Ο φαινότυπος των συχνών παροξύνσεων στην ΧΑΠ stavrostryfon@yahoo.gr
Venn Diagram(s) Friedlander AM, COPD 2007
2009 1ος φαινότυπος (20,2%) 1. IL8 πτύελα 2. Ουδετερόφιλα πτυέλων 3. TNFa πλάσματος 3ος φαινότυπος (15,1%) 1. FEV1 2. Απαντητικότητα στη βρογχοδιαστολή 2ος φαινότυπος (18,2%) 1. Εωσινόφιλα πτυέλων 2. FeNO 4ος φαινότυπος (11,4%) 1. CRP
Κλινικό Προσανατολισμό: - Πρόγνωση - θεραπευτική προσέγγιση - Κλινική και Ερευνητική αξία
INTACT 1: Lack of benefit in combination with chemotherapy Proportion event free 1.0 0.8 0.6 0.4 Median survival, months 1-year survival rate, % Log rank vs placebo WE DIDN T KNOW ABOUT EGFR MUTATION 9.92 43 0.7759 (p=0.4377) 9.86 41 1.0290 (p=0.3034) Gefitinib 500 mg/day Gefitinib 250 mg/day Placebo 11.07 45 0.2 At risk 0.0 0 4 8 12 16 20 24 Survival time (months) 1093 898 641 463 152 11 Population: intention to treat
K Kobayashi et al, P ASCO 2009
PATIENT RECALLED EXACERBATION FREQUENCY AND ACTUAL EXACERATION FREQUENCY % patients by recall 87.1% 86.8% Data from London COPD cohort % Recalling themselves to be IE % Recalling themselves to be FE Sensitivity 86.8% Specificity 87.1% Positive predictive value 0.81 infrequent exacerbators Classified by diary cards frequent exacerbators Quint et al ERJ In press
FREQUENT COPD EXACERBATORS AMONG COPD SUBJECTS WITH OR WITHOUT CHRONIC COUGH AND SPUTUM Burgel P. et.al. Chest 2009;135:975-982
GOLD κριτήρια: η ΧΑΠ χαρακτηρίζεται από την ελάττωση της εκπνευστικής ροής, που εμφανίζει άλλοτε άλλου βαθμού μερική αναστρεψιμότητα
Microsatellite Instability and ECOPD frequency Makris D, ERJ 2008
Microsatellite Instability and ECOPD frequency Makris D, ERJ 2008
PRedicting Outcome using systemic Markers In Severe Exacerbations of COPD - The PROMISE-COPD Cohort Study Baseline 6 Mo 12 Mo 18 Mo Final Visit Inclusion SV 4 History / Vitals SF-36 / SGRQ MMRC / LRTI VAS Biomarkers Spirometry 6MWT/ Sputum SV 1 Scheduled Vitals / Diary Questionnaires Biomarkers 6MWT/Sputum UVamb UV FU SV UVhosp UV FU 2 SV 3 Scheduled Vitals / Diary Questionnaries Biomarkers 6MWT/Sputum Scheduled Vitals / Diary Questionnaires Biomarkers 6MWT/Sputum History / Vitals SF-36 / SGRQ MMRC/LRTI VAS Biomarkers Spirometry 6 MWT / Sputum Unscheduled out-patient History / Vitals / SF-36 / SGRQ / MMRC / LRTI VAS Spirometry / Bimoarkers Unscheduled in-patient History / Vitals / SF-36 / SGRQ / MMRC / LRTI VAS Spirometry / Biomarkers Chest-X-rax / Thorax-CT Scan Sputum / Bronchoscopy Echocardiography Stolz D, University Hospital Basel, Switzerland
DEPRESSION AND COPD EXACERBATION FREQUENCY p = 0.03 Quint et al ERJ 2008
Jeffrey H. Jennings, Bruno DiGiovine, Dany Obeid and Cathy Frank The Association Between Depressive Symptoms and Acute Exacerbations of COPD Lung. 2009 Mar-Apr;187(2):128-35. Epub 2009 Feb 7.
ECLIPSE 1 year data Exacerbation rates increased with GOLD stage, irrespective of severity 22%, 33% and 47% of GOLD stage II, III and IV subjects respectively, were frequent exacerbators ( 2/yr) in year 1 7%, 18% and 33% of GOLD stage II, III and IV subjects respectively, were hospitalised for an exacerbation in year 1
ECLIPSE EXACERBATION ANALYSIS
Ερωτήσεις για την ECLIPSE Ποια είναι η σχέση μεταξύ συχνότητας παροξυσμών και σταδίου της ΧΑΠ (GOLD stage)? Ο φαινότυπος Frequent Exacerbator μήπως υπάρχει ανεξάρτητα από την FEV 1? Πόσο σταθερά εμφανιζόμενος είναι ο φαινότυπος αυτός σε βάθος 3 ετών? 2164 patients across 46 sites in 12 countries 2138 with follow-up data for this analysis 1679 completed 3 years follow up
Methodology Recruitment Baseline Assessment
Methodology YEAR PRIOR Number of courses of antibiotics/steroids / hospitalizations for exacerbation in prior year asked and recorded Recruitment Baseline Assessment
Methodology YEAR PRIOR YEAR 1 Number of courses of antibiotics/steroids / hospitalizations for exacerbation in prior year asked and recorded Recruitment Baseline Assessment Number of courses of antibiotics/steroids / hospitalizations for exacerbation in year one COUNTED
Methodology YEAR PRIOR YEAR 1 Number of courses of antibiotics/steroids / hospitalizations for exacerbation in prior year asked and recorded Recruitment Baseline Assessment Number of courses of antibiotics/steroids / hospitalizations for exacerbation in year one COUNTED COUNTED in CRFs: data on dates of onset and resolution, and therapy and hospitalization of clinician diagnosed exacerbations
Methodology YEAR PRIOR YEAR 1 YEAR 2 YEAR 3 Number of courses of antibiotics/steroids / hospitalizations for exacerbation in prior year asked and recorded Recruitment Baseline Assessment Number of courses of antibiotics/steroids / hospitalizations for exacerbation in year one COUNTED Number of courses of antibiotics/steroids / hospitalizations for exacerbation in year two COUNTED Number of courses of antibiotics/steroids / hospitalizations for exacerbation in year three COUNTED
Methodology YEAR PRIOR YEAR 1 YEAR 2 YEAR 3 Number of courses of antibiotics/steroids / hospitalizations for exacerbation in prior year asked and recorded Recruitment Baseline Assessment Number of courses of antibiotics/steroids / hospitalizations for exacerbation in year one COUNTED Number of courses of antibiotics/steroids / hospitalizations for exacerbation in year two COUNTED Number of courses of antibiotics/steroids / hospitalizations for exacerbation in year three COUNTED ANALYSIS 1 How do baseline variables relate to observed exacerbations in year 1?
