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Treatment and Outcomes of Severe GAS Infections

Treatment and Outcomes of Severe GAS Infections. Louis Valiquette MD M.Sc. Associate professor Dept. Microbiology and ID Université de Sherbrooke, Québec. Disclosures. Research Support FRSQ CIHR CMPA Wyeth Clinical trials Arpida BD Genzyme Merck Optimer Wyeth.

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Treatment and Outcomes of Severe GAS Infections

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  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 Valiquette et al. IDSA 2006.

  12. Clinical syndromes Valiquette et al. IDSA 2006.

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

  14. Complications Valiquette et al. IDSA 2006.

  15. Management/outcomes Valiquette et al. IDSA 2006.

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

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

  22. Other risk factors Valiquette et al. IDSA 2006.

  23. Management/outcomes Valiquette et al. IDSA 2006.

  24. 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 managementfor 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.

  40. Risk factors for mortality

  41. Risk factors for mortality

  42. Cumulative dose of IVIG (g/kg)

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

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

  45. Predictors of mortality

  46. Predictors of mortality

  47. 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

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

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

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