Shiga Toxin-Producing

Escherichia coli:

The Human Health Perspective

P. I. Tarr

Division of Gastroenterology and Nutrition

Washington University School of Medicine

NOTE: Some slides could include data that have not yet been published, or subject to peer review, and should not be quoted and should be considered to be preliminary

Perspective

E. coli O157:H7: ~ .9/100,000 people/year (MMWR Morb Mortal Wkly Rep 2011;60:749-55)

HUS: 500-750 cases per annum, 90% < 18 yo

Rare infections need good systems, protocols,

and vigilance

• How can we optimally diagnose this infection?

• Can we attenuate human illnesses?

• What misconceptions do we need to address?

Time is not on your side!

-3 -2 -1 0 1 2 3 4 5 6 7

Diarrhea

Bloody

diarrhea

First Contact (frequently ER) Profile:

Memorial Day to Thanksgiving

Holtz, et al, Gastroenterology. 2009 ;136:1887

Klein, et al, J Pediatr. 2002;141:172

Strategic Microbiology

• Culture!

(C. difficile optional –

await bacterial

culture)

• Hustle stool to the lab

First Medical Contact

Microbiologic Evaluation is

CRITICAL

Stool

Broth

Incubate O/N

Shiga Toxin EIA

Microbiologic Evaluation is Critical

Agar vs. Assay

Pediatrics. 1987;80:37

J Infect Dis. 1990;162:553

J Pediatr. 1998;132:777

J Infect Dis. 2001;183:1063

J Pediatr. 2002;141:172

Foodborne Pathog Dis. 2006;3:88

Epidemiol Infect. 2007 Mar 5 (epub)1-7

Arch Pediatr Adolesc Med. 2011;165:884-9.

Agar detects only O157:H7, but this single

serotype remains the nearly exclusive (>95%)

cause of HUS in US, UK, Canada, Japan, and

South America

How much HUS do non-O157:H7

STEC cause in US?

83 patients with HUS, (1987-91), nationwide surveillance (Banatavala, et al*).

70 patients had stool cultures with growth, median of 8 days after illness onset.

30 patients had STEC; 25 of these were O157 (overall O157 rate: 35%) (only 1/3 of HUS patients have O157:H7 if cultured on admission with HUS**, but 96% are + if cultured early in illness)

Of 5 patients from whom non-O157:H7 STEC were recovered, 4 had serology, and

3 of these 4 had evidence of a recent infection with E. coli O157.

Of 31 cases from whom no STEC were recovered, 21 had antibodies to O157. (Sera obtained up to 80 days after illness onset, well after seropositivity peak***, so this rate is possibly low.

Little room left for non-O157:H7 STEC to cause HUS

in US

*J Infect Dis. 2001;183:1063 ** J Infect Dis 1990;162:553 *** J Infect Dis 2002;186:566

Recent Study of HUS

50 children with diarrhea – associated HUS, from 10

centers in US (UC Davis, Seattle, Indiana, Little Rock,

Milwaukee, Albuquerque, Columbus, Cincinnati, St.

Louis) and 1 in Scotland (Glasgow) (Hickey, et al*)

Years: 2008-2009.

27+ for O157, 1 + for O121:H19, All other were negative

*Arch Pediatr Adolesc Med. 2011;165:884

Shiga toxin–producing Escherichia coli (STEC) isolates by method of

initial detection and STEC serotype, Connecticut, 2000–2009.

Hadler J L et al. Clin Infect Dis. 2011;53:269-276

© The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases

Society of America. All rights reserved. For Permissions, please e-mail:

journals.permissions@oup.com.

Connecticut 2000-2009

• 499 broth + EIAs

• 163 were O157:H7 (33%)

– 10% HUS rate

• 229 were non-O157:H7 STEC (46%);

– 0.4% HUS rate

• 78 (16%) were not + at State Laboratory

• 29 (6%) no STEC recovered

Clin Infect Dis 2011;53:269

O157/non-O157 Acuity Pyramid

HUS 95/5 - 99/1 in multiple studies

Seattle Children’s Hospital Emergency Room

19911: 13/5

1998-20012: 28/11

Statewide, MT (1998-2000)3 and CT (2000-2009) 4

MT : 32/50 (#2 was O26, with 16 isolates)

CT: 163/229 (#2 was O111, with 44 isolates) 1Gastroenterology. 1993;105:1724; 2J Pediatr. 2002;141:172; 3 J Infect Dis.2003;188:719; 4Clin Infect Dis 2011;53:269

Toxin Screening misses O157:H7

(i.e., sorbitol MacConkey

agar is more sensitive)

• Klein, E, et al, J Peds 2002; 172;

• Emerg Infect Dis. 2000 Sep-Oct;6(5):530-3.

