 patients with bronchiectasis who were included in the stable baseline cohort. 49 (17%) of 281 patients provided more than one sample when clinically stable and were included in the longitudinal analysis. 64 (23%) patients provided both stable and exacerbation samples. In both stable bronchiectasis and during exacerbations, a sputum microbiome dominated by Proteobacteria and Firmicutes was observed. Individual patients' microbiome profiles were relatively stable over time, during exacerbations and at disease stability. Lower microbiome diversity, measured using the Shannon-Wiener diversity index, was associated with more severe bronchiectasis defined by the bronchiectasis severity index, lower FEV1, and more severe symptoms. Random forest analysis of baseline samples identified Pseudomonas, Enterobacteriaceae, and Stenotrophomonas as being associated with severe bronchiectasis (bronchiectasis severity index ≥9) and greater lung inflammation and Pseudomonas and Enterobacteriaceae with more frequent exacerbations. Patients in whom Pseudomonas was dominant (n=35) were at increased risk of all-cause mortality (hazard ratio 3·12, 95% CI 1·33-7·36; p=0·0091) and had more frequent exacerbations (incident rate ratio 1·69, 95% CI 1·07-2·67; p=0·024) during follow-up compared with patients with other dominant genera (n=246). INTERPRETATION: A reduction in microbiome diversity, particularly one associated with dominance of Pseudomonas, is associated with greater disease severity, higher frequency and severity of exacerbations, and higher risk of mortality. The microbiome might therefore identify subgroups of patients at increased risk of poor outcomes who could benefit from precision treatment strategies. Further research is required to identify the mechanisms of reduced microbiome diversity and to establish whether the microbiome can be therapeutically targeted. FUNDING: British Lung Foundation and European Respiratory Society EMBARC2 consortium.
Experiment 1
Needs review
Subjects
- Location of subjects
- United Kingdom
- Host species Species from which microbiome was sampled. Contact us to have more species added.
- Homo sapiens
- Body site Anatomical site where microbial samples were extracted from according to the Uber Anatomy Ontology
- Sputum Expectoration,Sputum,sputum
- Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology
- Bronchiectasis Polynesian bronchiectasis,Bronchiectasis,bronchiectasis
- Group 0 name Corresponds to the control (unexposed) group for case-control studies
- Less severe bronchiectasis
- Group 1 name Corresponds to the case (exposed) group for case-control studies
- Severe bronchiectasis
- Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
- Stable sputum samples with more severe bronchiectasis severity index (BSI) score [BSI ≥ 9]
- Group 0 sample size Number of subjects in the control (unexposed) group
- 281
- Group 1 sample size Number of subjects in the case (exposed) group
- 281
- Antibiotics exclusion Number of days without antibiotics usage (if applicable) and other antibiotics-related criteria used to exclude participants (if any)
- None
Lab analysis
- Sequencing type
- 16S
- 16S variable region One or more hypervariable region(s) of the bacterial 16S gene
- V3-V4
- Sequencing platform Manufacturer and experimental platform used for quantifying microbial abundance
- Illumina
Statistical Analysis
- Data transformation Data transformation applied to microbial abundance measurements prior to differential abundance testing (if any).
- relative abundances
- Statistical test
- PERMANOVA
- Random Forest Analysis
- Significance threshold p-value or FDR threshold used for differential abundance testing (if any)
- 0.05
- MHT correction Have statistical tests be corrected for multiple hypothesis testing (MHT)?
