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Biomarkers in COPD: are we still far from finding the correct biomarker to monitor response to therapy?

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Biomarkers in COPD: are we still far from finding the correct biomarker to monitor response to therapy?

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Biomarkers in COPD: are we still far from finding the correct biomarker to monitor response to therapy?

  1. 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. 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. 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. 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. 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. 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. 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. 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. 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. 10. Steven Pascoe et al. Eur Respir J 2018;52:OA2127
  11. 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. 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. 13. Two pivotal studies (METREX and METREO)
  14. 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. 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. 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. 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. 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. 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. 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. 21. Scientific Reports (2019) 9:2796
  22. 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. 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. 24. Thanks for your attention!

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