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Eurosurveillance, Volume 12, Issue 10, 01 October 2007
Euroroundup
Results of a Europe-wide investigation to assess the presence of a new variant of Chlamydia trachomatis

Citation style for this article: Savage EJ, Ison C, Van de Laar MJ, European Surveillance of Sexually Transmitted Infections (ESSTI). Results of a Europe-wide investigation to assess the presence of a new variant of Chlamydia trachomatis. Euro Surveill. 2007;12(10):pii=736. Available online: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=736

 

EJ Savage (Emma.Savage@HPA.org.uk)1, CA Ison1, MJW van de Laar2 and the ESSTI network*

1. ESSTI- European Surveillance of STIs network, Health Protection Agency, London, UK
2. European Centre for Disease Prevention and Control, Stockholm, Sweden

* Angelika Stary, Reinhild Strauss, Austria; Tania Crucitti, André Sasse , Belgium; Chrystalla Hadjianastassiou, Cyprus; Susan Cowan, Steen Hoffmann, Denmark; Anneli Uusküla, Rutta Voiko, Estonia; Eija Hiltunen-Back, Finland; Véronique Goulet, Patrice Sednaoui, Tony Nardone, France; Osamah Hamouda, Peter Kohl, Germany; Vasileia Konte, Eva Tzelepi, Greece; Guðrún Sigmundsdóttir, Guðrun Hauksdottir, Iceland, Aidan O'Hora, Brian O’Connell, Ireland; Paola Stefanelli, Barbara Suligoi, Italy; Judite Pirsko, Elvira Lavrinovica, Latvia; Christopher Barbara, Jackie Maistre Melillo, Malta; Marianne van der Sande, Joke Spaargaren, Netherlands; Hilde Klovstad, Jorgen Lassen, Norway; Slawomir Majewski, Magdalena Malejczyk, Poland; Jacinta Azevedo, Maria José Borrego, Portugal; Jan Mikas, Slovak Republic; Irena Klavs, Alenka Andlovic, Slovenia; Mercedes Diez, Julio Vazquez, Spain; Inga Velicko, Hans Fredlund, Anders Blaxhult, Sweden; Peyman Altan, Turkey; Gwenda Hughes, Lesley Wallace, Hugh Young, Mike Catchpole, Michelle Cole, Kathy Lowndes, United Kingdom. Non-ESSTI contributors: Jørgen Skov Jensen, Denmark; Jukka Suni, Finland; Bertille de Barbeyrac, France; Sarah Alexander, Harry Mallinson, Margaret Sillis, United Kingdom.


Abstract
In 2006, a new variant of Chlamydia trachomatis was reported in Sweden. Three countries – Ireland, Norway, and Denmark – have detected the variant to date, but very few cases in total have occurred. The European network for STI surveillance (ESSTI) and the European Centre for Disease Prevention and Control (ECDC) assessed the potential spread of the variant in other European countries, and concluded that there is currently no evidence that the variant has spread widely across Europe. However, the variant strain has been reported in between 10% and 65% of infected patients in Sweden. It is too early to tell whether the variant will remain confined to Sweden or whether the number of cases will significantly increase. Enhanced surveillance will need to be continued to address these concerns.

Introduction
In 2006, the occurrence of a new variant of Chlamydia trachomatis was reported in Sweden [1,2]. The variant had been detected following an unexpected 25% decrease in the number of infections observed in Halland county, southwest Sweden. The variant contains a 377 base pair deletion in the cryptic plasmid, which is the region targeted by the nucleic acid amplification tests (NAAT) manufactured by both Cobas Amplicor, Cobas Taqman48 and Abbott m2000 (manufactured by Roche and Abbott) [1] Patients infected with this variant of C. trachomatis would therefore be given a false negative result if a laboratory used either of these assays as its diagnostic test. Other commercially available NAAT tests such as the the ProbeTec Strand Displacement Assay (SDA) (Becton Dickinson), Aptima Combo 2 (AC2) test (Genprobe), and RealArt CT Kit (Qiagen), target other areas of the cryptic plasmid, the 16SrRNA and omp gene respectively and therefore will detect this variant of C. trachomatis.

