Enterovirus D68: an underestimated pathogen - Prof. Niesters

Prof. dr. Bert Niesters
Department of Medical Microbiology
Division of Clinical of Virology
University Medical Center Groningen
The Netherlands
Division of Clinical Virology
Enterovirus D68
an underestimated pathogen

What is enterovirus D68
• For the first time isolated in 1962
• From respiratory material
• Children with bronchiolitis, usually in the summer period
• Between 1970 and 2005, only 26 times reported

Before 2010
• 2005 to 2010 reports from France, Philippines, USA, UK,
Netherlands, Japan…
• Mostly respiratory problems, bronchiolitis type illness
• Summer and early fall

2010 Groningen
• Bronchiolitis-type illness
• Some severe cases requiring
intensive care treatment
• Many patients had underlying
condition

Explaining illness: EV68
0
1
2
3
4
5
6
7
8
wk31 wk32 wk33 wk34 wk35 wk36 wk37 wk38 wk39 wk40 wk41
Week number (2010)
numberofpatients
August-November 2010: 24 patients with only dEV68 etection
‘RS-like illness’
In same period: peak in EV68 detections in sentinel surveillance system into
respiratory illness among patients seen by general practitioner; upsurge of EV68 in
USA, Japan and other countries worldwide

Patients and clinical data
• 19 (79.2%) with underlying illness
• 14 (58.3%) related to pulmonary tract: hyperreactivity,
chronic oxygen need, lung transplantation
• median age 14 years (0-72 years)
• 41.7% under 2 years of age
• hospitalization in 23 patients (95.8%):
– median duration of hospitalization
5 days (1-25)
– ICU admission:
5 patients (20.8%)
• one without previous underlying illness
pneumonia
exacerbation
asthma/wheezing
upper respiratory
tract infection

Patients and clinical data
• Hospitalization in 23 patients (95.8%):
– three hospital acquired infections
– median duration of illness at admission
3 days (0-10)
– median duration of hospitalization
5 days (1-25)
– ICU admission:
5 patients (20.8%)
• one without previous underlying illness
• need for mechanical ventilation

Sequence analysis and phylogeny
• 24 patients in 2010, 4 patients in 2009
• based on VP4/VP2 sequence analysis: two distinct
phylogenetic clusters
– One with all 2009 and part of 2010 isolates
– One with only 2010 isolates
• VP1 partial sequencing: 3 nucleotide deletion in 2010
cluster

Labmicta, Enschede
Isala, Zwolle
Izore, Leeuwarden
UMCG
LvI
Apeldoorn
Dr. Donker, Prof. Grundmann, UMCG
UMCG
Regional Center
Satellite
Connectivity between regional centers
(does not cross borders)

TYPENED and REGIOtype
• Sequencing of enterovirus,
parechovirus, rhinovirus and
norovirus in the region and in
real time

Stockman et al. MMWR Weekly
Volume 60, No. 38
September 30, 2011

After 2010
• Very few reported cases
• Many labs fail to detect EV-
D68 in quality assurance
panels
• No EV-D68 specific test
• Not all rhinovirus PCRs pick
up EV-D68
• Not all labs look for rhinovirus

August 2014
• First reports of serious respiratory disease in children in
Missouri (USA)
• Within one week, more reports of severe and
complicated respiratory disease in Illionois (USA)
• Sequencing by CDC
• 19/22 Missouri EV-D68
• 11/14 Illionois EV-D68

Enterovirus D68 outbreak 2014
• Children (<16 years)
• 68% had prior history of wheezing
• Nearly all patients required intensive care treatment
• Many reports from other states and Canada
• Testing (sequencing) at CDC: only severe cases

EV-D68 in USA 2014
• At least 1121 positives in 47 states
• 40% of screened patients positive for EV-D68
• Incidence now reduced
• 12 children died
• Mostly seen bronchiolitis

