Sputum bacterial load and bacterial composition correlate with lung function and are altered by long-term azithromycin treatment in children with HIV-associated chronic lung disease
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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.
URI
Authors
Abotsi RE, Dube FS, Rehman AM, Claassen-Weitz S, Xia Y, Simms V, Mwaikono KS, Gardner-Lubbe S, McHugh G, Ngwira LG, Kwambana-Adams B, Heyderman RS, Odland JØ, Ferrand RA, Nicol MP
Journal
Microbiome
Year
2023
Keywords:
Adolescents, Africa, Bacteriome, FEV1z, HIV, Haemophilus, Microbiome, Moraxella, Obliterative bronchiolitis
BACKGROUND: Long-term azithromycin (AZM) treatment reduces the frequency of acute respiratory exacerbation in children and adolescents with HIV-associated chronic lung disease (HCLD). However, the impact of this treatment on the respiratory bacteriome is unknown. METHOD: African children with HCLD (defined as forced expiratory volume in 1 s z-score (FEV1z) less than - 1.0 with no reversibility) were enrolled in a placebo-controlled trial of once-weekly AZM given for 48-weeks (BREATHE trial). Sputum samples were collected at baseline, 48 weeks (end of treatment) and 72 weeks (6 months post-intervention in participants who reached this timepoint before trial conclusion). Sputum bacterial load and bacteriome profiles were determined using 16S rRNA gene qPCR and V4 region amplicon sequencing, respectively. The primary outcomes were within-participant and within-arm (AZM vs placebo) changes in the sputum bacteriome measured across baseline, 48 weeks and 72 weeks. Associations between clinical or socio-demographic factors and bacteriome profiles were also assessed using linear regression. RESULTS: In total, 347 participants (median age: 15.3 years, interquartile range [12.7-17.7]) were enrolled and randomised to AZM (173) or placebo (174). After 48 weeks, participants in the AZM arm had reduced sputum bacterial load vs placebo arm (16S rRNA copies/µl in log10, mean difference and 95% confidence interval [CI] of AZM vs placebo - 0.54 [- 0.71; - 0.36]). Shannon alpha diversity remained stable in the AZM arm but declined in the placebo arm between baseline and 48 weeks (3.03 vs. 2.80, p = 0.04, Wilcoxon paired test). Bacterial community structure changed in the AZM arm at 48 weeks compared with baseline (PERMANOVA test p = 0.003) but resolved at 72 weeks. The relative abundances of genera previously associated with HCLD decreased in the AZM arm at 48 weeks compared with baseline, including Haemophilus (17.9% vs. 25.8%, p < 0.05, ANCOM ω = 32) and Moraxella (1% vs. 1.9%, p < 0.05, ANCOM ω = 47). This reduction was sustained at 72 weeks relative to baseline. Lung function (FEV1z) was negatively associated with bacterial load (coefficient, [CI]: - 0.09 [- 0.16; - 0.02]) and positively associated with Shannon diversity (0.19 [0.12; 0.27]). The relative abundance of Neisseria (coefficient, [standard error]: (2.85, [0.7], q = 0.01), and Haemophilus (- 6.1, [1.2], q < 0.001) were positively and negatively associated with FEV1z, respectively. An increase in the relative abundance of Streptococcus from baseline to 48 weeks was associated with improvement in FEV1z (3.2 [1.11], q = 0.01) whilst an increase in Moraxella was associated with decline in FEV1z (-2.74 [0.74], q = 0.002). CONCLUSIONS: AZM treatment preserved sputum bacterial diversity and reduced the relative abundances of the HCLD-associated genera Haemophilus and Moraxella. These bacteriological effects were associated with improvement in lung function and may account for reduced respiratory exacerbations associated with AZM treatment of children with HCLD. Video Abstract.
Experiment 1
Reviewed Marked as Reviewed by Peace Sandy on 2024-2-24
Subjects
- 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
- Azithromycin (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-11-,10q24.1-q25.1,aritromicina,Azenil,Azifast,Azigram,Azimakrol,azithromycine,azithromycinum,Azitromin,AZM,Hemomycin,InChIKey=MQTOSJVFKKJCRP-BICOPXKEBK,Zithromax,Zmax,Azithromycin,azithromycin
- Group 0 name Corresponds to the control (unexposed) group for case-control studies
- Placebo at 48 Weeks
- Group 1 name Corresponds to the case (exposed) group for case-control studies
- Azithromycin(AZM) at 48 weeks
- Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
- Participants with HIV-associated Chronic Lung Disease (HCLD) who received azithromycin (AZM)
- Group 0 sample size Number of subjects in the control (unexposed) group
- 150
- Group 1 sample size Number of subjects in the case (exposed) group
- 154
- Antibiotics exclusion Number of days without antibiotics usage (if applicable) and other antibiotics-related criteria used to exclude participants (if any)
- NIL
Lab analysis
- Sequencing type
- 16S
- 16S variable region One or more hypervariable region(s) of the bacterial 16S gene
- 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).
- centered log-ratio
- Statistical test
- ANCOM
- 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)?
- Yes
- Confounders controlled for Confounding factors that have been accounted for by stratification or model adjustment
- age, sex
Alpha Diversity
- Shannon Estimator of species richness and species evenness: more weight on species richness
- unchanged
Signature 1
Reviewed Marked as Reviewed by Peace Sandy on 2024-2-24
Curated date: 2023/10/11
Curator: Chinelsy
Revision editor(s): Chinelsy, Peace Sandy, ChiomaBlessing
Source: Figure S 24
Description: Heatmap displaying the q values of the genera detected as differentially abundant between AZM and placebo arms at 48 weeks by 10 statistical methods. For ANCOM2, taxa with w 0.6, 0.7, 0.8 and 0.9 were assigned q value of 0.01, 0.001, 0.0001 and 0.00001 respectively. Five genera were detected as differentially abundant by all methods (Lautropia, Moraxella, Rothia, Treponema and Veilonella).
