Experiences with non-0157 STEC and Implications on Public ...

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Experiences with non-O157 Experiences with non-O157 STEC and implications on STEC and implications on Public Health Programs Public Health Programs FLEMMING SCHEUTZ FLEMMING SCHEUTZ STATENS SERUM INSTITUT STATENS SERUM INSTITUT The International The International Escherichia Escherichia and and Klebsiella Klebsiella Centre (WHO) Centre (WHO) Copenhagen Copenhagen

Transcript of Experiences with non-0157 STEC and Implications on Public ...

Page 1: Experiences with non-0157 STEC and Implications on Public ...

Experiences with non-O157 Experiences with non-O157 STEC and implications on STEC and implications on Public Health ProgramsPublic Health Programs

FLEMMING SCHEUTZFLEMMING SCHEUTZ

STATENS SERUM INSTITUTSTATENS SERUM INSTITUT

The International The International EscherichiaEscherichia and and KlebsiellaKlebsiella Centre (WHO) Centre (WHO)

CopenhagenCopenhagen

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Publications “O157”, “non-O157”, Publications “O157”, “non-O157”,

VTEC, STEC & Shiga-Like Toxin in VTEC, STEC & Shiga-Like Toxin in

Title/Abstract in PubMed (1982 - Title/Abstract in PubMed (1982 -

2007)2007)

0

50

100

150

200

250

300

350

400

450

500

1982

1984

1986

1988

1990

1992

1994

1996

1998

2000

2002

2004

2006

O157 referencesNon-O157 references

VTECSTEC

Shiga-Like Toxin

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Non-O157 STEC studiesNon-O157 STEC studiesK. E. Johnson et al. CID 2006;43K. E. Johnson et al. CID 2006;43

16 countries, 1988-2006 (1,402/2,892)16 countries, 1988-2006 (1,402/2,892)48%48%

Range 19%-100%Range 19%-100%USA, Canada, UK, Germany, Spain, Italy, Czech Republic, Belgium, USA, Canada, UK, Germany, Spain, Italy, Czech Republic, Belgium, France, Denmark, Finland, Sweden, Australia, Chile, Argentina & Japan France, Denmark, Finland, Sweden, Australia, Chile, Argentina & Japan

Netherlands, 2006Netherlands, 2006 80%80%

Australia, 2004Australia, 2004 64% 64%

Belgium, 2006Belgium, 2006 81%81%

Brazil, 2007Brazil, 2007 100%100%

Poland, 2004Poland, 2004 100%100%

Germany, 1998Germany, 1998 88%88%

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Non-O157 Non-O157 STECSTEC surveillancesurveillance27 countries; 18,302 27 countries; 18,302 isolatesisolates% Non-O157 in the Enter-net database% Non-O157 in the Enter-net database

0%0%

10%10%

20%20%

30%30%

40%40%

50%50%

60%60%

70%70%

80%80%

90%90%

100%100%

CZCZ GRGR MTMT PLPL SKSK GBGB ESES GZGZ NZNZ IEIE NLNL EEEE SESE JPJP BEBE FRFR HUHU ATAT FIFI NONO CHCH ITIT LULU DKDK DEDE SISI ZAZA

7070 33 2020 1313 66

59495949

8787

15171517

607607642642457457 2727 510510

15761576

314314322322 4848 312312115115130130 1818 164164 4242 872872

42324232

246246 33

CountryCountry

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Non-O157 Non-O157 STECSTEC surveillancesurveillance27 countries; 6,480 isolates27 countries; 6,480 isolates

O Groups in the Enter-net database O Groups in the Enter-net database

00

200200

400400

600600

800800

10001000

12001200

2626103

103

Non

-O15

7

Non

-O15

79191 14

514

5NTNT11

111

114

614

612

812

8

O rou

gh

O rou

gh11

311

35555 22 767617

717

7 88 5511

711

717

417

412

112

1

Oth

ers

Oth

ers

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STEC incidences in EuropeSTEC incidences in Europe

Selected incidences of STECData from ”The Enter-net database”

0

2

4

6

2000 2001 2002 2003 2004 2005 2006

Cases

per

100.0

00/Y

r

ScotlandDenmarkIrelandE, W & NIGermanyBelgiumAustriaNetherlandsNorwayFinlandItaly

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22

00

55

33

3232

33

00

55

88

2020

No casesNo cases

1 - 1 - 1,491,49

1,5 – 1,5 – 1,991,99

Incidence of Incidence of STEC STEC

(per 100.000)(per 100.000)

0 - 0,490 - 0,490,5 - 0,990,5 - 0,99

2 – 3,992 – 3,991313

1212

> 4> 4

STEC in DenmarkSTEC in Denmark20062006

2929

00

112525

Number of diagnosed STEC infections by county, and Number of diagnosed STEC infections by county, and annual incidence of annual incidence of allall STEC infections in 2006 STEC infections in 2006

12 !12 !

