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Severe asthma: A review of the current status and a report of the ERS/ATS Task Force Δύσκολο άσθμα Μίνα Γκάγκα ΝΝΘΑ
Disclosures Research grants Glaxo-Smith-Kline, Astra-Zeneca, Sherring-Plough, Novartis, Merck, Τeva, Cephalon
Άσθμα: Οι περισσότεροι ασθματικοί ελέγχονται με μικρές ή μέτριες δόσεις ICS+LABA 2-12% των ασθματικών ασθενών 50% του κόστους Σοβαρές επιπτώσεις στην υγεία και QoL Τι κάνει το άσθμα δύσκολο?
Genes Gene expression Airway histology Lung function The patient Severe asthma phenotyping
Assessment of severity - NAEPP Components of severity Severe asthma Impairment Symptoms Throughout the day Nighttime awakenings SABA use for relief Interference of daily activity Often x7/week Several times per day Extremely limited Lung function FEV1< 60% Risk Exacerbations requiring oral steroids >2/year Consider frequency and severity
Assessment of control - NAEPP Components of severity Very poorly controlled Impairment Symptoms Throughout the day Nighttime awakenings SABA use for relief Interference of daily activity Often x7/week Several times per day Extremely limited Lung function FEV1< 60% Risk Validated questionnaire ATAQ ACQ ACT Exacerbations requiring oral steroids 3-4 NA <15 >2/year Consider frequency and severity
Severe asthma: A review of the current status and a report of the ERS/ATS Task Force Members Fan Chung/Sally Wenzel Ian Adcock, Eric Bateman, Elisabeth Bel, Eugene Bleecker, Louis-Philippe Boulet, Chris Brightling, Andy Bush, Bill Busse, Mario Castro, Pascal Chanez, Sven- Eric Dahlen, Ratko Djukanovic, Urs Frey, Mina Gaga, Peter Gibson, Qutayba Hamid, Thais Mauad, Gerry Teague. (Jan Brozek, Kevin Wilson)
Σοβαρό άσθμα, ορισμός, ERS/ATS TF Σοβαρό ορίζεται το άσθμα που χρειάζεται αγωγή με υψηλές δόσεις εισπεομένων στεροειδών (ICS) και ένα ακόμη ρυθμιστικό φάρμακο (και/ή συστημικά στεροειδή) ώστε να παραμείνει ελεγχόμενο Ή παραμένει μη- ελεγχόμενο
Σοβαρό/δύσκολο άσθμα, ορισμός ERS/ATS TF 1. Άσθμα δυσάγωγο/ανθιστάμενο σε αγωγή 2. Άσθμα που εμμένει λόγω της παρουσίας συννοσηρότητας πού δεν ελέγχεται πχ ιγμορίτις, παχυσαρκία, επαγγελματική έκθεση... Ο ορισμός αυτός δεν περιλαμβάνει το άσθμα που δεν λαμβάνει αγωγή
Διάγνωση Είναι άσθμα?. Είναι σοβαρό άσθμα?. Είναι ελεγχόμενο ή μη-ελεγχόμενο?
Initial evaluation of uncontrolled /difficult asthmatic Σπιρομέτρηση Πριν και μετά βρογχοδιαστολή Κλινική εκτίμηση Είναι άσθμα? Υπάρχουν ερεθιστικοί παράγοντες ή συννοσηρότητες? Παίρνει κατάλληλη αγωγή? Συμμόρφωση?
Επανεκτίμηση Είναι άσθμα? Εκτίμηση ελέγχου (σπιρομέτρηση και ACQ). Κάθε 2 εβδομάδες έως 3 μήνες Τουλάχιστον 6μηνη παρακολούθηση
Εάν είναι ΣΑ Περισσότερες πληροφορίες: a) Αλλεργίες? Εποχιακή, γύρεις, ζώα, υγρασία b) NSAIDs? πολύποδες, ιγμορίτις? c) Επάγγελμα? Υπήρξε αλλαγή? d) Λοίμωξη, βρογχίτις? e) Ορμόνες? Προεμμηνορρυσιακό? f) Συννοσηρότητες?
