Pulmonary Exacerbations: Out of the Wilderness

1. Pulmonary Exacerbations:Out of the Wilderness Patrick A. Flume, M.D. Medical University of South Carolina D. R. VanDevanter, Ph.D. Case Western Reserve University School of Medicine

2. MUSC Cystic Fibrosis Team

3. Dictionary definition of exacerbation • Exacerbate (transitive verb) • To make more violent, bitter, or severe • Exacerbation (noun) • A worsening. In medicine, exacerbation may refer to an increase in the severity of a disease or its signs and symptoms.

4. Clinician definition of (pulmonary) exacerbation? “I shall not today attempt further to define [it] … within that shorthand description; and perhaps I could never succeed in intelligibly doing so. But I know it when I see it …” Supreme Court Justice Potter Stewart Jacobellis v. Ohio, 378 U.S. 184 (1964)

5. A typical definition of a CF pulmonary exacerbation is… • An acute worsening of signs and symptoms • Weight loss, cough, increased sputum, hemoptysis, malaise accompanied by… • An acute decrease in lung function (i.e. FEV1)

6. A typical definition of a CF pulmonary exacerbation is … signs /symptoms FEV1 better Worsening of clinical status and FEV1 Status intervene worse Time

7. But, are all exacerbations acute events? signs /symptoms FEV1 better Status intervene worse Time

8. But, are all exacerbations acute events? encounter better Status intervention worse Time

9. Why are exacerbations important? • Resource-intensive to manage • Lieu et al., Pediatrics. 1999;103:e72 • Ouyang et al., Pediatr Pulmonol. 2009;44:989-96 • Negative effect on patient quality of life • Orenstein et al., Chest. 1990;98:1081-4 • Bradley et al., Eur Respir J. 2001;17:712-5 • Britto et al., Chest. 2002;121:64–72. • Associated with decreased survival • Liou et al., Am J Epidemiol. 2001;153:345-52 • Mayer-Hamblett et al., AJRCCM 2002;166:1550-5 • Emerson et al., Pediatr Pulmonol. 2002;34:91-100 • Ellaffi et al., AJRCCM 2005;171:158-64.

10. Why are exacerbations important? They occur frequently PEx treated with IV antibiotics in 2010 Among 26,351 patients in the 2010 CFF Registry

11. Antibiotic treatments by age group:Epidemiologic Study of Cystic Fibrosis Antibiotic Treatments for PEx, 2003-2005 Wagener et al., Ped Pulmonol 2008;S31:359

12. Why are exacerbations important? They occur frequently PEx treated with IV antibiotics in 2010 PEx treated with any antibiotics (estimated) Among 26,351 patients in the 2010 CFF Registry

13. Despite the frequency of these events we still find ourselves wandering in the wilderness

14. Cystic Fibrosis Pulmonary Guidelines: Treatment of Pulmonary Exacerbations Site of treatment (home vs. hospital) Chronic medications Inhaled plus IV tobramycin Airway clearance 1 vs. 2 antibiotics for Pseudomonas Aminoglycosides: once daily v. multidose Continuous infusion -lactam antibiotics Duration of antibiotics Routine synergy testing Corticosteroids I B* I B* I C I I D I about antibiotics *Consensus recommendation (see previous guidelines) Am J Respir Crit Care Med 2009; 180: 802-808

15. Classical approach to pulmonary exacerbation management Bacteria cause exacerbations Antibiotics cure them Old Testament

16. Matters of faith • We know an exacerbation when we see it • Antibiotics improve outcomes

17. Matters of faith • We know an exacerbation when we see it • Do clinicians share the same “vision”? • Has our collective vision changed?

18. Do clinicians share the same vision? < 18 years old ≥ 18 years old 100% 100% 80% 80% Patients Treated w/IVs 60% 60% 40% 40% 20% 20% 0% 0% Care Centers Care Centers 30 30 Median Days Treated 20 20 10 10 0 0 Care Centers Care Centers CFF Center Director’s Report, 2009

19. Has our collective vision changed? Exacerbations are associated with impairment of lung function 2.0 Lowest PFT decile 1.6 1.2 Highest PFT decile Mean IV treatments/yr 0.8 0.4 0 40% 60% 120% 100% 80% Mean FEV1 % predicted Goss and Burns, Thorax 2007;62:360-7

20. Improving FEV1 in the US CF cohort:1995-2005 6-12 yrs 13-17 yrs Mean FEV1 (% predicted) 18-24 yrs >25 yrs Year VanDevanter et al., Pediatr Pulmonol 2008; 43:739-44

21. Reducing risk of exacerbation:an important clinical trial outcome • Dornase alfa • Fuchs et al., N Engl J Med. 1994;331:637–642 • Quan et al., J Pediatr. 2001;139(6):813-820 • Inhaled antibiotics • Ramsey et al., N Engl J Med. 1999;340:23–30 • Murphy et al., PediatrPulmonol. 2004;38:314–320 • McCoy et al., AJRCCM. 2008;178:921-8 • Oral macrolides • Saiman et al., JAMA. 2003;290(13):1749-1756 • Clement et al., Thorax 2006;61(10):895-902 • Hydrators • Elkins et al., N Engl J Med. 2006;354:229–240

22. Has our collective vision changed? If exacerbation incidence inversely correlates with FEV1 % predicted1… and mean FEV1 for the US CF cohort has steadily improved over the past decades2… then shouldn’t the mean rate of IV treatment for exacerbations be falling? 1Goss and Burns, Thorax 2007; 62: 360-367 2VanDevanter et al., Pediatr Pulmonol 2008; 43: 739-744

23. Annual IV antibiotic treatment incidence:US CF cohort 1994 - 2009 Patients treated at least once with IVs for exacerbation CFF Patient Registries, 1994 - 2009

24. Matters of faith • We know an exacerbation when we see it • Do clinicians share the same “vision”? • Has our collective vision changed? • Antibiotics improve outcomes • Which outcomes? • How do we measure them?

