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The Dutch story of molecular
epidemiology in tuberculosis
surveillance
Gerard de Vries, MD MSc PhD
Coordinator TB control the Netherlands
KNCV Tuberculosis Foundation/RIVM-CIb
UNION European Region conference, Bratislava, Slovakia, 23 June 2016
How is DNA fingerprinting used in the
Netherlands?
Typing method:
1993 -2008
2004 -2008
2009 - now
2016
RFLP IS 6110
MIRU VNTR / RFLP
MIRU VNTR 4 loci
WGS
4
5
4
2
54442
VNTR pattern: numerical code 24 digits
DNA fingerprint
identical with a
previous isolate?
No
Unique
fingerprint
Yes
Cluster
Clustered
fingerprint
Previous TB patient
in cluster <2 years?
No
Yes
Cluster
investigation
Recent clustering
(high priority for
cluster investigation)
Confirmed
epi-link with
another patient
No confirmed
epi-link with
another patient
No recent clustering
(low priority for
cluster investigation)
Procedure
1. National reference laboratory (NRL, RIVM) performs the genotyping (now:
MIRU VNTR)
2. Information is entered into the (electronic) TB notification system
3. GGD (Municipal Public Health Centre) can make a cluster download (Excel)
Jaar
OSIRIS
diagnose NR
EIGENAAR
2013
2013
2013
2013
1069965 GGD Haaglanden
GGD Rotterdam
1071339 Rijnmond
GGD Gelderland1073645 Midden
GGD Rotterdam
1075633 Rijnmond
2013
GGD Rotterdam
1079597 Rijnmond
GGD Rotterdam
1087985 Rijnmond
2013
GGD Rotterdam
1096573 Rijnmond
2013
GGD Rotterdam
1104885 Rijnmond
2013
NTR19A4:
VNTR
NUMMER1
9000109
9000109
IGZ3001:
PAT
DIAGNOSE IGZ2000: GEBOORTE
DATUM
GESLACHT JAAR
xx-xx-2013 Man
xx-xx-2013 Man
19xx
19xx
NTR5:
NTR5C: IN
GEBOORTELAND NEDERLAND NTR13:
NTR4: SOORT NTR17A:
NTR17B:
PATIENT
SINDS
RISICOGROEP TBC
SPUTUMONDERZOEK UITSLAG BAL
Nederland
Nederland
9000109
xx-xx-2013 Vrouw
19xx
Nederland
9000109
xx-xx-2013 Man
19xx
Nederland
9000109
xx-xx-2013 Man
19xx
Turkije
9000109
xx-xx-2013 Man
19xx
Nederland
9000109
xx-xx-2013 Vrouw
19xx
Nederland
9000109
xx-xx-2013 Man
Zuurvaste staven Geen epidemiologisch verband
negatief
aangetoond
Geen epidemiologisch verband
Onbekend
aangetoond
Zuurvaste staven
negatief
Zuurvaste staven
positief
Zuurvaste staven Geen epidemiologisch verband
negatief
aangetoond
pulmonaal
pulmonaal
Gedocumenteer
d contact van
besmettelijke
patient
extrapulmonaal Niet gedaan
Zuurvaste staven
negatief
Niet gedaan
Aangetoond epidemiologisch verband
Niet gedaan
Aangetoond epidemiologisch verband
Zuurvaste staven Geen epidemiologisch verband
negatief
aangetoond
pulmonaal
xx-xx-xxxx
extrapulmonaal Niet gedaan
Niet gedaan
pulmonaal en
extrapulmonaal Onbekend
Zuurvaste staven Geen epidemiologisch verband
negatief
aangetoond
9000109
xx-xx-2014 Vrouw
19xx
2014
GGD Rotterdam
1122271 Rijnmond
9000109
xx-xx-2014 Man
19xx
Nederland
xx-xx-2014 Man
pulmonaal en
extrapulmonaal Niet gedaan
Zuurvaste staven
pulmonaal
positief
xx-xx-xxxx
1110349 GGD Haaglanden
9000109
Niet gedaan
Geen epidemiologisch verband
aangetoond
Aangetoond epidemiologisch
verband
Marokko
2014
GGD Rotterdam
1145971 Rijnmond
xx-xx-xxxx
Niet gedaan
NTR19A3: RESULTAAT EPI-VERBAND
19xx
Nederlandse
Antillen
2014
Verslaafd aan
alcohol
Zuurvaste staven
pulmonaal
positief
Zuurvaste staven
extrapulmonaal negatief
19xx
Kaapverdie
xx-xx-xxxx
Dak- en
thuisloze,
Verslaafd aan
alcohol
pulmonaal
Zuurvaste staven
positief
Niet gedaan
Geen epidemiologisch verband
aangetoond
Geen (of onvoldoende) clusteronderzoek
verricht
4. Depending on patients’ characteristics the TB nurse will contact other TB
nurses to investigate relationships (cluster investigation)
 Confirmed epi-link when two persons were at the same place at
the same time (usually knowing each other)
1.
