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Human infections with E. coli O157:H7 and other Shiga toxin-producing bacteria
P. I. Tarr, M.D.Washington University School of Medicine
FDA AIDAC MeetingRockville, MDApril 12, 2007
SpontaneousResolution
(~85%)
HUS(~15%)
-3 -2 -1 0 1 2 3 4 5 6 7
Diarrhea Bloodydiarrhea
Culture
+ culture
HCT < 30%
Plts < 150K
Cr > ULN
Adapted from: Lancet 2005; 365:1073
Opportunities
• About 90% are seen by a physician pre-HUS
• Toxemic disorder
Challenge – Assess therapies to prevent HUS • Identify infected patients
– Quickly, accurately• Low incidence, sporadic epidemiology, rural
predominance – Many sites of presentation
• Narrow window to prevent sequelae– Vascular injury already is underway
• What is outcome of interest?– HUS vs. severe HUS
• Informed consent in urgent situation, multi-site randomization
Challenges – Use of an approved therapeutic
Safety
Efficacy
Cost
Carrying Costs to Institution
Diagnostic ChallengesTarget pathogen:
All STEC?Only E. coli O157:H7?
USA, Canada, Japan, UK, and South America:E. coli O157:H7 predominant, and nearly exclusive (> 95%), cause
of HUS.
Pediatrics. 1987;80:37 J Infect Dis. 1990;162:553 J Pediatr. 1998;132:777J Infect Dis. 2001;183:1063 J Pediatr. 2002;141:172 Foodborne Pathog Dis. 2006;3:88 Epidemiol Infect. 2007 Mar 5 (epub)1-7
EIA vs. SMAC, point of care,1998-2001
1626 ER stools, 225 from private practice (all children)
39 signals in Meridian EIA (broth) (in ER)
Klein, E, et al, J Peds 2002; 172
39 EIA positives
•11 non-O157:H7 STEC (> 1/5 colonies)O103:H2 (4), O118:H16 (2), O26:H11, O111:nm, O111:H8, O121:H19, Orough:H11 (1 each) (1 with C. jejuni)
• 3 signals, no STEC (20 colonies and broth tested)
• 25 E. coli O157:H7
Klein, E, et al, J Peds 2002; 172
39 STECs
O157 (28) non-O157 (11)
HUS 18% 0%
Bloody 92% 50%
Laboratory blood 70% 22%
Klein, E, et al, J Peds 2002; 172
Why not test stool for toxin?
• Difficult analyte
• Often not there, especially when patient subsequently develops HUS
• Test misses about 10% of patients infected with E. coli O157:H7
Cornick NA, et. al., J Infect Dis, 2002; 57-63
Is EIA signal for real, if SMAC is negative?
Prior probability: Probability of disease before performing a diagnostic test
If high, then positive result likely to be valid
If low, then positive test less likely to be valid
EIA+, SMAC no O157
Test applied to:
ER PopulationBloody diarrhea Highly credible, low risk Painful diarrheaHospitalized diarrhea
Signal from pathogenic STEC (i.e., O26, O45, O103, O111, O113, O118, O121, O145, 177)
STEC Testing
Test applied to:
Chronic diarrhea
Infantile diarrhea Not highly credible
Non-painful, non- if positive
bloody diarrhea
No STEC recovered, non-major serogroup isolated
Summary of Diagnostic Challenges
• O157 preferential testing should be performed before action
• Direct stool tests insensitive
• Choose population well (i.e., not large volume commercial laboratories)
• Time to positive critical
SpontaneousResolution
(~85%)
HUS(~15%)-3 -2 -1 0 1 2 3 4 5 6 7
Diarrhea Bloodydiarrhea
Culture
+ culture
Bloody Diarrhea
• Diagnose, then treat, or …
• Treat all bloody diarrhea (would miss ~20% of E. coli O157:H7 patients, and most (> 90%) won’t have target infection)
• Syndromic profiling to increase specificity
Syndromic Profiling – Bloody Diarrhea as entry criteria
• Diarrhea for X days – X > 1– X < 5-7
• ≥ 3 bowel movements/day• 9 months – 10 years• No documented fever in health care
setting• Abdominal pain, especially when
defecating
Syndromic Profiling
• Best in high acuity venues
• Will miss ~ 20% of cases
• Will have ~ 2-3:1 false positive rate
• Must be coupled with expeditious testing
• If in research setting, needs support for negatives
Presymptomatic/Contacts
• Epidemics, household
• 10% of cases are 20, but few (of many) contacts become 20 cases
• Massive outbreaks on wane at time of “discovery.” Few symptomatic subjects subsequently come to light.
