Azithromycin versus placebo for the treatment of HIV-associated chronic lung disease in children and adolescents (BREATHE trial): study protocol for a randomised controlled trial

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Abstract

Background

Human immunodeficiency virus (HIV)-related chronic lung disease (CLD) among children is associated with substantial morbidity, despite antiretroviral therapy. This may be a consequence of repeated respiratory tract infections and/or dysregulated immune activation that accompanies HIV infection. Macrolides have anti-inflammatory and antimicrobial properties, and we hypothesised that azithromycin would reduce decline in lung function and morbidity through preventing respiratory tract infections and controlling systemic inflammation.

Methods/design

We are conducting a multicentre (Malawi and Zimbabwe), double-blind, randomised controlled trial of a 12-month course of weekly azithromycin versus placebo. The primary outcome is the mean change in forced expiratory volume in 1 second (FEV ₁) z-score at 12 months. Participants are followed up to 18 months to explore the durability of effect. Secondary outcomes are FEV ₁ z-score at 18 months, time to death, time to first acute respiratory exacerbation, number of exacerbations, number of hospitalisations, weight for age z-score at 12 and 18 months, number of adverse events, number of malaria episodes, number of bloodstream Salmonella typhi infections and number of gastroenteritis episodes. Participants will be followed up 3-monthly, and lung function will be assessed every 6 months. Laboratory substudies will be done to investigate the impact of azithromycin on systemic inflammation and on development of antimicrobial resistance as well as impact on the nasopharyngeal, lung and gut microbiome.

Discussion

The results of this trial will be of clinical relevance because there are no established guidelines on the treatment and management of HIV-associated CLD in children in sub-Saharan Africa, where 80% of the world’s HIV-infected children live and where HIV-associated CLD is highly prevalent.

Trial registration

ClinicalTrials.gov, NCT02426112. Registered on 21 April 2015.

Electronic supplementary material

The online version of this article (doi:10.1186/s13063-017-2344-2) contains supplementary material, which is available to authorized users.

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Most cited references 3

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Azithromycin reduces airway neutrophilia and interleukin-8 in patients with bronchiolitis obliterans syndrome.

J Dupont, Henriëtte E. van der Horst, Geert Verleden … (2006)

Bronchiolitis obliterans syndrome (BOS) remains the leading cause of death after lung transplantation. Treatment is difficult, although azithromycin has recently been shown to improve FEV(1). The exact mechanism of action is unclear. (1) Azithromycin reduces airway neutrophilia and interleukin (IL)-8 and (2) airway neutrophilia predicts the improvement in FEV(1). Fourteen lung transplant patients with BOS (between BOS 0-p and BOS 3) were treated with azithromycin, in addition to their current immunosuppressive treatment. Before and 3 mo after azithromycin was introduced, bronchoscopy with bronchoalveolar lavage (BAL) was performed for cell differentiation and to measure IL-8 and IL-17 mRNA ratios. The FEV(1) increased from 2.36 (+/- 0.82 L) to 2.67 L (+/- 0.85 L; p = 0.007), whereas the percentage of BAL neutrophilia decreased from 35.1 (+/- 35.7%) to 5.7% (+/- 6.5%; p = 0.0024). There were six responders to azithromycin (with an FEV(1) increase of > 10%) and eight nonresponders. Using categorical univariate linear regression analysis, the main significant differences in characteristics between responders and nonresponders were the initial BAL neutrophilia (p < 0.0001), IL-8 mRNA ratio (p = 0.0009), and the postoperative day at which azithromycin was started (p = 0.036). There was a significant correlation between the initial percentage of BAL neutrophilia and the changes in FEV(1) after 3 mo (r = 0.79, p = 0.0019). Azithromycin significantly reduces airway neutrophilia and IL-8 mRNA in patients with BOS. Responders have a significantly higher BAL neutrophilia and IL-8 compared with nonresponders and had commenced treatment earlier after transplantation. BAL neutrophilia can be used as a predictor for the FEV(1) response to azithromycin.

