STEC Disease Severity Scale Martin Bitzan, M.D. Department of Pediatrics, McGill University...

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

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

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

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

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

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

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

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

STEC disease scale

• Enteropathy• Vasculopathy/coagulation• Hemolytic anemia and

thrombocytopenia• Nephropathy• Extraintestinal and extrarenal

complications

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

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

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)

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

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

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)

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

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

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

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

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

“Damage (is) underway by time of presentation, but in a potentially treatable cascade” (Phil Tarr)