Research Priorities in Bronchiectasis

Chestclinic

RESEARCH UPDATE

Research priorities in bronchiectasisAnthony De Soyza,1 Jeremy Stuart Brown,2 Michael R Loebinger,3 on behalf of theBronchiectasis Research & Academic Network

1Institute of Cellular Medicine,Newcastle University &Freeman Hospital AdultBronchiectasis Service,Newcastle upon Tyne, Tyneand Wear, UK2Centre for Inammation andTissue Repair, Rayne Institute,University College London,London, UK3Host Defence Unit, Division ofRespiratory Medicine, RoyalBrompton Hospital HostDefence Unit & ImperialCollege London, London, UK

Correspondence toDr Anthony De Soyza, LungBiology and Transplantationgroup, University of Newcastle,William Leech Centre, FreemanHospital, Heaton, Ty NE7 7DN,UK;[email protected]

Received 18 October 2012Accepted 23 November 2012Published Online First15 December 2012

To cite: De Soyza A,Brown JS, Loebinger MR,et al. Thorax 2013;68:695696.

ABSTRACTTaking a network approach, we have identied researchpriorities in non-cystic brosis bronchiectasis. We discussthese in the context of increasing recognition ofbronchiectasis and increasing mortality rates.

Bronchiectasis is dened by damaged dilatedbronchi that presents clinically as chronic sputumproduction with recurrent respiratory infections.Conditions as diverse as cystic brosis (CF), previ-ous lung infections, rheumatoid arthritis, inamma-tory bowel disease, immune deciencies andgastro-oesophageal reux are associated with bron-chiectasis, and impact on the management andoutcome.1 With the exception of cystic brosis,there is a striking paucity of research into bronchi-ectasis. As a consequence, there are large gaps inour knowledge of the pathogenesis of the disease,and the evidence base for effective management ispoor. Ground-breaking research into bronchiectasiswas supported by the UK Medical ResearchCouncil in the 1950s, but the development of anti-biotics has perhaps led to the perception that sig-nicant bronchiectasis is rare, and when identied,is easily managed and not clinically particularlyimportant. Both perceptions are wrong. In theUSA, the current prevalence of adult bronchiectasiswas estimated at 52/100 000,2 suggesting there areat least 30 000 bronchiectasis patients in the UK.However, accurate data are lacking, and in just nineUK centres, 5000 patients with bronchiectasis areunder regular follow-up suggesting the true preva-lence is even higher. Furthermore, bronchiectasis isnot a benign process, but has a signicant morbid-ity and mortality.3 4 In the national British ThoracicSociety (BTS), 2011 audit patients with bronchiec-tasis had an annual exacerbation rate of 2.6, andlocal data from UK centres suggest hospital admis-sions for treatment of bronchiectasis and bed occu-pancy are both rising. Bronchiectasis has widerrelevance for respiratory medicine as it is associatedwith asthma, interstitial lung disease and chronicobstructive pulmonary disease (COPD). In thelatter, it correlates with more persistent infections,prolonged hospital admissions and increasedhealthcare costs.2 Unfortunately, the treatment ofbronchiectasis remains largely empirical, or extra-polated from other respiratory conditions, such asCF and COPD,1 although very recent controlledtrials conrming the efcacy of prophylactic macro-lide regimens in bronchiectasis have demonstratedthat clinical research into bronchiectasis is pos-sible.5 There is a clear and urgent need for add-itional research into bronchiectasis to help reduce

the growing clinical burden of this neglecteddisease.While there are many studies that need to be

undertaken, the research priorities can be simplycategorised into the following three areas:1. Epidemiology. Accurate data on the age and

sex-related incidence, prevalence andcomorbidities is essential in order to identifythe size of the clinical burden, and which sub-jects are most at risk of bronchiectasis and,potentially, could indicate previously unsus-pected aetiological factors. Prospective health-care utilisation data and the mortality fromthe disease (or from associated comorbidities)are needed to fully dene the severity of theclinical problem. This may also identify whereimproved management could impact the moston health, or identify which patient subgroupsneed closest follow-up and will assist effectivecommissioning of healthcare for patients withbronchiectasis.