Summer 2014 in UMCG
Genotype number of samples
EV-D68 17
CV-A6 11
E-16 6
CV-A2 4
CV-A4 4
E-25 3
E-18 2
CV-B3 2
CV-A16 2
EV-C104 1
EV-C105 1
E-3 1
CV-B4 1
CV-B1 1
CV-A10 1
CV-A11 1
ND 14
TBA 4

patient Sex age date symptoms ICU/days Underlying conditon
1 F 1y/ 11m Feb 2014 Moderate bronchilitis-type
respiratory illness
no none
2 F 1y/ 7m May 2014 Severe respiratory illness,
intubaton, mechanical
ventilation
Yes/4 none
3 F 6m June 2014 Mild cold symptoms no Congenital heart disease
4 M 3y/ 9m June 2014 Severe respiratory illness,
intubation, mechanical
ventilation
Yes/8 Sickle cell anemia
5 M 65y July 2014 Moderate wheezing and
cough
no Lung transplantation
6 M 1 y July 2014 Severe respiratory illness,
ventilation
Yes/5 none
7 F 6w July 2014 Feeding problem no Gastro-esophageal reflux
8 M 3y/ 10m July 2014 Severe respiratory illness,
ventilation
Yes/1 Ex-premature
9 M 6m Aug 2014 Mild cold symptoms * Congenital heart disease
10 M 14y Aug 2014 Mild cold symptoms * Traumatic brain injury
11 F 1y/ 6m Aug 2014 Mild cold symptoms no epilepsy
12 M 1m Aug 2014 Severe respiratory illness,
ventilation
Yes/1 Ex-premature
13 F 22y Aug 2014 Cough, SOB, fatigue No Heart transplantation
14 F 44y Aug 2014 Cough, SOB No COPD
15 M 1y/ 5m Sep 2014 Moderate wheezing, cough No Tracheomalacia, heart disease
16 F 63y Sep 2014 Asthma exacerbation no asthma
17 F 53y Sep 2014 Wheezing, pneumonia no Renal transplantation
* These children were admitted to ICU for other reasons
SOB=shortness of breath

Is EV-D68 detected?
• QCMD: most laboratories do not detect or look for EV-D68
• Commercial assays:
• Fast-track diagnostics YES
• Argene YES
• GenMark NOT
• Cepheid YES, but not validated
• FilmArray YES, but rhino/entero together
• Luminex YES, but rhino/entero together
• Pathofinder MLPA YES, but rhino/entero together
• Seegene, NOT
• bioMerieux NASBA NucliSENS EasyQ Enterovirus, NOT
• Laboratory Developed Tests: not always
• Routinely, enterovirus is not always included for respiratory diagnostics

What’s up
• Several labs have started looking for EV-D68
• Sequencing provides most info (a lot of work)
• 2 new targeted specific PCRs to detect EV-D68 available

To take home
• In the USA in 2014: EV-D68 outbreak ongoing
• In the UMCG EV-D68 several severe infections
• Few labs have routine screening tests that detect EV-
D68
• How much EV-D68 is there really in Europe???

How is the situation in Europe?
ECDC: I see no problem…………

ESCV

0
5
10
15
20
25
30
35
40
45
50
27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48
NumberofEV-D68positives
Week
NA
Clade B
Clade A
ESCV 2014, Prague
Epidemiological curve
July 1st December 1st
*17 samples are not included in this graph, due to a lack of sampling
date

EV-D68 / EV Genus
0 %
1-5 %
5-20 %
20-35 %
*
*
*
European detection rates per country
*
• 42 laboratories
from 18 countries
• 17,248 samples
tested
• 389 EV-D68
positives

