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

Microbiome

Research

Grace McHugh¹  Rashida A. Ferrand²  Kilaza S. Mwaikono³  Jon Ø. Odland⁴  Felix S. Dube⁵  Regina E. Abotsi⁶  Sugnet Gardner-Lubbe⁷  Shantelle Claassen-Weitz⁸  Mark P. Nicol⁹  Andrea M. Rehman^1,10  Victoria Simms^1,11  Lucky G. Ngwira^1,12  Yao Xia^1,13  Robert S. Heyderman^1,14  Brenda Kwambana-Adams^1,14 

[1] Biomedical Research and Training Institute, Harare, Zimbabwe;Biomedical Research and Training Institute, Harare, Zimbabwe;Clinical Research Department, London School of Hygiene and Tropical Medicine, London, UK;Computational Biology Group and H3ABioNet, Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa;Department of Science and Laboratory Technology, Dar es Salaam Institute of Technology, Dar es Salaam, Tanzania;Department of Community Medicine, University of Tromsø, Tromsø, Norway;International Research Laboratory for Reproductive Ecotoxicology (IL RET), The National Research University Higher School of Economics, Moscow, Russia;School of Health Systems and Public Health, University of Pretoria, Pretoria, South Africa;Department of Molecular and Cell Biology & Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa;Department of Molecular and Cell Biology & Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa;Department of Pharmaceutical Microbiology, School of Pharmacy, University of Health and Allied Sciences, Ho, Ghana;Department of Statistics and Actuarial Science, Stellenbosch University, Stellenbosch, South Africa;Division of Medical Microbiology, Department of Pathology, University of Cape Town, Cape Town, South Africa;Division of Medical Microbiology, Department of Pathology, University of Cape Town, Cape Town, South Africa;Marshall Centre, Division of Infection and Immunity, School of Biomedical Sciences, University of Western Australia, Perth, Australia;International Statistics and Epidemiology Group, London School of Hygiene and Tropical Medicine, London, UK;International Statistics and Epidemiology Group, London School of Hygiene and Tropical Medicine, London, UK;Biomedical Research and Training Institute, Harare, Zimbabwe;Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi;Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, UK;Marshall Centre, Division of Infection and Immunity, School of Biomedical Sciences, University of Western Australia, Perth, Australia;NIHR Global Health Research Unit on Mucosal Pathogens, Research Department of Infection, Division of Infection and Immunity, University College London, London, UK;

关键词: Africa;    Bacteriome;    Microbiome;    HIV;    Haemophilus;    Moraxella;    Obliterative bronchiolitis;    Adolescents;    z;   

DOI  :  10.1186/s40168-023-01460-x

 received in 2022-02-23, accepted in 2023-01-04,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundLong-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.MethodAfrican 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.ResultsIn 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).ConclusionsAZM 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.7vbprNKyGgPWNKm5AZ24DEVideo Abstract

【 授权许可】

CC BY   
© The Author(s) 2023

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