2. Pathogenesis. The cause of bronchiectasis isonly dened in 50% of patients, and the vari-ability in severity and clinical progression inaddition to the opportunity to treat the under-lying cause, make research into this area a prior-ity. Translational studies of mucociliaryfunction, systemic and mucosal immunity arerequired to identify potential causes or exacer-bators of bronchiectasis. We need to take advan-tage of modern immunological techniques andnew ndings that have improved our under-standing of host/pathogen interactions.Adequately powered genetic studies are neces-sary to assess the susceptibility of the host tobronchiectasis, its progression and to infectionwith particular pathogens. Further microbialresearch is needed to elucidate drivers ofexacerbations and the progression of bronchiec-tasis, for instance, specic pathogen research,such as Pseudomonas virulence determinantsnecessary for chronic infection in bronchiec-tasis, and the investigation and the compositionand perturbation of airway polymicrobial com-munities with molecular techniques. Similarly,the role of viruses and fungi needs to beassessed in driving exacerbations or chronicdisease progression, with the former having anestablished role in COPD exacerbations, butwith no conclusive data available inbronchiectasis.

3. Management. The recent BTS bronchiectasisguidelines are dominated by low-grade evidenceand limited controlled trial data, mandatingfurther clinical trials for both established and

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newer therapies. Widely used therapies, such as inhaled cor-ticosteroids, have a poor evidence base in bronchiectasis, yetmay carry a risk of pneumonia. Airway clearance techniques,a cornerstone of therapy, are supported by some trial data,yet the optimum method remains unclear. The appropriateduration of antibiotics for exacerbations is unknown, andcould potentially be individualised if biomarkers thatmonitor treatment response can be identied. We need moretrials to dene the patient groups most likely to benet fromthe different antibiotic prophylaxis regimens, duration oftreatment, and to assess their effects on bacterial resistanceor microbiome content. There is also a pressing need toinvestigate whether early identication of acquisition ofPseudomonas (perhaps using molecular techniques), fol-lowed by an optimal eradication regimen results in reducedmorbidity, or slows disease progression. Epidemic strains ofPseudomonas have led to signicant morbidity in CF, yet welack data on whether cross-infection is similarly a problemfor bronchiectasis.Fortunately, several recent developments will help improve

research into bronchiectasis. First, technological advances, suchas microarrays, rapid and relatively cheap whole-genomesequencing are now available and will help answer some of theimportant aetiological and pathogenesis questions. Directsequencing of microbial nucleic acid from sputum provides verydetailed data on the microbial content of the airways, and willallow monitoring of longitudinal bacterial airways ecology andin response to therapeutic interventions. Second the pharma-ceutical industry has started signicant development pro-grammes into combating airway infection with novel inhaledantibiotic preparations. Additional development streams includenovel inhaled mucolytics and therapies targeting neutrophilicinammation (the probable main driver for airway damage).Recent experiences with clinical trials have shown that patientswith bronchiectasis are highly engaged in clinical research, sug-gesting that rapid advances are likely. Third, the recent BTSguidelines and successive UK national audits in bronchiectasiscare in 2010 and 2011 have helped support and dene anincreasing interest in bronchiectasis from physicians andresearchers alike, while highlighting the lack of high-qualityresearch data, and the consequent signicant variations in clin-ical practice. A major impediment to effective research has beenthe heterogeneity of bronchiectasis due to signicant variabilityin aetiology and clinical courses. Only through collaborativeresearch between several centres can enough patients represent-ing particular subgroups of bronchiectasis be recruited forauthoritative clinical trials and translational studies. To that end,nine centres within the UK have formed the BronchiectasisResearch & Academic Network aiming to construct a compre-hensive database of well-characterised bronchiectasis patients tosupport translational research into the areas described above.The registry will also facilitate clinical trials in bronchiectasisand help make the UK a key destination for trials of new therap-ies. In the USA, a similar national bronchiectasis registry hasalready been established by the US COPD Foundation, and hasrecruited over 1200 patients across multiple centres. More

