bronchiectasis in non cystic fibrosis patients

Bronchiectasis in non cystic fibrosis patients

Francesco Blasi

Department of Pathophysiology and Transplantation

University of Milan

Recurrent cough, sputum and respiratory infections

Common- reported prevalence of 52/100,000

Failed bacterial clearance with chronic bacterial colonisation and neutrophilic airway inflammation

The cause is unknown in >60% of cases

No licensed therapies- Historically neglected

Bronchiectasis

Neutrophils: Proinflammatory cytokinesProteases (elastase, cathepsins,MMP’s)Macrophages: Proinflammatory cytokinesFailed clearance of apoptotic cellsEpithelial cells: IL-8, TNF-alpha secretion

Primary host defences Secondary host defences

Fuschillo ERJ 2008

Aetiology

Why should COPD experts and researchers care about bronchiectasis?

N=2164Bronchiectasis5% GOLD III, 7% GOLD IV

N=3636Bronchiectasis20.8%- associated with more exacerbations, worse FEV1

Single centre studies-50-60% of patients with moderate to severe COPD-More bacterial colonisation-More P. aeruginosa-Independent predictor of death

Stewart et al, AJRCCM 2012Agusti et al, Respir Res 2012Martinez et al AJRCCM 2013Getheral et al COPD 2014

Why should bronchiectasis experts and researchers care about COPD?

750 million people in Europe

5-10% have COPD

5-50% of these have bronchiectasis

A conservative estimate suggests at least 1m people in Europe have COPD associated bronchiectasis

Idiopathic -Lower lobe disease-Good prognosis-60 year old females

ABPA-Central disease-History of asthma-Staphylococcus aureus colonisation

Non tuberculous Mycobacteria-Middle age females-Middle lobe disease-Possible genetic/morphological associations

COPD-Bilateral lower lobe cylindrical bronchiectasis-Chronic bronchitis-Severe disease and poor prognosis

Cystic fibrosis-Upper lobe disease-Colonisation with S.aureus/P. aeruginosa-Early onset

Phenotypes

Non-CF Bronchiectasis OR Non-COPD bronchiectasis?

Disease predominantly affecting the middle age and elderly

Typically associated with airflow obstruction

Colonisation with H. influenzae and M. catarrhalis

P. aeruginosa in severe disease

Neutrophil dominated airway inflammation

COPD Bronchiectasis

Defined by fixed airflow obstruction Defined by Radiology

Inhaled corticosteroids

Bronchodilators

PDE4 inhibitors

Macrolides

Inhaled antibiotics

Mucoactive therapies

What bronchiectasis can learn from COPD

• Large scale epidemiological studies

• Severity classification

• Phenotyping of patients

• Recognition of the importance of co-morbidities

• Large scale randomized controlled trials and collaboration with pharmaceutical industry

What is EMBARC?

A pan-European collaborative network to promote research in bronchiectasis

Funded and supported by the European Respiratory Society as a clinical research collaboration

An alliance between national networks, expert centres and investigator

Open to everyone

International bronchiectasis networks

Members from 35 countries

212 registered centres

EMBARC registry

EMBARCThe European Bronchiectasis Registry.

What can we achieve with a European Bronchiectasis Registry?

Data from 1310 patients in 4 countriesThe first validated prediction rule for bronchiectasis

DundeeEdinburgh

Newcastle

Leuven

Milan

5 European Centres•Dundee•Edinburgh•Leuven•Milan•Newcastle

Total study population 1310

EdinburghDerivation

Validation

Dundee

Leuven

Milan

Newcastle

Components of the BSIAge 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)

www.bronchiectasisseverity.com

Use of the Bronchiectasis Severity Index for discovery science

Mild severe

1. PCA scores plot indicates that sputum protein profiles are associated with disease severity2. Patients 2, 10, 16, 17 18, 29 and 44 clustered with the majority of severe patients- potentially higher priority

for therapeutic treatments. 3. Conversely patients 11, 12 and 41 are closer to the majority of mild patients, thus potentially no need for

active treatment.

Grouping

Sputum proteomics using label-free LC/MS

N=60 bronchiectasis patients (30 mild, 30 severe by BSI)

Better understanding of the natural history of bronchiectasis

Understanding the impact of disease phenotypes

Promote a higher profile for bronchiectasis research

Facilitate Clinical Trials

What EMBARC needs to achieve

Novel specific anti-pseudomonals

Neutrophil elastase inhibitors

Inhaled amikacin

Inhaled Colistin

Inhaled ciprofloxacin

Statins

CXCR2 antagonists

CFTR specific therapies

Mannitol

Pulmonary epithelium Airway neutrophil

P. aeruginosa

Circulating neutrophils

H.influenzae

Current Clinical Trials

PROMIS study- Inhaled Colistin

Haworth AJRCCM 2014

Underpowered due to•Recruitment target cut from 260 to 144 following recruitment problems•Placebo group had nearly 50% fewer exacerbations than expected

Nebulised Aztreonam

Barker Lancet Respir Med 2014

Nebulised Aztreonam

Barker Lancet Respir Med 2014

Dry powder Mannitol- Discordent results from CF

Missed primary end-pointSmall improvement in QoL

N=233 N=228

Registries can help with Clinical Trials

FeasibilityRepresentativenessHealth economics

N=1630

Summary- Why take part in bronchiectasis research

• Common

• Disabling

• Neglected

• Tractable

Chalmers J et al. ERJ in press

AcknowledgementsExecutive committee Stefano AlibertiEva Polverino

Scientific CommitteeAnthony De SoyzaFelix RingshausenMarlene MurrisMontserrat VendrellWim BoersmaStefano Aliberti

Steering CommitteeFrancesco BlasiAntoni TorresTobias WelteDiana BiltonRobert WilsonCharles HaworthGernot Rohde Michael LoebingerKaterina DimakouStuart Elborn

www.bronchiectasis.eu