Treatment and Outcomes of Severe GAS Infections

Louis Valiquette MD M.Sc.Associate professor

Dept. Microbiology and IDUniversité de Sherbrooke, Québec

DisclosuresResearch SupportFRSQCIHRCMPAWyeth

Clinical trialsArpidaBDGenzymeMerckOptimerWyeth

Ad Boards/Speakers Bureau

AbbottBayerIrokoOryxSanofi AventisWyeth

Stock OwnershipNone

Plan

• Invasive GAS infections 1992-2001, Ontario– Epidemiology– Outcomes

• Necrotizing fasciitis 1992-2004, Ontario– Clinical characteristics and outcomes

• IVIG in severe GAS infection

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

Population

• Total of 2357 cases• 1207 ♂ (51%)• 1150 ♀ (49%)• Age

– Median: 44 – IQR: 25-68– Range: 0-102

Valiquette et al. IDSA 2006.

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.

Invasive GAS population incidence 1992-2001

1992 1993 1994 1995 1996 1997 1998 1999 2000 2001

Nb

r ca

ses/

10

0,0

00

0,0

0,5

1,0

1,5

2,0

2,5

3,0

3,5

Valiquette et al. IDSA 2006.

Age-specific incidence rates and CFR

# c

as

es

pe

r 1

00

,00

0

0

2

4

6

8

10

12

14

Ca

se

-fa

tali

ty r

ate

(%

)

0

10

20

30

40

50

Valiquette et al. IDSA 2006.

Seasonality-1

Months

92 93 94 95 96 97 98 99 00 01 02

Num

ber

of c

ases

0

10

20

30

40

50

60

70

All

STSS

Valiquette et al. IDSA 2006.

Most common M-types

25%

11%10%

6%

8%

3%

3%

13%

21%1

3

12

4

28

6

5

NT

Other types

M-types

Valiquette et al. IDSA 2006.

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.

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.

Invasive GAS infections, Ontario GAS Study 1992-

2001 : Outcomes

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.

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.

CFR trend in invasive GAS infections

1992 1994 1996 1998 2000 2002

Nbr

cas

es/1

00,0

00

0,0

0,5

1,0

1,5

2,0

2,5

3,0

3,5

Cas

e-fa

talit

y ra

te (

%)

0

5

10

15

20

25

30

R= 0.1 (p=0.8)

R= 0.9 (p=<.001)

Valiquette et al. IDSA 2006.

CFR trend in STSS

1992 1993 1994 1995 1996 1997 1998 1999 2000 2001

Nbr

cas

es/1

00,0

00

0,0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

Cas

e-fa

talit

y ra

te (

%)

0

20

40

60

80

100

R= -0.7 (p=0.03)

R= 0.9 (p=0.001)

Valiquette et al. IDSA 2006.

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?

Necrotizing fasciitis, 1992-2004

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.

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.

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.

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.

Valiquette et al. IDSA 2006.

IVIG and severe GAS infections

Mechanisms of action of IVIG

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

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.

ID specialists recommended management

for severe GAS infections

Valiquette et al. Scand J Inf Dis. 2006.

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.

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.

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.

Cost

For a 2g/kg treatment to a 70kg patient:

11,000$

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.

Canadian observational study– IVIG vs. no IVIG

Canadian observational study - mortality

European RCT - Outcomes

European RCT – change in SOFA score

Darenberg et al. CID. 2003.

IVIG in GAS TSS: a reassessment of

efficacy

Valiquette et al. IDSA 2008.

Risk factors for mortality

Risk factors for mortality

Cumulative dose of IVIG (g/kg)

IVIG in GAS NF

Valiquette et al. IDSA 2006.

IVIG + conservative surgical approach in GAS

NF

Norrby-Teglund A et al.Scand J Infec Dis. 2005.

Predictors of mortality

Predictors of mortality

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

Summary

• No dose-related effect in GAS TSS

• In GAS NF, the benefits of IVIG are considerably less spectacular

• Importance of surgical procedures

List for Santa Claus

• Severity score to identify patients who would benefit most of IVIG

• Re-evaluation of IVIG dosage

• Randomized controlled trial?

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.

AcknowledgmentsMembers 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).