Bronchiectasis in 2016

James D Chalmers MD PhD FRCPE

Senior Lecturer and Honorary Consultant Physician

University of Dundee and Ninewells Hospital and Medical School

Scotland, UK

Presenter disclosures

Clinical TrialsAstraZeneca, Aradigm corporation, Bayer Healthcare, GSK

Research Grant SupportWellcome Trust, Chief Scientist Office, Medical Research Council, AstraZeneca, EU Innovative Medicines Initiative, European Respiratory Society, Tenovus Scotland, Bayer Healthcare, Aradigm Corporation, Griffols, Pfizer inc

ConsultancyBayer Healthcare, Griffols, AstraZeneca, Basilea, Napp, Raptor

An old disease re-emerging

What is bronchiectasis?Radiological appearance- Cyclindrical- Varicose- Cystic- + additional features

Clinical syndrome- Cough- Sputum production- Recurrent infections- Chronic bacterial colonisation

Radiological heterogeneity

Lower lobes- Idiopathic- COPD associated- Post-infectious- Aspiration- PCD

Central- ABPA- Tracheobronchomegaly

Middles lobes- NTM infection

Upper lobes- Cystic fibrosis

UK prevalence data

UK Clinical Practice Research datalink (CPRD) 2004-2013

Headline prevalence566/100,000 in women in 2013485 per 100,000 in men

Men Women

Quint ERJ 2016

Comparing the prevalence of BE to COPD in Europe

7

COPD7.6%

Bronchiectasis0.07%-0.56%

Incidence >65 years0.2%-0.87%

14-108 cases of COPD for each case of bronchiectasis

Prevalence in > 65 years:14.2%

Rate of bronchiectasis prevalence increasing in several European countries

References1. Quint JK, et al Changes in the incidence, prevalence and mortality of bronchiectasis in the UK from 2004-2013: a population based cohort study. Eur

Respir J 2015; Nov 5. pii: ERJ-01033-2015. doi: 10.1183/13993003.01033-2015. [Epub ahead of print]2. Ringshausen FC et al. Bronchiectasis in Germany: a population-based estimation of disease prevalence. Eur Respir J 2015; 46(6):1805-7. 3. Halbert RJ, Natoli JL, Gano A, et al. Global burden of COPD: systematic review and meta-analysis. Eur Respir J 2006; 28: 523–532.

“Bronchiectasis one of the most neglected diseases in respiratory medicine”

ERS White Book 2014

A disease characterised by recurrent respiratory tract infections and chronic bacterial “colonisation”

Neutrophil dominated lung inflammation

No licensed therapies but most treatments are antibiotic based and target airway infection

Bronchiectasis

Neutrophils drive the disease

Chalmers et al, Submitted 2016N=381 stable patients with bronchiectasis, 36 month follow-up

Sputum neutrophil elastase predicts exacerbations and mortality

Chalmers et al, Submitted 2016

Released desmosine and isodesmosine

Bacteria and neutrophilic inflammation are linked

Chalmers et al, AJRCCM 2012;186(7):657-65N=385, single centre UK study

Prognostic impact of airway infection

n=608 patients over 4 years in a

single centre Scottish study

Chalmers et al, Am J Respir Crit Care Med. 2014;189(5):576-85

Exacerbations

• P. aeruginosa colonization vs lack of P. aeruginosa

– Mortality increased by ~3x*

– Hospital admissions ~7x increased risk

– Average of 1 additional exacerbation per patient per year

– 15% lower FEV1 % predicted

– Clinically significant impact on quality of life as measured by SGRQ

Finch et al, Ann Am Thoracic Soc. 2015 12(11):1602-11

Study of Subgroup

Odds Ratio Odds Ratio

M-H, Random, 95% CI M-H, Random, 95% CI

Aliberti 2004 31.16 [1.58, 616.55]

Chalmers 2014 2.85 [1.50, 5.43]

Chalmers 2015 2.09 [0.77, 5.64]

Goeminne 2014 10.25 [3.81, 27.57]

Loebinger 2009 1.82 [0.65, 5.15]

Martinez-Garcia 2014 2.42 [1.46, 4.01]

McDonnell 2014 1.73 [0.68, 4.38]

McDonnell 2015 3.46 [1.55, 7.73]

Total (95% CI) 2.95 [1.98, 4.40]*

0.05 0.2 1 5 20

Protective Harmful

Heterogeneity: Tau2=0.13; Chi2=11.72, df=7 (P=0.11); I2=40%Test for overall effect: Z=5.29 (P < 0.00001)

Components of the BSI- predictors of mortality and hospital admission

Age Points<50 050-69 270-79 480+ 6

BMI Points<18.5 2>18.5 0

FEV1% pred. Points>80% 050-80% 130-49% 2<30% 3

Hospital adm. PointsYes 5No 0

Exacerbation frequency Points3 or more per year 2<3 per year 0

MRC dyspnoea score Points1-3 04 25 3

Colonisation status PointsNo 0Colonised 1P. aeruginosa 3

Radiology Points3 or more lobes or 1 cystic changes<3 lobes involved 0

Classification of the BSIMild = 0-4 Severe = 9+Moderate = 4-8 (Range = 0-25)Chalmers et al, Am J Respir Crit Care Med. 2014;189(5):576-85

Microbiome in bronchiectasis

Tunney et al. Am J Respir Crit Care Med. 2013;187(10):1118-26.

Remarkable stability over time

Tunney et al. Am J Respir Crit Care Med. 2013;187(10):1118-26.