ten Brinke et al, ERJ 2005
Asthma Severity and Obesity in Women Varasso et al AJRCCM 2005
Αντιμετώπιση ΣΑ Χρειάζεται να σκεφτόμαστε: 1. Φαινότυπους 2. Ετερογένεια απόκρισης/αντοχή σε φάρμακα (CS/β-AR/LTRA) 3. Θεραπεία στοιχείων της νόσου: Φλεγμονή, ΒΥ, remodelling, 4. Συμμόρφωση 5. Νέα σκευάσματα 6. Πρόληψη
Υπάρχουν καλά καθορισμένοι φαινότυποι? Κλινικοί Type of exacerbation: rapid/slow Pattern of airflow obstruction (PEF) Fixed airflow obstruction Co-morbidities Παθολογοφυσιολογικοί Eosinophils and/ or neutrophils Structural change: remodelling Site of inflammation: large vs small airways Smooth muscle abnormality Genetic polymorphisms Φαρμακολογικοί Corticosteroid insensitivity (corticosteroid-dependent) b-adrenergic hyporesponsiveness
Asthma Phenotypes Cluster Analysis-SARP 5 phenotypes-clinical heterogeneity/ endotypes Moore W, AJRCCM 2010 Lötvall J,. J. Allergy Clin. Immunol. 2011 Wenzel S. Clin. Exp. Allergy 2012
Cluster analysis of clinical asthma phenotypes Haldar et al., Am J Respir Crit Care Med 2008
Treatment of severe asthma- GINA 2009
Corticosteroid responsiveness normal Mild asthma Steroid-responsive Severe asthma steroid-dependent Steroid resistant Dose of corticosteroid
Correlates in Asthma Poor Control, Inflammation Smooth muscle Exacerbations BHR Distal changes Asthma deaths Airflow impairment BHR Epithelium/RBM
Question. Should treatment guided by sputum eosinophil count, rather than treatment guided by clinical criteria alone, be used in patients with severe asthma? Simpson JL, AJRCCM 2005
Question Should treatment guided by sputum eosinophil count, rather than treatment guided by clinical criteria alone, be used in patients with severe asthma? Recommendation In adults with severe asthma, we suggest treatment guided by clinical criteria and sputum eosinophil counts performed in centres experienced in using this technique rather than by clinical criteria alone (conditional recommendation, very low quality evidence). In children with severe asthma, we suggest treatment guided by clinical criteria alone rather than by clinical criteria and sputum eosinophil counts (conditional recommendation, very low quality evidence).
Question. Should treatment guided by exhaled nitric oxide (FeNO), rather than treatment guided by clinical criteria alone, be used in patients with severe asthma? High FENO identified those severe asthma patients characterized by the greatest airflow obstruction and hyperinflation and most frequent utilization of emergency care in the previous year Dweik, AJRCCM 2010, Van Veen IH, ERJ 2008
Question. Should treatment guided by exhaled nitric oxide (FeNO), rather than treatment guided by clinical criteria alone, be used in patients with severe asthma? Recommendation We suggest that clinicians do not use FeNO to guide therapy in patients (adults or children) with severe asthma (conditional recommendation very low quality evidence). Values and preferences This recommendation places a higher value on avoiding additional resource expenditure and a lower value on uncertain benefit from monitoring FeNO.
Question. Should a monoclonal anti-ige antibody be used in patients with severe allergic asthma? Soler et al, ERJ 2001, Tzortzaki, et al., Pulm Phar Ther, 2012
Ασφάλεια Από 1 Ιουνίου 2003 έως 31 Δεκεμβρίου 2006, σε 57.300 ασθενείς (post-marketing safety database εκτίμηση), 124 περιστατικά αναφυλαξίας (0,2%). Προσεκτική ανάλυση αυτών των περιστατικών, όπου δηλώθηκε αλλεργική αντίδραση, από το AAAAI Omalizumab Joint Task Force κατέληξε σε νέα εκτίμηση του ποσοστού στο 0,09%. Corren Jet al, Expert Opin Drug Saf. 2011 AAAAI Omalizumab Joint Task Force 2011 Cox, L. et al. J Allergy Clin Immunol, 2007 Limb et al. J Allergy Clin Immunol 2007
Question. Should a monoclonal anti-ige antibody be used in patients with severe allergic asthma? Recommendation In patients with severe allergic asthma we suggest a therapeutic trial of omalizumab both in adults (conditional recommendation low quality evidence) and in children (conditional recommendation very low quality evidence).