Early in Timeline(Pre-Bloody Stage)
• Contact of known case (but most symptomatic contacts are not infected)
• Strain – specific replicates
Onsest Presentation HUS
• 10,000 diagnosed cases per annum 2,500 cases < age 10
• 48 cases < age 10 per week, of whom 7 will develop HUS (15% rate)
• One child in the US daily develops HUS. • Today, two children in the US are in the
opportune post-presentation, pre-deterioration, window.
• Today, 14 children are in that window but will not develop HUS
Extrapolations
First Encounter
• High acuity setting (ED)• ‘Primed’ point of care• Research projects
focusing on diarrhea, bloody diarrhea, and E. coli O157:H7
• Outstanding microbiology
ER KINETICS
Inter-defecation interval (O157:H7+): 206 min
70% chance of producing stool on site if in ER for 4 hours
CHRMC ED, 1998 - 2001
• 4799 children with “diarrhea” or “gastroenteritis”
• 1626 “enrolled”• 39 STEC• 28 E. coli O157:H7 (every 39 days)• 5 HUS (all O157:H7) (every 219 days)
Klein, EJ, J Pediatrics (2002) 141:172; Clin Infect Dis (2006) 43:7
CHRMC ED, 1998 - 2001
• 4799 children with “diarrhea” or “gastroenteritis”
• 1626 “enrolled” (34%)• 28 (1.7%) + for O157:H7• 372 specimens submitted as cups; 5.4% +• 1254 non-cups (largely swabs); 0.6% +
Klein, EJ, J Pediatrics (2002) 141:172; Clin Infect Dis (2006) 43:7
Target Population
Bloody diarrhea → culture + → 22/237 9.3% (miss 6) (once every 7 weeks)
Bloody diarrhea → HUS → 4/237 1.7%(miss 1) (once every 39 weeks)
SpontaneousResolution
(~85%)
HUS(~15%)-3 -2 -1 0 1 2 3 4 5 6 7
Diarrhea Bloodydiarrhea
Culture
+ culture
Does host injury precede presentation/ diagnosis?
Adapted from: Lancet 2005; 365:1073
ControlUncomplicated
Pre-HUS
38
Fra
gm
en
t 1
+2
(n
mo
l/L
)
A
ControlUncomplicated
Pre-HUS
112
t-P
A a
ntig
en
(n
g/m
L)
D
ControlUncomplicated
Pre-HUS
20
50
PA
I-1
activi
ty (
IU/m
L)
B
ControlUncomplicated
Pre-HUS
710
log
D-d
ime
er
(lo
g n
g/m
L)
E
ControlUncomplicated
Pre-HUS
010
t-P
A/P
AI-
1 c
om
ple
xe
s (
ng
/mL
)
C
ControlUncomplicated
Pre-HUS
1000
3000
PA
P c
om
ple
xe
s (
ng
/mL
)
F
*
F 1+2: Thrombin generation before HUS
NEJM 2002; 346:23 P<0.01 p<0.001
THROMBIN + F 1+2FXa
PROTHROMBIN
NEJM 2002; 346:23
ControlUncomplicated
Pre-HUS
38
Fra
gm
en
t 1
+2
(n
mo
l/L
)
A
ControlUncomplicated
Pre-HUS
112
t-P
A a
ntig
en
(n
g/m
L)
D
ControlUncomplicated
Pre-HUS
20
50
PA
I-1
activ
ity
(IU
/mL
)
B
ControlUncomplicated
Pre-HUS
710
log
D-d
ime
er
(lo
g n
g/m
L)
E
ControlUncomplicated
Pre-HUS
010
t-P
A/P
AI-
1 c
om
ple
xe
s (
ng
/mL
)
C
ControlUncomplicated
Pre-HUS
1000
3000
PA
P c
om
ple
xe
s (n
g/m
L)
F
D-dimer Before HUS, as Lesion Evolves
**
NEJM 2002; 346:23
Fibrin Degradation
• D-dimer signifies fibrin degradation, infers fibrin presence
D DE D DED D D
Cross-linked fibrin polymers D-DimerPlasmin
LABORATORY VALUES - ALL GROUPS
Normal Uncomp Pre-HUS
HCT (%) 36 3 37 3 38 5
Plts (k/mm3) 321 70 317 74 322 97
Cr (mg/dL) 0.4 .1 0.4 .1 0.4 .2
NEJM 2002; 346:23
Stx vanishing from Stool
DOES SHIGA TOXIN IN STOOL RELATE TO HUS RISK?