Norway Oslo NIPH 66 25 9
Oslo Ullevål 354 71 34
Trondheim 157 101 6 49 24,9%
Sweden Stockholm Karolinska/PHI/ 30* 30 7 7 23,3%
Finland Turku UTU 700 140 10
Helsinki HUS 109 15 4
Helsinki THL 91 29 3 17 9,2%
Scotland Glasgow 488* 488 22 22 4,5%
Ireland NVRL Dublin 1010 51 4 4 7,8%
Wales Cardiff NHS 604 62 9 9 14,5%
Netherlands Erasmus MC Rotterdam 198 46 7
Leiden UMC 780 185 3
Radboud UMC 270 6 1
Regional health service Haarlem 252 62 4
UMC Groningen 2397 531 19
RIVM Bilthoven NIH 370 130 22 56 5,8%
Denmark Statens serum institut SSI 252 50 8 8 16,0%
Germany Bonn 351 35 1
Freiburg 136* 136 6
Berlin, Robert Koch Institut *** 1658 58 15
Leipzig, Institute of Virology 364 93 9 31 9,6%
Poland Warsaw NIH 144 22 0 0
Romenia Bucharest 56 0 0 0
Austria Vienna 778 47 1 1 2,1%
Slovenia Ljubljana 702 234 48 48 20,5%
Italy Milan 176 97 4
Pavia 195* 195 9 13 4,5%
Luxembourg Luxembourg 19* 19 1 1 5,3%
France Lyon/Nat ref center EV 1589 439 39
Clermont-Ferrand/Nat ref center EV 710 191 25
Brest 199 86 9
Caen 367 175 22
Dijon 159 37 5
Paris 49 25 0
Saint-Etienne 104 36 6
Strasbourg 203 102 9
Versailles 109 34 2 117 10,4%
Spain Barcelona 529 53 5
Valencia 458 89 0
Santander 15* 15 0
Valladolid 33* 33 1 6 3,2%
Portugal Lisbon 17 0 0 0
Total number of countries** Total number of labs
17 42 17248 4273 389
EV68/EV Genus (%)Country lab/city Tested EV Genus (= EV and/or HRV) EV-D68 Total/Country

Underlying disease presented in the different age groups
Statistic note:
55% (n=17) of the 31 EV68 positive patients older than 17 year were immunocompromised.
Only 8% (n=8) of the 100 EV68 positive patients younger than 17 were immunocompromised.
This difference is very significant: odds ratio 13,9 (95% CI 4,6 – 44,0), p < 0,001 (Chi-Square Test)
0-1 120 20(16,7%) 3(2,5%) 10(8,3%) 58(48,3%) 29(24,2%)
2-5 135 27(20,0%) 5(3,7%) 12(8,9%) 28(20,7%) 63(46,7%)
6-16 56 16(28,6%) 1(1,8%) 6(10,7%) 11(19,6%) 22(39,3%)
≥17 78 9(11,5%) 17(21,8%) 5(6,4%) 14(17,9%) 33(42,3%)
Total 389 72(18,5%) 26(6,7%) 33(8,5%) 111(28,5%) 147(37,8%)
age EV68positive
Underlying disease
Not assignedNoneNon respiratory illnessImmunocompromisedChronicrespiratory illness

AFP case France
• Boy age 4
• 20 September meningitis syndrome
• 190 leukocytes in CSF, 92% lymphocytes
• 27 September paralysis en dysphagia
• EV-D68 in faeces and nasopharynx

Clinical picture reported from these countries
• Respiratory complaints
• 3 Acute Flacid Paralysis (France and Norway)
• 1 death
• A lot of children with underlying disease
• Also adults
• Some real outbreaks: Wales and Slovenia
• Different approach of diagnostics for viral infections
gives a different picture in different countries

Are they connected?
USA
USA
USA
UMCG

Nr of Samples
25
10
5
1
Yamagata ’10
Clade C
Fermon
A2
B
A1
Colors represents the country of origin.
LEGEND
NOR GER
FIN SVN
IRE ITA
WAL FRA
NLD SPA
DNK USA

• In USA 2014: EV-D68 outbreak
• In Europa circulation of same EV-D68 genotypes
• Different approach of diagnostics for viral infections
gives a different picture in different countries
How do we take care that “emerging viruses” do
become detected?

Conclusion
• Highlight the need for incorporating molecular
diagnostics into routine testing
detection and identification of these viruses could
help in explaining serious illness, giving guidance to
medical care and preventing unnecessary treatment
with antibiotics

The AID-Stewardship Portfolio
• The Antibiotic/Antimicrobial Stewardship
• The Infection Control Stewardship
• The Diagnostic Stewardship
Determine and communicate the value of molecular
diagnostics!
– Take the lead (use of POC/POI; E-health)
– Cost effectiveness
– Awareness (communicate)