• Eur J Clin Microbiol Infect Dis. 2003

Nov;22(11):689-92. Epub 2003 Oct 23.

• Emerg Infect Dis. 2007 Feb;13(2):318-21.

• J Clin Microbiol. 2007 Oct;45(10):3377-80. Epub

2007 Aug 1. PubMed PMID: 17670920;

• J Clin Microbiol. 2003 Jun;41(6):2650-3.

Toxin Assays Slow

Diagnosis of O157:H7

• Not read daily in many centers

• Often sent to commercial laboratories

• Isolation devolves to state PHL

• State of isolation isn’t always state of

presentation or residence

• Specimen transport issues

Why rapidly diagnose O157?

• E. coli O157:H7 thrombotic complications,

epidemics; other serotypes rarely do

• Syndromic profiling helpful, but clinician needs

+ or - culture result ASAP

• HD needs isolate

• Intervention appears possible

Best Practices - Microbiology

Plate 24/7, don’t wait for morning shift, swabs are fine

Report presumptive positives

Receipt to telephone call:

23 hr, 53 min (14 – 56 h)

CDC Guidelines

Recommendations for Diagnosis of Shiga Toxin--Producing

Escherichia coli Infections by Clinical Laboratories LH Gould, C Bopp, N Strockbine, R Atkinson, V Baselski, B Body, R Carey, C Crandall, S Hurd, R Kaplan, M Neill, S

Shea, P Somsel, M Tobin-D'Angelo, P M Griffin, P Gerner-Smidt

“All stools submitted for testing from patients with acute community-

acquired diarrhea … should be cultured for O157 STEC on selective

and differential agar.”

Best practice: Agar and toxin assay

MMWR Recomm Rep. 2009;58(RR-12):1-14

What’s the rush?

Control

Uncomplicated

Pre-HUS

38

Fra

gm

en

t 1

+2

(n

mo

l/L) A

Control

Uncomplicated

Pre-HUS

112

t-P

A a

ntig

en

(n

g/m

L) D

Control

Uncomplicated

Pre-HUS

20

50

PA

I-1

act

ivity

(IU

/mL

) B

Control

Uncomplicated

Pre-HUS

710

log

D-d

ime

er

(lo

g n

g/m

L)

E

Control

Uncomplicated

Pre-HUS

010

t-P

A/P

AI-

1 c

om

ple

xes

(ng

/mL

)

C

Control

Uncomplicated

Pre-HUS

1000

3000

PA

P c

om

ple

xes

(ng

/mL

)

F

D-dimer Before HUS

*

*

NEJM 2002; 346:23

Child at Presentation

• Little or no toxin in stool

• Coagulation system activated, but CBC normal

• Pathogen still present in stool

• Kidneys not yet injured

What’s a provider to do?

Admit, Isolate

Inpatient (contact) precautions:

dedicated equipment, gowns, gloves

Outpatient advice:

“Wash your hands well!”

Werber, et al, Clin Infect Dis. 2008;46:1189-96.

0 10 20 30 40 50 60 70

OR

1997-1999 , n=71

Withhold antibiotics

N Engl J Med. 2000;342:1930-6.

• Antibiotics are a risk for HUS in MN

Smith, K, et al, Pediatr Infect Dis J. 2011 Sep 1

• Antibiotics are commonly prescribed

36%, US and Scotland (Hickey, et al, Arch Pediatr Adolesc Med. 2011; 165:884)

23%, Minnesota (Smith, K, et al, Pediatr Infect Dis J. 2011 Sep 1)

44% in a multi-state CDC analysis (Nelson, et al, Clin Infect Dis. 2011;52:1130)

Volume Expand

• Comfort

• Vascular protection in view of HUS risk

• q12 h CBC (drop the hemoglobin)

• daily BUN, creatinine, electrolytes

• K is OK if K is normal or low

• Wait for platelets to rise

(single determination rarely sufficient)

0.5 0.5

1.4

2.3

5.14.9

5.5 5.6

6.0

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 Illness

0.4 0.3 0.4

1.3

1.9

2.22

1.3

0.90.7 0.6

2 3 4 5 6 7 8 9 10 11 12

Day of Illness

Non-oligoanuric

Oligoanuric

creatinine creatinine

0.5 0.5

1.4

2.3

5.14.9

5.5 5.6

6.0

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 Illness

0.4 0.3 0.4

1.3

1.9

2.22

1.3

0.90.7 0.6

2 3 4 5 6 7 8 9 10 11 12

Day of Illness

Non-oligoanuric

Oligoanuric

creatinine creatinine

Oakes RS, Kirkham JK, Nelson RD, Siegler RL. Duration of oliguria and anuria as predictors of chronic renal-related sequelae in post-diarrheal hemolytic uremic syndrome. Pediatr Nephrol. 2008;23:1303–8.

