03 BRN Research Forum Bronquiectasias. Parte III por Oriol Sibila

03 BRN Research Forum Bronquiectasias. Parte III por Oriol Sibila
USO DE BIOMARCADORES EN LA CONSULTA DE BRONQUIECTASIAS Oriol Sibila Servei de Pneumologia Hospital Clínic @OSibila
¿mucoactive treatments? ¿inhaled antibiotics? ¿macrolides? ¿antiinflamatories therapies?
Polverino E et al, Eur Respir J 2017 ✓ Conditional recomendation ✓ Low (or very low) quality of evidence ✓ No licensed treatment
RECENT RANDOMISED CLINICAL TRIALS IN BRONCHIECTASIS
Sibila O, Eur Respir J 2022 Response to treatment: - Changes in QoL above MCID -Changes in FEV1 of ≥ 100 ml -Abcense of Exacerbations Endpoints: -QoL -FEV1 -Exacerbations n=461 n=83 n=538
Sibila O, Eur Respir J 2022 -Mannitol RCT
Sibila O, Eur Respir J 2022 -Mannitol RCT FEV1 Responders (≥ 100 ml)
Sibila O, Eur Respir J 2022 -Mannitol RCT QOL Responders (↓SGRQ ≥ 4 points)
Sibila O, Eur Respir J 2022 -Mannitol RCT No exacerbation ≥1 exacerbation
Sibila O, Eur Respir J 2022 -Azythromicin RCT
Sibila O, Eur Respir J 2022 -Aztreonam RCT
Clinical predictors to treatment response Sibila O, Eur Respir J 2022
N=1000 patients Follow-up: 36 months BRIDGE project Bronchiectasis Research Integrating Data with Genomics and Endotyping
3.1 Primary Objective -To determine molecular endotypes of bronchiectasis which can guide response to treatment. 3.2 Secondary Objectives -To determine and validate candidate biomarkers to use in stratified medicine -To determine molecular endotypes of stable bronchiectasis -To determine the causes and inflammatory profiles of bronchiectasis exacerbations -To perform in-vivo or in-vitro proof of concept studies using phenotypic data to identify patient populations likely to benefit in future randomized controlled trials BRIDGE project Bronchiectasis Research Integrating Data with Genomics and Endotyping
Biomarkers in Bronchiectasis • Mucins • Antimicrobial peptides • Neutrophil elastasa • NETS • Bacterial load • Eosinophils • VOCs
Denney L, Biomedical Journal 2018 MUCINS
Science 2009 Nature 2014
Sibila O et al, Respirology 2016
Ramsey K et al, Am J Respir Crit Care Med 2021
Luppeti A, Lancet Infect Dis 2003 Lactoferrin Lysozime LL-37 SLPI Antimicrobial Peptides (AMPs):
Multicenter 1 year follow-up LL-37 Lysozime Lactoferrine SLPI Sputum and serum Sibila O et al, Thorax. 2019; 74(9):835-842 N o n -in fe c te d 0 1 0 0 2 0 0 3 0 0 4 0 0 P .a e ru g in o s a O th e r p a th o g e n s S p u tu m la c t o f e r r in ( µ g /m l) p=0.04 LL-37 Lactoferrin SLPI
SLPI (Secretory Leukocyte Protease Inhibitor) Sibila O et al, Thorax. 2019; 74(9):835-842
Perea L et al, Chest 2021
Perea L et al, submitted
Int J Mol Sci 2019 NEUTROPHIL ELASTASE
Am J Respir Crit Care Med 2017
Am J Respir Crit Care Med 2017
Eur Respir J 2019
Eur Respir J 2019 >6 Exacerbations
Chalmers JD et al, N Eng J Med 2020 n=256
Chalmers JD et al, N Eng J Med 2020
Int J Mol Sci 2021
Neutrophil Extracellular Traps (NETs) Dicker AJ, J Allergy Clin Immunol 2018
Keir HR et al, Lancet Resp Med 2021
Keir HR et al, Lancet Resp Med 2021 p<0.001
Chalmers JD et al, Am J Respir Crit Care Med 2012 BACTERIAL LOAD
Am J Respir Crit Care Med 2019 Airway Bacterial Load: -Low (<105 ufc/g) -Moderate (105-106) -High (>106)
1) BL is associated worse QOL and severity of disease Sibila O et al, AJRCCM 2019
Log 10 cfu/g B a s e l i n e A f t e r t r e a t m e n t F o l l o w - u p 0 1 2 3 4 5 6 7 8 9 1 0 H ig h M o d e ra te L o w 1 3 5 7 1 4 0 1 2 3 4 5 6 7 8 9 1 0 Log 10 cfu/g Day from enrolment 2) Bacterial load is an stable trait Sibila O et al, AJRCCM 2019
Sibila O et al, AJRCCM 2019 3) Response to inhaled aztreonam was evident only in patients with high BL in the AIR-BX studies
Crichton M, et al. Eur Respir J 2020
Non-published data
EOSINOPHILS J Allergy Clin Immunol 2020 Lancet Resp Med 2018 GOLD 2022
RIBRON REGISTRY N=906 THRESHOLD 100 c/ML Wang et al, Int J Environ Res Public Health 2021
22,6% >300 c/mL Shoemark et al, Am J Respir Crit Care Med 2022 (in press)
Shoemark et al, Am J Respir Crit Care Med 2022 (in press)
Shoemark et al, Am J Respir Crit Care Med 2022 (in press)
. .. . . . . . . . . . . . : .. . . . . . . . . . : .. . . . . . . . . . : Volatile Organic Compounds (VOCs) E-nose
Resp Med 2014 Am J Respir Crit Care Med 2009
Resp Med 2018
Oliveira L et al, Clin Chem Acta 2021 Control (n=9) Bronchiectasis (n=13) Bronchiectasis with P.aeruginosa (n=12)
-Gas Chromatography-Mass Spectometry (GC-MS) Oliveira L et al, Clin Chem Acta 2021
¿mucoactive treatments? ¿inhaled antibiotics? ¿macrolides? ¿antiinflamatories therapies? CONCLUSIONS Mucins AMP, Bacterial load NETs Eosiophils (ICS??) Neutrophil Elastase (Brensocatib?)
ACKNOWLEDGMENTS University of Dundee (Scotland, UK) -James D Chalmers -Amelia Shoemark -Holly R Keir University of Milano (Italy) -Stefano Aliberti -Martina Oriano -Andrea Gramegna Hospital Clínic, IDIBAPS -Belen Solarat -Silvia Morales -Lídia Perea -Rosa Faner -Tamara Garcia -Núria Mendoza -Alvar Agustí Hospital Sant Pau, IIB -Ana Rodrigo-Troyano -Guillermo Suarez-Cuartin -Elisabet Cantó -Silvia Vidal
osibila@clinic.cat

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03 BRN Research Forum Bronquiectasias. Parte III por Oriol Sibila