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0,01,02,03,04,05,06,07,08,0

1997 1998 1999 2000 2001 2002 2003 2004 2005 2006

RA

TIO

Detection ratio of STEC in counties using molecular methods vs "other methods" in Denmark

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O22:H8O22:H8O26:H11O26:H11O103:H2O103:H2O103:H25O103:H25O104:H21O104:H21O111:H- / H2 / O111:H- / H2 /

H8H8

O113:H21O113:H21

O117:H4O117:H4O118:H2O118:H2O119O119O121:H19 / H21O121:H19 / H21O128:H2O128:H2O145:H-O145:H-O?:H19O?:H19

Citrobacter Citrobacter freundiifreundii

Non-O157 STEC outbreaks

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O103:H25 outbreak in O103:H25 outbreak in NorwayNorway

HUS HUS ”outbreak” ”outbreak” notifiednotified

Date of onset of diseaseDate of onset of disease

HUS casesHUS casesDiarrhea casesDiarrhea cases

20 21 22 23 24 25 26 27 28 29 30 31 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 1 2 3 4 5 6 7 8 9 10 11 12

JanuaryJanuary FebruaryFebruary MarchMarch

7 8 9 103 4 5 6

O103 pos / O103 pos / stx2stx2 neg negstx2stx2 pos pos

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Source: Sliced, Source: Sliced, dry dry fermented fermented lamb’s lamb’s sausagesausage

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Product and environmental Product and environmental samplessamples

O103 positiveO103 positive

Cured meat productsCured meat products 24622462 5353Sheep meatSheep meat 171171 99EnvironmentEnvironment 296296 00Spices, additives, cultureSpices, additives, culture5757 00Minced meatMinced meat 10001000 00

All isolates were All isolates were stx2stx2 negative & negative & eaeeae pos.pos.BUT clustered with patient isolates by BUT clustered with patient isolates by MLVA (DNA fingerprint)MLVA (DNA fingerprint)

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O26:H11 O26:H11 outbreak in outbreak in DenmarkDenmarkstx1 & eaestx1 & eae

20 cases; all children20 cases; all children

median 2 yearsmedian 2 years

Very mild symptomsVery mild symptoms

Discovered by PFGEDiscovered by PFGE

Little media attentionLittle media attention

17 cases; 15 children17 cases; 15 children

10 with HUS10 with HUS

1 child died 1 child died

HUS notificationHUS notification

Massive media Massive media attentionattention

O103:H25 O103:H25 outbreak in outbreak in NorwayNorwaystx2 & eaestx2 & eae

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Lessons learned in NorwayLessons learned in Norway

• Outbreak Outbreak ddiscovered due to iscovered due to notification of cases of HUSnotification of cases of HUS

• Methods in clinical laboratories were Methods in clinical laboratories were inadeqaute for detection of non-O157 inadeqaute for detection of non-O157 in 5 out of the six first cases of HUSin 5 out of the six first cases of HUS

• stx2stx2 negative isolates dominated negative isolates dominated

• MLVA was used to identify cases and MLVA was used to identify cases and the sourcethe source

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Lessons learned in Lessons learned in DenmarkDenmark

• Real-time PFGE of Danish non-O157 Real-time PFGE of Danish non-O157 detected a ”mild” outbreakdetected a ”mild” outbreak

• Only possible because isolates were Only possible because isolates were available for typingavailable for typing

Source identified usingSource identified using• access to purchase recordsaccess to purchase records• cooperation with supermarkets cooperation with supermarkets

searching their central computerssearching their central computers

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HUS & STECHUS & STEC Australia, Australia, Cyprus, Denmark, Germany, Cyprus, Denmark, Germany,

77 Hungary, Japan, PolandHungary, Japan, Poland

Notification dates from 1998 – 2005Notification dates from 1998 – 2005

STEC onlySTEC only Austria, CanadaAustria, Canada, Estonia, , Estonia, Finland, Finland,

1313 Greece,Iceland, Ireland, Luxembourg, Greece,Iceland, Ireland, Luxembourg, Malta , Malta , New Zealand, Norway, Slovenia, New Zealand, Norway, Slovenia, Sweden Sweden

