an update in copd
TRANSCRIPT
An Update in COPD
John Hurst PhD FRCP
Reader in Respiratory Medicine / Honorary Consultant
University College London / Royal Free London NHS Foundation Trust
What’s new in COPD – papers affecting clinical practice
• 1. Trajectories of disease progression
• 2. Phenotyping COPD
• 3. The Airway Microbiome
• 4. Co-Morbidity in COPD
• 5. Models of Care
What’s new in COPD – affecting clinical practice
• 1. Trajectories of disease progression
• 2. Phenotyping COPD
• 3. The Airway Microbiome
• 4. Co-Morbidity in COPD
• 5. Models of Care
COPD
Chronic Bronchitis Emphysema
COPD
Chronic Bronchitis Emphysema
PATHOLOGICAL diagnosis
COPD
Chronic Bronchitis Emphysema
PATHOLOGICAL diagnosis CLINICAL diagnosis
COPD
Chronic Bronchitis Emphysema
PHYSIOLOGICAL
DIAGNOSIS:
Post-BD FEV1/FVC <0.7
COPD
Chronic Bronchitis Emphysema
PHYSIOLOGICAL
DIAGNOSIS:
Post-BD FEV1/FVC <0.7
COPD Definition
COPD, a common preventable and treatable disease, is
characterised by persistent airflow limitation that is
usually progressive and associated with an enhanced
chronic inflammatory response in the airways and the
lung to noxious particles or gases. Exacerbations and
comorbidities contribute to the overall severity in
individual patients.
WHO/GOLD 2013 (www.goldcopd.org)
COPD Definition
COPD, a common preventable and treatable disease, is
characterised by persistent airflow limitation that is
usually progressive and associated with an enhanced
chronic inflammatory response in the airways and the
lung to noxious particles or gases. Exacerbations and
comorbidities contribute to the overall severity in
individual patients.
COPD: natural history
Fletcher C and Peto R. BMJ 1977;6077:1645-1648
www.hebs.sco.nhs.uk
COPD: natural history
Fletcher C and Peto R. BMJ 1977;6077:1645-1648
www.hebs.sco.nhs.uk
[with written patient permission]
STABLE EXACERBATION
The mean decline in FEV1 was 24 ml per year in trajectory 1
(Panel A), 2 ml per year in trajectory 2 (Panel B), 53 ml per year
in trajectory 3 (Panel C), and 27 ml per year in trajectory 4 (Panel
D). The decline in FEV1 in trajectory 3 was considered to be rapid.
Accelerated decline in FEV1 is not an obligate feature of COPD.
Disease Activity and Severity
EARLY vs. LATE
MILD vs. SEVERE
SEVERITY
“Distance Travelled”
ACTIVITY
“Speed”
A B
Disease Activity and Severity
SEVERITY
“Distance Travelled”
•Cross-Sectional
– FEV1
– CT
ACTIVITY
“Speed”
•Longitudinal
– FEV1 decline rate
– CT changes
•Inflammation?
Clinical Message
• COPD is diverse. Current assessments of
disease severity do not address the more
important question of disease activity
– Rate of lung function decline
– Exacerbations
What’s new in COPD – affecting clinical practice
• 1. Trajectories of disease progression
• 2. Phenotyping COPD
• 3. The Airway Microbiome
• 4. Co-Morbidity in COPD
• 5. Models of Care
COPD
Chronic Bronchitis Emphysema
PHYSIOLOGICAL
DIAGNOSIS:
Post-BD FEV1/FVC <0.7
Complexity in COPD
Phenotypes in COPD
[with written patient permission]
FEV1 (Physiological)
Exacerbations (Clinical)
Co-Morbidities
Chronic Bronchitis (Symptom based)
Emphysema (Radiological, incl. ILD)
Inflammation
(Biomarker)
Alpha-1 (Genetic)
Needs to be STABLE and MEASURABLE. Phenotypes may overlap.
Frequent
Exacerbation
Soler-Cataluna JJ et al. Thorax 2005
Seemungal TAR et al. AJRCCM 1998
Donaldson GC et al. Thorax 2002
32 vs. 40ml/yr, p<0.05
↑Costs
∆15 units, p<0.001
32 vs. 40 ml/year, p<0.05
High Risk Patients
ECLIPSE Methodology
Recruitment
Baseline
Assessment
Number of courses of
antibiotics/steroids /
hospitalisations for
exacerbation in prior
year asked and
recorded
YEAR PRIOR
Number of courses
of
antibiotics/steroids
/ hospitalisations
for exacerbation in
year one
COUNTED
Number of courses
of
antibiotics/steroids
/ hospitalisations
for exacerbation in
year two
COUNTED
Number of courses
of
antibiotics/steroids
/ hospitalisations
for exacerbation in
year three
COUNTED
YEAR 1 YEAR 2 YEAR 3
ANALYSIS 1
How do baseline variables relate to
observed exacerbations in year 1?