Effect of Long-term, Low-Dose Erythromycin on Pulmonary

Exacerbations Among Patients With Non–Cystic Fibrosis

Bronchiectasis: The BLESS Randomized Controlled Trial

Each point represents a separate protocol-defined pulmonary exacerbation

(PDPE). Individual participants could account for more than 1 event each.

P = .003 for the comparison with placebo for the rate of pulmonary

exacerbations per patient per year. Serisier et al. JAMA. 2013;309(12):1260-7.

Microbiome- BLESS

Taylor et al, Ann Am Thorac Soc. 2015;12(5):701-7.Rogers et al. Thorax. 2013;68(8):731-7

Bronchiectasis microbiome

B20R

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B77N

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% O

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Dicker et al. Presented at ATS 2016

Exacerbations

0

1-2

3+

Dicker et al. Presented at ATS 2016

Long-term nebulized gentamicin for BE

• Objectives

– To assess efficacy of continuous nebulized gentamicin over 1 year in patients with NCFB chronically infected with a variety of pathogens

– To assess if treatment effects were sustained over a 3-month, treatment-free follow-up period

– Primary endpoint

– A ≥1 log unit reduction in sputum bacterial load (baseline pathogens: P. aeruginosa, H. influenzae, S. aureus, S. pneumoniae, Moraxella catarrhalis and other (coliforms)

Murray MP et al. Am J Respir Crit Care Med 2011;183:491

Phase IV, randomized, single-blind study

Nebulized gentamicin 80 mg bid for 12 months with 3-month, treatment-free follow-up

Nebulized 0.9% saline bid for 12 months with 3-month, treatment-free follow-up

65 patients randomized: 32 to gentamicin, 33 to saline;65 patients analyzed for safety, 57 for efficacy

Long-term nebulized gentamicin for NCFB: key results

Exacerbation frequency 33.3% of patients treated with gentamicin experienced exacerbations during the 12 month treatment period (range 0–1) compared with 80% in the saline group (P=0.0005)

Pulmonary function No significant differences in FEV1 or FVC between the groups at any time point throughout the study

Bacterial burden In the gentamicin group ,13/27 (48.1%) patients infected with P. aeruginosa at baseline. Four of these patients (30.8%) achieved eradication at 12 months

Daily symptoms At end of month 12, the gentamicin group achieved a clinically significant improvement in LCQ vs saline (81.4% vs. 20%, p<0.01) and also in SGRQ (87.5% vs. 19.2%, p<0.004), respectively. Effect was only sustained at follow-up for the SGRQ score

Safety Gentamicin: Two non-treatment-related deaths occurred; two patients discontinued owing to being unable to tolerate treatment; seven of 32 patients (21.9%) had bronchospasms and received adjunctive treatment

Saline: Two of 33 (6%) patients had bronchospasms and received adjunctive treatment. Both discontinued treatment

LCQ: Leicester Cough Questionnaire; SGRQ: St George’s Respiratory Questionnaire

Murray MP et al. Am J Respir Crit Care Med 2011;183:491

2014-02-10

Additional trials for Colistin, Tobramycin and aztreonam inconclusive

Trials with inhaled ciprofloxacin, tobramycin and colistin ongoing

Graph showing participants remaining exacerbation-free during the 6 month

treatment period and the follow-up period.

Azithromycin for prevention of exacerbations in non-cystic

fibrosis bronchiectasis (EMBRACE): a randomized, double-

blind placebo controlled trial

Dose= 500mg three time per week

Participants from 40 countries

232 registered centres

TARGET:

•1000 patients by April 2016

•10,000 patients by March 2020

Results at end of May 2016

3377 patients data entered

Demographics59% femaleAverage age= 65 years

Most common aetiology-• Idiopathic= 36%• post-infective= 29%

Never smoked =55.7%Ex smoker= 35.3%

RECRUITMENT DISTRIBUTION SUMMARY

Belgium Bulgaria

Croatia Czech Rpb

England Greece

Israel Italy

Kyrgyzstan Macedonia

Malta Moldova

N.Ireland Netherlands

Poland Portugal

Romania Scotland

Serbia Slovenia

Spain Switzerland

Turkey Wales

4115 patients consented

Disease impact- exacerbations

Outpatient exacerbations Severe exacerbations

Inhaled and mucoactive therapies

Antibiotic therapies

Summary

• Bronchiectasis is driven by neutrophilic inflammation and bacterial infection

• The most effective therapies are chest clearance and prophylactic oral and inhaled antibiotics for severe patients.

• Current data suggests in much of Europe bronchiectasis is treated “like COPD” and there remains are high burden of disease

Acknowledgements

www.bronchiectasis.eu

Executive groupEva PolverinoStefano Aliberti

iABC co-ordinatorStuart Elborn

Steering committeeFrancesco BlasiDiana BiltonWim BoermaAnthony De SoyzaKaterina DimakouMichael LoebingerCharlie HaworthAdam HillRosario MenendezMarlene MurrisFelix RingshausenAntoni TorresMontserrat VendrellTobias WelteRobert Wilson

ELFSarah MasefieldPippa PowellPatient advisory grp.

Advisory groupTim AksamitAnne O’DonnellCharles FeldmanOscar RizzoLucy Morgan

National leadsDaiana StolzMichal SchteinbergVictor BotnaruCharlotte UlrikMenno van EerdenGernot Rohde Branislava MilenkovicPerluigi Paggiaro

Study co-ordinatorMegan Crichton