Loirat C. [Post-diarrhea hemolytic-uremic syndrome: clinical aspects]. Arch Pediatr. 2001;8 Suppl 4:776s–84s.

Siegler RL, Pavia AT, Christofferson RD, Milligan MK. A 20-year population-based study of postdiarrheal hemolytic uremic syndrome in Utah. Pediatrics. 1994;94:35–40.

Siegler RL, Milligan MK, Burningham TH, Christofferson RD, Chang SY, Jorde LB. Long-term outcome and prognostic indicators in the hemolytic-uremic syndrome. J Pediatr. 1991;118:195–200.

Garg AX, Suri RS, Barrowman N, Rehman F, Matsell D, Rosas-Arellano MP, et al. Long-term renal prognosis of diarrhea-associated hemolytic uremic syndrome: a systematic review, meta-analysis, and meta-regression. JAMA. 2003;290:1360–70.

Robson WL, Leung AK, Brant R. Relationship of the recovery in the glomerular filtration rate to the duration of anuria in diarrhea-associated hemolytic uremic syndrome. Am J Nephrol. 1993;13:194–7.

Tonshoff B, Sammet A, Sanden I, Mehls O, Waldherr R, Scharer K. Outcome and prognostic determinants in the hemolytic uremic syndrome of children. Nephron. 1994;68:63–70.

Huseman D, Gellermann J, Vollmer I, Ohde I, Devaux S, Ehrich JH, et al. Long-term prognosis of hemolytic uremic syndrome and effective renal plasma flow. Pediatr Nephrol. 1999;13:672–7.

Mizusawa Y, Pitcher LA, Burke JR, Falk MC, Mizushima W. Survey of haemolytic-uraemic syndrome in Queensland 1979-1995. Med J Aust. 1996;165:188–91.

Spizzirri FD, Rahman RC, Bibiloni N, Ruscasso JD, Amoreo OR. Childhood hemolytic uremic syndrome in Argentina: long-term follow-up and prognostic features. Pediatr Nephrol. 1997;11:156–60.

Gianantonio CA, Vitacco M, Mendilaharzu F, Gallo G. The hemolytic-uremic syndrome. Renal status of 76 patients at long-term follow-up. J Pediatr. 1968;72:757–65.

Gianantonio CA, Vitacco M, Mendilaharzu F, Gallo GE, Sojo ET. The hemolytic-uremic syndrome. Nephron. 1973;11:174–92.

Dolislager D, Tune B. The hemolytic-uremic syndrome: spectrum of severity and significance of prodrome. Am J Dis Child. 1978;132:55–8.

de Jong MC, Monnens LA. Recurrent haemolytic uraemic syndrome. Padiatr Padol. 1976;11:521–7.

Mencia B. S., Martinez de Azagra A, de Vicente A. A., Monleon L. M., J. CF. Uremic hemolytic syndrome. Analysis of 43 cases. An Esp Pediatr 1999;50:467–70.

Good

Bad

Variable Good

outcome

Poor outcome P

Presentation Day 2 Day 3 0.066

First culture Day 2 Day 3 0.02

First IV

started

Day 3

(0-4)

Day 4.5

(2-9)

0.01

First Cultue

obtained

Day 2

(0-4)

Day 3

(2-9)

0.02

Culture + Day 4 (2-4) Day 7 (3-9) 0.001

What variables are associated with good outcomes?

Pediatrics. 2005;115:e673-80

Copyright ©2005 American Academy of Pediatrics

Fig 2. Volume and characteristics of fluids that were administered during first 4 days of

illness

Pediatrics. 2005

Jun;115(6):e673-80

Copyright restrictions may apply.

Hickey, C. A. et al. Arch Pediatr Adolesc Med 2011;165:884-889.

Logistic Models

Detection Acceleration

Every second counts:

presentation specimen

(come in now)

Specimen inoculation (swab OK)

Inoculation interpretation

(don’t worry about H7, coli confirmation)

Report health department (do it now)

4H Management

• Hospitalize

• Hydrate

• Hold antibiotics

• Health Department