stec disease severity scale martin bitzan, m.d. department of pediatrics, mcgill university...
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STEC Disease Severity Scale
Martin Bitzan, M.D.
Department of Pediatrics, McGill University
Pediatric Nephrology
Montreal Children’s Hospital
Montreal, Canada
FDA Joint Advisory Committee Meeting April 12, 2007
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Objectives
• Discuss the concept of Shiga Toxin Mediated Events (STME)
• Propose a scoring system for the severity of infections by Shiga toxin producing bacteria/STEC
FDA Joint Advisory Committee Meeting April 12, 2007
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Alternative Approach to the HUS-Centered Perspective
• Identify set of Stx-related clinical and laboratory changes (Shiga toxin mediated events, STME)
• Target reduction of STME including HUS as “proof of principle”
• Reduction of STME will reduce HUS and other Shiga toxin-related complications
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Shiga Toxin Mediated Events (STME)
• Signs and symptoms that are directly or indirectly attributable to the biologic action of Shiga toxins, based on – In vitro studies– Animal models– Clinico-pathological observations
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HC and HUS-like lesions in Shiga toxin injected animals
Signs Species References
Watery diarrhea rabbit, rat Richardson 1992, Krishnan 1999, Ritchie 2003
Bloody diarrhea rabbit, greyhound, baboon
Richardson 1992, Raife 2004, Taylor 1999
TMA, hemolysis, thrombocytopenia
greyhound, baboon
Fenwick/Cowan 1998, Fenwick Raife 2004Taylor 1999
Renal tubular injury
mouse Wadolkowski 1990, Tesh 1993, Wolski 2002
Renal glomerular injury
greyhound, baboon, mouse
Taylor 1999, Fenwick Raife 2004, Fernandez 2000
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Bitzan M, Richardson SE, Karmali MA. 1994
Intravenously injected Stx 1 in rabbit. Toxin detection after 2 h in endothelium by IIF with anti-Stx Ab/FITC antibody
Crypt
Mucosal blood vessel
Intravenous Shiga toxin injection targets mucosal blood vessels in colon and cecum
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Ideal features of a scoring system
• Simple• Quantitative • Clinical symptoms easy to assess and
record by non-professionals (families)• Concordance between observers• Combination of clinical and laboratory
parameter• Relates to important clinical outcomes
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Development of STEC Disease Severity Scale
• Set of candidate clinical and laboratory signs (Shiga toxin mediated events)
• Grading adapted from Common Terminology Criteria for Adverse Events (CTCAE)
• Evaluated in retrospective analysis of large cohort of bona fide STEC O157 infections
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STEC disease scale
• Enteropathy• Vasculopathy/coagulation• Hemolytic anemia and
thrombocytopenia• Nephropathy• Extraintestinal and extrarenal
complications
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Enteropathy (hemorrhagic colitis)0 1 2 3 4
Diarrhea(daily frequency of soft stools)
Baseline(no
diarrhea)
1 - <5 5 - <10 10 - <15 ≥15or paralytic
ileus
Abdominal pain/cramps
None Mild Moderate Severe, pain medication
Unbearable
Bloody diarrhea
No visible blood
Occasional/small
amounts of blood
Blood mixed with
stool, streaks of
fresh blood
Frank blood (hemorrhage)
Hemorrhage requiring
colonoscopy or surgery
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Microangiopathic Hemolytic Anemia and Nephropathy
0 1 2 3 4Hemoglobin [g/l]
≥115 <115 - 105 <105 - 90 <90 – 65 <65or PRBC
Platelets [N/nl]
≥150 <150 – 125 <125 - 75 <75 – 25 <25or transfusion,
hemorrhage
Hematuria None or trace
Small Moderate Large Anuria
Serum creatinine
Normal(for age)
>1 - 2x upper
normal
>2 - 4xupper
normal
>4xupper
normal
Dialysis
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Evaluation of the Disease Scale Epidemiology Cohort
Microbiology records 08/1992 – 07/2006
STEC isolates (E. coli O157)
N = 186
Chart identification and review
Hospital records availableN = 164
Age 6.1 ± 4.7 yrs (0.3 – 18)Non-HUS 84 %HUS 16%Hospitalized 33%Dialyzed 6% (39 % of HUS)
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Maximal Score Patients Odds ratio p
Bloody diarrhea 164 1.5 .140
Abdominal cramps 159 1.5 .060
Diarrhea frequency 164 1.7 .014
Hemoglobin 95 1858 <.0001
Platelets 91 46.9 <.0001
Hematuria 103 9.6 <.0001
Creatinine 120 94.2 <.0001
Retrospective data analysis Univariate logistic regression
Association of STMEs with HUS
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Maximal score Patients Corr coeff* p
Bloody diarrhea 164 0.26 .0008
Abdominal cramps 159 0.38 <.0001
Diarrhea frequency 164 0.29 .0002
Anemia 95 0.70 <.0001
Thrombocytopenia 91 0.74 <.0001
Hematuria 103 0.62 <.0001
Creatinine 120 0.69 <.0001
Correlation of STMEs with Duration of Hospitalization
*Spearman rank correlation
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Maximal score Patients Corr Coeff p
Bloody diarrhea 138 0.31 .0002
Abdominal cramps 135 0.38 <.0001
Diarrhea frequency 138 0.29 .005
Anemia 70 0.08 0.502
Thrombocytopenia 66 0.09 0.483
Hematuria 82 0.08 0.497
Creatinine (score) 94 -0.09 0.367
Correlation of STMEs with Duration of Hospitalization (excluding HUS)
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Estimated Risk of Hospitalization related to
Enteropathy Scores
Score 0 1 2 3 4Diarrhea frequency 3% 7% 14% 27% 46%
Abdominal pain 1% 6% 22% 59% 88%
Bloody diarrhea 2% 7% 21% 50% 79%
Excluding HUS Patients
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Platelets (N/nL)Creat (μmol/L)
0
200
400
600
800
1 3 5 7 9 11 13 15 17 19 21 23
Days of Onset
0
25
50
75
100
125
Serum creatinine
Platelets
Hemoglobin
Hemoglobin (g/L)
1 3 5 7 9 11
13
15
17
18
21
23
HUS Case #1
Bloody diarrhea
Abd cramps
Diarrhea
Fever
Oliguria/edema/U hem
Irritability
PRBC transfusion
HospitalER
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Scoring of HUS patient
0
3
6
9
12
15
18
21
1 3 5 7 9 11 13 15
Days of Diarrhea Onset
Sc
ore
s
Creatinine elevated
Hematuria
Thrombocytopenia
Anemia
Diarrhea frequency
Abd cramps
Bloody diarrhea
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STEC Disease Severity Scores
0
4
8
12
16
20
1 3 5 7 9 11 13 150
4
8
12
16
20
1 3 5 7 9 11 13 150
4
8
12
16
20
1 3 5 7 9 11 13 15
HUS Uncomplicated HC“Incomplete” HUS
Days after Onset of Diarrhea
Score
s
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Conclusions• Shiga toxin mediated events (STME)
defined as measurable, biological effects of Shiga toxins
• STEC Disease Severity Scale is associated with clinically relevant outcomes
• Allows to integrate disease severity and duration
• Tool for standardized documentation and evaluation of STEC disease
• Useful for prospective studies, preventive or therapeutic intervention
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“Damage (is) underway by time of presentation, but in a potentially treatable cascade” (Phil Tarr)
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