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Patricia A. Somsel, DrPH

Director, Division of Infectious Diseases

Bureau of Labs, MDCH

Detection of S-TEC:New Guidelines for Clinical and

Public Health Labs

MI ClinLabNetwork, 11/2009

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WHY?

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1982• Cases of “hemorrhagic colitis” first recognized as a

distinct entity• Oregon, Feb-Mar 25 cases; mean age 28 yrs (8-76) • Michigan, May-June 18 cases; mean age 17 yrs (4-58) • Illness associated with consumption at Chain A

restaurant of sandwiches with beef patty, rehydrated onions, pickles

• E coli O157:H7 isolated from cases and one lot of meat served in Michigan

NEJM 1983; 308:681-5

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SpontaneousResolution

(~85%)

HUS(~15%)-3 -2 -1 0 1 2 3 4 5 6 7

Diarrhea Bloodydiarrhea

Culture

+ culture

Adapted from: Lancet 2005; 365:1073

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Estimated Foodborneillness in US*

0

1

2

3

4

5

6

7

8

9

10

Salmonella STEC

% of total foodborneillness

% o

f to

tal

Shigella

0.6% 0.7%

*Mead et al, 1999. Emerg Infect Dis 5(5):607-625

(Shiga toxin-producing E.coli)

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Frequency of pathogens in diarrheal stools,

New Mexico study, Apr – Oct 2000*

0

0.5

1

1.5

2

2.5

Campylobacter STEC

*All stools from acute, community-acquired diarrhea were tested in study

2.3

1.1 1.10.9

Campylobacter Salmonella STEC Shigella

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Estimates of annual STEC infections in the US

• E.coli O157– 73,000 acute illnesses– 2,200 hospitalizations– 61 deaths

• Non-O157 STEC– 36,700 acute illnesses– 1,100 hospitalizations– 30 deathsMead et al, 1999. Emerg Infect Dis 5(5):607-625

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HUS: Incidence Estimates in US

• Estimate 4,400 cases per year due to O157– Roughly estimate 310 – 880 cases per year due to

Non-O15

• 68% of cases occur in children < 5 years of age.

• Estimate 96 cases per week in all ages from all serotypes.

• One child in the US develops HUS each day.

*Mead et al, 1999. Emerg Infect Dis 5(5):607-625

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The Cost?

• Outpatient physician care: $440

• Hosp, spontaneous resolution: $5,600

• Hosp, HUS w/o ESRD: $31,000

• Hosp, HUS, ESRD: $5,100,000

Frenzen PD J Food Protect 2005

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MI STEC Study: 2001-2005

Manning SD et al. 2007. Surveillance for Shiga toxin-producing Escherichia coli, Michigan, 2001-2005. Emerg Infect Dis. Feb; 13(2):318-21.

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Evaluation of the enhanced surveillance using EIA on all stools

• Overall, 66 additional cases were identified that would not have otherwise been detected from 2001-05– Among these 66,

• 31 (47%) were non-O157 • 27 of 64 (42%) were less than 18 years old• 22 of 51 (43%) were hospitalized• 39 of 51 (76%) had bloody diarrhea

MI STEC Study: 2001-2005

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Barriers to Full and Prompt Recovery of STEC*

• Acute disease not easily defined– ~25% in the MI study NOT bloody– WBC’s may/may not be present– Generally not associated with fever– Seasonality not predictable with changing

‘menu’ of implicated foods

*Without full recovery of STEC, the true burden of Non-O157 STEC disease is hidden

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Barriers, cont’d

• Physicians may not think of STEC in patient w/out classic ‘bloody diarrhea’

• Physicians may not know what testing clinical labs routinely perform (and they may use multiple labs)

• Physicians often do not understand the role of non-O157 E.coli and the testing necessary to demonstrate it

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Barriers, cont’d

• Clinical laboratories typically test for STEC:– Upon request of physician, or hx of bloody

diarrhea– Only in summer/fall, if at all– If specimen bloody (stools come in

transport which is often red!)

