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Use of a whole genome sequencing-based approach for Mycobacterium tuberculosis surveillance in Europe in 2017–2019: an ECDC pilot study

Elisa Tagliani, Richard Anthony, Thomas A. Kohl, Albert de Neeling, Vlad Nikolayevskyy, Csaba Ködmön, Florian P. Maurer, Stefan Niemann, Dick van Soolingen, Marieke J. van der Werf, Daniela Maria Cirillo on behalf of the ECDC molecular surveillance project participants
European Respiratory Journal 2021 57: 2002272; DOI: 10.1183/13993003.02272-2020
Elisa Tagliani
1Emerging Bacterial Pathogens Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
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Richard Anthony
2Tuberculosis Reference Laboratory, Infectious Diseases Research, Diagnostics and Laboratory Surveillance (IDS), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
11Both authors contributed equally
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Thomas A. Kohl
3Molecular and Experimental Mycobacteriology, National Reference Center for Mycobacteria, Research Center, Borstel, Germany
4German Center for Infection Research, partner site Borstel-Hamburg-Lübeck-Riems, Borstel, Germany
11Both authors contributed equally
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Albert de Neeling
2Tuberculosis Reference Laboratory, Infectious Diseases Research, Diagnostics and Laboratory Surveillance (IDS), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
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Vlad Nikolayevskyy
5Public Health England, London, UK
6Imperial College London, London, UK
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Csaba Ködmön
7European Centre for Disease Prevention and Control, Stockholm, Sweden
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Florian P. Maurer
8Diagnostic Mycobacteriology, National Reference Center for Mycobacteria, Borstel, Germany
9Institute of Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Stefan Niemann
3Molecular and Experimental Mycobacteriology, National Reference Center for Mycobacteria, Research Center, Borstel, Germany
4German Center for Infection Research, partner site Borstel-Hamburg-Lübeck-Riems, Borstel, Germany
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Dick van Soolingen
2Tuberculosis Reference Laboratory, Infectious Diseases Research, Diagnostics and Laboratory Surveillance (IDS), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
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Marieke J. van der Werf
7European Centre for Disease Prevention and Control, Stockholm, Sweden
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Daniela Maria Cirillo
1Emerging Bacterial Pathogens Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
10See Acknowledgements for full details
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Figures

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  • FIGURE 1
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    FIGURE 1

    Percentage of multidrug-resistant (MDR)-tuberculosis (TB) coverage per European Union/European Economic Area country in 2018. The number of MDR-TB cases among all laboratory-confirmed TB cases notified to the European Centre for Disease Prevention and Control in 2018 was used as reference. The map was generated using the online tool available at www.mapchart.net/.

  • FIGURE 2
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    FIGURE 2

    a, b) Lineage distribution of the 2151 rifampicin-resistant (RR)/multidrug-resistant (MDR) Mycobacterium tuberculosis complex (MTBC) isolates included in the EUSeqMyTB study. Lineages: 1: East-African Indian (EAI) (includes EAI and EAI Manila); 2: East-Asian (includes 2.2.1 Beijing and 2.1 East-Asian non-Beijing); 3: Delhi-CAS; 4.1: Euro-American (includes 4.1 and 4.1.2: Euro-American; 4.1.1: X-type; and 4.1.2.1: Haarlem); 4.2: Euro-American (includes 4.2 and 4.2.2: Euro-American; 4.2.1: Ural; and 4.2.2.1: TUR); 4.3: LAM; 4.4 (includes 4.4.1.1: S-type); 4.5: Euro-American; 4.6: Euro-American; 4.7: mainly T; 4.8: mainly T; 4.9: H37Rv-like; 5: West-Africa 1.

  • FIGURE 3
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    FIGURE 3

    Map showing the percentage of rifampicin-resistant/multidrug-resistant tuberculosis cases of foreign origin in cross-border clusters per European Union/European Economic Area country. The map was generated using the online tool available at www.mapchart.net/.