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Chronic lung disease in HIV-infected children established on antiretroviral therapy

Jamie Rylance, Grace Mchugh, John Metcalfe … (2016)

Objective: Respiratory disease is a major cause of morbidity and mortality in HIV-infected children. Despite antiretroviral therapy (ART), children suffer chronic symptoms. We investigated symptom prevalence, lung function and exercise capacity among older children established on ART and an age-matched HIV-uninfected group. Design: A cross-sectional study in Zimbabwe of HIV-infected children aged 6–16 years receiving ART for over 6 months and HIV-uninfected children attending primary health clinics from the same area. Methods: Standardized questionnaire, spirometry, incremental shuttle walk testing, CD4+ cell count, HIV viral load and sputum culture for tuberculosis were performed. Results: A total of 202 HIV-infected and 150 uninfected participants (median age 11.1 years in each group) were recruited. Median age at HIV diagnosis and ART initiation was 5.5 (interquartile range 2.8–7.5) and 6.1 (interquartile range 3.6–8.4) years, respectively. Median CD4+ cell count was 726 cells/μl, and 79% had HIV viral load less than 400 copies/ml. Chronic respiratory symptoms were rare in HIV-uninfected children [n = 1 (0.7%)], but common in HIV-infected participants [51 (25%)], especially cough [30 (15%)] and dyspnoea [30 (15%)]. HIV-infected participants were more commonly previously treated for tuberculosis [76 (38%) vs 1 (0.7%), P < 0.001], had lower exercise capacity (mean incremental shuttle walk testing distance 771 vs 889 m, respectively, P < 0.001) and more frequently abnormal spirometry [43 (24.3%) vs 15 (11.5%), P = 0.003] compared with HIV-uninfected participants. HIV diagnosis at an older age was associated with lung function abnormality (P = 0.025). No participant tested positive for Mycobacterium tuberculosis. Conclusion: In children, despite ART, HIV is associated with significant respiratory symptoms and functional impairment. Understanding pathogenesis is key, as new treatment strategies are urgently required.

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High-dose corticosteroid therapy for bronchiolitis obliterans after bone marrow transplantation in children.

F Ratjen, O Rjabko, B Kremens (2005)

Bronchiolitis obliterans (BO) is a rare but serious complication of paediatric allogenic bone marrow transplantation (BMT). Currently, there is no clear evidence that therapeutic interventions have a positive impact on the course of the disease. We here report our experience with high-dose pulse methylprednisolone therapy in children after BMT. Nine patients fulfilling clinical and radiologic signs of BO were included in this analysis. The total amount of treatment cycles with pulse methylprednisolone therapy ranged from 1 to 6 cycles (median four cycles). Oxygen saturation increased significantly with normalization of oxygen saturation at the end of therapy in all individuals. Normal oxygen saturation was maintained in all but one patient during follow-up (mean follow-up period 42 {plus/minus} 20 months, range 19-67 months). Forced expiratory volume in 1 s (FEV1) was within the normal range prior BMT and significantly diminished at the time of BO diagnosis. Treatment led to stabilization of lung function, with a significant improvement of FEV1 after 2 months. In all, 7/9 patients remained in clinically stable condition without further deterioration of lung function during follow-up. These data would suggest that anti-inflammatory therapy may be a valuable treatment option in paediatric patients with bronchiolitis obliterans after BMT.

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Author and article information

Contributors

Carmen Gonzalez-Martinez: +265 (0)1 876444 , carmen.gonzalez@lstmed.ac.uk

Katharina Kranzer: katharina.kranzer@lshtm.ac.uk

Grace McHugh: graceandandre@gmail.com

Elizabeth L. Corbett: liz.corbett@lshtm.ac.uk

Hilda Mujuru: drhamujuru@gmail.com

Mark P. Nicol: mark.nicol@uct.ac.za

Sarah Rowland-Jones: sarah.rowland-jones@ndm.ox.ac.uk

Andrea M. Rehman: andrea.rehman@lshtm.ac.uk

Tore J. Gutteberg: tore.gutteberg@unn.no

Trond Flaegstad: trond.flaegstad@unn.no

Jon O. Odland: jon.oyvind.odland@uit.no

Rashida A. Ferrand: rashida.ferrand@lshtm.ac.uk

Journal

Journal ID (nlm-ta): Trials

Journal ID (iso-abbrev): Trials

Title: Trials

Publisher: BioMed Central (London )