ANALYSIS 2
How stable is exacerbation frequency
over 3 observed years, and in relation
to patient self report?
Exacerbations and COPD Severity
Multivariate Analysis
Hurst JR et al. NEJM 2010;363:1128-1138
Multivariate Analysis
Hurst JR et al. NEJM 2010;363:1128-1138
Suggests groups of patients or ‘phenotypes’ who are
inherently susceptible versus resistant to
exacerbations (or at least reporting exacerbations)
IS THIS STABLE OVER TIME?
Exacerbation Phenotypes in COPD
Hurst JR et al. NEJM 2010;363:1128-1138
Identifying the Frequent Exacerbator
“How many courses of antibiotics and/or steroids did
you need for you chest over the last year?”
Better targeting (personalised / stratified medicine).
[with written patient permission]
GOLD 2011 Staging Revision: Exacerbations
A: Low Risk, Fewer Symptoms
B: Low Risk, More Symptoms
C: High Risk, Fewer Symptoms
D: High Risk, More Symptoms C D
A B
4
3
2
1
RISK
GOLD
Stage
≥2
1
0
RISK
Exacerbations
mMRC ≥2
CAT≥10
mMRC 0-1
CAT<10 SYMPTOMS
Clinical Message
• COPD is diverse. Therapy should be directed
against the phenotype(s) present, at baseline and
exacerbation
– Targeting the frequent exacerbator
What’s new in COPD – papers affecting clinical practice
• 1. Trajectories of disease progression
• 2. Phenotyping COPD
• 3. The Airway Microbiome
• 4. Co-Morbidity in COPD
• 5. Models of Care
This talk, circa 2006
“The healthy human airway is sterile, with several
innate immune mechanisms acting in coordination to
maintain this sterility. Smoking appears to disrupt
these innate immune mechanisms, and as a
consequence, microbial pathogens are able to
persist in the lower airway in COPD”
AJRCCM 2006
“free from bacteria or other living microorganisms; totally clean”
www.gettyimages.com
We identified 5,054 16S rRNA bacterial
sequences from 43 subjects.
The bronchial tree was not sterile, and
contained a mean of 2,000 bacterial
genomes per cm2 surface sampled.
Pathogenic Proteobacteria, particularly
Haemophilus spp., were much more frequent in
bronchi of adult asthmatics or patients with
COPD than controls.
Conversely, Bacteroidetes, particularly
Prevotella spp., were more frequent in controls
than adult or child asthmatics or COPD
patients.
“Bacterial Colonisation”
‘PPM’ Prevalence
Monso E et al. AJRCCM 1995;152:1316-1320
25% 52%
Exacerbation Ecology
Sethi S et al. J Clin Micro 2014: in press
“Volcano plots indicating taxa that are significantly increased (upper right quadrant) or decreased
(upper left quadrant) in pair-wise comparisons. Dashed lines indicate significant FDR-adjusted p-
values and changes in relative abundance of at least 2-fold. Taxa exhibiting significant changes
are coloured by phylum-level classification. Note that in addition to highlighted taxa, many other
microbiota members exhibit smaller scale changes in abundance, which cumulatively may
contribute importantly to microbiome community function.”
Viral infection predisposes to secondary
bacterial infection
AJRCCM 2013;188:1224-1231
MACROLIDES
HR for exacerbation per patient-year in the azithromycin group =0.73 (95% CI,
0.63 to 0.84; p<0.001).
Increased macrolide resistance, and hearing impairment
Clinical Message
• The presence of an organism in sputum doesn’t
necessarily mean that the organism is causing a
problem
– The field is moving quickly; we just don’t know what to
do with the data yet…
What’s new in COPD – papers affecting clinical practice
• 1. Trajectories of disease progression
• 2. Phenotyping COPD
• 3. The Airway Microbiome
• 4. Co-Morbidity in COPD
• 5. Models of Care
Case Study
A 75 year old female is
hospitalised following a
deterioration of her COPD
symptoms, consistent with an
exacerbation.
She had previously been
prescribed combination ICS-
LABA and LAMA.
She was known to have
cardiovascular disease
(previous MI) and diabetes
mellitus.
[with written patient permission]
Questions
• 1. Does the presence of IHD and diabetes affect
the outcome of the exacerbation?
• 2. What are the implications of COPD for the
therapy of IHD and diabetes?
• 3. Are these co-morbidities more likely because
of the underlying COPD, or her COPD therapy?
