Biomarkers in Practice: Making an

Impact on Patient Management

John Hurst
UK
 Biomarkers in Practice: Making an
Impact on Patient Management

Dr John Hurst PhD FRCP

Director, UCL-Royal Free COPD Centre
Reader in Respiratory Medicine
UCL Respiratory Medicine, London, UK
j.hurst@ucl.ac.uk
Question 1

I use biomarkers to inform my management of lower

respiratory tract infection, such as COPD
exacerbation?
–  NO
–  YES
Question 1
I use biomarkers to inform my management of lower
respiratory tract infection, such as COPD exacerbation?

1 0
1.  NO

2.  YES 2 0

1 2

0:15 Voted: 0
Overview
•  1. COPD and COPD Exacerbations
•  2. Biomarkers and COPD
–  A Biomarker to Identify Exacerbations
–  A Biomarker to Differentiate Viral from Bacterial
Exacerbations – in the real world
1.
COPD and COPD Exacerbations
Emphysema Chronic Bronchitis

COPD
 Emphysema Chronic Bronchitis

PATHOLOGICAL diagnosis

COPD
 Emphysema Chronic Bronchitis

PATHOLOGICAL diagnosis CLINICAL diagnosis

COPD
Emphysema Chronic Bronchitis

PHYSIOLOGICAL
COPD DIAGNOSIS:
Post-BD FEV1/FVC <0.7
Emphysema Chronic Bronchitis

PHYSIOLOGICAL
COPD 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 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: 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
 COPD: natural history

Fletcher C and Peto R. BMJ 1977;6077:1645-1648

www.hebs.sco.nhs.uk

STABLE EXACERBATION
EXACERBATION: pathogenesis

Inflamed COPD airway

EXACERBATION: pathogenesis
Triggers Bacteria Viruses Pollutants

Inflamed COPD airway

EXACERBATION: pathogenesis
Triggers Bacteria Viruses Pollutants

Inflamed COPD airway

Greater airway inflammation

EXACERBATION: pathogenesis
Triggers Bacteria Viruses Pollutants

Inflamed COPD airway

Greater airway inflammation

Effects

V/Q mismatch Mucus Oedema Bronchoconstriction

Hypersecretion

Hypoxaemia Increased work of

breathing
 ∆15 units, p<0.001

Seemungal TAR et al. AJRCCM 1998

Soler-Cataluna JJ et al. Thorax 2005

Frequent
32 vs. 40ml/yr, p<0.05
Exacerbation

↑Costs
Donaldson GC et al. Thorax 2002

32 vs. 40 ml/year, p<0.05

Exacerbation Susceptibility

Hurst JR et al. N Engl J Med 2010;363:1128-1138

Exacerbation Susceptibility

Hurst JR et al. N Engl J Med 2010;363:1128-1138

The Story So Far
•  COPD is present when a susceptible smoker develops
airflow obstruction
•  The disease comprises heterogeneous phenotypes
•  The natural history of COPD, defined by a progressive
decline in lung function, is punctuated by deteriorations in
respiratory health called exacerbations
•  Most exacerbations are caused by respiratory infection
•  Exacerbations cause much of the morbidity and mortality
in COPD
•  There is a ‘Frequent Exacerbator’ Phenotype who
experiences a particular burden of disease
2.
Biomarkers and COPD
Definition of a Biomarker
“a characteristic that is objectively measured and
evaluated as an indicator of normal biologic
processes, pathogenic processes, or
pharmacologic responses to a therapeutic
intervention”

1998 NIH
What might a biomarker in COPD do?

1. Identify COPD Phenotypes

2. Differentiate Stable COPD from Exacerbation
3. Differentiate viral from bacterial exacerbations
4. Predict a treatment response
5. Predict a specific prognosis
What makes a good Biomarker?

1.  Easily obtained

2.  Easy and cheap to measure
3.  Measurement that is reproducible and sensitive
and or specific
Assessing Biomarker Utility
Frequency
Baseline

Biomarker Concentration
Assessing Biomarker Utility
Frequency
Baseline Exacerbation

Biomarker Concentration
Assessing Biomarker Utility
Frequency Cut-Off
Baseline Exacerbation

Biomarker Concentration
Frequency
Baseline Exacerbation

Biomarker Concentration
 Cut-Off A

Frequency
Baseline Exacerbation

SENSITIVE
Less Specific

Biomarker Concentration
 Cut-Off B

Frequency
Baseline Exacerbation

SPECIFIC
Less Sensitive

Biomarker Concentration
 1
Sensitivity

Receiver-Operating
Characteristic (ROC) Curve
AUC ≥0.8

0 1
1-Specificity
What might a biomarker in COPD do?