Notification dates from 1990 – 2005Notification dates from 1990 – 2005

Not mandatoryNot mandatory England & Wales, France †, Italy ‡,England & Wales, France †, Italy ‡,

77 Romania, Spain, Scotland*, South AfricaRomania, Spain, Scotland*, South Africa

Pediatric- nephrology network since Pediatric- nephrology network since

† † 1996 < 15 Yrs1996 < 15 Yrs ‡ 1988 < 14 Yrs‡ 1988 < 14 Yrs

*Laboratory based since mid-eight’ies*Laboratory based since mid-eight’ies

HUS and STEC notifications worldwide

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SubtypeSubtype Non-HUS *Non-HUS * HUS*HUS*

stx2stx2 6060 1111

stx2cstx2c 4949 11

stx2dstx2d--activatableactivatable 44

stx2dstx2d 3939

stx2estx2e 22

stx2stx2--variantvariant 33

stx2stx2 + + stx2cstx2c 2323 77

stx2stx2 + + stx2dstx2d 11

2x 2x stx2stx2--activatableactivatable 44

stx2cstx2c + + stx2stx2--activatableactivatable 11

TotalTotal 186186 1919

Ethelberg et al. 2004 EID; 10Ethelberg et al. 2004 EID; 10

Shiga toxin 2 (Shiga toxin 2 (stx2stx2) subtype and clinical presentation) subtype and clinical presentation

stx2stx2 OR* 32.5 > OR* 32.5 > stx2cstx2c OR* 4.7 for HUS OR* 4.7 for HUS*) OR: odds ratio; multivariant analysis adjusted for age*) OR: odds ratio; multivariant analysis adjusted for age

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Virulence profile and Virulence profile and clinical manifestation in clinical manifestation in 559 Danish 559 Danish STECSTEC patients 1994-2005 patients 1994-2005

0%

20%

40%

60%

80%

100%

stx2 +eae

stx1 +stx2 +

eae

stx1 +eae

stx2 stx1 +stx2

stx1

Other

D

PD

BD

PBD

HUS

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Stx1 : 4 subtypes Stx1 : 4 subtypes aa - d - d7-8 variants7-8 variants

dd

bb

cc

aaStx1a-S._dysenteriae-3818T

Stx1a-S._sonnei-CB7888

Stx1b-O111-CB168

Stx1b-O157-EDL933

Stx1b-O48-94C

Stx1b-O111-PH

Stx1c-O174-DG131-3

Stx1d-ONT-MHI813

A1 A2 BBSP SP

Pairwise (OG:100%,UG:0%) (FAST:2,10) Gapcost:0%

VT1 translated sequences

10

0

99

98

97

96

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Pairwise (OG:100%,UG:0%) (FAST:2,10) Gapcost:0% Disc. unk.

vtx_TRANSL

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98

97

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82

vtx2d-O157-7279

vtx2d-O174-EC1720a

vtx2d-O91-a-B2F1

vtx2d-O91-b-B2F1

vtx2d-O8-C466-01B

vtx2d-C_freundii-LM76..

vtx2d-O6-NV206

vtx2d-O22-KY-O19

vtx2d-O73-C165-02

vtx2a-O157-EDL933

vtx2a-O26-FD930

vtx2a-O157-SF

vtx2a-O48-94C

vtx2a-O26-126814

vtx2a-E_cloacae-95MV2

vtx2c-O157-E32511

vtx2c-O157-FLY16

vtx2c-O157-C394-03

vtx2c-O157-469

vtx2c-O174-b-031

vtx2g-O2-7v

vtx2g-O2-S86

vtx2g-Out-S-8

vtx2b-O111-S-3

vtx2b-O96-S-6

vtx2b-O22-3143-97

vtx2b-ONT-5293-98

vtx2b-O118-EH250

vtx2b-O16-6451-98

vtx2b-O174-a-031

vtx2b-O111-PH

vtx2e-O139-412

vtx2e-O22-3615-99

vtx2e-O101-E-D43

vtx2f-O128-T4-97

dd

ff

bb

ggcc

aa

ee

Stx2 :Stx2 :7 subtypes7 subtypesaa - - gg

35 variants35 variants

A1 A2 BBSP SP

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A1 A2 BBSP SP

95 AA95 AA 64 AA 64 AA

VT2B VT2B VT2A VT2A

225225

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Only 12 Stx2Only 12 Stx2 variants found variants found in Danish patientsin Danish patients