  • FIGURE 4
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    FIGURE 4

    Minimum spanning tree of a) snpCL1, b) snpCL3 and c) snpCL8. The numbers on the branches indicate the genetic distance in single nucleotide polymorphism (SNP) differences to the nearest isolate. SNP differences between distant isolates can be reconstituted by summing the number of SNPs on the branches. Different colours indicate the different European Union/European Economic Area countries where the strains were isolated.

Tables

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  • TABLE 1

    Mycobacterium tuberculosis isolates submitted to the EUSeqMyTB consortium by year of isolation

    CountryIsolates submitted by year of isolation nTotal n
    201720182019
    Austria019625
    Belgium58619
    Bulgaria25241665
    Croatia0213
    Cyprus0000
    Czech Republic591125
    Denmark0448
    Estonia28251366
    Finland44210
    France8662599
    Germany7712445246
    Hungary513422
    Ireland671023
    Italy634420127
    Latvia18333485
    Lithuania776042179
    Luxembourg0000
    Malta0000
    Netherlands126624
    Norway26210
    Poland31571098
    Portugal1219637
    Romania335336195866
    Slovakia2428
    Slovenia0101
    Spain17371266
    Sweden911525
    UK27302481
    Total per year7689495012218
  • TABLE 2

    Drug-resistance profile of the 2217 Mycobacterium tuberculosis isolates included in the database stratified by lineage

    LineageRHMDR-TBZSLIDsFQsXDR-TB
    1 (EAI)32 (1.5)31 (1.6)30 (1.5)13 (1.0)0 (0.0)1 (0.20 (0.0)
    2 (Beijing/East-Asian non-Beijing)638 (29.7)632 (31.9)630 (32.1)443 (34.4)337 (48.4)257 (44.2)179 (54.1)
    3 (Delhi-CAS)63 (2.9)53 (2.7)53 (2.7)22 (1.7)2 (0.3)10 (1.7)1 (0.3)
    4.1 (Euro-American)390 (18.1)347 (17.5)341 (17.4)206 (16.0)71 (10.2)77 (13.3)38 (11.5)
    4.2 (Euro-American)199 (9.3)191 (9.6)189 (9.6)122 (9.5)48 (6.9)49 (8.4)25 (7.6)
    4.3 (LAM)183 (8.5)166 (8.4)163 (8.3)95 (7.4)38 (5.5)50 (8.6)19 (5.7)
    4.4, 4.5, 4.6 (Euro-American)77 (3.6)70 (3.5)69 (3.5)48 (3.7)22 (3.2)5 (0.9)1 (0.3)
    4.7, 4.8, 4.9 (Euro-American)555 (25.8)483 (24.3)476 (24.3)333 (25.9)175 (25.1)131 (22.5)67 (20.2)
    5 (West-Africa 1)1 (0.0)1 (0.1)1 (0.1)0 (0.0)0 (0.0)0 (0.0)0 (0.0)
    Unknown13 (0.6)10 (0.5)10 (0.5)4 (0.3)4 (0.6)1 (0.2)1 (0.3)
    Total2151 (97.0)1984 (89.5)1962 (88.5)1286 (58.0)697 (31.4)581 (26.8)331 (15.4)

    Data are presented as n (%). R: rifampicin; H: isoniazid; MDR: multidrug resistant; TB: tuberculosis; Z: pyrazinamide; SLID: second-line injectable drug; FQ: fluoroquinolone; XDR: extensively drug resistant.

    • TABLE 3

      Cross-border clusters identified using an SNP-based approach

      SNP-based cross-border clusters (≤5 SNPs threshold)
      Cross-border cluster nameIsolates nCountries involved nLineage classification
      snpCL 13034.8 (mainly T)
      snpCL 22024.2.1 (Ural)
      snpCL 31644.6.2 (Euro-American)
      snpCL 41424.8 (mainly T)
      snpCL 51324.2.1 (Ural)
      snpCL 61334.8 (mainly T)
      snpCL 71232.2.1 (Beijing)
      snpCL 81244.2.2 (Euro-American)
      snpCL 91224.8 (mainly T)
      snpCL 101224.1.2.1 (Haarlem)
      snpCL 111024.3.3 (LAM)
      snpCL 121054.2.2 (Euro-American)
      snpCL 13962.2.1 (Beijing)
      snpCL 14742.2.1 (Beijing)
      snpCL 15752.2.1 (Beijing)
      snpCL 16722.2.1 (Beijing)
      snpCL 17544.3.3 (LAM)
      snpCL 18522.2.1 (Beijing)
      snpCL 19524.8 (mainly T)
      snpCL 20524.3.3 (LAM)
      snpCL 21524.2.2.1 (TUR)
      snpCL 22524.1.2.1 (Haarlem)
      snpCL 23434.3.3 (LAM)
      snpCL 24432.2.1 (Beijing)
      snpCL 25–34#32 to 3
      snpCL 35–56¶22

