Letter to the editor: Chlamydia trachomatis samples testing falsely negative in the Aptima Combo 2 test in Finland, 2019

Unemo, Magnus; Getman, Damon; Hadad, Ronza; Cole, Michelle; Thomson, Nicholas R.; Puolakkainen, Mirja; Spiteri, Gianfranco

doi:10.2807/1560-7917.es.2019.24.24.1900354

Cited by 13 publications

(33 citation statements)

References 5 publications

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“…Both the two repeatedly AC2 CT-negative/ACT-positive specimens contained the CT 23S rRNA C1515T mutation, which was recently confirmed as the cause of the false-negative/equivocal AC2 CT results of F-nvCT specimens [2]. These two Swedish F-nvCT specimens were sampled in May 2019 from one Swedish male and one Swedish female in their early 20s.…”

Section: Confirmed Cases Of the Finnish New Variant Of Chlamydia Tracmentioning

confidence: 82%

“…The black line (RLU ≥ 15) shows the currently recommended cut-off for confirmatory reflex testing using the Aptima Chlamydia trachomatis assay [2].…”

Section: Initial Investigations Of Possible Aptima Combo 2 False-negamentioning

confidence: 99%

“…AC2 CT-negative/equivocal specimens, mostly having relative light unit (RLU) signals of 20–85, were confirmed as CT positive using the Aptima Chlamydia trachomatis assay (ACT) (target: 16S rRNA) [1]. A C1515T mutation in the CT 23S rRNA gene was confirmed as the reason that the Finnish new variant of CT, F-nvCT, escapes detection in AC2 [2]. It is essential to timely investigate presence of F-nvCT internationally.…”

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confidence: 99%

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Finnish new variant of Chlamydia trachomatis escaping detection in the Aptima Combo 2 assay also present in Örebro County, Sweden, May 2019

et al. 2019

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We identified the first two cases of the Finnish new variant of Chlamydia trachomatis (F-nvCT) beyond Finland in two clinical urogenital specimens in Örebro County, Sweden. These Aptima Combo 2 assay-negative specimens were Aptima Chlamydia trachomatis (CT) assay positive and had the characteristic C1515T mutation in the 23S rRNA gene. From 22 March to 31 May 2019, 1.3% (2/158) of the CT-positive cases in Örebro County were missed because of the F-nvCT. International awareness, investigations and actions are essential.

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Section: Confirmed Cases Of the Finnish New Variant Of Chlamydia Tracmentioning

confidence: 82%

“…The black line (RLU ≥ 15) shows the currently recommended cut-off for confirmatory reflex testing using the Aptima Chlamydia trachomatis assay [2].…”

Section: Initial Investigations Of Possible Aptima Combo 2 False-negamentioning

confidence: 99%

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confidence: 99%

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Finnish new variant of Chlamydia trachomatis escaping detection in the Aptima Combo 2 assay also present in Örebro County, Sweden, May 2019

et al. 2019

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“…The emergence of nvCT in Sweden was, to our knowledge, the first reported example of a strain mutating to escape detection by a diagnostic test, but was not unique. In May 2019, researchers in Finland reported false-negative chlamydia test results using the Aptima Combo 2 test, resulting from a single point mutation in the 23 s rRNA gene 23 24. These events in the field of diagnostics can be compared with the phenomenon of immune escape, where viral pathogens such as HIV evade recognition by cytotoxic T lymphocytes through mutation in their epitopes 25.…”

Section: Discussionmentioning

confidence: 99%

Rise and fall of the new variant of Chlamydia trachomatis in Sweden: mathematical modelling study

et al. 2019

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ObjectivesA new variant of Chlamydia trachomatis (nvCT) was discovered in Sweden in 2006. The nvCT has a plasmid deletion, which escaped detection by two nucleic acid amplification tests (Abbott-Roche, AR), which were used in 14 of 21 Swedish counties. The objectives of this study were to assess when and where nvCT emerged in Sweden, the proportion of nvCT in each county and the role of a potential fitness difference between nvCT and co-circulating wild-type strains (wtCT).MethodsWe used a compartmental mathematical model describing the spatial and temporal spread of nvCT and wtCT. We parameterised the model using sexual behaviour data and Swedish spatial and demographic data. We used Bayesian inference to fit the model to surveillance data about reported diagnoses of chlamydia infection in each county and data from four counties that assessed the proportion of nvCT in multiple years.ResultsModel results indicated that nvCT emerged in central Sweden (Dalarna, Gävleborg, Västernorrland), reaching a proportion of 1% of prevalent CT infections in late 2002 or early 2003. The diagnostic selective advantage enabled rapid spread of nvCT in the presence of high treatment rates. After detection, the proportion of nvCT decreased from 30%–70% in AR counties and 5%–20% in counties that Becton Dickinson tests, to around 5% in 2015 in all counties. The decrease in nvCT was consistent with an estimated fitness cost of around 5% in transmissibility or 17% reduction in infectious duration.ConclusionsWe reconstructed the course of a natural experiment in which a mutant strain of C. trachomatis spread across Sweden. Our modelling study provides support, for the first time, of a reduced transmissibility or infectious duration of nvCT. This mathematical model improved our understanding of the first nvCT epidemic in Sweden and can be adapted to investigate the impact of future diagnostic escape mutants.