Methodology YEAR PRIOR YEAR 1 YEAR 2 YEAR 3 Number of courses of antibiotics/steroids / hospitalizations for exacerbation in prior year asked and recorded Recruitment Baseline Assessment Number of courses of antibiotics/steroids / hospitalizations for exacerbation in year one COUNTED Number of courses of antibiotics/steroids / hospitalizations for exacerbation in year two COUNTED Number of courses of antibiotics/steroids / hospitalizations for exacerbation in year three COUNTED ANALYSIS 1 How do baseline variables relate to observed exacerbations in year 1? ANALYSIS 2 How stable is exacerbation frequency over 3 observed years, and in relation to patient self report?
Exacerbation in prior year most associated with occurrence of exacerbation Parameters ordered by strength of association (left to right) ECLIPSE 1 year data Hurst JR, et al. N Engl J Med. 2010;363:1128-38
0 1 2 ECLIPSE - STABILITY OF THE FREQUENT EXACERBATOR PHENOTYPE Year 1 Year 2 Year 3 0% % % % % % 0 1 2 0% % % % % % 0 1 2 0% % % % % % 71% of Frequent Exacerbators in Year 1 and Year 2 were Frequent Exacerbators in Year 3
ECLIPSE - STABILITY OF THE FREQUENT EXACERBATOR PHENOTYPE Year 1 Year 2 Year 3 0% % % % % % 0 1 2 0% % % % % % 0 1 2 0% % % % % % 0 1 2 0% % % % % % 0 1 2 0% % % % % % 0 1 2 0% % % % % % 0 1 2 74% of patients having no exacerbations in Years 1 and Year 2 had no exacerbators in Year 3
FEV 1 DECLINE OVER 4 YEARS AND EXACERBATION FREQUENCY 0.95 Frequent exacerbators 0.90 Infrequent exacerbators FEV 1 (l) 0.85 0.80 0.75 0 1 2 3 4 Years Donaldson et al Thorax 2002
EFFECT OF EXACERBATIONS ON DISEASE PROGRESSION Hansel T, Barnes P Lancet 2009
LONGITUDINAL CHANGES IN TIME SPENT OUTDOORS AND EXACERBATION FREQUENCY Donaldson et al. AJRCCM 2005
Συχνές παροξύνσεις, έκπτωση FEV 1 και επιβίωση 0.95 1.0 Χωρίς παροξύνσεις FEV 1 (L) 0.90 0.85 0.80 Probability of surviving 0.8 0.6 0.4 0.2 3 4 παροξύνσεις 1 2 παροξύνσεις 0.75 0 1 2 3 4 Years 0.0 0 10 20 30 40 50 60 Time (months) Σπάνιες παροξύνσεις (<2.92/έτος) Συχνές παροξύνσεις (>2.92/έτος) * Παρακολούθηση για 4 έτη Συχνότητα παροξύνσεων & 5ετής επιβίωση Donaldson GC, Thorax 2002 Soler-Cataluna JJ, Thorax 2005
EXACERBATION RECOVERY Donaldson et al AJRCCM 2005 50 OPEN CIRCLES Housebound % of patients 45 40 35 3 CLOSED CIRCLES 2 1 Symptom count 30 0-14 -7 0 7 14 21 28 35 Days
EXACERBATION FREQUENCY AND CRP RECOVERY Perera et al ERJ 2007
DATA FROM THIN GP DATABASE EXACERBATION FREQUENCY AND MYOCARDIAL INFARCTION Donaldson et al Chest 2010
EXACERBATION FREQUENCY IS A SUSCEPTIBILITY PHENOTYPE Susceptible Patient Non-Susceptible Patient Sufficient Trigger EXACERBATION
FREQUENT COPD EXACERBATORS O Frequent exacerbator μπορεί να εντοπισθεί σε όλα τα στάδια της ΧΑΠ κατά GOLD O Frequent exacerbator μπορεί να αναγνωρισθεί ανακαλώντας το ιστορικό του με προσεκτικές/στοχευμένες ερωτήσεις Οι συχνές παροξύνσεις αποτελούν την πρώτη ένδειξη για την ύπαρξη του συγκεκριμένου φαινοτύπου και η σχετική σταθερότητα της συχνότητάς τους πιστοποιεί την παρουσία του Είναι σημαντικός φαινότυπος για στοχευμένες θεραπείες
Severity of airflow limitation Frequency and severity of exacerbations Comorbidities