1. Dra. Salud Santos
Unidad Funcional de EPOC (Servei Pneumologia)
Hospital U. Bellvitge
Biomarkers in COPD:
are we still far from finding the
correct biomarker to monitor
response to therapy?
YES, WE ARE STILL FAR!

2. Purpose / utilities:
Clinical variables (symptoms, severity, pulmonary function test,
arterial blood gas)
Prediction of clinical outcomes (recovery, length of hospital day,
mortality)
Causal diagnosis
Response to treatment (therapeutic target)
INTRODUCTION: Biomarkers to monitor response to
therapy in COPD

3. • COPD as heterogenous disease (clinical and biological
heterogeneity)
• The identification of an endotype implies the recognition of several
shared disease features including:
clinical characteristics
genetics
physiology
histopathology
epidemiology
and treatment response
• Subgroup identification using biomarkers or clinical traits may
enable precision health
INTRODUCTION: Biomarkers to monitor response to
therapy in COPD

4. Precision health
Agustí A et al. Lancet 2017;390:980
Endotypes: subgroup of patients defined by biological mechanism
Are there different patient endotypes?

5. Recognized Endotypes in COPD
1. Alpha-1 antitrysin deficiency (mutations in the SERPINA I gene, distinct
histopathology-panacinar emphysema, epidemiology-onset early,
biomarkers are critical for diagnosis and proper treatment
2. Emerging endotype: Eosinophilic COPD (inflammation tipe II)
3. Inflammation T-helper (Th) cell type 1 (Th 1)
4. Airway microbiota may be relevant in COPD
5. Th17 cells and their principal cytokine, IL-17, may be particularly
important in the pathogenenis of emphysema (autoimmunity against
elastine)
6. Chronic bronchitis and pathological mucus abnormalities (mucins)
7. Other pathogenics pathways

6. • Paradigm Asthma-COPD overlap (ACO)
• Predominant symptoms: dyspnea, cough
and "wheezing"
• In exacerbation (different type): negative
relationship between blood eosinophilia and
bacterial isolation in sputum.
• Better response to corticosteroids (inhaled
and sistemic)
• Biomarker to monitor response to ICS
therapy: blood eosinophil count ?
• Future: biological therapy with targeted
monoclonal Ac (anti IL 5, IL 13)
Endotype “Eosinophilic COPD” (Inflammation Th2)
Inflammation type II in COPD
-eosinophilic-

7. From end of 2015 to the present…
SEVERAL POST-HOC STUDIES have been published
Looking for LEVELS OF EOSINOPHILS THAT HELP YOU DISCRIMINATE when it is
better to prescribe ICS
1. Reduction of AECOPD: 29% response to CIS when >2% eosinophils vs 10%
(FF/V vs V)
Pascoe S et al, Lancet Respir Med 2015
2. A post-hoc analysis of the INSPIRE and TRISTAN study: eosinophils > 2%,
better response to ICS/LABA vs TIOTROPIO
Pavord ID et al, COPD 2016
3. FLAME study (IND/GLI vs ICS/LABA) eosinophils ≥ 300 cel/µL
Wedzicha et al, N Engl J Med 2016
4. A post-hoc analysis of the WISDOM trial. ≥ 4% eosinophils o 300 cel/µL (1·63
[1·19-2·24]
Watz H et al, Lancet Respir Med 2016
5. TRIBUTE study . 20% response to CIS when >2% eosinophils vs 6%.
Papi A, et al. Lancet 2018
Barnes et al, post-hoc del ISOLDE, ERJ 2016 (AECOPD reduction with ICS was greater in the low blood Eos group (<2%)

8. 10.861 patients of 10 trials
Blood eosinophil count of <2%(≈40%) was associated with an increased risk of pneumonia
in patients with COPD, irrespective of administration of inhaled corticosteroid
The risk of pneumonia in patients on inhaled
corticosteroids seemed to be greater, although not
significantly, in patients with less than 2%
eosinophils than in those with 2% eosinophils or
more (events occurred in 107 [4·5%] vs 164 [3·9%],
HR 1·25, 95% CI 0·98–1·60).

9. IMPACT STUDY: Annual rate moderate/severe exacerbations
according to blood eosinophil count (10.355 patients)
Lipson DA, et al. N Engl J Med 2018
32%
(IC al 95%: 25,
38)
p=< 0,001
12%
(IC al 95%: 4, 19)
p = 0,003
0,0
0,2
0,4
0,6
0,8
1,0
1,2
1,4
1,6
1,8
2,0
<150 cells/µL ≥150 cells/µL
20%
(IC al 95%: 12,
27)
p < 0,001
12%
(IC al 95%: 1,
22)
p = 0,034
0,85
(IC al 95%:
0,80; 0,91)
1,06
(IC al 95%:
0,99; 1,14)
0,97
(IC al 95%:
0,88; 1,07)
0,95
(IC al 95%:
0,90; 1,01)
1,08
(IC al 95%:
1,02; 1,14)
1,39
(IC al
95%:
1,29;
1,51)
AnnualRatemod/severeexacerbations
(ICal95%)
FF/UMEC/VI
n = 1844
FF/VI
n = 1769
UMEC/VI
n = 869
< 150 cels/µl
FF/UMEC/VI
n = 2296
FF/VI
n = 2355
UMEC/VI
n = 1195
≥ 150 cels/µl