      A sequential number from 1 to 56 was assigned to each cross-border cluster identified by SNP-based analysis, based on the size of the cluster and starting from the largest one. SNP: single nucleotide polymorphism; snpCL: SNP-based cluster. #: 10 clusters comprising three isolates from three (n=1) and two (n=9) countries, with the lineage distribution comprising 2.2.1 Beijing (n=3), 4.8 mainly T (n=2), 4.7 mainly T (n=1), 4.1.2.1 Haarlem (n=2), 4.2.2 Euro-American (n=1) and 4.1.1.1 X-type (n=1); ¶: 22 clusters comprising two isolates from two countries, with the lineage distribution comprising 2.2.1 Beijing (n=7), 4.8 mainly T (n=3), 4.1.2.1 Haarlem (n=3), 4.2.1 Ural (n=2), 4.3.3 LAM (n=2), 4.3.1 LAM (n=1), 4.1.2 Euro-American (n=1), 4.2.2 Euro-American (n=1), 4.9, H37Rv-like (n=1) and 3 Delhi-CAS (n=1).

      • TABLE 4

        Country contribution to cross-border clusters#

        CountryRR/MDR-TB cases in cluster nPercentage among clustered isolatesPercentage of clustered RR/MDR-TB cases among submitted ones¶
        Austria92.836.0
        Belgium51.626.3
        Bulgaria61.99.2
        Croatia0––
        Czech Republic61.924.0
        Denmark0––
        Estonia51.67.6
        Finland20.622.2
        France113.511.1
        Germany4012.716.3
        Hungary20.69.1
        Ireland30.913.0
        Italy3812.029.9
        Latvia30.93.5
        Lithuania4313.624.0
        Netherland51.620.8
        Norway10.310
        Poland72.27.1
        Portugal0––
        Romania10132.011.7
        Slovakia20.625.0
        Slovenia0––
        Spain92.813.6
        Sweden82.532.0
        UK103.212.3
        Total31610014.3

        RR: rifampicin resistant; MDR: multidrug resistant; TB: tuberculosis. #: a cross-border cluster is defined as two or more RR/MDR Mycobacterium tuberculosis complex isolates having a single nucleotide polymorphism difference ≤5, and isolated in at least two different countries; ¶: n=2217.

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        Use of a whole genome sequencing-based approach for Mycobacterium tuberculosis surveillance in Europe in 2017–2019: an ECDC pilot study
        Elisa Tagliani, Richard Anthony, Thomas A. Kohl, Albert de Neeling, Vlad Nikolayevskyy, Csaba Ködmön, Florian P. Maurer, Stefan Niemann, Dick van Soolingen, Marieke J. van der Werf, Daniela Maria Cirillo
        European Respiratory Journal Jan 2021, 57 (1) 2002272; DOI: 10.1183/13993003.02272-2020

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        Use of a whole genome sequencing-based approach for Mycobacterium tuberculosis surveillance in Europe in 2017–2019: an ECDC pilot study
        Elisa Tagliani, Richard Anthony, Thomas A. Kohl, Albert de Neeling, Vlad Nikolayevskyy, Csaba Ködmön, Florian P. Maurer, Stefan Niemann, Dick van Soolingen, Marieke J. van der Werf, Daniela Maria Cirillo
        European Respiratory Journal Jan 2021, 57 (1) 2002272; DOI: 10.1183/13993003.02272-2020
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