Stx Frequency Titer
Pre-HUS: 40% 320 (160-1280)
Uncomplicated: 48% 1689 (160-40 K)
At HUS: 16%
Cornick, N., J Infect Dis. 2002;186:57
Additional Pre-HUS findings and host perturbations
Stx not on circulating PMNs(“PMN are not acting as transporter for Stx in the pathogenesis of HUS.”)(Nephrol Dial Transplant 2007; 22:749)
PAF activated(Pediatr Nephrol 2002;17:1047)
Platelets activated(Blood 2006; 108:167)
vWF multimers show signs of shear-induced cleavage (? from nascent thrombi)(Pediatr Res 2001; 49:653)
Outcome Definition
Hemolysis: Packed cell volume <30%, smear evidence of intravascular erythrocyte destruction
Thrombocytopenia: Platelets <150,000 mm-3
Renal insufficiency: Creatinine > ULN age
Urinalysis not in criteria (difficulty obtaining a reliable specimen, non-functional data)
Outcome Subgroups
• Mild HUS: transfusions, no dialysis,
nonanuric. LOS: 6 days
• Severe HUS: dialysis, anuria, LOS: 12 days
• Anuric HUS: best predictor of chronic renal injury (JAMA 2003; 290:1360; J Pediatr 1991; 118:195)
Ake, J. A. et al. Pediatrics 2005;115:e673
Anuric vs. Non-anuric HUSCHRMC, 1997-2003
• 16 children with anuric HUS
• 13 children with non-anuric HUS
• All E. coli O157:H7 +
• Variable routes of enrollment (syndromic profiling (2), contact (1), culture + (19), arrive with HUS (7))
• All pre-HUS variables examined
Copyright ©2005 American Academy of Pediatrics
Ake, J. A. et al. Pediatrics 2005;115:e673
Fig 1. Timing of critical events during illness
Copyright ©2005 American Academy of Pediatrics
Fig 2. Volume and characteristics of fluids that were administered during first 4 days of illness
Ake, J. A. et al. Pediatrics 2005;115:e673
Multivariate AnalysisVARIABLE ADJUSTED
RELATIVE RISK(95% C.I.)
P
Age (yr) 1.9 (.8-4.4) 0.15
Female sex 1.5 (.1-19.4) 0.77
Pre-HUS antibiotics 1.1 (0.1-17.0) 0.95
Free water in IVF (mL/m2)
1.0 (.999-1.001)
0.49
Na in IVF (mmol/m2) 0.994 (.989-.999)
.017
Pediatrics. 2005 Jun;115(6):e673-80 Ake, J. A. et al. Pediatrics 2005;115:e673
Target Population
Bloody diarrhea → culture + → 22/237 9.3% (miss 6) (once every 7 weeks)
Bloody diarrhea → HUS → 4/237 1.7%(miss 1) (once every 39 weeks)
Bloody diarrhea → anuric HUS → 0/237
Four patterns of outcome
0.3 0.3 0.3
2 3 4
Day of I llness
432
323
365
2 3 4
Day of I llness
275
177
10575
4617 12
34 4368
2 3 4 5 6 7 8 9 10 11
Day of I llness
34 34
30
25
19
26
19
28
25 26
2 3 4 5 6 7 8 9 10 11
Day of I llness
286262
217
4215 17 14 26
9066
143
2 3 4 5 6 7 8 9 10 11 12
Day of I llness
44 45 45
36
28
2523
15
29 28 29
2 3 4 5 6 7 8 9 10 11 12
Day of I llness
286
210
30 28 32 29 33 36
122
221198
281
225
117
150166
254
342
419
6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Day of I llness
44 43 4340
28
2219
2421 20
32
2830
36 3633 33 33
36
6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Day of I llness
0.5 0.5
1.4
2.3
5.14.9
5.5 5.66.0
5.6
4.3 4.3 4.2
2.9 2.8 2.7 2.7 2.7 2.8
6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Day of I llness
32 32 33
2 3 4
Day of I llness
0.4 0.3 0.4
1.3
1.92.2
2
1.3
0.90.7 0.6
2 3 4 5 6 7 8 9 10 11 12
Day of I llness
0.40.6 0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.6
2 3 4 5 6 7 8 9 10 11
Day of I llness
Pattern 1 Pattern 2 Pattern 3 Pattern 4
Pla
tele
ts
HHe
Hem
atoc
ritC
reat
inin
e
Tarr, PI, et al, in Yamada, T., Textbook of Gastroenterology, Blackwell, 5th ed., in press
Trial Specifications
• Diagnose early, accurately• Intervene early• Support all patients with aggressive volume
expansion (IV)• Collect data in usable fashion for subsequent
users• Benefits (what outcomes are to be averted?) to
be weighed against risk• Address important consent issues re urgent
enrollment• Might need to address Stx2c
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• Eileen J. Klein, MD, MPH, Jennifer R. Stapp, BS, Carla R. Clausen, PHD, Daniel R. Boster, BS, Joy G. Well, MS, Xuan Qin, PhD, David L. Swerdlow, MD, and Philip I. Tarr, MD. Shiga toxin-producing Escherichia coli in children with diarrhea: A prospective point-of-care study. The Journal of Pediatrics 2002;172-178.
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