Question. Should methotrexate be used in the treatment of severe asthma? Recommendation We suggest that clinicians do not use methotrexate in adult or pediatric patients with severe asthma (conditional recommendation low quality evidence).
Question. Should macrolide antibiotics be used in patients with severe asthma? Recommendation We suggest that clinicians do not use macrolide antibiotics in patients with severe asthma at any age for the treatment of asthma (conditional recommendation very low quality evidence). This recommendation places a relatively higher value on prevention of development of resistance to macrolide antibiotics, and relatively lower value on uncertain clinical benefits.
Question. Should antifungal agents be used in patients with severe asthma? Recommendation We suggest antifungal agents be used in patients with severe asthma and recurrent exacerbations of allergic bronchopulmonary aspergillosis(abpa) (conditional recommendation very low quality evidence). We suggest that clinicians do not use antifungal agents for the treatment of asthma in patients with severe asthma without ABPA irrespective of sensitization to fungi (i.e. positive skin prick test or fungus-specific IgE in serum) (conditional recommendation very low quality evidence).
Question. Should bronchial thermoplasty be used in patients with severe asthma? Castro et al,ajrccm 2010 Recommendation We recommend that bronchial thermoplasty is performed in patients with severe asthma only in the context of a formal clinical research setting (strong recommendation very low quality evidence).
Investigative treatments for severe asthma New combinations LABA + ICS; other combinations Anti-IL-5 (anti-eosinophil) Anti-TNFα (anti remodelling/inflammatory) Anti-IL-13 (anti-th2/anti-remodelling) Anti-neutrophilic approaches(anti-cxcr2) p38 MAPK inhibition (CS enhancer)
Effect of mepolizumab (anti-il-5) on exacerbations in severe eosinophilic asthma Cumulative No, of Exacerbations 120 100 80 60 40 20 0 Start of treatment 4 14 3 7 25 13 34 21 47 27 58 33 1 2 3 4 5 6 7 8 9 10 11 12 Month 69 36 79 40 85 44 97 49 108 Placebo 55 57 Mepolizumab 109 Haldar P. et al. N Engl J Med 360 : 973-984 (2009)
Characteristic Associations Specifically-targeted treatments Severe allergic asthma Eosinophilic asthma High eosinophil High IgE High IgE Recurrent exacerbations Anti-IgE (adults & children) Anti-IL4/IL-13 IL4Receptor Anti-IL5, Anti-IL-4/-13 IL-4R Neutrophilic asthma2 Corticosteroid insensitivity Bacterial infections Anti-IL-8 CXCR2 antagonists Anti-LTB4 (adults and children) Macrolides (adults and children)
Characteristic Associations Specifically-targeted treatments Chronic airflow obstruction Airway wall remodelling as increased airway wall thickness Anti-IL13 Recurrent exacerbations Eosinophils in sputum Reduced response to ICS ± OCS Anti-IL5 Anti-IgE (adults and children) Corticosteroid insensitivity High neutrophils in sputum 2 p38 MAPK inhibitors Theophylline (adults and children) Macrolides (adults and children)
Οι περισσότεροι ασθενείς θα βελτιωθούν μετά από Συστηματική διερεύνηση Αποφυγή εκλυτικών αιτίων Εξατομικευμένη θεραπεία
Οταν αντιμετωπίζουμε ΣΑ. Είναι σημαντικό να Συνυπολογίζουμε όλα τα προβλήματα και τις ανάγκες του ασθενούς και να δίνουμε εξατομικευμένη αγωγή Να μη δίνουμε μόνο φάρμακα αλλά να αντιμετωπίζουμε ολιστικά τον ασθενή-δίαιτα, κάπνισμα, άσκηση, υποστήριξη (ομάδα) Μακροχρόνια παρακολούθηση Chanez et al JACI 2007, Gaga et al, Curr Med Chem 2007