1. Treatment and Outcomes of Severe GAS Infections Louis Valiquette MD M.Sc. Associate professor Dept. Microbiology and ID Université de Sherbrooke, Québec

2. Disclosures Research Support FRSQ CIHR CMPA Wyeth Clinical trials Arpida BD Genzyme Merck Optimer Wyeth Ad Boards/Speakers Bureau Abbott Bayer Iroko Oryx Sanofi Aventis Wyeth Stock Ownership None

3. Plan Invasive GAS infections 1992-2001, Ontario –Epidemiology –Outcomes Necrotizing fasciitis 1992-2004, Ontario –Clinical characteristics and outcomes IVIG in severe GAS infection

4. Invasive GAS infections, Ontario GAS Study 1992-2001 : Epidemiology and Clinical characteristics

5. Population Total of 2357 cases 1207 ♂ (51%) 1150 ♀ (49%) Age –Median: 44 –IQR: 25-68 –Range: 0-102 Valiquette et al. IDSA 2006.

6. Invasive GAS incidence 2.2 per 100,000 population/year –1.2/100,000 pop./year in 1992 –3.2/100,000 pop./year in 2000 Age <5 years  3.0 per 100,000 pop./year Age 65 to 84  5.9 per 100,000 pop./year Age ≥ 85  12.8 per 100,000 pop./year Valiquette et al. IDSA 2006.

7. Invasive GAS population incidence 1992-2001 Valiquette et al. IDSA 2006.

8. Age-specific incidence rates and CFR Valiquette et al. IDSA 2006.

9. Seasonality-1 All STSS Valiquette et al. IDSA 2006.

10. Most common M-types M-types Valiquette et al. IDSA 2006.

11. Underlying illnesses Chronic system diseases466 (23%) Chronic lung disease254 (11%) Congestive heart failure188 (8%) Chronic renal failure71 (3%) Hepatic cirrhosis60 (3%) Diabetes262 (12%) Immunosuppression253 (11%) Valiquette et al. IDSA 2006.

12. Clinical syndromes Soft tissue infection/SSI1301 (57%) Pneumonia314 (14%) Bacteremia (no focus)295 (13%) Necrotizing fasciitis292 (12%) Arthritis274 (12%) URTI273 (12%) Others218 (10%) Valiquette et al. IDSA 2006.

13. Invasive GAS infections, Ontario GAS Study 1992-2001 : Outcomes

14. Complications STSS438 (19%) Hypotension628 (28%) Acute renal failure418 (19%) Coagulopathy348 (16%) ARDS132 (6%) Liver involvement300 (15%) Valiquette et al. IDSA 2006.

15. Management/outcomes Admission to ICU613 (28%) Mechanical ventilation358 (17%) IVIG (all)254 (17%) IVIG (STSS)133 (42%) Death (all)395 (17%) Death (STSS)278 (64%) Valiquette et al. IDSA 2006.

16. CFR trend in invasive GAS infections R= 0.1 (p=0.8) R= 0.9 (p=<.001) Valiquette et al. IDSA 2006.

17. CFR trend in STSS R= -0.7 (p=0.03) R= 0.9 (p=0.001) Valiquette et al. IDSA 2006.

18. Summary Increase in the incidence of invasive GAS from 1992-2001. –Case-fatality rate is stable. Increase in the incidence of GAS TSS from 1992-2001 –Case-fatality rate seems to decline. –Better management?

19. Necrotizing fasciitis, 1992-2004

20. Results 392 cases from 1992-2004 (52% histology+) ♂ =56% ♀ =44% (Men were younger 46 vs. 53) From 1992-2001, mean pop. Incidence = 0.3/100,000 pop. Age groups –0.1/100,000  <25 years –0.3/100,000  25-64 –0.6/100,000  ≥65 years Valiquette et al. IDSA 2006.

21. Underlying illnesses Chronic system diseases69 (18%) Chronic lung disease41 (11%) Congestive heart failure19 (5%) Chronic renal failure10 (3%) Hepatic cirrhosis6 (2%) Diabetes63 (17%) Immunosuppression24 (6%) Valiquette et al. IDSA 2006.

22. Other risk factors Substance abuse41 (11%) Penetrating trauma56 (30%) Blunt trauma143 (25%) NSAIDs91 (28%) Chronic skin condition63 (28%) Varicella (3 weeks)262 (12%) Valiquette et al. IDSA 2006.

23. Management/outcomes Toxic shock syndrome190 (49%) IVIG193 (62%) Surgical procedures330 (86%) Death All NF97 (25%) NF + STSS89 (47%) Valiquette et al. IDSA 2006.