Stx2aStx2a

stx2cstx2c

stx2dstx2d

stx2estx2e

stx2gstx2g

stx2bstx2b

Stx2a-O48-94CStx2a-O48-94C

Stx2a-O157-EDL933Stx2a-O157-EDL933

Stx2c-O157-FLY16Stx2c-O157-FLY16

Stx2d-O8-C466-01BStx2d-O8-C466-01B

Stx2d-O157-7279Stx2d-O157-7279

Stx2e-ONTStx2e-ONT-26725-97-26725-97

Stx2g-O2-7vStx2g-O2-7v

Stx2b-O118-EH250Stx2b-O118-EH250

0.010.01

Stx2c-O157-C394-03Stx2c-O157-C394-03

Stx2d-O73-C165-02Stx2d-O73-C165-02

Stx2e-O101-E43Stx2e-O101-E43

Stx2b-O111-PHStx2b-O111-PH

New variantsNew variants

First time in First time in humanshumans

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Attack rate of Stx2 variants Attack rate of Stx2 variants associated with HUSassociated with HUS

O157O157

Stx2a-O157-EDL933 + Stx2c-O157-FLY16Stx2a-O157-EDL933 + Stx2c-O157-FLY16 6/236/23

26%26%

Stx2a-O157-EDL933Stx2a-O157-EDL933 3/173/17 18%18%

Stx2c-O157-FLY16Stx2c-O157-FLY16 1/181/18 6%6%

Stx2a-O157-SF + Stx2c-O157-FLY16Stx2a-O157-SF + Stx2c-O157-FLY16 1/11/1 --

Non-O157Non-O157

Stx2a-O48-94CStx2a-O48-94C 6/206/20 30%30%

Stx1b + Stx2a-O157-EDL933Stx1b + Stx2a-O157-EDL933 1/31/3 --

Stx2a-O157-EDL933 +Stx2a-O157-EDL933 + Stx2c-O157-FLY16Stx2c-O157-FLY16 1/21/2 --

Stx1b + Stx2a-O48-94CStx1b + Stx2a-O48-94C 1/51/5 20%20%

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ConclusionsConclusionsTwo Stx2aTwo Stx2a variants associated with HUSvariants associated with HUS

Stx2a-O157-EDL933Stx2a-O157-EDL933 in NSF O157in NSF O157(& Stx2-O157-FLY16)(& Stx2-O157-FLY16)

Stx2a-O157-SF Stx2a-O157-SF in SF O157in SF O157Stx2a-O48-94CStx2a-O48-94C in in Non-O157Non-O157

New Paradigm:New Paradigm:

How may STEC be classified?How may STEC be classified?

Are certain virulence ”cocktails” associated with Are certain virulence ”cocktails” associated with severe disease rather than the serotype?severe disease rather than the serotype?

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Based on the reported occurrence of serotypes in human Based on the reported occurrence of serotypes in human disease, in outbreaks and/or in hemolytic-uremic syndrome (HUS)disease, in outbreaks and/or in hemolytic-uremic syndrome (HUS)

Classification of STEC in 5 Sero-Classification of STEC in 5 Sero-pathotypespathotypesKarmali Karmali et al.et al. , 2003, J. Clin. Microbiol., 41:4930-40 , 2003, J. Clin. Microbiol., 41:4930-40

Sero-Sero-pathotypepathotype

Relative Relative incidence incidence

Frequency Frequency of of

involvement involvement in outbreaksin outbreaks

Association Association with severe with severe

disease disease (HUS or HC)(HUS or HC)

SerotypesSerotypes

AA HighHigh CommonCommon YesYes O157:H7, O157:NMO157:H7, O157:NM

BB ModerateModerate UncommonUncommon YesYes O26:H11, O103:H2, O26:H11, O103:H2, O111:NM, O121:H19,O111:NM, O121:H19,O145:NMO145:NM

CC LowLow RareRare YesYes O91:H21, O113: H21, O91:H21, O113: H21, O104:H21, othersO104:H21, others

DD LowLow RareRare NoNo multiplemultiple

EE Non Non human human only only

multiplemultiple

New ParadigmNew Paradigm

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Problems with this Problems with this classificationclassification

Association with serotype and not with Association with serotype and not with virulence profilevirulence profile

• More than 120 O:H serotypes have been More than 120 O:H serotypes have been associated withassociated withHUS (Bergey’s Manual of Systematic Bacteriology, HUS (Bergey’s Manual of Systematic Bacteriology, 2nd ed.)2nd ed.)