• 4. Is this really an exacerbation, or an undetected
co-morbidity?
The COPD “Co-Morbidome”
Divo M et al. AJRCCM 2012;186:pp 155–161
Mortality in COPD
COPD and Cardiovascular Disease
Cumulative incidence of first MI Cumulative incidence of first CVA
The Absence of Evidence
Study A • able to use medication correctly
• Serious, uncontrolled disease (including
serious psychological disorders) likely to
interfere with the study and/or likely to
cause death within the 3-year study
duration
Study B • Able to inhale study drug
• Significant diseases other than COPD
which, in the opinion of the investigator,
may either put the patient at risk
because of participation in the study or
a disease which may influence the
results of the study or the patient’s
ability to participate in the study.
• A recent history (i.e., six months or less)
of myocardial infarction.
• Any unstable or life threatening cardiac
arrhythmia or cardiac arrhythmia...
• Hospitalization for heart failure (NYHA
Class III or IV) within the past year.
• Patients with known moderate to severe
renal impairment.
Clinical Message
• Many patients with COPD have many other
diagnoses (‘co / multi-morbidities’) – Some of these are more prevalent in COPD through shared risk factors,
therapy, or ‘systemic consequences’
– These may impact the course of COPD, or complicate COPD therapy, and
COPD can impact the natural history of the co-morbidity
• However co-morbidity arises, outcomes will be
better with a take a personalised, holistic
approach to COPD management
What’s new in COPD – papers affecting clinical practice
• 1. Trajectories of disease progression
• 2. Phenotyping COPD
• 3. The Airway Microbiome
• 4. Co-Morbidity in COPD
• 5. Models of Care
Sources
Methodology
• Regular national COPD Audits: 2003, 2008, 2014
• Organisational
• Secondary Care
• Primary Care
• PR
• “All first-episode admitted exacerbations February
– April 2015”
• COPD Admissions risen 13% since 2008
Dataset
• 13414 patient exacerbations
• 100% of Trusts in E+W took part
• 183 English units in 142 Trusts
• Median (IQR) 61 (38-86) per unit
• Median (IQR) percentage of audit cases to total
eligible (coded!) cases 67% (48%-91%)
Socio-Demographics
• First COPD audit in which females make up the majority (51%) of cases.
• Admitted patients were notably deprived in respect of income, employment, health
deprivation/disability and education/skills/training.
• There is a clear association between age and area of residence with deprivation;
younger COPD patients in England and more likely to live in the more deprived
areas.
National RFH
Female 51% 50%
Mean Age (y) 72 71.4
Living in Most Deprived Quintile 34% 22%
Outcomes
• Mortality has fallen from 7.5-8% in 2003 and 2008
• Mortality doesn’t vary by day of admission, except
highest deaths on a Tuesday for patients admitted
on a Monday (and case-mix the same)
• Mortality 6.8% vs. 3.6% with consolidation
• LOS has fallen from 6→5 →4 days
7/7 working?
Specialist Advice
• Takes longer to see a specialist (if at all) for those
in at the weekend, and on a Monday
• Recording of key information better if see a
specialist
• Recommendation:
– All patients whose primary diagnosis is COPD
exacerbation should receive a specialist respiratory
opinion within 24 hours of admission. Patients with
COPD exacerbation who need to remain in hospital
should be managed on a respiratory ward.
Camden Model
Integrated COPD Care Community Respiratory Service
Close working links with both Acute Trusts
Regular MDT and joint clinics
Shared governance
Primary Care education and support
Case finding
Close links with others teams
London Respiratory Value Pyramid
Clinical Message
• How can you achieve cost-effective care of
patients with COPD in your services?
Questions
• Fixed airflow obstruction (‘COPD’) may arise as
an adult consequence of premature lung disease
– 1 YES
– 2 NO
– 3 Unsure
Questions
• It is possible to identify specific groups of COPD
patients who respond better to specific therapies
(stratified medicine)
– 1 YES
– 2 NO
– 3 Unsure
Questions
• I would prescribe antibiotics to a patient with
COPD who has Haemophilus influenzae identified
on a routine sputum culture
– 1 YES
– 2 NO
– 3 Unsure
Questions
• Most patients with COPD will die with, not from
their COPD
– 1 YES
– 2 NO
– 3 Unsure
Questions
• 7 days access to specialist care is likely to
improve outcomes in COPD
– 1 YES
– 2 NO
– 3 Unsure
Summary
• Diversity of COPD
– Trajectories of decline, disease severity and activity
– Phenotype based care
• The Airway Microbiome
• The Importance of Co-Morbidity in COPD
• The challenges of unplanned care in COPD