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Barriers, cont’d

• Clinical labs typically test for STEC by culture, which can only detect E.coli O157– Other serotypes also produce disease– Culture and prelim identification requires

24-48 hours– Media and serotyping reagents expensive

and may outdate if testing rarely ordered, so many labs may ‘send-out’ this testing to commercial labs, resulting in additional delay of 1-2 days

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Barriers, cont’d

• EIA (toxin) detects all serotypes, but– Clinical labs unsure if they can do both culture

and EIA and get reimbursed– Confusion about appropriate billing for EIA– Some PHLabs will not accept broths– Subculture of broth to solid media may result in

delayed result– EIA may not fit into the ‘routine’ as easily as

SMAC plate– False Positives?– Workforce issues

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Barriers, cont’d

• Once a likely STEC is isolated, it must be shipped to a PHLab for further characterization, including PFGE and uploading to PulseNet.– Effective Oct 2, 2009 STEC isolates MUST

by law be submitted in MI– STEC is a Category A agent, which

requires special handling and extra expense.

– Labor, materials, and shipping costs for public health purposes not reimbursable

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Barriers, cont’d

• Specimens sent to commercial laboratories which may not be in the state of the patient residence, so STEC recovered may not go to the PHLab in the state responsible for follow-up/investigation

• Unless STEC isolates reach PH for complete characterization, the full picture of STEC disease is unrecognized, investigations are incomplete and appropriate interventions are hampered.

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Response

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Importance of Culture Confirmationof Shiga Toxin-producingEscherichia coli Infection

as Illustrated by Outbreaksof Gastroenteritis — New York

and North Carolina, 2005

Morbidity and Mortality Weekly ReportSeptember 29, 2006 / Vol. 55 / No. 38

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Conclusion: Rapid tests can facilitate the detection of outbreaks of STEC, but when used alone may produce false positive results

Described the investigation of two outbreaks of gastroenteritis in which laboratories used non-culture methods to detect Shiga toxin.

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• Health care providers should notify clinical labs if STEC is suspected

• Clinical labs should strongly consider adding STEC O157 to routine enteric cultures

• Ideally clinical labs should screen all stools for STX using an EIA AND culture for O157

• Clinical labs that use an EIA only should sub positives ASAP for STEC O157

• All STEC O157 isolates and positive broths from which O157 has not been recovered should be forwarded ASAP to PHLabs

• Clinical and PHLabs work together for correct diagnosis and follow-up

Recommendations:

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Results of a 2007 Survey of Clinical Labs in MI (69/123)

• 26% (18) offered testing on-site*• ~50% of these tested all stools for O157• ~20% of these tested bloody stools only• ~20% tested only when requested

*if didn’t offer testing on-site, sent to reference laboratory upon request#2009 update: approximately 30 clinical labs in MI now performEIA; not clear if this is on all stools.

Barriers, cont’d

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Why this didn’t work

• Published in MMWR - Did not reach target audience – effected little change in clinical practice

• Difficulties in reimbursement• All PHLabs not on the same page

– Commercial/reference laboratories might have multiple, mutually exclusive requirements to meet for PHLabs in different states

– Requirements of PHLabs not always accomadating of clinical lab reality

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Meeting Convened at CDC in 2007:

Role of Commercial Diagnostic and Public Health Laboratories in Enteric Disease Surveillance and Response

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Issues Identified

• Reimbursement problems• Lack of communication to clinical labs• Inconsistent requirements from PHLabs• Inconsistent cooperation from diagnostic

labs

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Needs Identified

• Establish a standard of practice for detection of STEC by clinical labs

• Establish consistent expectations for PHLabs

• Establish consistent expectations for clinical, commercial/reference labs

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Plan of Action• Produce a new MMWR to establish standards

of practice diagnostic labs• Produce a companion piece detailing

standards of practice for PHLabs• Follow-up with broad dissemination of

guidelines via conferences and additional publications to reach non-doctoral level microbiologists, pathologists, physicians

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• Authored by 15 microbiologists from clinical, commercial and public health labs, as well as ID physicians – a consensus document

• Presents evidence to support culture and toxin testing of ALL stools submitted for routine culture.

• Details implementation of guidelines• Describes the performance characteristics of

commercially available assays, and acceptable specimens

New MMWR ~ October 16, 2009

MMWR Vol 58:RR-12. October 2009.

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• Will establish a standard against which microbiology practices might be compared

• Will establish an expectation for reimbursement for culture AND toxin testing

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How?