25. IVIG and severe GAS infections

26. Mechanisms of action of IVIG

27. Clinical evidence of IVIG efficacy in GAS TSS Randomized controlled study –Darenberg et al. Observational study (1) –Kaul et al. Case series (2) and case reports

28. Clinical equipoise Important variability in use of IVIG between physicians –EIN/IDSA (1999) 46% patients with GAS TSS treated with IVIG 72% respondents thought that a RCT would assist their treatment decision –Laupland et al. (2002) 76% would use IVIG in GAS TSS 50% would use IVIG in NF without TSS 67% thought that a RCT would be ethical EIN Query Results Report, http://www.idsociety.org. 1999. Laupland et al. J Crit Care. 2004.

29. ID specialists recommended management for severe GAS infections Valiquette et al. Scand J Inf Dis. 2006.

30. Can-ID survey : Evidence of IVIG therapy Strength of current evidence : median response = 6 (IQR 5-7) Importance the results of a high quality RCT in GAS TSS : median response = 8 (IQR 7-9) Importance the results of a high quality RCT in NF without STSS : median response = 8 (IQR 7-9) Valiquette et al. Scand J Inf Dis. 2006.

31. Can-ID survey : Is a RCT ethical? RCT ethically justified –GAS TSS = 70% (131/187) –NF without TSS = 88% (162/186) Willing to enroll –GAS TSS = 67% (125/188) –NF without TSS = 81% (152/188) Valiquette et al. Scand J Inf Dis. 2006.

32. Adverse effects Many side-effects have been reported with IVIG use. –Mild side-effects: 3-10% –Severe side effects: Anaphylaxis, aseptic meningitis, thrombo-embolic events, acute renal failure etc. Transmission of infectious pathogens due to infusion of a blood product Complications related to infusion of a colloid solution Valiquette et al. Scand J Inf Dis. 2006.

33. Cost For a 2g/kg treatment to a 70kg patient: 11,000$

34. Clinical evidence of IVIG efficacy in GAS TSS Randomized controlled study –Darenberg et al. Observational study –Kaul et al. Case series and case reports Darenberg et al. CID. 2003. Kaul et al. CID 1999.

35. Canadian observational study– IVIG vs. no IVIG

36. Canadian observational study - mortality

37. European RCT - Outcomes

38. European RCT – change in SOFA score Darenberg et al. CID. 2003.

39. IVIG in GAS TSS: a reassessment of efficacy Valiquette et al. IDSA 2008.

41. Risk factors for mortality

43. Cumulative dose of IVIG (g/kg)

44. IVIG in GAS NF Valiquette et al. IDSA 2006.

45. IVIG + conservative surgical approach in GAS NF Norrby-Teglund A et al. Scand J Infec Dis. 2005.

46. Predictors of mortality

48. Summary No statistically significant effect of IVIG in GAS NF and GAS TSS For GAS TSS, effect is smaller than initially expected (absolute reduction of 12% vs. 34% in first comparative study) –Sample size/power issues –If true, still a clinically significant effect

49. Summary No dose-related effect in GAS TSS In GAS NF, the benefits of IVIG are considerably less spectacular Importance of surgical procedures

50. List for Santa Claus Severity score to identify patients who would benefit most of IVIG Re-evaluation of IVIG dosage Randomized controlled trial?

51. Acknowledgments Don E. Low Allison J. McGeer Karen Green François Lamontagne Andrée-Anne Beaulieu Ontario patients, families, physicians, infection control practitioners, microbiology laboratory staff and public health unit staff who have contributed their time, experience and expertise to this study.

52. Acknowledgments Members of the Ontario Group A Streptococcal Study Donald E. Low, MD, FRCPC, Allison McGeer, MD, FRCPC, and Karen A. Green, RN, MSc (Department of Microbiology, Toronto Medical Laboratories and Mount Sinai Hospital, Toronto); Andrew E. Simor, MD, FRCPC (Department of Microbiology, Sunnybrook and Women's College Health Sciences Centre, Toronto); Mark Loeb, MD, FRCPC (Department of Medicine, Hamilton Health Sciences Corporation, Hamilton, Ontario); Daniel Gregson, MD, FRCPC (Calgary Laboratory Services, Calgary, Alberta); H. Dele Davies, MD, FRCPC (Alberta Children's Hospital, Calgary); Michael John, MD, FRCPC (London Regional Health Sciences Centre, London, Ontario); Raphael Saginur, MD, FRCPC, and Peter Jessamine, MD, FRCPC (The Ottawa Hospital, Ottawa, Ontario); James Talbot, MD, FRCPC, and Marguerite Lovgren, ART (National Centre for Streptococcus, Edmonton, Alberta); Barbara Mederski, MD, FRCPC (North York General Hospital, North York, Ontario); Alicia Sarabia, MD, FRCPC (Peel Memorial Hospital, Brampton, Ontario); Liljana Trpeski, MD, Barbara Willey, ART, Agron Plevneshi, MD, and Margaret McArthur, RN (Mount Sinai Hospital, Toronto); and Sharon Walmsley, MD, FRCPC (University Health Network, Toronto).