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 An acute decrease in lung function (i.e. FEV 1 ) accompanied by…

6. Status better worse Time intervene signs /symptoms FEV 1 Worsening of clinical status and FEV 1 A typical definition of a CF pulmonary exacerbation is …

7. Status better worse Time intervene signs /symptoms FEV 1 But, are all exacerbations acute events?

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

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 D I *Consensus recommendation (see previous guidelines) Am J Respir Crit Care Med 2009; 180: 802-808 about antibiotics

15. Classical approach to pulmonary exacerbation management III. B ACTERIA CAUSE EXACERBATIONS IV. A NTIBIOTICS CURE THEM III. B ACTERIA CAUSE EXACERBATIONS IV. A NTIBIOTICS 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? CFF Center Director’s Report, 2009 100% 80% 60% 40% 20% 0% 30 20 10 0 < 18 years old≥ 18 years old Median Days Treated Patients Treated w/IVs 30 20 10 0 100% 80% 60% 40% 20% 0% Care Centers

19. Has our collective vision changed? Goss and Burns, Thorax 2007;62:360-7 80% 60% 40% 100%120% 2.0 1.6 1.2 0.8 0.4 0 Mean IV treatments/yr Mean FEV 1 % predicted Highest PFT decile Lowest PFT decile Exacerbations are associated with impairment of lung function

20. Improving FEV 1 in the US CF cohort: 1995-2005 6-12 yrs 13-17 yrs 18-24 yrs >25 yrs Year Mean FEV 1 (% predicted) 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., Pediatr Pulmonol. 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 FEV 1 % predicted 1 … and mean FEV 1 for the US CF cohort has steadily improved over the past decades 2 … then shouldn’t the mean rate of IV treatment for exacerbations be falling? 1 Goss and Burns, Thorax 2007; 62: 360-367 2 VanDevanter 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. Status better worse Time intervene signs /symptoms FEV 1 Antibiotics are a common treatment for an exacerbation

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 FEV 1 – Antibiotics improve FEV 1 – How is treatment duration related to response?

29. Killing the bacteria will solve… which problems? FEV 1 – Antibiotics improve FEV 1 better worse Time antibiotics signs /symptoms FEV 1 Status treatment duration  treatment goal historical exacerbation definition Sanders DB, et al. Am J Respir Crit Care Med 2010; 182:627–632

30. Antibiotics improve FEV 1 Relative FEV 1 Response Time (days) Exacerbating Patients Regelmann et al., N = 8 Regelmann et al., Am Rev Respir Dis 1990;141:914-21

31. Antibiotics improve FEV 1 Relative FEV 1 Response Time (days) Regelmann et al., N = 5 Exacerbating Patients Collaco et al., N = 492 VanDevanter et al., N = 50 VanDevanter et al., N = 45 Collaco et al., AJRCCM 2010; 182(9):1137-1143 Regelmann et al., Am Rev Respir Dis 1990;141:914-21 VanDevanter et al., Respir Res, 2010;11:137

32. Antibiotics improve FEV 1 Relative FEV 1 Response Time (days) Ramsey et al., N = 262 Stable Patients McCoy et al., N = 135 McCoy et al., Am J Respir Crit Care Med 2008; 178: 921-928 Ramsey et al., New Eng J Med 1999; 340: 23–30

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? Tunney MM et al: Thorax 2011; 66: 579-584 Exacerbation (N = 16) 9 8 7 6 5 4 3 Total Viable Pa Count (log 10 CFU/g)

36. Does abundance matter? Tunney MM et al: Thorax 2011; 66: 579-584 Exacerbation (N = 16) End of Treatment (N = 16) 9 8 7 6 5 4 3 Total Viable Pa Count (log 10 CFU/g)

37. Does abundance matter? Tunney MM et al: Thorax 2011; 66: 579-584 Exacerbation (N = 16) End of Treatment (N = 16) Stable (N = 9) 9 8 7 6 5 4 3 Total Viable Pa Count (log 10 CFU/g)

38. You all look alike to me

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

40. CF Pseudomonas populations are highly diverse Ceftazidime Rhamnolipids Growth w/o AA Swimming Tobramycin Ciprofloxacin + + - - + - - + - + + + Sub- population 1 2 = = Courtesy of Ben Staudinger and Pradeep Singh Rare populations may be very important Subpopulations 123456789101112131415161718192021222324 0 10 20 30 40 50 Population diversity based on tests % of total

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

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

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

44. Courtesy of Ben Staudinger and Pradeep Singh The relative abundance of subpopulations changes at exacerbation onset 0 10 20 30 40 50 Well period % of total Exacerbation ("sick") period 0 10 20 30 40 % of total 24681012141820222414 Could increases in these subpopulations have caused the flare?

