Treatment and Outcomes of Severe GAS Infections

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 lt5 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 diseases 466 (23)
Chronic lung disease 254 (11)
Congestive heart failure 188 (8)
Chronic renal failure 71 (3)
Hepatic cirrhosis 60 (3)
Diabetes 262 (12)
Immunosuppression 253 (11)
Valiquette et al. IDSA 2006.
12
Clinical syndromes
Soft tissue infection/SSI 1301 (57)
Pneumonia 314 (14)
Bacteremia (no focus) 295 (13)
Necrotizing fasciitis 292 (12)
Arthritis 274 (12)
URTI 273 (12)
Others 218 (10)
Valiquette et al. IDSA 2006.
13
Invasive GAS infections, Ontario GAS Study
1992-2001 Outcomes
14
Complications
STSS 438 (19)
Hypotension 628 (28)
Acute renal failure 418 (19)
Coagulopathy 348 (16)
ARDS 132 (6)
Liver involvement 300 (15)
Valiquette et al. IDSA 2006.
15
Management/outcomes
Admission to ICU 613 (28)
Mechanical ventilation 358 (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 0.9 (plt.001)
R 0.1 (p0.8)
Valiquette et al. IDSA 2006.
17
CFR trend in STSS
R 0.9 (p0.001)
R -0.7 (p0.03)
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 ? lt25 years
• 0.3/100,000 ? 25-64
• 0.6/100,000 ? 65 years

Valiquette et al. IDSA 2006.
21
Underlying illnesses
Chronic system diseases 69 (18)
Chronic lung disease 41 (11)
Congestive heart failure 19 (5)
Chronic renal failure 10 (3)
Hepatic cirrhosis 6 (2)
Diabetes 63 (17)
Immunosuppression 24 (6)
Valiquette et al. IDSA 2006.
22
Other risk factors
Substance abuse 41 (11)
Penetrating trauma 56 (30)
Blunt trauma 143 (25)
NSAIDs 91 (28)
Chronic skin condition 63 (28)
Varicella (3 weeks) 262 (12)
Valiquette et al. IDSA 2006.
23
Management/outcomes
Toxic shock syndrome 190 (49)
IVIG 193 (62)
Surgical procedures 330 (86)
Death
All NF 97 (25)
NF STSS 89 (47)
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.or
g. 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
(No Transcript)
41
Risk factors for mortality
42
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
47
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).