Abundance in Group 1: increased abundance in Azithromycin(AZM) at 48 weeks
| NCBI | Quality Control | Links |
|---|---|---|
| Lautropia | ||
| Moraxella | ||
| Rothia | ||
| Treponema |
Revision editor(s): Chinelsy, Peace Sandy, ChiomaBlessing
Experiment 2
Reviewed Marked as Reviewed by Peace Sandy on 2024-2-24
Differences from previous experiment shown
Subjects
- Group 0 name Corresponds to the control (unexposed) group for case-control studies
- Placebo at 72 weeks
- Group 1 name Corresponds to the case (exposed) group for case-control studies
- AZM at 72 weeks
- Group 0 sample size Number of subjects in the control (unexposed) group
- 117
- Group 1 sample size Number of subjects in the case (exposed) group
- 123
Lab analysis
Statistical Analysis
- Data transformation Data transformation applied to microbial abundance measurements prior to differential abundance testing (if any).
- relative abundances
Alpha Diversity
- Shannon Estimator of species richness and species evenness: more weight on species richness
- unchanged
Signature 1
Reviewed Marked as Reviewed by Peace Sandy on 2024-2-24
Source: Fig.5
Description: Table S 6. Results of differential abundance testing of bacterial taxa from AZM and Placebo samples from 72 weeks using DESeq2.
Table S 7. Results of differential abundance testing of bacterial taxa from AZM and Placebo samples from 72 weeks using Ancom-II
Abundance in Group 1: increased abundance in AZM at 72 weeks
| NCBI | Quality Control | Links |
|---|---|---|
| Treponema | ||
| Lautropia |
Revision editor(s): Chinelsy, Peace Sandy, Davvve
Experiment 3
Reviewed Marked as Reviewed by Peace Sandy on 2024-2-24
Differences from previous experiment shown
Subjects
- Group 0 name Corresponds to the control (unexposed) group for case-control studies
- AZM at baseline - Azithromycin arm only
- Group 1 name Corresponds to the case (exposed) group for case-control studies
- AZM at 48 weeks - Azithromycin arm only
- Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
- Participants with HIV-associated Chronic Lung Disease (HCLD) who received azithromycin (AZM) at 48weeks
- Group 0 sample size Number of subjects in the control (unexposed) group
- 173
- Group 1 sample size Number of subjects in the case (exposed) group
- 154
Lab analysis
Statistical Analysis
- Data transformation Data transformation applied to microbial abundance measurements prior to differential abundance testing (if any).
- centered log-ratio
- Statistical test
- ANCOM
Alpha Diversity
- Shannon Estimator of species richness and species evenness: more weight on species richness
- unchanged
Signature 1
Reviewed Marked as Reviewed by Peace Sandy on 2024-2-24
Source: Table S 8.
Description: Results of differential abundance testing of bacterial taxa from samples from the AZM arm at baseline and 48 72 weeks using 10 methods.
Abundance in Group 1: increased abundance in AZM at 48 weeks - Azithromycin arm only
| NCBI | Quality Control | Links |
|---|---|---|
| Lautropia | ||
| Moraxella | ||
| Treponema | ||
| Oribacterium |
Revision editor(s): Chinelsy, Peace Sandy
Experiment 4
Reviewed Marked as Reviewed by Peace Sandy on 2024-2-24
Differences from previous experiment shown
Subjects
- Group 0 name Corresponds to the control (unexposed) group for case-control studies
- Placebo at 48 Weeks - Arm Only
- Group 1 name Corresponds to the case (exposed) group for case-control studies
- Placebo at 72 Weeks - Arm Only
- Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
- Placebo treatment at 72 Weeks (arm only)
- Group 0 sample size Number of subjects in the control (unexposed) group
- 174
- Group 1 sample size Number of subjects in the case (exposed) group
- 174
Lab analysis
Statistical Analysis
- Data transformation Data transformation applied to microbial abundance measurements prior to differential abundance testing (if any).
- raw counts
- Statistical test
- DESeq2
Alpha Diversity
- Shannon Estimator of species richness and species evenness: more weight on species richness
- unchanged
Signature 1
Reviewed Marked as Reviewed by Peace Sandy on 2024-2-24
Source: Table S 10.
Description: Results of differential abundance testing of bacterial taxa from Placebo samples from 48 and 72 weeks using DESeq2.
Abundance in Group 1: increased abundance in Placebo at 72 Weeks - Arm Only
| NCBI | Quality Control | Links |
|---|---|---|
| Moraxella |
Revision editor(s): Peace Sandy
Experiment 5
Reviewed Marked as Reviewed by Peace Sandy on 2024-2-24
Differences from previous experiment shown
Subjects
- Group 0 name Corresponds to the control (unexposed) group for case-control studies
- Placebo at baseline
- Group 1 name Corresponds to the case (exposed) group for case-control studies
- Placebo at 72 weeks
- Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
- Placebo at 72 weeks
- Group 1 sample size Number of subjects in the case (exposed) group
- 117
Lab analysis
Statistical Analysis
Alpha Diversity
- Shannon Estimator of species richness and species evenness: more weight on species richness
- unchanged
Signature 1
Reviewed Marked as Reviewed by Peace Sandy on 2024-2-24
Source: Table S 11
Description: Results of differential abundance testing of bacterial taxa from Placebo samples from baseline and 72 weeks using DESeq2.
Abundance in Group 1: increased abundance in Placebo at 72 weeks
| NCBI | Quality Control | Links |
|---|---|---|
| Moraxella |
Revision editor(s): Peace Sandy
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