45. How would these bacteria move in the airways?

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

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 – GERD 1 Viral 2-4 Other (e.g. ABPA) 1 Boesche R et al: Abstract 488; 2 Flight W et al: Abstract 265; 3 Cochrane ER et al: Abstract 319; 4 Kong M et al: Abstract 78

51. Our problem(s) Exacerbations are an important clinical problem – Variable treatments must lead to variable outcomes We don’t understand the physiology of exacerbation – Room for many theories of “best” management Empirical tools to diagnose exacerbation and then to compare responses to different treatments are “underdeveloped” We can’t improve what we don’t measure

52. Patient-reported outcomes Important point of emphasis within FDA – Clinical Endpoint: “A characteristic or variable that reflects how a patient feels, functions, or survives” Historical precedents for PRO in CF – Cystic Fibrosis Questionnaire – Revised (CFQ-R) – Cystic Fibrosis Respiratory Symptom Diary (CFRSD) Ideal approach for transition from encounter- based to surveillance-based respiratory management Kraynack N, presented at NACFC 2010

53. Standardizing measurement of COPD exacerbations EXACT-Pro – Exacerbations of Chronic Pulmonary Disease Tool (EXACT) – Patient Reported Outcomes (PRO) 14-item daily diary – Reliable – Valid – Sensitive to changes during recovery from exacerbation Leidy NK et al Am J Respir Crit Care Med 2011; 183: 323-329

54. COPD exacerbation Exacerbation Prevention Trial Leidy et al. Value in Health 2010; 13: 965-975

55. Early intervention in pulmonary exacerbation - effect of monitored care - Aitken et al., NACFC 2011 Abstract 331: Workshop 08 50 40 0 Pulmonary exacerbations over 6 months Usual care (N = 16) Monitored care (N = 19) P = 0.19 30 20 10 P = NS

56. COPD exacerbation Acute Treatment Trial Leidy et al. Value in Health 2010; 13: 965-975

57. Advancing patient reported outcomes in children with cystic fibrosis Used CFRSD during 14 day treatment of exacerbations N=51, Age 13.2, 87.6% of diaries completed Conclusion: demonstrates feasibility and responsiveness Goss CH et al: Abstract 231

58. Update on the definition of a pulmonary exacerbation Working Group – Nancy K Leidy – Christopher Goss – Donald Patrick – Patrick Flume – Nathan Kraynack – Bruce Marshall Phase I – Review all CFRSD development documents – prepare an outline of the CFRSD briefing document – prepare a needs assessment Phase II – development of the briefing package – Submit to the FDA

59. Conclusions We have presumed that antibiotics are an important aspect of treatment of a pulmonary exacerbation, but our evidence is weak. Antibiotics are clearly effective in the treatment of chronic infection of the CF airways Is it likely that many of the “pulmonary exacerbations” were actually progression of disease, and not an acute event? – Our “definition” of a pulmonary exacerbation has been evolving – We need to improve our definition of pulmonary exacerbation and it will be a measure of patient reported outcomes.

60. Conclusions Is there yet a role for bacteria as a cause or contributor to pulmonary exacerbations? – Studies of the microbiome are compelling – If we don’t measure response rigorously, how will we compare/validate different micro models? Where do we go from here?

61. A call to arms Pulmonary exacerbation data tracked in PortCF Pharmacokinetics of inhaled and IV tobramycin 1 eICE study Prospective monitoring for exacerbations NHLBI proposal has been submitted – Pilot and feasibility study of comparative effectiveness using PortCF as a research tool 1 Stenbit A et al: Abstract 376

62. Peer Review Comments “With due respect to the eminent committee … I must admit to being quite underwhelmed... because of the actual paucity of data that is available to us all as clinicians in addressing the very real questions that are posed and addressed by the committee” Translation: Flume, presented at NACFC 2009

63. We know a little more jack We know Jack a little better Thank you