25. Antibiotics are a common treatmentfor an exacerbation signs /symptoms FEV1 better Status intervene worse Time

26. What is the evidence that antibiotics are necessary to treat exacerbation?

27. Killing the bacteria will solve… which problems? • Signs and symptoms • Antibiotics improve signs and symptoms • There has never been a demonstration that antibiotics change the time or magnitude of sign and symptom response

28. Killing the bacteria will solve… which problems? • Signs and symptoms • There has never been a demonstration that antibiotics change the time or magnitude of sign and symptom response • FEV1 • Antibiotics improve FEV1 • How is treatment duration related to response?

29. Killing the bacteria will solve… which problems? • FEV1 • Antibiotics improve FEV1 historical exacerbation definition treatment goal better D Status signs /symptoms FEV1 antibiotics worse Time treatment duration Sanders DB, et al. Am J Respir Crit Care Med 2010; 182:627–632

30. Antibiotics improve FEV1 Exacerbating Patients Regelmann et al., N = 8 Relative FEV1 Response Time (days) Regelmann et al., Am Rev Respir Dis 1990;141:914-21

31. Antibiotics improve FEV1 Exacerbating Patients Regelmann et al., N = 5 Collaco et al., N = 492 VanDevanter et al., N = 50 VanDevanter et al., N = 45 Relative FEV1 Response Time (days) Regelmann et al., Am Rev Respir Dis 1990;141:914-21 Collaco et al., AJRCCM 2010; 182(9):1137-1143 VanDevanter et al., Respir Res, 2010;11:137

32. Antibiotics improve FEV1 Stable Patients Ramsey et al., N = 262 McCoy et al., N = 135 Relative FEV1 Response Time (days) Ramsey et al., New Eng J Med 1999; 340: 23–30 McCoy et al., Am J Respir Crit Care Med 2008; 178: 921-928

33. Hypothesized causes of exacerbations • Bacteria • New or more bacteria • Change in virulence

34. This is the information we are accustomed to:

35. Does abundance matter? 9 8 Total Viable Pa Count (log10 CFU/g) 7 6 5 4 3 Exacerbation (N = 16) Tunney MM et al: Thorax 2011; 66: 579-584

36. Does abundance matter? 9 8 Total Viable Pa Count (log10 CFU/g) 7 6 5 4 3 Exacerbation (N = 16) End of Treatment (N = 16) Tunney MM et al: Thorax 2011; 66: 579-584

37. Does abundance matter? 9 8 Total Viable Pa Count (log10 CFU/g) 7 6 5 4 3 Exacerbation (N = 16) End of Treatment (N = 16) Stable (N = 9) Tunney MM et al: Thorax 2011; 66: 579-584

38. You all look alike to me

39. How diverse is the infecting population? CF Sputum Culture in lab Measure phenotypes related to infection pathogenesis Courtesy of Ben Staudinger and Pradeep Singh

40. CF Pseudomonas populations are highly diverse Sub-population + + - - + - 1 = - + - + + + = 2 50 Population diversity based on tests 40 30 % of total Rare populations may be very important 20 10 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Subpopulations Growth w/o AA Rhamnolipids Ciprofloxacin Tobramycin Ceftazidime Swimming Courtesy of Ben Staudinger and Pradeep Singh

41. Yet the isolates are genetically-related siblings L L Isolates with diverse phenotypes have the same genetic fingerprint lab strains Courtesy of Ben Staudinger and Pradeep Singh

42. Diversity arises from evolution of the infecting strain Genetic variant arises * * * * * * Initial strain * Diverse infecting community

43. Some subpopulations are more virulent than others P. aeruginosa LDH release Airway epithelia P. aeruginosa subpopulations Courtesy of Ben Staudinger and Pradeep Singh

44. The relative abundance of subpopulations changes at exacerbation onset 2 4 6 8 10 12 14 14 18 20 22 24 Could increases in these subpopulations have caused the flare? Well period 50 40 % of total 30 20 10 0 Exacerbation ("sick") period 40 30 % of total 20 10 0 Courtesy of Ben Staudinger and Pradeep Singh

45. How would these bacteria move in the airways?

46. Community structure around exacerbation Even more on bacterial diversity1, 2 J. LiPuma - unpublished 1Kong R et al: Abstract 260; 2Planet W et al: Abstract 262

49. Microbiology and treatment • The “old ways” of thinking about bacteria and exacerbation are not helpful • clinical micro doesn’t predict response • The search for better models of the bacterial role in exacerbation arises in part from recognition of this problem • Assumption: improved understanding of bacterial role in exacerbation will lead to: • More rationale selection of antibiotics for treatment • Better treatment outcomes

50. Hypothesized causes of exacerbations • Bacteria • New or more bacteria • Change in virulence • Environmental • Pollution • GERD1 • Viral2-4 • Other (e.g. ABPA) 1Boesche R et al: Abstract 488; 2Flight W et al: Abstract 265; 3Cochrane ER et al: Abstract 319; 4Kong M et al: Abstract 78