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“…This strain, designated Finnish new variant of C. trachomatis (FI-nvCT), harbours a single nt base mutation (C1515T; Escherichia coli numbering) in 23S rRNA. This mutation was determined to be the root cause for compromised detection of the organism by the Aptima Combo 2 (AC2) diagnostic test (Hologic Inc., San Diego, California, United States (US)), which targets C. trachomatis 23S rRNA [2,3]. Archived and newly received clinical specimens in Finland and Sweden with equivocal results or high-negative relative light units (RLU) from 15 to 99 in the AC2 test, and discrepant results between AC2 (target: 23S rRNA) and the separate Aptima Chlamydia trachomatis (ACT) test (target: 16S rRNA) (i.e.…”

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Validation of an Aptima-format Finnish new variant of Chlamydia trachomatis (FI-nvCT) surveillance assay, 2019

et al. 2020

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The Finnish new variant of Chlamydia trachomatis (FI-nvCT) is escaping diagnostics in Finland, Norway and Sweden. We have developed and validated an Aptima-format nucleic acid amplification test (NAAT) designed specifically to detect the FI-nvCT. This NAAT has high sensitivity (100%) and specificity (100%) for the FI-nvCT strain, enabling further investigation of the geographic distribution, prevalence and transmission of this diagnostic-escape mutant in screening populations in Europe.In February 2019, investigation of discrepant nucleic acid amplification test (NAAT) results led to the discovery of a new genetic variant strain of Chlamydia trachomatis in south-western Finland [1]. This strain, designated Finnish new variant of C. trachomatis (FI-nvCT), harbours a single nt base mutation (C1515T; Escherichia coli numbering) in 23S rRNA. This mutation was determined to be the root cause for compromised detection of the organism by the Aptima Combo 2 (AC2) diagnostic test (Hologic Inc., San Diego, California, United States (US)), which targets C. trachomatis 23S rRNA [2,3]. Archived and newly received clinical specimens in Finland and Sweden with equivocal results or high-negative relative light units (RLU) from 15 to 99 in the AC2 test, and discrepant results between AC2 (target: 23S rRNA) and the separate Aptima Chlamydia trachomatis (ACT) test (target: 16S rRNA) (i.e. AC2 negative/equivocal-ACT positive) signalled the presence of the new strain. Data collected in subsequent investigations suggested a recent emergence of FI-nvCT in south-western Finland, Norway and Sweden with relatively low prevalence (ca 1-6%) among patients with C. trachomatis infections [1,3-5]. We have developed and validated a research-use only Aptima-format surveillance NAAT designed specifically to detect the FI-nvCT strain. This assay should facilitate further investigations to determine the geographic distribution, prevalence and transmission of this diagnostic-escape mutant. New Aptima-format surveillance assay for the Finnish new variant of Chlamydia trachomatisTo understand the geographic distribution, prevalence and transmission dynamics of the FI-nvCT strain nationally and internationally, we have developed an Aptima-format NAAT that sensitively and specifically detects FI-nvCT (23S rRNA gene C1515T mutation) but not wild-type (C1515) C. trachomatis strains. This research-use only test uses target capture and transcription-mediated amplification chemistries on the automated Panther instrument (Hologic Inc.) to isolate and amplify C. trachomatis 23S rRNA, and an acridinium ester probe to selectively detect the C→T mutation at position 1515. Validation and verification results for the Aptima-format surveillance assay for the Finnish new variant of C. trachomatisAll validation and verification studies of the new FI-nvCT assay were conducted according to Clinical Laboratory Standards Institute (CLSI) standard protocols used for in vitro diagnostic assay validation [6]. The cut-off value of the test (100,000 RLU) was initially establis...

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Letter to the editor: Chlamydia trachomatis samples testing falsely negative in the Aptima Combo 2 test in Finland, 2019

Cited by 13 publications

References 5 publications

Finnish new variant of Chlamydia trachomatis escaping detection in the Aptima Combo 2 assay also present in Örebro County, Sweden, May 2019

Finnish new variant of Chlamydia trachomatis escaping detection in the Aptima Combo 2 assay also present in Örebro County, Sweden, May 2019

Rise and fall of the new variant of Chlamydia trachomatis in Sweden: mathematical modelling study

Validation of an Aptima-format Finnish new variant of Chlamydia trachomatis (FI-nvCT) surveillance assay, 2019

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