Genital chlamydial infection is the most prevalent bacterial sexually transmitted infection (STI) in many European countries [2] and any reduction in the detectability of infection has potential implications for public health in Europe. Initial data from Sweden showed that 39% of all chlamydia cases detected during one month were caused by the new variant of Chlamydia trachomatis [3]. Although the data from Sweden is so far limited, if this turns out to be the true representative proportion of chlamydial infection by the genetic variant in Sweden and this is then replicated across Europe, an inability to detect such a sizeable proportion of chlamydia infection could have serious consequences. Therefore, the European network for STI surveillance (ESSTI) and the European Centre for Disease Prevention and Control (ECDC) decided to assess the potential spread of the new variant in other countries across Europe [4].

Methods
ESSTI and ECDC designed a short survey to address this issue (A copy of the questionnaire is available upon request from the corresponding author). The questionnaire contained six questions and was sent with a cover letter to all ESSTI collaborators, both epidemiologists and microbiologists, in 25 countries (22 EU member states and Iceland, Norway and Turkey) in February 2007. The survey collected information on the type of NAATs used to diagnose chlamydia, the extent to which NAATs are used for chlamydia diagnosis and also requested information on any actions or investigations that a country or laboratory undertook in response to the appearance of the new variant. Finally, a question asked whether guidelines regarding the diagnosis of chlamydia in the respective countries had been issued or changedissued.

Results
In total, 21 countries had responded to the request by the beginning of May 2007, but only 19 were able to provide any information. Four countries did not respond. Several countries submitted more than one questionnaire, as the survey provided the option of describing information either for the whole country, a particular region or for an individual laboratory; two questionnaires were returned from Portugal and Estonia andthree from Slovenia and England, while Ireland provided results from 17 individual laboratories. Ten countries provided information for the whole country, seven provided information from individual laboratories, Finland gave information from a particular region and Estonia submitted data both from a regional source and an individual laboratory. Seventy-five percent of respondents (n=24/32) based their answers on actual laboratory data.

Table 1 describes the level of NAAT testing for chlamydia in the countries belonging to the ESSTI network and the number of chlamydia diagnoses. The proportion of chlamydia diagnoses performed by NAAT where information was available for the whole country ranged from 12% in Cyprus to 100% in Iceland, Malta, Netherlands, Norway and Scotland. Malta and Iceland were the only countries that used the Cobas Amplicor or Cobas Taqman48 exclusively, although there was widespread use of this test in individual laboratories in other countries (Figure 1). The Abbott m2000 assay which is also unable to detect the variant was only used in three countries and accounted for only a small number of routine diagnostic tests; France (<5%), Netherlands (5%) and Sweden (3.8%).

Twelve respondents reported that action was or is in the process of being undertaken in their country to assess whether the variant was present. Countries used one or a combination of the following three approaches: Retrospective testing, dual testing and monitoring of surveillance data (Table 2). Retrospective testing of samples was carried out in Denmark, France, Sweden, England, Finland and the Netherlands with varying approaches either by retesting specimens that had tested negative using a test unable to detect the variant or retesting samples that originally tested positive by a test known to detect the variant. New national guidelines for testing were issued in Sweden for laboratories changing from the Cobas Amplicor, Cobas Taqman48 and Abbott m2000 to other tests such as the ProbeTec Strand Displacement Assay (SDA) (Becton Dickinson). In Denmark, the National Board of Health wrote to laboratories recommending that they should either change to a method which could detect the mutant or to forward the specimen to another laboratory.

Discussion
This survey attempted to assess the potential spread of the new variant across Europe. However, it was not feasible in the available timeframe to survey directly all laboratories, both private and public, that carry out chlamydia diagnostics across Europe. A possible bias in the survey is that data is more likely to have been obtained from public laboratories, but there is no reason why the type of tests used would differ significantly in private laboratories. Although the results of this survey can not be considered comprehensive for all European countries, 10 respondents were able to provide information for the whole country and a further four countries surveyed more than one laboratory. The coverage obtained is therefore considered sufficient to determine whether the variant has spread outside Sweden to a great extent. Since the first report of the new variant, several European countries have undertaken extensive investigations to determine whether the variant is present in their country. Despite this active surveillance, only three countries – Ireland, Norway, and Denmark – have detected the variant to date and very few cases in total have occurred. Two cases of the new variant have been reported in both Norway and Ireland. One of the cases in Norway was of Swedish origin [5]. Similarly, in Ireland, one of the two cases, who were partners, was also of Swedish origin [6]. Since the questionnaire was completed, a single case of the variant has also been detected in Denmark – this case had no known link to Sweden [7]. Further epidemiological information on these cases of the new variant is currently unknown.

