The effect of macrolide therapy on sub-clinical infection and inflammation in human lung transplantation.

Lead Research Organisation: Newcastle University
Department Name: Institute of Cellular Medicine

Abstract

For many chronic lung diseases, such as cystic fibrosis in young people, lung transplantation can be the only present treatment for advanced disease. This can extend life expectancy and quality, and allows resumption of day to day activities, but chronic rejection is a major problem.

We will carry out research into how small amounts of infection, which do not cause immediate clinical problems, might cause subsequent chronic rejection. This has previously not been considered significant, and therefore has not been studied. This area of research has been chosen because it is a strength of respiratory medicine in the UK. The Freeman Hospital is one of the worlds largest transplant centres, making the work feasible. The question of why lung transplants develop chronic rejection is of national and international importance.

To do our work we will be using very sensitive molecular methods to quantify low levels of infection, to see if there is evidence to suggest that this may cause inflammation and scarring of the airways. We believe that this causes progressive shortness of breath and chronic transplant rejection.

New antibiotic therapies have been used in chronic rejection and this seems to help some people, but no one knows how this works. We will perform a formal scientific study of this approach to improve the available evidence. We will also perform experiments with lung samples from transplant patients that aim to investigate potential mechanisms, and why some people do well but others do not. To allow these experiments we will grow transplant cells from small samples to give the larger numbers of cells needed. All of our work will be done using human samples because these are the most appropriate for our research.

It is expected that our results will show that even low levels of infection are a problem to lung transplant patients and that antibiotic treatment helps this. This would change how chronic rejection is treated and we think this may help to protect transplanted lungs and extend life expectancy.

Technical Summary

Introduction
Five year mortality following lung transplantation is 50%, with chronic rejection, manifested functionally by bronchiolitis obliterans syndrome (BOS), the major cause of death. Current treatments have little impact on BOS, but we have recently shown that an open trial of the macrolide antibiotic azithromycin led to a clinically significant gain in lung function. The mechanisms for this improvement are not known.

Hypothesis
Sub-clinical airway infection and inflammation are key precursors of BOS. Macrolide antibiotics disrupt infection and are anti-inflammatory, leading to clinical benefit.

Methods
A longitudinal study of infection, airway inflammation and remodeling in lung transplantation, The effect of azithromycin therapy will be tested in a placebo controlled, parallel group design. Ex-vivo mechanistic studies will be made in primary bronchial epithelial cells from the same patients. All the proposed methods and the ability to recruit the required patient cohort are available to our laboratory.

Significance
This study will immediately impact on patient management.

Publications

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Aseeri A (2012) Bile acids are present in the lower airways of people with cystic fibrosis. in American journal of respiratory and critical care medicine

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Borthwick LA (2010) Inflammation and epithelial to mesenchymal transition in lung transplant recipients: role in dysregulated epithelial wound repair. in American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons

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Borthwick LA (2011) Pseudomonas aeruginosa accentuates epithelial-to-mesenchymal transition in the airway. in The European respiratory journal

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Borthwick LA (2013) TNFa from classically activated macrophages accentuates epithelial to mesenchymal transition in obliterative bronchiolitis. in American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons

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Brodlie M (2011) Ceramide and cystic fibrosis lung disease. in American journal of respiratory and critical care medicine

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Brodlie M (2010) Ceramide is increased in the lower airway epithelium of people with advanced cystic fibrosis lung disease. in American journal of respiratory and critical care medicine

 
Description An aerodigestive approach to lung disease
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
Impact Our work has led others to consider non alloimmune injury in the lung including reflux and aspiration
 
Description Education on treatment for lung rejection
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
Impact Treatment options for lung transplant rejection have been limited. The understanding that macrolide therapy may have a role is important in guiding thinking and treatment regarding this important clinical issue. (Results of trial awaited).
 