1. Identify COPD Phenotypes

2. Differentiate Stable COPD from Exacerbation
3. Differentiate viral from bacterial exacerbations
4. Predict a treatment response
5. Predict a specific prognosis
3.
A Biomarker to Identify Exacerbations
“In search of a respiratory troponin”
 Question 2
The best biomarker to identify an exacerbation is?

1 0%
1.  CRP

2.  Surfactant Protein D 2 0%

3.  Procalcitonin 3 0%

4.  Something else 4 0%

5.  There isn’t one 5 0%

1 2 3 4 5

0:15 Voted: 0
Definition of Exacerbation
an acute event characterised by a worsening of the
patient’s respiratory symptoms that is beyond
normal day-to-day variations and leads to a change
in medication

WHO/GOLD 2013 (www.goldcopd.org)

Clinical Diagnosis of Exclusion
Changes in Physiology
Changes in Inflammation
Systemic Biomarkers of Exacerbation

AUC= 0.74
Systemic Biomarkers of Exacerbation

CUT SENSITIVITY SPECIFICITY

2.3mg/l 90% 29%
27.6mg/l 40% 90%

AUC= 0.74
Summary
There is no single biomarker that can reliably
1. differentiate stable COPD from exacerbation
2. differentiate exacerbation from other causes of
symptom duration
Relapse and Recurrence

Symptom Symptom
Intensity Intensity

Time Time
 Exacerbation Recurrence
n=1923 inter-exacerbation intervals

p<0.001
27% of new exacerbations are
associated with a 2nd within 8
weeks
(20% higher than expected)

Hurst JR et al. Am J Respir Crit Care Med 2009;179:369-374

A Biomarker to Predict Recurrence

rs= ‒0.47, p<0.01 3.4 vs. 8.8mg/l,

p=0.007

Perera WR et al. Eur Respir J 2007;29:527-534

Exacerbation Prevention

•  Therapeutic paradigms: High-Risk Patients

Prevention Maintenance
M Prevention Exacerbation Rx

1 2
STABLE Exacerbation
Exacerbation Prevention

•  Therapeutic paradigms: High-Risk Time Periods

Prevention Maintenance
M Prevention Pre-Emptive Exacerbation Rx

1 2 3
STABLE Exacerbation

High-Risk Periods
EARLY exacerbation treatment
Exacerbation Heterogeneity

Tracheo-Bronchial Infection Pollutants

VIRUS
BACTERIA
(RV)
4.
A Biomarker to Differentiate Viral from Bacterial
Exacerbations
Mallia P et al. Am J Respir Crit Care Med 2011;183:734-742.
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”

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.
Exacerbation ‘Phenotyping’

Exacerbations grouped as “clinical phenotypes”

Unbiased cluster analysis of biomarkers identified “biological clusters”
These overlapped
Exacerbation Phenotyping

Sputum IL-1β

Blood Eosinophil

Serum IP-10
IP10 as a Biomarker of Viral Exacerbation
PCT as a Biomarker of Bacterial Exacerbation

Chest 2007;131:9-19
 Antibiotics at Exacerbation
Successful Anthonisen N et al. Ann Intern Med 1987
Treatment
* * p= NS

Mean FEV1 at
33.9% predicted

3 major 2 major 1 major

symptoms symptoms symptom
A ‘real world’ biomarker

CHANGE in sputum
=
BENEFIT from ANTIBIOTICS
Summary
•  Serum biomarkers may be able to differentiate
viral from bacterial exacerbations of COPD
•  In the ‘real world’, a change in sputum is
associated with benefit from antibiotics
Summary
•  The natural history of COPD is punctuated by
deteriorations in respiratory health called exacerbations,
caused by respiratory infection
•  Exacerbations cause much of the morbidity and mortality
in COPD
•  There is a ‘Frequent Exacerbator’ Phenotype
•  There is interest in Biomarkers to
–  Diagnose exacerbation
–  Differentiate viral from bacterial exacerbations
–  Predict treatment response
•  Change in sputum is a ‘real world’ biomarker that can
predict response to antibiotics
Discussion

John Hurst
University College London
London, UK
j.hurst@ucl.ac.uk