ISSN (Electronic): 1745-6215

Publication date (Electronic): 28 December 2017

Publication date PMC-release: 28 December 2017

Publication date Collection: 2017

Volume: 18

Electronic Location Identifier: 622

Affiliations

[1 ]ISNI 0000 0004 1936 9764, GRID grid.48004.38, Liverpool School of Tropical Medicine, ; Pembroke Place, Liverpool, L3 5QA UK

[2 ]GRID grid.419393.5, Malawi-Liverpool Wellcome Trust Clinical Research Programme, ; PO Box 30096, Chichiri, Blantyre 3, Malawi

[3 ]ISNI 0000 0001 2113 2211, GRID grid.10595.38, Department of Paediatrics and Child Health, , College of Medicine, University of Malawi, ; Private Bag 360, Chichiri, Blantyre 3, Malawi

[4 ]ISNI 0000 0004 0425 469X, GRID grid.8991.9, Department of Clinical Research, , London School of Hygiene and Tropical Medicine, ; Keppel Street, London, WC1E 7HT UK

[5 ]GRID grid.418347.d, Biomedical Research and Training Institute, ; 10 Seagrave Road, Harare, Zimbabwe

[6 ]ISNI 0000 0004 0425 469X, GRID grid.8991.9, Department of Infectious Disease Epidemiology, , London School of Hygiene and Tropical Medicine, ; Keppel Street, London, WC1E 7HT UK

[7 ]ISNI 0000 0004 0572 0760, GRID grid.13001.33, Department of Paediatrics, , University of Zimbabwe, ; PO Box A178, Avondale, Harare, Zimbabwe

[8 ]ISNI 0000 0004 1937 1151, GRID grid.7836.a, Division of Clinical Microbiology, , University of Cape Town, ; Anzio Road, Cape Town, South Africa

[9 ]ISNI 0000 0004 0630 4574, GRID grid.416657.7, National Health Laboratory Service, ; Johannesburg, South Africa

[10 ]ISNI 0000 0004 1936 8948, GRID grid.4991.5, Nuffield Department of Medicine, , Old Road Campus, University of Oxford, ; Roosevelt Drive, Oxford, OX3 7FZ UK

[11 ]ISNI 0000 0004 0425 469X, GRID grid.8991.9, MRC Tropical Epidemiology Group, , London School of Hygiene and Tropical Medicine, ; Keppel Street, London, WC1E 7HT UK

[12 ]ISNI 0000 0004 4689 5540, GRID grid.412244.5, Department of Microbiology and Infection Control, , University Hospital of North Norway, ; N-9038 Tromsø, Norway

[13 ]ISNI 0000000122595234, GRID grid.10919.30, Faculty of Health Sciences, , Arctic University of Norway, ; N-9037 Tromsø, Norway

[14 ]ISNI 0000 0004 4689 5540, GRID grid.412244.5, Department of Paediatrics, , University Hospital of North Norway, ; N-9038 Tromsø, Norway

[15 ]ISNI 0000 0001 2107 2298, GRID grid.49697.35, School of Health Systems and Public Health, Faculty of Health Sciences, University of Pretoria, ; Hatfield, South Africa

Article

Publisher ID: 2344

DOI: 10.1186/s13063-017-2344-2

PMC ID: 5745989

PubMed ID: 29282143

SO-VID: 36fa6b5b-6694-4a44-9ff0-4cec5319d18f

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 17 September 2017

Date accepted : 8 November 2017

Funding

Funded by: Medical Research Council Norway

Award ID: 234424/H10

Custom metadata

ScienceOpen disciplines: Medicine

Keywords: chronic lung disease,azithromycin,hiv,fev1,africa,children,obliterative bronchiolitis

Data availability:

ScienceOpen disciplines: Medicine

Keywords: chronic lung disease, azithromycin, hiv, fev1, africa, children, obliterative bronchiolitis

Azithromycin versus placebo for the treatment of HIV-associated chronic lung disease in children and adolescents (BREATHE trial): study protocol for a randomised controlled trial

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Abstract

Background

Methods/design

Discussion

Trial registration

Electronic supplementary material

Related collections

HIV Self-Testing

Most cited references 3

Azithromycin reduces airway neutrophilia and interleukin-8 in patients with bronchiolitis obliterans syndrome.

Chronic lung disease in HIV-infected children established on antiretroviral therapy

High-dose corticosteroid therapy for bronchiolitis obliterans after bone marrow transplantation in children.

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