- No
- Confounders controlled for Confounding factors that have been accounted for by stratification or model adjustment
- age, smoking status, Confounders controlled for: "macrolide use" is not in the list (abnormal glucose tolerance, acetaldehyde, acute graft vs. host disease, acute lymphoblastic leukemia, acute myeloid leukemia, adenoma, age, AIDS, alcohol consumption measurement, alcohol drinking, ...) of allowed values.macrolide use, Confounders controlled for: "inhaled antibiotic use" is not in the list (abnormal glucose tolerance, acetaldehyde, acute graft vs. host disease, acute lymphoblastic leukemia, acute myeloid leukemia, adenoma, age, AIDS, alcohol consumption measurement, alcohol drinking, ...) of allowed values.inhaled antibiotic use, Confounders controlled for: "previous exacerbations" is not in the list (abnormal glucose tolerance, acetaldehyde, acute graft vs. host disease, acute lymphoblastic leukemia, acute myeloid leukemia, adenoma, age, AIDS, alcohol consumption measurement, alcohol drinking, ...) of allowed values.previous exacerbations, Confounders controlled for: "FEV1" is not in the list (abnormal glucose tolerance, acetaldehyde, acute graft vs. host disease, acute lymphoblastic leukemia, acute myeloid leukemia, adenoma, age, AIDS, alcohol consumption measurement, alcohol drinking, ...) of allowed values.FEV1
Alpha Diversity
- Shannon Estimator of species richness and species evenness: more weight on species richness
- decreased
Signature 1
Needs review
Source: Figure 2C
Description: Random forest plot indicating the bacterial taxa associated with a more severe BSI score and a less severe BSI score
Abundance in Group 1: increased abundance in Severe bronchiectasis
| NCBI | Quality Control | Links |
|---|---|---|
| Enterobacteriaceae | ||
| Pseudomonas | ||
| Stenotrophomonas |
Revision editor(s): Scholastica
Signature 2
Needs review
Source: Figure 2C
Description: Random forest plot indicating the bacterial taxa associated with a more severe BSI score and a less severe BSI score
Abundance in Group 1: decreased abundance in Severe bronchiectasis
Revision editor(s): Scholastica
Experiment 2
Needs review
Differences from previous experiment shown
Subjects
- Group 0 name Corresponds to the control (unexposed) group for case-control studies
- Non-frequent exacerbating stable patients
- Group 1 name Corresponds to the case (exposed) group for case-control studies
- Frequent exacerbating stable patients
- Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
- Frequent exacerbating stable patients (≥ 3 exacerbation)
Lab analysis
Statistical Analysis
Alpha Diversity
- Shannon Estimator of species richness and species evenness: more weight on species richness
- decreased
Signature 1
Needs review
Source: Figure 3C
Description: Random forest plot showing the bacterial taxa associated with three or more exacerbations in the previous year and those associated with fewer exacerbations
Abundance in Group 1: increased abundance in Frequent exacerbating stable patients
| NCBI | Quality Control | Links |
|---|---|---|
| Enterobacteriaceae | ||
| Pseudomonas |
Revision editor(s): Scholastica
Signature 2
Needs review
Source: Figure 3C
Description: Random forest plot showing the bacterial taxa associated with three or more exacerbations in the previous year and those associated with fewer exacerbations
Abundance in Group 1: decreased abundance in Frequent exacerbating stable patients
Revision editor(s): Scholastica
Experiment 3
Needs review
Differences from previous experiment shown
Subjects
- Group 0 name Corresponds to the control (unexposed) group for case-control studies
- Stable samples
- Group 1 name Corresponds to the case (exposed) group for case-control studies
- Exacerbation samples
- Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
- Sputum samples at onset of exacerbation
- Group 0 sample size Number of subjects in the control (unexposed) group
- 64
- Group 1 sample size Number of subjects in the case (exposed) group
- 64
Lab analysis
Statistical Analysis
Alpha Diversity
- Shannon Estimator of species richness and species evenness: more weight on species richness
- decreased
Signature 1
Needs review
Source: Figure 4C
Description: Random forest plot showing the bacterial taxa associated with exacerbation samples, and those associated with stable samples from 64 pairs of one stable and one exacerbation sample per patient.
Abundance in Group 1: increased abundance in Exacerbation samples
| NCBI | Quality Control | Links |
|---|---|---|
| Eikenella | ||
| Granulicatella |
Revision editor(s): Scholastica
Signature 2
Needs review
Source: Figure 4C
Description: Random forest plot showing the bacterial taxa associated with exacerbation samples, and those associated with stable samples from 64 pairs of one stable and one exacerbation sample per patient.
Abundance in Group 1: decreased abundance in Exacerbation samples
| NCBI | Quality Control | Links |
|---|---|---|
| Agrobacterium | ||
| Campylobacter | ||
| Chryseobacterium | ||
| Fusobacterium | ||
| Gemellaceae | ||
| Haemophilus | ||
| Leptotrichia | ||
| Megasphaera | ||
| Neisseria | ||
| Prevotella | ||
| Pseudomonas | ||
| Streptococcus | ||
| Veillonella | ||
| Rothia |
Revision editor(s): Scholastica
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