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John Hurst
UK
Biomarkers in Practice: Making an
Impact on Patient Management
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
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.
STABLE EXACERBATION
EXACERBATION: pathogenesis
Frequent
32 vs. 40ml/yr, p<0.05
Exacerbation
↑Costs
Donaldson GC et al. Thorax 2002
1998 NIH
What might a biomarker in COPD do?
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 0%
1. CRP
3. Procalcitonin 3 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
AUC= 0.74
Systemic Biomarkers of Exacerbation
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)
Prevention Maintenance
M Prevention Exacerbation Rx
1 2
STABLE Exacerbation
Exacerbation Prevention
Prevention Maintenance
M Prevention Pre-Emptive Exacerbation Rx
1 2 3
STABLE Exacerbation
High-Risk Periods
EARLY exacerbation treatment
Exacerbation Heterogeneity
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
AJRCCM 2006
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
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