bronchiectasis in non cystic fibrosis patients
TRANSCRIPT
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