DNA fingerprinting
for outbreak management
RFLP cluster 15 / VNTR 9000296
20
18
16
14
2004-2008:
31% concordance
between RFLP and
VNTR.
12
Unknown
Other
10
Netherland
Eritrea/Ethiopia
8
Somalia
77% Somalia
13% Eritrea /
Ethiopia
3% NL
6
4
2
0
1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
‘Clustering is not identical as
(recent) transmission’
35
RFLP
510
30
25
20
15
Only RFLP
10
5
0
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
35
30
25
Unknown
20
Other
Country of birth
Netherlands Antilles
Surinam
15
Angola/ Mozambique / Portugal
Netherlands
Cape Verdean Islands
10
5
0
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
35
30
25
20
Illicit drug use/ homeless
No illicit drug use/ homeless
15
10
5
0
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
35
30
25
Mid 2001:
Start mobile
X-ray
screening
programme
20
Illicit drug use/ homeless
No illicit drug use/ homeless
15
10
1998-2001:
44% drugs/
homeless
5
0
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
35
30
25
20
GGD Noord en Oost Gelderland
GGD Amsterdam
GGD Haaglanden
15
GGD Rotterdam Rijnmond
10
5
0
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
35
30
25
20
Illicit drug use/ homeless
No illicit drug use/ homeless
15
10
By 2008:
188 patients
5
0
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
35
30
25
Unknown
20
Other
Netherlands Antilles
Surinam
15
Angola/ Mozambique / Portugal
Netherlands
Cape Verdean Islands
10
5
By 2008:
22% Cape Verdean
43% Netherlands
14% Surinam
/Neth. Antilles
Total: 14 CoB
0
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
35
RFLP
510

VNTR
9000148
30
25
20
15
2004-2008:
Only 1 RFLP
(out of 61) not
VNTR 9000148
10
5
0
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
RFLP-VNTR concordant
VNTR discordant
Only RFLP
35
30
25
20
2004-2008:
But 13 other
RFLPs with
VNTR 9000148
RFLP discordant
RFLP-VNTR concordant
VNTR discordant
15
Only RFLP
10
5
Concordance:
60/74=81%
0
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
35
30
Since 2009:
59 VNTRs
added
Total:
260 patients
25
20
Only VNTR
RFLP discordant
RFLP-VNTR concordant
VNTR discordant
15
Only RFLP
10
5
0
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
30
Pub outbreak (509/9000109)
25
2004-2008:
91% concordance
between RFLP and
VNTR.
20
Unknown
Other
15
Netherland
Eritrea/Ethiopia
Morocco
10
15% Morocco
15% Eritrea
32% Netherl.
Total: 16 CoB
5
0
1992 1994 1996 2002
2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
30
GGD Flevoland
25
GGD Kennemerland
GGD Zaanstreek-Waterland
GGD Gelderland-Midden
GGD Haaglanden
20
GGD Twente
GGD Groningen
GGD regio Utrecht
GGD Hollands-Midden
GGD Zeeland
15
GGD Brabant Zuid-Oost
GGD Den Haag
GGD IJsselland
GGD Amsterdam
10
GGD Rotterdam Rijnmond
Since 2003:
68% Rotterdam
5
0
1992 1994 1996 2002
2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
‘Not all TB in foreign-born
patients is acquired in their
country of origin!!’
‘Transmission between different
ethnic groups and to the nativeborn population occurs’
2.
DNA fingerprinting to identify
laboratory cross contamination
(LCC)
LCC is suspected if
- NRL identifies the same
VNTR in isolates from
two patients,
- and specimens were
received from the
same laboratory,
- and specimens were
processed <7 days
from each other.
