MANAGEMENT OF COPD EXACERBATIONS. WISIA WEDZICHA University College London, London, UK

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1 MANAGEMENT OF COPD EXACERBATIONS WISIA WEDZICHA University College London, London, UK

2 HOSPITALISATIONS IN THE UK Walker P, Calverley PMA. Lancet 2003

3 MORTALITY AFTER ADMISSION WITH COPD EXACERBATION % mortality Connors et al AJRCCM Mo 6Mo 12Mo 24Mo

4 IMPORTANCE OF EXACERBATIONS Poorer Quality of Life Greater Airway Inflammation Frequent Exacerbator Higher Mortality Faster Decline in Lung Function

5 EXACERBATION SEVERITY How is exacerbation severity determined? TYPE OF EXACERBATION THERAPY NATURE OF SYMPTOMS, SYMPTOM SCORES AND EXACERBATION LENGTH UNDERLYING DISEASE SEVERITY AND C0- MORBIDITY HOSPITAL ADMISSION RESPIRATORY FAILURE DEATH BIOMARKERS? LUNG FUNCTION EXACT-PRO

6 ALL EXACERBATIONS BY MONTH OF STUDY: from East London COPD cohort O N D J F M A M J J A S Y1 Y3 Y5

7 RESPIRATORY VIRUSES AND EXACERBATIONS Coronavirus Coinfection Up to 60% of COPD exacerbations associated with viruses More often found in sputum than in nasal samples Chlamydia Pneumoniae RSV Serology Adenovirus Parainfluenza Influenza B Rhinovirus Influenza A Seemungal et al Am J Respir Crit Care Med 2001 Seemungal et al ERJ 2000 Rohde Thorax 2003

8 REDUCTION IN EXACERBATION TRIGGERS Smoking cessation Vaccination Anti virals Pollution control Occupational factors

9 From Wedzicha, JA, Seemungal T Lancet 2007

10 ORAL STEROIDS AT COPD EXACERBATION DATA FROM HOSPITAL ADMISSIONS 100 Davies et al Lancet Corticosteroidtreated group Placebo group 0 25 Admission Day 1 Day 2 Day 3 Day 4 Day 5 Discharge Time point of measurement

11 ORAL PREDNISOLONE AND RECOVERY Seemungal et al Am J Respir Crit Care Med 2000 No Prednisolone Prednisolone Median (IQR) n Median (IQR) n p Rate PEFR recovery (ml/min/day) 0.44 ( 1.85 to 1.16) ( 4.55 to 0.39) Time to next exacerbation (days) from day of onset of initial exacerbation 60 (30 to 108) (47.5 to 177)

12 AMINOPHYLLINE AT COPD EXACERBATIONS Duffy et al Thorax 2005 Copyright 2005 BMJ Publishin Group Ltd.

13 EXACERBATION BACTERIAL ISOLATES % H. flu Strep M catt 1 Pseud Staph H paraflu Klebsiella NSG BACTERIA

14 ISOLATION OF BACTERIA BY PCR Perera et al BTS 2006 Isolation rates were higher by RT-PCR than by culture 40.00% 35.00% 30.00% 25.00% 20.00% 15.00% 10.00% 5.00% 0.00% * SP HI MC * p<0.001 Culture Rt-PCR

15 RELATIVE RISK OF EXACERBATION AND BACTERIAL STRAIN CHANGE Exacerbation visits % % of exacerbation visits were assoaciated with a new strain, compared to 15% of visits when no new strain was found P< New strain No new For H Influenzae, S pneumoniae, M Cattarhalis Sethi et al NEJM 2002

16 RCT of ANTIBIOTIC THERAPY Anthonisen et al Ann Intern Med Type 1 Type 2 Type 3 Mean FEV1 at 33.9% predicted Placebo Antibiotic 3 major symptoms 2 major symptoms 1 major symptom 1 minor symptom

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19 Moxifloxacin treatment for 5 days provides superior clinical cure rates in AECB vs standard therapy (MOSAIC) Patients (%) Moxifloxacin (n=354) Comparators (n=376) % CI: 1.4, Clinical cure Comparators (all given for 7 days): amoxicillin 500 mg tds (n=88); clarithromycin 500 mg bd (n=114); or cefuroxime 250 mg bd Clinical cure is return to pre-exacerbation status Wilson et al. CHEST 2004; 125:

20 Percent of patients MOSAIC: REQUIREMENT FOR ADDITIONAL ANTIBIOTIC THERAPY (PP POPULATION) Moxifloxacin (n=274) Comparators (n=298) p= Requirement for additional antibiotic Wilson et al. CHEST 2004; 125:

21 Days LONGER TIME TO NEXT EXACERBATION WITH MOXIFLOXACIN VS STANDARD THERAPY Moxifloxacin (n=324) Comparators (n=319) p= * Mean number of days to new AECB * Reporting period=from randomization up to new AECB occurring within the 9-month follow-up (ITT population) Wilson et al. CHEST 2004; 125:

22 Patients not experiencing composite event (%) MOSAIC: MOXIFLOXACIN SIGNIFICANTLY INCREASES TIME TO COMPOSITE EVENT FOR 5 MONTHS Moxifloxacin Comparator p= Reporting period: from randomization up to 9 months post-study therapy Log rank test showed statistically significant superiority of moxifloxacin for up to 5 months post-treatment *Composite event: treatment failure and/or new exacerbation and/or any further antibiotic treatment Anzueto et al. Poster based in abstract in CHEST 2003; 124: 134S-a

23 Patients not experiencing composite event (%) MOSAIC: MOXIFLOXACIN SIGNIFICANTLY INCREASES TIME TO TREATMENT FAILURE COMPOSITE EVENT* Stratification patients with an exacerbation 6 months prior to randomization (n=320): moxifloxacin is superior (p=0.01) to comparator Moxifloxacin Comparator p= Time since randomization (months) *Composite event: treatment failure and/or new exacerbation and/or any further antibiotic treatment Anzueto et al. Poster based in abstract in CHEST 2003; 124: 134S-a

24 Patients not experiencing composite event (%) MOSAIC POST HOC ANALYSIS: TIME TO FIRST COMPOSITE EVENT IN PATIENTS 65 YEARS Moxifloxacin Comparator n= p= Time since randomization (months) Wilson et al. Thorax 2006; 61:

25 Patients not experiencing composite event (%) MOSAIC POST HOC ANALYSIS: TIME TO FIRST COMPOSITE EVENT IN PATIENTS WITH 4 EXACERBATIONS IN THE PREVIOUS YEAR Moxifloxacin Comparator n= p= Time since randomization (months) Wilson et al. Thorax 2006; 61:

26 SIGNIFICANCE OF TREATMENT DELAY AND RECOVERY TIME Wilkinson et al AJRCCM 2004 Total Recovery Time Prodrome Treatment Delay Treated Recovery Time Exacerbation Onset Initiation of Treatment

27 Symptom recovery time (days) SYMPTOM ONSET AND EARLY START OFTHERAPY P< Patients who receive prompt therapy after symptom onset are likely to recover more rapidly than are patients whose treatment is delayed Wilkinson et al. Am J Respir Crit Care Med. 2004;169: Delay between onset and treatment (days)

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29 UNADJUSTED OUTCOMES BY ANTIBIOTIC EXPOSURE Rothberg, M. B. et al. JAMA 2010;303:

30 ASSOCIATION OF EARLY ANTIBIOTIC TREATMENT VS LATE OR NO TREATMENT WITH COST AND LENGTH OF STAY Rothberg, M. B. et al. JAMA 2010;303: Copyight restrictions may apply.

31 Housebound % of patients Symptom count EXACERBATION RECOVERY Donaldson et al AJRCCM OPEN CIRCLES 45 3 CLOSED CIRCLES Days

32 EXACERBATION CLUSTERING Hurst et al AJRCCM Exacerbations 1923 Exacerbation intervals 633 Exacerbations occurred between 3 and 8 weeks, 103 (19.4%) more than that predicted by the exponential function (p=0.040).

33 CRP AND EXACERBATION RECOVERY P=0.03 Perera et al ERJ 2007

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35 EXACERBATIONS: REPORTED AND UNREPORTED % not reported to study team (UNREPORTED EXACERBATIONS) Total Rep Unrep Seemungal et al AJRCCM 1998

36 IMPORTANCE OF UNREPORTED EXACERBATIONS Wilkinson et all AJRCCM 2004 SGRQ Rho = -0.22, p = = Total < 25% > 75% % Exacerbations Treated

37 RELATION BETWEEN EXACERBATION THERAPY AND HOSPITALISATION P<0.04 Wilkinson et al AJRCCM 2004

38 CONCLUSIONS Therapy with oral antibiotics and steroids are associated with both short term and long term outcomes. Prompt management of exacerbations is essential Careful monitoring of exacerbation recovery and follow up is required COPD patients must be encouraged to report and treat exacerbations.