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Clinical Lab RecommendationsCulture to selective and

differential media (e.g.,SMAC)

Enzyme ImmunoAssay (EIA) to detect TOXIN

AND

All Stool Specimens

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O157 STEC

Pos EIA with no O157 isolate suggesting non-

O157 STEC

OR

isolate

broth

Category A

UN 2814

PHL

Clinical Lab Recommendations

ASAP

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PHLab Recommendations

• Remove barriers to rapid submission of isolates and broths

• Expedite testing to rapidly recognize/report presence of Stx-2

• Organize testing to rapidly submit isolate patterns to PulseNet

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Public Health Recommendations -Details

If receive isolates of O157 STEC:

• confirm biochemically as E. coli

• serotype (O and H antigens)

• characterize Shiga toxin type

• stx gene specific PCR

• an antibody/antigen assay that can distinguish between Shiga toxin 1 and 2

• PFGE and upload to PulseNet

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If Receive Clinical Sample/broth:

• Cefixime and Tellurite Sorbitol MacConkey (CT-SMAC)

OR

• a chromogenic agar (e.g. CHROM™ Agar]

AND

• Sorbitol MacConkey agar (SMAC)

OR

• Washed sheep’s blood agar

Public Health Recommendations…

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• If no colonies resemble O157 STEC

• Test for the presence of Shiga toxin via colony sweep of the growth using

• EIA, Vero Cell Culture, or PCR

Public Health Recommendations…..

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•If this Stx screen is negative: • STOP

• If the Stx screen is positive: • screen up to 10 individual colonies for Shiga toxin• EIA, Vero Cell Culture or PCR

• Evidence indicates STEC may be isolated 90% of the time when 10 isolates are screened

Public Health Recommendations…..

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• Once a STEC is identified:• biochemically confirm as E. coli• serotype the isolate

• O antigen only: O26, O103, O111, O121, and O157•If not one of the above, forward to the CDC E. coli Reference Laboratory

• If an STEC is not identified after 10 isolates are tested

• forward to the CDC E. coli Reference Laboratory

Public Health Recommendations…..

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• Perform PFGE on all STEC isolates

Public Health Recommendations…..

• Upload to PulseNet

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STEC PHLab Best PracticeEIA Positive Broth

Selective culture

Screen colonies for O157 STEC

If no O157 – Screen for Shiga toxin by PCR

Negative Screen = stop work up

Serogroup

PFGE

Positive Screen =

search up to 20 colonies for STEC

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• Special consideration for specimens from HUS patients

• If the recommended guidelines do not produce an isolate:

• IMS – Immunomagnetic Separation Technique

•Key to work with physicians, clinical laboratories and epidemiology to get samples quickly

Public Health Recommendations…..

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• Companion Public Health Laboratory Guidelines, expected Fall 2009– Authored by 17 public health microbiologists (state and federal)– Details Best Practices for PHLabs to support the clinical labs in their

jurisdictions to assure rapid and comprehensive recognition of STEC

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STEC MMWR Workgroup

• L. Hannah Gould1

• Cheryl Bopp1

• Nancy Strockbine1

• Robyn Atkinson2

• Vickie Baselski3,4

• Barbara Brody5

• Roberta Carey1

• Claudia Crandall6

• Sharon Hurd7

• Ray Kaplan8

• Marguerite Neill9

• Shari Shea10

• Patricia Somsel11

• Melissa Tobin-D’Angelo12

• Patricia M. Griffin1

• Peter Gerner-Smidt1

1CDC, 2TN Dep’t Hlth, 3ASM, 4Univ of TN Hlth Sci Ctr, 5LabCorp, 6CA Dept Hlth,7CT Emerg Inf Prog, 8Quest Diagnostics,9Brown Univ,Wareen Alpert Sch of Med,10Assoc of Pub Hlth Labs, 11MI Dept Comm Hlth, 12GA Div of Pub Hlth

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APHL STEC Work Group:

John Besser – MN Cami Hartley - NCChris Carlson – SD Claudia Crandall - CACindy Fisher – UT Debbie Rutledge - DEKarim George – KY Patricia Somsel - MISteve Gladbach – MO Tim Monson - WIHugh Maguire – CO L. Hannah Gould - CDCNancy Strockbine – CDC Cheryl Bopp – CDCPeter Gerner-Smidt – CDC Sharon Shea - APHL

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Acknowledgements

• MDCH– Kendra Anspaugh– Barbara Evans– Robbie Madera– James Rudrik, PhD– Bill Schneider– Hao T. Trihn

• MSU– Late Tom Whittam,

PhD– Shannon Manning*– Microbial Evolution

Lab

*STEC surveillance project conducted by Dr. Manning during an EID fellowship