14
12
10
8
6
4
2
0
2009
2010
LCC confirmed
2011
2012
2013
LCC not confirmed
2014
unknown
3.
DNA fingerprinting to identify
missed opportunities
in contact investigation
Systematically investigate all cases with
- a recently clustered fingerprint,
- confirmed epidemiological link (by cluster
investigation),
- but not detected by contact investigation.
4.
DNA fingerprinting to identify
nosocomial transmission
1995-1999
28 HCWs with TB infected during work, i.e. 5-6 cases per year
HCWs with TB, 2000-2015
20
18
16
14
Unknown place of
infection
12
10
Infected abroad
8
6
Infected in the
Netherlands, but
not during work
4
2
Infected during
work in the
Netherlands
0
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
Stories
1. HCW, working at the cleaning and sterilization department, developed
pleural TB
• Strain identical with a patient who was operated on with TB of the ear
(9 months earlier)
• Documented that she cleaned the operating materials
• And that infection control measures were not properly implemented
2. Surgeon who operated a patient with TB lymphadenitis, developed PTB <12
months.
3. However, most HCW TB cases are due to delayed diagnosis of the index
patient.
4. Or, performing high-risk procedures (e.g. 4 bronchoscopy assistants)
5.
DNA fingerprinting to monitor
zoonotic transmission
Animal-human transmission
•
•
•
2000-2013: 169 human TB patients with Mycobacterium bovis – 161
isolates were typed with VNTR
• 90 unique fingerprints
• 71 clustered fingerprints (20 clusters; no epi-links between patients)
1976-2013: 169 M. bovis isolates from animals – 105 isolates were typed
with VNTR.
• 22 unique fingerprints
• 83 clustered fingerprints (15 clusters)
7 matches between human and animal M. bovis isolates
• 4 unlikely that there was transmission between the respective animal(s)
and the patient
• 3 likely that they the (human) patient was infected by the animal
• ALL WORKING IN A SLAUGHTER HOUSE (DIFFERENT
SLAUGHTER HOUSES)
• Incubation periods between infection and disease were long (5, 14
and 19 years)
6.
DNA fingerprinting to monitor
transmission nationally
- annually in Surveillance Report
- quarterly (Early Warning System)
Monitoring outbreaks
Monitoring recent transmission
7.
DNA fingerprinting to assist in
cross-border investigation and
collaboration
Stories (#1)
Colleagues from the United Kingdom asked whether we had a young Somalian
MDR-TB patient in the Netherlands, because they recently diagnosed MDR-TB
patient also in a young Somalian patient who told that her friend/cousin was in
a TB sanatorium with MDR-TB.
 VNTR digital code was sent  100% match!
 Contact investigation was extended.
Stories (#2)
Italian person diagnosed with pulmonary TB in Italy, but lived in Amsterdam in
the same house for several months with another Italian person who was
recently diagnosed with TB in the Netherlands. VNTR fingerprint was not seen
in the Netherlands before (unique fingerprint).
Request: Is VNTR typing done in Italy? Can isolates be compared?
Italy:
Netherlands:
ST ID
424 577 580 802 960 1644 1955 2163b 2165 2401 2996 3192 3690 4052 4156 specie
2
3
2
2
3
2
2
4
2
2
5
3
3
5
2 Haarlem
424 577 580 802 960 1644 1955 2163b 2165 2401 2996 3192 3690 4052 4156
2
3
2
2
3
4
2
4
2
2
5
3
3
5
2
Conclusion
•
DNA fingerprinting useful when done on country level + investigation of
epidemiological links
•
•
It reveals outbreaks and helps to monitor outbreaks over time
It helps to identify (new) risk groups (e.g. transmission between ethnic
groups)
It is quality instrument to see whether hospital infection control (TB in
HCWs) and laboratory practices (LCC) works
It helps to monitor zoonotic transmission and for cross-border TB
investigations
•
•
•
It also makes the work more interesting.
Acknowledgement
The Netherlands
• Rianne van Hunen, KNCV Tuberculosis Foundation
• Dick van Soolingen, NRL, RIVM
• Miranda Kamst, NRL, RIVM
• Vera Teepe, GGD Amsterdam
•
Daniela Cirillo and Valeria Ghisetti, Italy
Thank you for your attention!