• Many O:H serotypes display extensive Many O:H serotypes display extensive heterogeneityheterogeneity

Involvement in outbreak may rapidly changeInvolvement in outbreak may rapidly change

Relative incidence Relative incidence • is scewed by lack of effecient detection methodsis scewed by lack of effecient detection methods• will vary depending on the epidemiology of will vary depending on the epidemiology of

specific typesspecific types

New ParadigmNew Paradigm

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1.1. HUS inducing STEC and/or an epidemic outbreak potentialHUS inducing STEC and/or an epidemic outbreak potential

• eaeeae and and stx2astx2a• eaeeae negative and negative and stx2dstx2d (activatable) (activatable)• eaeeae and and stx1stx1 Less common but certain O:H serotypes Less common but certain O:H serotypes

have have been associated with HUSbeen associated with HUS

2.2. Diarrhea inducing in humans!Diarrhea inducing in humans!

• Many different virulence profilesMany different virulence profiles• Capacity to produce Stx and association with diarrhea in Capacity to produce Stx and association with diarrhea in

humanshumans

3.3. Animal-associated STECAnimal-associated STEC

• High prevalence in the animal reservoirHigh prevalence in the animal reservoir• Seems to be their natural habitat Seems to be their natural habitat • No human casesNo human cases• Candidates for this group are Candidates for this group are stx2estx2e positives positives

Alternative Alternative classificationclassification

New ParadigmNew Paradigm

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QuestionsQuestions

Should management and Should management and treatment of patients be treatment of patients be

adjusted according to adjusted according to virulence cocktail?virulence cocktail?

New ParadigmNew Paradigm

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Danish Practice since 2000Danish Practice since 2000ALL patients with STEC are excludedALL patients with STEC are excludedor quarantined if they areor quarantined if they are

• Children in institutions and day careChildren in institutions and day care• Staff of health care facilitiesStaff of health care facilities• Hospital staff or hospitalized patientsHospital staff or hospitalized patients• Food handlersFood handlers

BackgroundBackground

and until they have had two and until they have had two consecutive STEC negative stool consecutive STEC negative stool samples samples

Prolonged shedding of STEC has Prolonged shedding of STEC has resulted in huge social problems resulted in huge social problems especially for parentsespecially for parents

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Danish example of Danish example of consequencesconsequencesRevision of guidelines for treatment of Revision of guidelines for treatment of Danish patients with STEC may include Danish patients with STEC may include antibiotic treatment of asymptomatic antibiotic treatment of asymptomatic patients with patients with

• eaeeae negative STEC negative STEC• eaeeae & & stx1stx1 - except some serotypes - except some serotypes

Asymptomatic patients are likely to be Asymptomatic patients are likely to be allowed back in institutions and day care allowed back in institutions and day care after treatmentafter treatment

New ParadigmNew Paradigm

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• Adequate detection methods should include the isolation of Adequate detection methods should include the isolation of bacteriabacteria

• Typing methods should be standardizedTyping methods should be standardized

• Subtyping methods for Stx2aSubtyping methods for Stx2a variants associated with HUS variants associated with HUS should be implementedshould be implemented

• Urgent need for standardized nomenclatureUrgent need for standardized nomenclature

RecommendationsRecommendations

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QuestionsQuestions1.1. How much is detection and How much is detection and

surveillance scewed?surveillance scewed?

2.2. Can case definitions for HUS to Can case definitions for HUS to be notified within the Public be notified within the Public Health system be established?Health system be established?

3.3. Will management and treatment Will management and treatment of STEC patients depend onof STEC patients depend on

• a case-to-case based a case-to-case based assessment? assessment?

• an outbreak-to-outbreak an outbreak-to-outbreak approach?approach?

• local epidemiology?local epidemiology?

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QuestionQuestion

Should non-O157:H7 Should non-O157:H7 STECs be considered to STECs be considered to be adulterants as be adulterants as E. coliE. coli O157:H7? O157:H7?

YES - someYES - some

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AcknowledgementsAcknowledgementsStatens Serum Institut, CopenhagenStatens Serum Institut, CopenhagenJoan Neverman Jensen Joan Neverman Jensen Søren PerssonSøren PerssonKatharina E. P. OlsenKatharina E. P. Olsen

Co-authors on nomenclatureCo-authors on nomenclatureLothar Beutin, Lothar Beutin, Federal Institute for Risk Federal Institute for Risk Assessment, BerlinAssessment, Berlin

Denis Piérard, Denis Piérard, Academisch Ziekenhuis Vrije Academisch Ziekenhuis Vrije Universiteit, BrusselsUniversiteit, Brussels

Nancy A. Strockbine, Nancy A. Strockbine, National Center National Center for Zoonotic, Vector-borne and Enteric Diseases for Zoonotic, Vector-borne and Enteric Diseases (CDC), Atlanta(CDC), Atlanta