There is therefore no existing evidence that the variant has spread widely across Europe even into neighbouring countries and yet in Sweden the variant strain has been reported in between 10% and 65% of the total number of infected patients [8,9]. It is not known when the variant first appeared in Sweden but the increase in prevalence has been both rapid and recent. In Sweden, a considerable increase in chlamydial infection (53%) was reported in the first six months of 2007, compared to the same period in 2006. (Blaxhult, abstract isstdr page 391). It is unclear why the variant is present in such a sizeable proportion of cases in Sweden and yet has not made an impact in other countries. It may be present at very low levels in other countries but the results of the survey suggest that, following the extensive search for the variant by many countries, it would have been detected if it was present in the testing population. A possible reason why the variant does not appear to have spread outside Sweden may be found in a study carried out in one county in Sweden which reported that 79% of all sexual partners of chlamydia cases lived within 100km of each other8. Sex abroad may not be a significant risk factor for the acquisition and hence spread of chlamydia infection unlike in the case of other STIs such as syphilis where it is well documented. In Sweden, it has been hypothesised that a number of factors are present that may have resulted in selection of the variant, for example the high number of diagnostic tests carried out almost exclusively by the Roche assay, the lack of contact tracing performed for false negative persons and the treatment of symptomatic patients only[10].

Conclusions
The presence of a C. trachomatis variant that is not detectable, hence causing false negative test results, has serious implications for patient management, care and the transmission of C. trachomatis in the population. Therefore, experts in all EU Member States should remain vigilant. More epidemiological information regarding the affected population needs to be collected in order for targeted public health measures to be undertaken. The emergence of the variant suggests it may be more appropriate for any NAAT to include dual targets which is being considered by test manufacturers [8]. It is too early to tell whether the variant will remain confined to Sweden or whether the number of cases will significantly increase. Enhanced surveillance will need to be continued to address these concerns. ESSTI and ECDC aim to repeat the survey at the end of the year to determine if the picture across Europe remains the same.


References

  1. Ripa T, Nilsson P. A variant of Chlamydia trachomatis with deletion in cryptic plasmid: implications for use of PCR diagnostic tests. Euro Surveill 2006;11(11):E061109.2. Available from: http://www.eurosurveillance.org/ew/2006/061109.asp#2
  2. Fenton K A, Lowndes C m. Recent trends in the epidemiology of sexually transmitted infections in the European Union. Sex Transm Infections 2004; 80(4):255-263
  3. Söderblom T, Blaxhult A, Fredlund H, Herrmann B. Impact of a genetic variant of Chlamydia trachomatis on national detection rates in Sweden. Euro Surveill 2006;11(12):E061207.1. Available from: http://www.eurosurveillance.org/ew/2006/061207.asp#1
  4. Van de Laar M, Ison C. Europe-wide investigation to assess the presence of new variant of Chlamydia trachomatis in Europe. Euro Surveill 2007;12(2):E070208.4. Available from: http://www.eurosurveillance.org/ew/2007/070208.asp#4
  5. Moghaddam A, Reinton N. Identification of the Swedish Chlamydia trachomatis variant among patients attending a STI clinic in Oslo, Norway. Euro Surveill 2007;12(3):E070301.3. Available from: http://www.eurosurveillance.org/ew/2007/070301.asp#3
  6. Lynagh Y, Walsh A and Crowley B. First report of the new variant strain of Chlamydia trachomatis in Ireland. Epi-Insight 2007; 8(7):4.
  7. Jensen JS. Chlamydia trachomatis mutant. Epi-News. 2007. No.19.
  8. Ripa T,.Nilsson PA. A Chlamydia trachomatis strain with a 377-bp deletion in the cryptic plasmid causing false-negative nucleic acid amplification tests. Sex Transm Dis. 2007;34:255-6.
  9. Nordvik M, Liljeros F, Österlund A and Herrmann B. Spatial bridges and the spread of chlamydia; The case of a county in Sweden. Sex Transm Dis 2007; 34:47-53.
  10. Unemo M, Olcén P, Agné-Stadling I, Feldt A, Jurstrand M, Herrmann B, and al. Experiences with the new genetic variant of Chlamydia trachomatis in Örebro county, Sweden – proportion, characteristics and effective diagnostic solution in an emergent situation. Euro Surveill 2007;12(4), Available from: http://www.eurosurveillance.org/em/v12n04/1204-223.asp

 



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