Austria:
-(Department of Virology, Medical University of Vienna) Theresia Popow-Kraupp, Stephan W. Aberle.
Denmark:
-(Virus Surveillance and Research Unit, Department of Microbiological Diagnostics and Virology, Statens Serum Institut and Clinical Institute, University of Southern Denmark) Thea Kølsen Fischer;
-(National WHO Polio Reference Laboratory at Statens Serum Institut) Sofie Midgley;
-(Virology Unit, Department of Clinical Microbiology at Rigshospitalet) Claus Bohn Christiansen.
Finland:
-(Department of Virology, University of Turku) Matti Waris, Riikka Österback, Tytti Vuorinen;
-(National Institute for Health and Welfare, Virology unit, Helsinki) Carita Savolainen-Kopra, Francesca Latronico#, Soile Blomqvist, Niina Ikonen; (#*European Public Health Microbiologytraining programme (EUPHEM), European Centre for Disease Prevention and Control, Stockholm, Sweden)
-(Department of Virology and Immunology, University of Helsinki and Helsinki University Hospital)
Maija Lappalainen, Anne Jääskeläinen, Teemu Smura.
France:
-(Microbiology laboratory, University hospital of Brest) Léa Pilorge, Marie-Christine Legrand-Quillien, Christopher Payan;
-(Virology laboratory, University hospital of Caen) Joëlle Petitjean, Astrid Vabret, Mélanie Ribault;
-(National Reference Center for Enteroviruses and Parechoviruses, University Hospital of Clermont-Ferrand) Audrey Mirand, Hélène Peigue-Lafeuille, Cécile Henquell;
-(Virology laboratory, University hospital of Dijon) Catherine Manoha, Jean-Baptiste Bour, Magali Darniot;
-(Virology laboratory, National Reference Center for Enteroviruses and Parechoviruses, Hospices Civils de Lyon) Isabelle Schuffenecker, Laurence Josset, Bruno Lina;
-(Université Paris Diderot, Sorbonne Paris Cité, Microbiology laboratory, Hôpital Saint-Louis, APHP, Paris) Jérôme Le Goff, Séverine Mercier-Delarue, Catherine Scieux;
-(Laboratory of infectious agents and hygiene, University Hospital of Saint-Etienne, Saint-Etienne) Sylvie Pillet, Bruno Pozzetto;
-(Virology institute, University hospital of Strasbourg) Quentin Lepiller, Samira Fafi-Kremer, Françoise Stoll-Keller;
-(Microbiology laboratory, Hospital of Versailles) Stéphanie Marque-Juillet; Aymeric Coutard, Marlène Amara.
Germany:
-(Berlin, Robert Koch Institute, National Reference Centre for Poliomyelitis and Enteroviruses) Sindy Böttcher, Sabine Diedrich; The Robert Koch Institute collateddata from the followingDepartments and Institutes: Institute of Virology and Immunobiology,University Hospitalof Würzburg, Christiane Prifert, Benedikt Weißbrich; Institute of Virology,University Hospital of Düsseldorf, Ortwin Adams;
Department of Virology,Labor Berlin - Charite VivantesGmbH), Angela Stein, Jörg Hofmann; Department of Infectious Diseases,Virology,University HospitalHeidelberg,Paus Schnitzler;
-(Institute of Virology, University of Bonn Medical Centre) Anna Maria Eis-Hübinger, Souhaib Aldabbagh, Ulrike Reber;
-(Institute of Virology, Albert-Ludwigs University Freiburg) Marcus Panning, Daniela Huzly, Sibylle Bierbaum;
-(Institute of Virology, University of Leipzig) Uwe G. Liebert, Melanie Maier.
Ireland:
-(National Virus Reference Laboratory, University College Dublin) Michael J. Carr, Gráinne Tuite, Jorge Abboud Guerra ,Joanne O’Gorman, CillianDe Gascun
Italy:
-(University of Pavia, Fondazione IRCCS Policlinico San Matteo, Pavia) Fausto Baldanti; (Fondazione IRCCS Policlinico San Matteo, Pavia), Antonio Piralla
-(Milan, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pediatric Highly Intensive Care Unit), Susanna Esposito, Nicola Principi, Luca Ruggiero
Luxembourg:
-(Dudelange, Laboratoire National de Santé) Matthias Opp
Netherlands:
-(Bilthoven, Centre for Infectious Disease Research, Diagnostics and Screening, National Institute of Public Health and the Environment) Adam Meijer, Harrievan der Avoort, Kimberley Benschop; (Bilthoven, Centre for Infectious Diseases, Epidemiology and Surveillance, National Institute of Public Health) Marit de Lange; (Utrecht, Netherlands institute for health services research) Gé Donker;
-(University Medical Center Groningen) Hubert Niesters, Randy Poelman, Coretta van Leer-Buter, Renze Borger, Liesbeth Scholvinck;
-(Haarlem, Regional Laboratory for Public Health Kennemerland) Wil van der Reijden, Dick Veenendaal;
-(Department of Medical Microbiology, Leiden University Medical Center Leiden) Eric C.J. Claas, Ann C.T.M. Vossen ;
-(Nijmegen, Department of Medical Microbiology, Radboud University Medical Center) Janette Rahamat-Langendoen, Willem J.G. Melchers ;
-(Rotterdam, ErasmusMC, Department of Viroscience) Marion P.G. Koopmans, Annemiek A. van der Eijk, Suzan D. Pas
Norway:
-(Department of Medical Microbiology, Oslo University Hospital) Anne-Marte Bakken Kran;
-(Oslo, Norwegian Institute of Public Health) Karoline Bragstad, Susanne Gjeruldsen Dudman;
-(Trondheim, Department of Medical Microbiology, St.Olavs University Hospital) Andreas Christensen, Sidsel Krokstad
Poland:
-(National Institute of Public Health-NIH Warsaw) Katarzyna Pancer, Edyta Abramczuk.
Portugal:
-(Lisbon, National Influenza Reference Laboratory) Raquel Guiomar, Pedro Pechirra, Paula Cristovão, Ines Costa.
Romania:
-(Bucharest, Cantacuzino National Research and Development Institute for Microbiology and Immunology) Cristina Tecu, Emilia Lupulescu, Carmen Cherciu.
Scotland:
-(West of Scotland Specialist Virology Centre Glasgow) Emily Goldstein, Susan Bennett, Amanda Bradley-Stewart, Rory Gunson.
Slovenia:
-(Ljubljana, Laboratory for Public Health Virology. National Laboratory of Health, Environment and Food) Natasa Berginc, Katarina Prosenc.
Spain:
-(Respiratory Virus Unit/Virology Section, University Hospital Vall d’Hebron, Barcelona) Magda Campins, Laura Gimferrer, Andres Anton;
-(Virology Laboratory, Genomics and Health Area, FISABIO-Public Health, Generalitat Valenciana, Valencia / CIBERESP, Instituto de Salud Carlos III) F. Xavier López-Labrador; Laura Cano Pérez; (Vaccines Research Area, FISABIO-Public Health, Generalitat Valenciana, Valencia) Joan Puig-Barberá;
-(Microbiology Service, General Hospital of Valencia) Concepción Gimeno Cardona, M Dolores Ocete Mochón;
-(Microbiology Service, Hospital Clinico of Valencia) Javier Buesa, David Navarro;
-(University Hospital of Valladolid) R. Ortiz de Lejarazu Leonardo, Iván Sanz Muñoz, Silvia Rojo;
-(Service of Microbiology, University Hospital Marqués de Valdecilla-IDIVAL, Santander) Mónica Gozalo-Margüello, Jesús Agüero Balbín.
Sweden:
-(Stockholm, Department of Clinical Microbiology, Karolinska University Hospital) Jan Albert, Agneta Samuelson, Maria Rotzén Östlund, Robert Dyrdak
-(Stockholm, Public Health Agency of Sweden) Mia Brytting, Elenor Hauzenberger, Katherina Zakikhany
-(Stockholm, Astrid Lindgren Children's Hospital) Margareta Eriksson
Wales:
-(Public Health Wales Microbiology Cardiff, University Hospital of Wales) Catherine Moore.
European Centre for Disease Prevention and Control (Stockholm Sweden)
-Eeva Broberg, Pasi Penttinen.
Quality Control for Molecular Diagnostics (Scotland/United Kingdom)
-Elaine McCulloch, Caterina Di Lorenzo, Paul Wallace, Anton Van Loon
List of participants ESCV-ECDC
Enterovirus D68 ad-hoc study group

Cost Effectiveness of AID-Stewardship

Enterovirus D68: an underestimated pathogen - Prof. Niesters

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