registries across the globe encompassing genetic, environmentaland microbiological variability will be needed to make signi-cant improvements in our understanding and effective manage-ment of patients with bronchiectasis.As the research and evidence base improves for bronchiec-

tasis, a key challenge is ensuring that these patients are gettingthe best possible care, and that new research ndings are trans-lated into patient management. Although many patients remainstable and might be adequately managed in primary care andgeneral respiratory services, a network of specialised centres forpatients with complex bronchiectasis would both stimulateresearch and improve patient care. This model works well forcomplex asthma. The need for specialised bronchiectasis carehas already been recognised for some subgroups, with specialistcommissioning of the care for patients with primary ciliary dys-kinesia in the UK. Other patients with bronchiectasis who mightbenet from management in centres with specialist expertiseinclude those with rapidly progressive disease, or who areinfected with opportunistic, but recalcitrant pathogens, such asresistant Gram-negative bacteria, Aspergillus species and non-tuberculous mycobacteria. The recognition by commissioners ofhealthcare of the need for specialised care for some patientswith bronchiectasis will ensure that any innovations identiedby new research are translated into clinical practice.

Acknowledgements We acknowledge the support and comments from the UKBronchiectasis Research & Academic Network (BRAN) in writing this article; (1) DBilton, R Wilson, Royal Brompton Hospital, (2) A Hill Edinburgh Royal Inrmary, (3)A Sullivan Birmingham, (4) T Wilkinson Southampton University, (5) JS Elborn, JBradley Belfast City Hospital, (6) J Hurst University College London, (7) J DuckersLlandough Hospital, Wales, (8) A Floto, C Howarth and J Foweraker, PapworthHospital, Cambridge, (9) T Small, K Hester, Freeman Hospital Newcastle upon Tyne.

Contributors The authors (ADS, JB and ML) drafted and revised the opinion piece.The collaborators reviewed and advised on the contents.

Funding ADS acknowledges a HEFCE Clinical Academic Senior Lecturership andNewcastle NIHR Biomedical Research Centre in Ageing grant support. ML wassupported by the NIHR Respiratory Disease Biomedical Research Unit at the RoyalBrompton and Hareeld NHS Foundation Trust and Imperial College London. UCLH/UCL receive funding from the Department of Healths NIHR Biomedical ResearchCentres funding scheme and work in Professor Brown's laboratory is supported bythe Medical Research Council, Rosetrees Trust, and the Wellcome Trust.

Disclaimer The views expressed in this publication are those of the authors andnot necessarily those of the NHS, The National Institute for Health Research or theDepartment of Health.

Competing interests None.

Provenance and peer review Not commissioned; internally peer reviewed.

REFERENCES1 Pasteur MC, Bilton D, Hill AT. British thoracic society non-CF bronchiectasis guideline

group. British thoracic society guideline for non-CF bronchiectasis. Thorax2010;65:577.

2 Weycker D, Edelsberg JE, Oster G, et al. Prevalence and economic burden ofbronchiectasis. Clin Pulm Med 2005;12:2059.

3 Seitz AE, Olivier KN, Adjemian J, et al. Trends in bronchiectasis among medicarebeneciaries in the United States, 20002007. Chest 2012;142:4329.

4 Wong C, Jayaram L, Karalus N, et al. Azithromycin for prevention of exacerbations innon-cystic brosis bronchiectasis (EMBRACE): a randomised, double-blind,placebo-controlled trial. Lancet 2012;380:6607.

5 Loebinger MR, Wells AU, Hansell DM, et al. Mortality in bronchiectasis: a long-termstudy assessing the factors inuencing survival. Eur Respir J 2009;34:8439.

696 De Soyza A, et al. Thorax 2013;68:695696. doi:10.1136/thoraxjnl-2012-202893

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Research priorities in bronchiectasis

behalf of the Bronchiectasis Research & Academic NetworkAnthony De Soyza, Jeremy Stuart Brown, Michael R Loebinger and on

doi: 10.1136/thoraxjnl-2012-2028932013 68: 695-696 originally published online December 15, 2012Thorax

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Research Priorities in Bronchiectasis