10. Steven Pascoe et al. Eur Respir J 2018;52:OA2127

11. Bafadhel M ,Am J Respir Crit Care Med. 2012 Jul 1;186(1):48
Investigate the usefulness of blood eosinophils to direct
corticosteroid therapy during exacerbations
Noninferiority study in
CRQ
Eos<2%
42 exac (30 patients):
placebo+ab
• 1 treatment failure
(2%)
39 exac (26 patients):
prednis+ab
• 6 treatment failures
(15%)

12. NRL
AECOPD P Stable stage P
Saltürk, et al.
2015
Eosinophils >2% 4,6 (IQR 3,2-6,8)
0,001
3,7 (IQR 2,7-6,6)
0,001No Eos* 13,0 (7,3-23,1) 6,8 (4,0-12,6)
Duman, et al.
2015
Eosinophils >2% 3,6 (IQR 2,57-4,95)
0,001
3,7 (IQR 2,6-5,1)
0,001No Eos* 7,99 (4,36-13,87) 6,0 (3,65-10,6)
*these patients presented greater therapeutic failure after corticosteroid treatment
for the exacerbation.
Neutrophil-to-lymphocyte ratio (NLR) and Blood
eosinophils count
*The combination of both markers could be used to monitor the exacerbation
and to support therapeutic decision making.
Pascual-González Y et al, Int J COPD. 2018

13. Two pivotal studies (METREX and METREO)

14. www.bellvitgehospital.cat
The intra-patient variability of eosinophils
in a cohort of severe COPD (GOLD group
D) with triple inhaled therapy was of
152±141 (mean±SD) cels/mL
In patients with a blood eosinophil count
≥ 300 cells/µL, NNT for ICS is 9
Cost-effective biomarker derived from
routine complete blood count
Blood eosinophil count: Is the correct biomarker to
monitor response to ICS therapy?
Although there is not a clear threshold of eosinophilia that indicates
the ICS treatment, it could be indicative for the clinician a blood
eosinophil count ≥ 300 cel / µL

15. Endotype “Inflammation Th 1”
• Predominant symptom: cough and
expectoration
• Chronic bronchial infection and
bronchiectasis (clear association)
• Relationship with exacerbations of bacterial
cause (40-55%)
• Neutrophilic inflammation type leads to a
lower response to systemic corticosteroids
• Studies integrating perturbations in
microbial composition with host
inflammatory responses will be necessary to
developed a mechanistic link
• Prolonged therapy with antibiotics
(macrolides) could be a more effective
treatment
• Biomarkers to monitor response?
Inflammation type I in COPD
-neutrophilic-
Tripple JW et al. Immunol Allergy Clin N Am 37 (2017) 345

16. • RCT: 1142 subjects with COPD
• Plasma at enrolment and after 3 months
of treatment, and performed ELISA for
CRP, IL-6, IL-8 and sTNFR75.
• A decline in sTNFR75 (TNF receptor type
2) concentrations at 3 months identified
subjects who benefited clinically from
azithromycin
• TNFR75 is only found in cells of the
immune system and endothelial cells
Albert RK, et al. NEJM 2011;365:689
Azitromicin treatment in COPD
Prescott G. W , et al. ERJ. 2014; 43(1): 295

17. AzitroCOPD study
• 40% of patients increased > 30m in the 6MWT (“responders”)
• a decline of IL-8 and IL-13 concentrations between baseline visit and 3
months identified subjects who benefited from azithromycin
no Responders (NR) vs Responders (R) in baseline and 3 months
p=0,046
p=0,018
V1 V2

18. Longitudinal profiling of the lung microbiome in the AERIS study
demonstrates repeatability of bacterial and eosinophilic COPD exacerbations
Mayhew D et al, Thorax2018

19. Innovative sampling techniques have led to the
identification of several pulmonary biomarkers
• Differents techniques for collecting pulmonary sampled
biomarkers:
noninvasive (exhaled air, exhaled breath condensate, sputum)
semi-invasive (induced sputum)
invasive (BAL, biopsies)
AIRWAYS BIOMARKERS OF
OXIDATIVE STRESS IN COPD
Journal of Cellular Physiology, First published: 25 March 2019, DOI: (10.1002/jcp.28482)

20. Purpose/utilities Assessed biomarkers
Response to treatment FeNO (fractional exhaled nitric oxide)
Exhaled breath condensate: Cys-LTs, H2O2, IL-
6, 8-isoprostane, LTB4, PGE2, TNFα
Sputum: IL-8, TNFα
Biomarkers to monitor response to therapy in COPD
exacerbations
Koutsokera et al. Respir Res 2013, 14:111

21. Scientific Reports (2019) 9:2796

22. GENE EDITING TECHNOLOGY
(Pharmacogenomics)
Journal of Cellular Physiology, First published: 25 March 2019, DOI: (10.1002/jcp.28482)
Upcoming pioneer technologies (ZFNs,
TALenS, AND cRISpR/Cas9) for gene
editing as therapeutics
The disease can be cured by targeting
DNA
But…nowadays is a real
challenge

23. Conclusions:
1. Innovative sampling techniques have led to the identification of several
pulmonary biomarkers
2. Although some molecules are promising, their usefulness in clinical
practice is not yet established
3. Clinical trials that incorporate biomarkers in decisional algorithms are
scarce (the majority of the studies are post-hoc). However, they are
needed.
4. There have been several published genome-wide association studies and
other omics studies in COPD pharmacogenomics; however, clinical
implementation remains far away.
5. Futher progress is needed in the definition of additional endotypes and
correct biomarkers.
YES, we are still far from finding the correct biomarker to monitor
response to therapy (“many challenges, less facts”)

24. Thanks for your attention!