Description Engagement with Menzies Institute Australia 
Organisation University of Tasmania
Department Menzies Institute for Medical Research
Country Australia 
Sector Hospitals 
PI Contribution Expertise in cellular mechanisms involved in airway remodelling in chronic lung disease.
Collaborator Contribution Publications (ten papers)
Impact Honorary appointment with the Menzies Research Institute, University of Tasmania [Principal Research Fellow] In 2011 the overall research collaboration at the University of Tasmania, of which this is a part, was awarded A$2.5 million over 5 years as a National Health & Medical Research Council Centre of Research Excellence. Output has also been papers: 1.Evaluation of epithelial mesenchymal transition in patients with chronic obstructive pulmonary disease. Sohal SS, Reid D, Soltani A, Ward C, Weston S, Muller HK, Wood-Baker R, Walters EH. Respir Res. 2011 Oct 5;12:130. 2. Infection and remodelling: a 21st century model of bronchiectasis? Ward C, Rydell-Törmänen K, Westergren-Thorsson G, Eriksson LT, Walters H. Eur Respir J. 2011 Oct;38(4):758-60. No abstract available. 3.Assessment of airway inflammation using sputum, BAL, and endobronchial biopsies in current and ex-smokers with established COPD. Wen Y, Reid DW, Zhang D, Ward C, Wood-Baker R, Walters EH. Int J Chron Obstruct Pulmon Dis. 2010 Oct 5;5:327-34. 4.Reticular basement membrane fragmentation and potential epithelial mesenchymal transition is exaggerated in the airways of smokers with chronic obstructive pulmonary disease. Sohal SS, Reid D, Soltani A, Ward C, Weston S, Muller HK, Wood-Baker R, Walters EH. Respirology. 2010 Aug;15(6):930-8. Epub 2010 Jul 12. 5.Bronchodilator reversibility, airway eosinophilia and anti-inflammatory effects of inhaled fluticasone in COPD are not related. Reid DW, Wen Y, Johns DP, Williams TJ, Ward C, Walters EH. Respirology. 2008 Nov;13(6):799-809. 6.Angiogenesis: a potentially critical part of remodelling in chronic airway diseases? Walters EH, Reid D, Soltani A, Ward C. Pharmacol Ther. 2008 Apr;118(1):128-37. Epub 2008 Feb 15. Review. 7.Vascular remodelling in asthma. Walters EH, Soltani A, Reid DW, Ward C. Curr Opin Allergy Clin Immunol. 2008 Feb;8(1):39-43. Review. 8.Innate immune activation in neutrophilic asthma. Walters EH, Wood-Baker R, Reid DE, Ward C. Thorax. 2008 Jan;63(1):88-9. No abstract available. 9.Nonpharmacological and pharmacological interventions to prevent or reduce airway remodelling. Walters EH, Reid DW, Johns DP, Ward C. Eur Respir J. 2007 Sep;30(3):574-88. Review. 10.Airway cell and cytokine changes in early asthma deterioration after inhaled corticosteroid reduction. Khor YH, Feltis BN, Reid DW, Ward C, Johns DP, Wood-Baker R, Walters EH. Clin Exp Allergy. 2007 Aug;37(8):1189-98. 11.Effects of inhaled fluticasone on angiogenesis and vascular endothelial growth factor in asthma. Feltis BN, Wignarajah D, Reid DW, Ward C, Harding R, Walters EH. Thorax. 2007 Apr;62(4):314-9. Epub 2006 Nov 14. 12.Increased vascular endothelial growth factor and receptors: relationship to angiogenesis in asthma. Feltis BN, Wignarajah D, Zheng L, Ward C, Reid D, Harding R, Walters EH. Am J Respir Crit Care Med. 2006 Jun 1;173(11):1201-7. Epub 2006 Mar 9.
 
Title Azithromycin therapy in Bronchiolitis Obliterans Syndrome (BOS) post lung transplantation. 
Description We hypothesised that azithromycin therapy is superior to placebo in patients with BOS. We tested this by conducting a prospective, single-centre, randomised double blind placebo controlled study funded by the MRC. The primary outcome was change in FEV1 from baseline to 12 weeks. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Small-scale adoption
Year Development Stage Completed 2011
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Our understanding is that this is the only randomised placebo controlled trial of azithromycin therapy in patients who have developed BOS. Azithromycin was superior compared to placebo treatment. This therefore represents an important piece of evidence in support of clinical practice worldwide. 
URL http://www.clinicaltrialsregister.eu/ctr-search/trial/2006-000485-36/GB